(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 i i . _ 18 May 2012 (18.05.2012) WO 2012/064973 A2 (51) International Patent Classification: fredo C. [US/US]; 43 Wildwood Street, Winchester, MA A61K 31/52 (2006.01) C07D 471/04 (2006.01) 01890 (US). EVANS, Catherine A. [US/US]; 83 Jacques CI2N 9/99 (2006.01) A61K 31/519 (2006.01) Street, Somerville, MA 02145 (US). SNYDER, Daniel A. C07D 473/34 (2006.01) C07D 487/04 (2006.01) [US/US]; 94 Jacques Street, Somerville, MA 02145 (US). A61K 31/5377 (2006.01) A61K 31/5025 (2006.01) (74) Agent: MCCARTHY, Catherine, M.; LANDO & C07D 498/08 (2006.01) A61P 29/00 (2006.01) ANASTASI LLP, Riverfront Office Park, One Main A61K 31/5386 (2006.01) A61P 37/06 (2006.01) Street, Suite 1100, Cambridge, MA 02142 (US). C07D 513/04 (2006.01) A61K 31/553 (2006.01) C07D 413/14 (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, BR, BW, BY, BZ, PCT/US20 11/060212 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 10 November 201 1 (10.1 1.201 1) HN, HR, HU, ID, J , IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (25) Filing Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Langi English NO, NZ, OM, 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, 61/412,384 10 November 2010 (10.1 1.2010) US ZM, ZW. 61/509,454 19 July 201 1 (19.07.201 1) US (84) Designated States (unless otherwise indicated, for every (71) Applicants (for all designated States except US): INFIN¬ kind of regional protection available): ARIPO (BW, GH, ITY PHARMACEUTICALS, INC. [US/US]; 780 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Memorial Drive, Cambridge, MA 02139 (US). INTEL- UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, LIKINE, INC. [US/US]; 1093 1 N. Torrey Pines Road, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, Suite 103, La Jolla, CA 92037 (US). DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, (72) Inventors; and LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, (75) Inventors/ Applicants (for US only): REN, Pingda [CN/ SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, US]; 5534 Havenridge Way, San Diego, CA 92130 (US). GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). LIU, Yi [US/US]; 4841 Barlows Landing Cove, San Published: Diego, CA 921 30 (US). LI, Liansheng [CN/US]; 8155 — without international search report and to be republished Cargill Ave. #39, San Diego, CA 92122 (US). CHAN, upon receipt of that report (Rule 48.2(g)) Katrina [US/US]; 11178 Batavia Circle, San Diego, CA 92126 (US). WILSON, Troy Edward [US/US]; 575 Old Mill Road, San Marino, CA 9 1108 (US). CASTRO, Al¬ < © o (54) Title: HETEROCYCLIC COMPOUNDS AND USES THEREOF (57) Abstract: Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, in cluding PI3 kinase activity, are described herein. HETEROCYCLIC COMPOUNDS AND USES THEREOF [0001] This application claims the benefit of U.S. Provisional Application Serial No. 61/509,454, filed on July 19, 201 1, and U.S. Provisional Application Serial No. 61/412,384, filed on November 10, 2010, each of which is incorporated herein by reference in its entirety. 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 and disorders. 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, p i 10β, p i 10δ, and p i 10γ) 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. PI3K δ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. PI3K 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, PI3K 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 PI3K γ , which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus. [0008] Unlike PI3K δ, the beta (β) isoform of class I PI3K appears to be ubiquitously expressed. PI3K β has been implicated primarily in various types of cancer including PTEN-negative cancer (Edgar et al. Cancer Research (2010) 70(3): 1164-1 172), and HER2-overexpressing cancer such as breast cancer and ovarian cancer. SUMMARY [0009] 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 PI3K- δ/γ activity. [0010] In one aspect, described herein are compounds of Formula (I): Formula (I) or its pharmaceutically acceptable forms thereof, wherein W5 is N, CHR4 or CR4; R4 is hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro,