NZ714846B2 - Treatment of cancers using pi3 kinase isoform modulators - Google Patents

Abstract

Provided herein are methods, kits, and pharmaceutical compositions that include a PI3 kinase inhibitor (especially duvelisib) for treating cancers or hematologic disorders to overcome resistance to prior treatment (especially prior BTK inhibitor treatment). Provided herein are methods, compositions, and kits for treating or preventing cancers or diseases, such as hematologic malignancies, which have a high expression level of one or more isoform (s) of PI3K (e.g., P13K-? and/or ??3?-?). In one embodiment, the methods, compositions, and kits provided herein relate to administering an isoform-selective PI3K modulator. and kits for treating or preventing cancers or diseases, such as hematologic malignancies, which have a high expression level of one or more isoform (s) of PI3K (e.g., P13K-? and/or ??3?-?). In one embodiment, the methods, compositions, and kits provided herein relate to administering an isoform-selective PI3K modulator.

Description

TREATMENT OF CANCERS USING PI3 KINASE M MODULATORS BACKGROUND The activity of cells can be regulated by al s that stimulate or inhibit intracellular events. The process by which stimulatory or tory s 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, ing numerous forms of cancer, inflammatory disorders, metabolic disorders, ar and neuronal es (Gaestel et al. Current Medicinal try (2007) 14:2214–2234).

Kinases represent a class of important signaling molecules. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases t dual specificities. Protein kinases are s 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., mTorC1, mTorC2, ATM, ATR, DNAPK , Akt), and dual-specificity kinases which phosphorylate substrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived ically 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 e phosphoinositide(s) kinases (e.g., nases, PI4-kinases), diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide ses (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 e states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive ary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.

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 kinases with distinct substrate specificities, expression patterns, and modes of regulation. The class I PI3Ks (p110, p110, p110, and p110) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt/PDK1 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 l cell growth (mTORC1) or r genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

There are four mammalian isoforms of class I PI3Ks: , β,  (class Ia PI3Ks) and PI3K- (a class Ib PI3K). These enzymes catalyze the production of phosphatidylinositol )- trisphosphate (PIP3), leading to activation of downstream effector pathways important for cellular survival, differentiation, and function. PI3K-α and PI3K-β are widely expressed and are important mediators of signaling from cell surface receptors. PI3K-α is the isoform most often found mutated in cancers and has a role in insulin signaling and glucose homeostasis (Knight et al. Cell (2006) 125(4):733–47; Vanhaesebroeck et al. Current Topic Microbiol. Immunol. (2010) 347:1–19). PI3K-β is activated in cancers where phosphatase and tensin homolog (PTEN) is d. Both isoforms are targets of small molecule therapeutics in development for cancer.

PI3K- and - are preferentially expressed in leukocytes and are important in leukocyte function. These ms also contribute to the development and maintenance of inflammatory and mune diseases, and hematologic malignancies (Vanhaesebroeck et al. Current Topic Microbiol.

Immunol. (2010) 347:1–19; Clayton et al. J Exp Med. (2002) 196(6):753–63; Fung-Leung Cell Signal. (2011) 23(4):603–8; Okkenhaug et al. Science (2002) 297(5583):1031–34). PI3K-δ is activated by cellular receptors (e.g., receptor tyrosine s) through interaction with the Sarc homology 2 (SH2) domains of the PI3K regulatory t (p85), or through direct interaction with RAS.

PI3K-γ is associated with ein coupled receptors (GPCRs), is responsible for the very rapid induction of PIP3 in response to GPCRs, and can also be activated by RAS downstream of other receptors. PIP3 produced by PI3K activates or pathways downstream through interaction with pleckstrin homology (PH) domain containing enzymes (e.g., PDK-1 and AKT [PKB]).

Both PI3K-δ and -γ isoforms have been shown to be ant in many aspects of leukocyte biology. Central regulatory roles for either or both enzymes have been trated in B cells (Vanhaesebroeck et al. t Topic Microbiol. Immunol. (2010) 347:1–19; Clayton et al. J Exp Med. (2002) :753–63; Fung-Leung Cell . (2011) 23(4):603–8; Al-Alwan et al. J l. (2007) 178(4):2328–35; Bilancio et al. Blood (2006) 107(2):642–50; Dil et al. Mol l. (2009) 46(10):1970– 78; Durand et al. J Immunol. (2009) 183(9):5673–84; Srinivasan et al. Cell (2009) :573–86; Zhang et al. J. Allergy & Clin. Immunol. (2008) 122(4):811–9.e2), T cells (Vanhaesebroeck et al. Current Topic Microbiol. Immunol. (2010) 19; Garcon et al. Blood (2008) 111(3):1464–71; Haylock-Jacobs et al. J Autoimmun. (2011) 36(3–4):278–87; Jarmin et al. J. Clin. Invest. (2008) 118(3):1154–64; Ji et al. Blood (2007) 110(8):2940–47; Liu et al. J l. (2010) 184(6):3098–105; Okkenhaug et al. J. Immunol. (2006) 177(8):5122–28; Reif et al. J. Immunol. (2004) 173(4):2236–40; Soond et al. Blood (2010) 115(11):2203–13; Webb et al. J. Immunol. (2005) :2783-87), neutrophils (Schmid et al. Cancer Cell (2011) 19(6):715–27), macrophages/monocytes (Schmid et al. Cancer Cell (2011) 715–27, Konrad et al. J. Biol. Chem. (2008) 283(48):33296–303; Marwick et al. Am J Respir Crit Care Med. (2009) 179(7):542–48; Randis et al. Eur J Immunol. (2008) 38(5):1215–24), mast cells (Ali et al. Nature (2004) 431(7011):1007–11; Kim et al. Trends Immunol. (2008) 29(10):493–501; Lee et al. FASEB J. (2006) (3):455–65), and NK cells (Guo et al. J Exp Med. (2008) 205(10):2419–35; Kim et al. Blood (2007) 110(9):3202–08; Saudemont et al. Proc Natl Acad Sci U S A. (2009) 106(14):5795–800; Tassi et al. ty. (2007) 27(2):214–27).

Both PI3K-δ and -γ are believed to be important for the development and tence of autoimmune disease and hematologic malignancies.

There remains a significant need for improved therapy for cancers such as hematologic ancies.

SUMMARY Provided herein are methods, compositions, and kits for treating or preventing cancers or diseases, such as hematologic malignancies, which have a high expression level of one or more isoform(s) of PI3K (e.g., PI3K-δ and/or PI3K-γ). In one embodiment, the methods, compositions, and kits provided herein relate to administering an isoform-selective PI3K modulator (e.g., a compound provided herein, which selectively reduces or inhibits the activity of one or more PI3K isoform(s), e.g., PI3K-δ and/or PI3K- γ), alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian t, e.g., a human, having a cancer or disease, such as a logic malignancy, which has a high sion level of the one or more PI3K isoform(s).

In one embodiment, ed herein are methods, itions, and kits for treating or preventing a specific type of cancer or disease, such as, a specific type of hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K. In one embodiment, provided herein are methods, compositions, and kits for treating or preventing a specific sub-type of cancer or disease, such as, a specific sub-type of hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K. In one embodiment, the specific type or specific sub-type of cancer or hematologic malignancy has a high expression of PI3K isoform(s), including one or more of PI3K-δ or PI3K-γ, or a combination thereof. In one embodiment, the specific type or specific sub-type of cancer or hematologic malignancy has a high expression of PI3K-δ, or PI3K-γ, or both PI3K-δ and PI3K-γ.

In one embodiment, the methods, compositions, and kits comprise, or relate to, the step of selecting a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of hematologic ancy, for treatment, using a biomarker provided herein (e.g., selecting a specific type or sub-type of cancer or hematologic malignancy that has a high expression level of one or more isoform(s) of PI3K as determined using a biomarker provided herein). In one embodiment, the methods, compositions, and kits comprise, or relate to, the step of administering to a subject having a ic type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a ic sub-type, of hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K, a PI3K tor that selectively modulates (e.g., ively inhibits) the PI3K isoform(s) that is highly expressed in the specific type or subtype of disease.

In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific type, or a specific pe, of cancer or disease, e.g., a specific type, or a specific sub-type, of hematologic malignancy, which has a high expression level of PI3K-δ. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific pe, of a hematologic malignancy, which has a high expression level of PI3K-γ. In specific embodiments, ed herein are methods, compositions, and kits for ng or ting a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of a hematologic malignancy, which has a high expression level of PI3K-δ and PI3K-γ. In specific embodiments, provided herein are s, compositions, and kits for treating or preventing a ic type, or a specific sub-type, of cancer or e, e.g., a specific type, or a specific sub-type, of a logic ancy, which has a high expression level of PI3K-γ and PI3K-α. In specific embodiments, provided herein are methods, compositions, and kits for treating or ting a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of a hematologic malignancy, which has a high expression level of PI3K-γ and .

In specific embodiments, ed herein are methods, compositions, and kits for treating or preventing a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific pe, of a hematologic malignancy, which has a high expression level of PI3K-δ and . In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of a hematologic malignancy, which has a high expression level of PI3K-δ and PI3K-β. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of a hematologic malignancy, which has a high sion level of , PI3K-γ, and PI3K-α. In specific embodiments, provided herein are methods, itions, and kits for treating or preventing a specific type, or a specific sub-type, of cancer or disease, e.g., a specific type, or a specific sub-type, of a logic malignancy, which has a high expression level of PI3K-δ, PI3K-γ, and PI3K-β.

In one embodiment, provided herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, such as, a hematologic malignancy, n the particular patient or group of patients ) a high expression level of one or more isoform(s) of PI3K. In one embodiment, the PI3K isoform includes one or more of PI3K-δ or PI3K-γ, or a combination thereof. In one embodiment, the specific patient or group of patients, having a cancer or a hematologic malignancy, has(ve) a high expression of PI3K-δ or PI3K-γ, or both PI3K-δ and PI3K-γ.

In one embodiment, the methods, compositions, and kits comprise, or relate to, the step of selecting a patient or group of patients having a cancer or disease for treatment, using a biomarker provided herein (e.g., selecting a patient or group of patients that has(ve) a high expression level of one or more isoform(s) of PI3K as determined using a biomarker provided herein). In one embodiment, the s, compositions, and kits comprise, or relate to, the step of administering to the patient or group of patients having a high expression level of one or more isoform(s) of PI3K, a PI3K modulator that selectively modulates (e.g., ively inhibits) the PI3K isoform(s) that is/are highly sed in the patient(s).

In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, e.g., a hematologic malignancy, that has a high expression level of PI3K-δ. In specific embodiments, provided herein are methods, compositions, and kits for treating or ting a specific patient or group of patients, having a cancer or e, e.g., a hematologic malignancy, that has a high expression level of PI3K-γ. In specific embodiments, provided herein are methods, itions, and kits for treating or preventing a ic patient or group of patients, having a cancer or disease, e.g., a hematologic malignancy, which has a high expression level of PI3K-δ and PI3K-γ. In specific ments, provided herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, e.g., a hematologic malignancy, which has a high expression level of PI3K-γ and PI3K-α. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, e.g., a hematologic malignancy, which has a high sion level of PI3K-γ and PI3K-β. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific t or group of ts, having a cancer or disease, e.g., a hematologic malignancy, which has a high expression level of PI3K-δ and PI3K-α. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, e.g., a hematologic malignancy, which has a high expression level of PI3K-δ and PI3K-β. In specific embodiments, provided herein are methods, compositions, and kits for treating or preventing a specific t or group of ts, having a cancer or disease, e.g., a hematologic malignancy, which has a high expression level PI3K-δ, PI3K-γ, and PI3K-α. In specific embodiments, ed herein are methods, compositions, and kits for treating or preventing a specific patient or group of patients, having a cancer or disease, e.g., a logic malignancy, which has a high expression level of PI3K-δ, PI3K-γ, and PI3K-β.

In n embodiments, the expression level of one or more than one particular PI3K isoform in a cancer or a disease (e.g., a hematologic ancy), or a patient or a group of patients, can be determined by detecting the expression level of protein of a particular PI3K isoform, or DNA of a particular PI3K isoform, or RNA of a particular PI3K isoform, for example, using a method provided herein or a method known in the art. In other embodiments, the expression level of one or more than one particular PI3K isoform in a cancer or a disease (e.g., a hematologic malignancy), or a patient or a group of patients, can be determined by measuring a biomarker provided herein (e.g., a signaling pathway ker, a protein mutation biomarker, a protein sion biomarker, a gene mutation biomarker, a gene expression biomarker, a ne biomarker, a ine biomarker, or a biomarker for ular cancer cells, among others). In yet another embodiment, the expression level of one or more than one particular PI3K isoform in a cancer or a disease (e.g., a hematologic malignancy), or a patient or a group of ts, can be determined based on information known in the art or based on prior studies on the cancer or disease (e.g., a hematologic malignancy), or prior g of the patient or group of patients.

In one embodiment, the methods, compositions and kits provided herein relate to administering a PI3K modulator (e.g., a compound that selectively reduces the activity of one or more PI3K isoform(s)), alone or in combination with one or more other agents or therapeutic modalities, to a t, e.g., a mammalian subject, e.g., a human. In one embodiment, the PI3K modulator is selective toward one or more isoform(s) of PI3K over the other isoform(s) of PI3K. In one embodiment, the PI3K modulator (e.g., a compound provided herein) is selective toward PI3K-δ; selective toward PI3K-γ; selective toward PI3K-δ and PI3K-γ; selective toward PI3K-γ and ; selective toward PI3K-γ and PI3K-β; selective toward PI3K-δ and PI3K-α; selective toward PI3K-δ and ; selective toward PI3K-δ, PI3K-γ, and PI3K-α; or selective toward PI3K-δ, , and PI3K-β; over other PI3K isoform(s). In one embodiment, the selectivity of the PI3K modulator (e.g., a compound provided herein) for one isoform of PI3K over another m of PI3K is about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 30-fold, about 40- fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 1000-fold, about 2000-fold, about 5000-fold, about 10000-fold, or greater than about 10000-fold. In one embodiment, the ivity of a compound provided herein for one isoform of PI3K over another isoform of PI3K is greater than about 2-fold, greater than about 5-fold, greater than about 10-fold, greater than about -fold, greater than about 30-fold, greater than about 40-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about ld, greater than about 400-fold, greater than about ld, greater than about 1000-fold, greater than about 2000-fold, greater than about 5000-fold, or greater than about fold.

In certain embodiments, the ivity of a PI3K modulator (e.g., a compound provided herein) for one or more PI3K isoform(s) over other PI3K isoform(s) can be determined by measuring the activity of the PI3K modulator toward PI3K isoforms (e.g., , PI3K-β, PI3K-δ, and/or PI3K-γ), for example, using a method provided herein or a method known in the art.

In one embodiment, ed herein is a method of treating or managing cancer or hematologic malignancy in a subject who ped resistance to a prior treatment comprising identifying a subject who received prior treatment and administering to the subject a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, alone or in combination with one or more other therapeutic agents.

In one embodiment, the prior treatment is a ent with one or more BTK tors, anti-CD20 antibodies, proteasome inhibitors, or alkylating agents. In one embodiment, the prior treatment is treatment with one or more BTK inhibitors.

In one embodiment, the BTK inhibitor is ibrutinib (1-[(3R)[4-Amino(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl]piperidinyl]propenone) or AVL-292 (N-(3-((5- fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide). In one embodiment, the BTK tor is RN-486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5- (4-methyl-piperazinyl)-pyridinylamino]oxo-1,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolin one), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5- dihydropyrazinyl)methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 ( N- [3-(8-anilinoimidazo[1,2-a]pyrazinyl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2- methyl(4-methyl((4-(morpholinecarbonyl)phenyl)amino)oxo-4,5-dihydropyrazin yl)phenyl)benzamide), HM-71224, 59, ACP-196, CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), or LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide).

In one embodiment, the method provided herein further ses obtaining a biological sample from the subject and detecting the presence of one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on residue 481 of BTK ), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to e mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene ), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the ma2 gene (H244R), and WHIM-like CXCR4 mutationin the sample.

In one ment, the prior treatment is treatment with one or more proteasome tors. In one embodiment, the proteasome tor is bortezomib. In one embodiment, the prior ent is ent with one or more alkylating agents. In one embodiment, the alkylating agent is nitrogen mustard. In one embodiment, the prior treatment is treatment with one or more anti-CD20 antibodies. In one embodiment, wherein the D20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab.

In one embodiment, ed herein is a method of treating a subject with a cancer or hematologic malignancy comprising: identifying a subject with one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to ne mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine on on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine on on residue 707 of the ma2 gene (S707Y), ine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), and WHIM-like CXCR4 mutation; and administering a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, to the subject fied with one or more of the mutations.

In another embodiment, the administration further comprises combining with one or more other therapeutic agents to the subject fied with one or more of the mutations.

In one embodiment, the identifying comprises obtaining a biological sample from the subject and detecting one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), e to alanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), and WHIM-like CXCR4 mutation in the sample. In one embodiment, the detecting comprises performing polymerase chain on (PCR) or hybridization to detect one or more of the mutations.

In one ment, provided herein is a method of selecting a s ubject diagnosed with a cancer or hematologic malignancy as a candidate for ent w ith a therapeutically effective amount of a PI3K tor, or a pharmaceutically acceptable form thereof, comprising: (a) detecting the presence or absence of one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), ne to phenylalanine on on residue 481 of BTK (C481F), arginine to tryptophan mutation on e 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to alanine mutation on residue 845 of the PLCgamma2 gene ), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), and WHIM-like CXCR4 mutation in a sample obtained from the subject, wherein the presence of one or more of the ons indicates that the subject is a candidate for treatment with a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof; and (b) administering to the subject a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, when one or more of t he mutations are present in the sample.

In one embodiment, the administration further ses combining with one or more other therapeutic agents to the subject identified with one or more of the mutations.

In one embodiment, the PI3K modulator is Compound 292. In another embodiment, the PI3K tor is or CAL-101 (GS-1101, isib, (S)(1-(9H-purinylamino)propyl)fluoro phenylquinazolin-4(3H)-one).

In one embodiment, the other therapeutic agent is a chemotherapeutic agent or a therapeutic antibody. In one ment, the chemotherapeutic agent is selected from mitotic tors, alkylating agents, anti-metabolites, proteasome inhibitor, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological se modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

In one embodiment, the therapeutic antibody is selected from anti-CD37 antibody, anti- CD20 antibody, and anti-CD52 antibody. In one embodiment, the therapeutic antibody is anti-CD20 antibody. In one embodiment, the D20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab. In one embodiment, the anti-CD20 antibody is obinutuzumab.

In one embodiment, the molar ratio of the PI3K modulator to the other therapeutic agent is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1.In one embodiment, the PI3K tor is administered at a daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 10 mg, about 20 mg, or about 50 mg; or at a twice daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, about 20 mg, about mg, or about 50 mg; and the other therapeutic agent is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 1000.

In one embodiment, the PI3K modulator is administered at a daily dosage of about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg; obinutuzumab is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg.

In one embodiment, the PI3K modulator is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and the other agent is administered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, the PI3K modulator is administered at an amount to reach an area under the plasma concentration-time curve at steady-state ) at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 hr, about 7000 ng/mL*hr, about 7500 ng/mL*hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 hr; the other agent is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 ng/mL*hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr.

In one embodiment, the PI3K modulator is Compound 292, or a pharmaceutically able form thereof, and the other therapeutic agent is obinutuzumab.

In another embodiment, the PI3K modulator is CAL-101, or a pharmaceutically acceptable form thereof, and the other therapeutic agent is obinutuzumab.

In one embodiment, the molar ratio of Compound 292 to obinutuzumab is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one ment, the molar ratio is 25:1 to about 1:1. In one embodiment, the molar ratio is about 20:1 to about 5:1. In one embodiment, the molar ratio is about 20:1 to about 10:1. In one embodiment, the molar ratio is about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, or about :1. In one embodiment, the molar ratio is about 16:1. In one embodiment, the molar ratio is about 17:1.

In one embodiment, the molar ratio of CAL-101 to uzumab is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one embodiment, the molar ratio is about 150:1 to about 50:1. In one embodiment, the molar ratio is about 150:1 to about 75:1. In one embodiment, the molar ratio is about 125:1 to about 75:1. In one embodiment, the molar ratio is about 110:1 to about 90:1. In one embodiment, the molar ratio is about 100:1.

In one ment, Compound 292 is administered at a daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 10 mg, about 20 mg, or about 50 mg; or at a twice daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, about 20 mg, 25 mg, or about 50 mg; and obinutuzumab is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 1000 mg.

In one embodiment, Compound 292 is administered at a daily dosage of about 5 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg. In one embodiment, nd 292 is administered at a daily dosage of about 50 mg. In one embodiment, Compound 292 is administered at a twice daily at a dosage of about 5 mg to about 30 mg, about 15 mg to about 30 mg, or about 20 mg to about 30 mg. In one embodiment, Compound 292 is administered at twice daily at a dosage of about 25 mg. In one embodiment, obinutuzumab is stered at a daily dosage of about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one embodiment, uzumab is administered at a daily dosage of about 1000 mg.

In one embodiment, CAL-101 is administered at a daily dosage of about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg; and obinutuzumab is stered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one embodiment, CAL- 101 is administered at a daily dosage of about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg. In one embodiment, CAL-101 is administered at a daily dosage of about 300 mg. In one embodiment, CAL-101 is administered at twice daily at a dosage of about 10 mg to about 250 mg, about 75 mg to about 200 mg, about 100 mg to about 200 mg, or about 125 mg to about 1750 mg.

In one embodiment, CAL-101 is administered twice daily at a dosage of about 150 mg. In one embodiment, obinutuzumab is administered at a daily dosage of about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one embodiment, obinutuzumab is administered at a daily dosage of about 1000 mg.

In one embodiment, Compound 292 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and obinutuzumab is administered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, Compound 292 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1500 ng/mL to about 1000 ng/mL, about 1500 ng/mL to about 1200 ng/mL, about 1500 ng/mL to about 1300 ng/mL, or about 1500 ng/mL to about 1400 ng/mL. In one embodiment, Compound 292 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1487 ng/mL. In one embodiment, Cmaxss is at least 700 ng/mL, at least 1000 ng/mL, at least 1200 ng/mL, at least 1400 ng/mL, at least 1450 ng/mL, or at least 1480 ng/mL. In one ment, obinutuzumab is administered at an amount to reach Cmaxss at about 750 ng/mL to about 900 ng/mL, about 750 ng/mL to about 850 ng/mL, or about 750 ng/mL to about 800 ng/mL. In one embodiment, obinutuzumab is administered at an amount to reach Cmaxss at about 741 ng/mL. In one embodiment, Cmaxss is at least 200 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 720 ng/mL, or at least 740 ng/mL.

In one embodiment, CAL-101 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and obinutuzumab is administered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, CAL-101 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 2500 ng/mL, 1500 ng/mL to about 2500, or about 2000 ng/mL to about 2500 ng/mL. In one embodiment, CAL-101 is administered at an amount to reach is stered at an amount to reach Cmaxss at about 2200 ng/mL. In one embodiment, the Cmaxss is at least 1000 ng/mL, at least 1500 ng/mL, at least 1750 ng/mL, at least 2000 ng/mL, at least 2100 ng/mL, at least 2150 ng/mL, at least 2175 ng/mL, or at least 2200 ng/mL. In one embodiment, uzumab is administered at an amount to reach Cmaxss at about 750 ng/mL to about 900 ng/mL, about 750 ng/mL to about 850 ng/mL, or about 750 ng/mL to about 800 ng/mL. In one embodiment, obinutuzumab is administered at an amount to reach Cmaxss at about 741 ng/mL. In one embodiment, Cmaxss is at least 200 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 720 ng/mL, or at least 740 ng/mL.

In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr, about 7500 ng/mL*hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr; and obinutuzumab is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 ng/mL*hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr.

In one embodiment, nd 292 is administered at an amount to reach an AUCss at about 7000 ng/mL*hr to about 9000 ng/mL*hr or about 8000 hr to about 8500 ng/mL*hr. In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr. In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 8787 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 4044 hr.

In one embodiment, CAL-101 is administered at an amount to reach an AUCss at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr, about 7500 ng/mL*hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 hr; and obinutuzumab is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 ng/mL*hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 hr.

In one embodiment, CAL-101 is administered at an amount to reach AUCss at about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 8000 ng/mL*hr, about 6000 ng/mL*hr to about 7500 ng/mL*hr, or about 6500 ng/mL*hr to about 7500 ng/mL*hr. In one embodiment, CAL-101 is administered at an amount to reach AUCss at about 7000 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 3000 hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 4044 hr.

In one ment, the cancer or hematologic malignancy is CLL, Waldenström macroglobulinemia (WM), mantle cell, NHL, iNHL, diffuse large B-cell lymphoma, or T-cell lymphoma.

In another embodiment, the cancer or hematologic malignancy is follicular lymphoma.

In one embodiment, provided herein is a method of treating or preventing a specific cancer or disease, such as, a hematologic malignancy (e.g., a specific type, or a specific sub-type, of hematologic malignancy), which has a high expression level of one or more isoform(s) of PI3K, wherein the method comprises: (1) determining the expression level of one or more PI3K isoform(s) in the cancer or disease; (2) selecting a treatment agent (e.g., a PI3K modulator having a particular selectivity profile for one or more PI3K isoform(s)), based on the expression levels of PI3K isoforms in the cancer or disease to be d; and (3) administering the treatment agent to a patient having the cancer or disease, alone or in ation with one or more other agents or therapeutic ties. In one embodiment, the expression level of one or more PI3K isoform(s) in the cancer or disease can be measured by determining the expression level of PI3K isoform protein, DNA, and/or RNA; or by measuring one or more biomarkers provided herein (e.g., a signaling y biomarker, a protein mutation biomarker, a protein sion biomarker, a gene mutation biomarker, a gene expression biomarker, a cytokine biomarker, a chemokine biomarker, or a biomarker for particular cancer cells, among others). In other embodiments, the expression level of one or more PI3K isoform(s) in the cancer or disease can be determined based on information known in the art or information obtained in prior s on the cancer or disease.

Certain cancer or er, e.g., a hematologic malignancy (e.g., a specific type, or a specific sub-type, of hematologic malignancy), can exhibit geneity in PI3K isoform expression among patient populations. In one embodiment, provided herein is a method of treating or preventing a specific patient or group of patients, having a cancer or disease, such as, a hematologic ancy, wherein the method comprises: (1) ining the expression levels of one or more PI3K isoform(s) in the patient or group of ts having the cancer or disease; (2) selecting a treatment agent (e.g., a PI3K modulator having a particular selectivity profile for one or more PI3K isoform(s)) based on the expression levels of PI3K isoforms in the patient(s) to be treated; and (3) administering the treatment agent to the patient(s), alone or in combination with one or more other agents or eutic modalities. In one embodiment, the expression level of one or more PI3K isoform(s) in the patient or group of patients can be measured by determining the expression level of PI3K isoform n, DNA, and/or RNA in the patient or group of ts; or by measuring one or more biomarkers provided herein in the t or group of ts (e.g., a signaling pathway biomarker, a protein mutation biomarker, a protein expression biomarker, a gene mutation biomarker, a gene expression biomarker, a cytokine biomarker, a chemokine ker, or a biomarker for particular cancer cells, among others). In other embodiments, the expression level of one or more PI3K isoform(s) in the patient or group of patients can be determined based on information known in the art or information obtained in prior testing of the patient or group of patient(s).

In specific embodiments, the methods, compositions and kits ed herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is ive toward PI3K-δ over the other isoforms of PI3K. In specific embodiments, the s, itions and kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-γ over the other isoforms of PI3K. In specific embodiments, the methods, compositions and kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-δ and PI3K-γ over the other isoforms of PI3K. In specific embodiments, the s, compositions and kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or eutic ties, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-γ and PI3K-α over the other isoforms of PI3K. In specific embodiments, the methods, compositions and kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-γ and PI3K-β over the other isoforms of PI3K. In specific embodiments, the methods, compositions and kits provided herein relate to administering a PI3K modulator, alone or in ation with one or more other agents or therapeutic ties, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is ive toward PI3K-δ and PI3K-α over the other ms of PI3K. In specific embodiments, the methods, compositions and kits provided herein relate to stering a PI3K modulator, alone or in combination with one or more other agents or therapeutic ties, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-δ and PI3K-β over the other isoforms of PI3K. In specific ments, the methods, compositions and kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or eutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-δ, PI3K-γ, and PI3K-α over other isoform of PI3K. In specific embodiments, the methods, compositions and kits ed herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective toward PI3K-δ, PI3K-γ, and PI3K-β over other isoform of PI3K.

In one embodiment, the methods, compositions, or kits provided herein relate to administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human; wherein the PI3K modulator is selective for one or more PI3K isoform(s) over other isoforms of PI3K (e.g., PI3K-δ selective, PI3K-γ ive, or PI3K-δ and PI3K-γ ive); and the subject being treated has a high expression level of the particular PI3K isoform(s) (e.g., high expression of PI3K-δ, high expression of PI3K-γ, or high expression of both PI3K-δ and PI3K-γ). Without being d to a particular theory, the methods, compositions, or kits provided herein can provide reduced side effects and/or improved cy. Thus, in one ment, provided herein is a method of treating or ting a cancer or disease, such as hematologic malignancy, or a specific type or sub-type of cancer or disease, such as a specific type or sub-type of hematologic malignancy, having a high expression level of one or more isoform(s) of PI3K, wherein the adverse s associated with administration of PI3K inhibitors are reduced.

In one embodiment, ed herein is a method of treating or preventing a cancer or disease, such as logic malignancy, or a specific type or sub-type of cancer or disease, such as a specific type or sub-type of hematologic malignancy, with a PI3K-γ selective inhibitor, wherein the adverse effects associated with administration of inhibitors for other isoform(s) of PI3K (e.g., PI3K-α or PI3K-β) are reduced. In one embodiment, provided herein is a method of treating or preventing a cancer or disease, such as hematologic malignancy, or a ic type or sub-type of cancer or disease, such as a specific type or sub-type of hematologic malignancy, with a PI3K-γ ive inhibitor, at a lower (e.g., by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, or by about 80%) dose as compared to treatment with a PI3K-γ non-selective or less selective inhibitor (e.g., a PI3K pan inhibitor (e.g., PI3K-α, β, γ, δ)).

In one embodiment, the methods, compositions, or kits ed herein relate to administering a PI3K modulator, in combination with one or more second active agent(s), e.g., one or more cancer therapeutic agent(s). In one embodiment, the second active agents that can be used in the methods, compositions, or kits provided herein include, but are not limited to, one or more of: a BTK inhibitor, such as, e.g., ibrutinib, RN-486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5-(4-methylpiperazinyl )-pyridinylamino]oxo-1,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolinone), GDC- 0834 ([R-N-(3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl )methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 ( 8- anilinoimidazo[1,2-a]pyrazinyl)phenyl]tert-butylbenzamide), CGI-1746 rt-butyl)-N-(2-methyl- 3-(4-methyl((4-(morpholinecarbonyl)phenyl)amino)oxo-4,5-dihydropyrazin yl)phenyl)benzamide), HM-71224(Hammi Pharmaceticals), ONO-4059 (Ono Pharmaceuticals Co., LTD), 4 (4-(4-((4-((3-acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N- methylpicolinamide), LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide) and AVL-292 (N-(3-((5-fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide), which can also be ed to as CC-292 ; an HDAC inhibitor, such as, e.g., belinostat, vorinostat, panobinostat, or romidepsin; an mTOR inhibitor, such as, e.g., everolimus (RAD 001); a proteasome inhibitor, such as, e.g., bortezomib or carfilzomib; a JAK inhibitor or a JAK/STAT inhibitor, such as, e.g., Tofacitinib, INCB16562, or AZD1480; a BCL-2 tor, such as, e.g., ABT-737, ABT-263, or Navitoclax; a MEK inhibitor, such as, e.g., AZD8330 or ARRY-424704; an olate, such as, e.g., pralatrexate; a farnesyl erase tor, such as, e.g., tipifarnib; an antibody or a biologic agent, such as, e.g., obinutuzumab (GA101), alemtuzumab, rituximab, umab, or brentuximab vedotin (SGN-035); an antibody-drug conjugate, such as, e.g., inotuzumab ozogamicin, or brentuximab vedotin; a cytotoxic agent, such as, e.g., bendamustine, gemcitabine, oxaliplatin, cyclophosphamide, vincristine, vinblastine, anthracycline (e.g., daunorubicin or daunomycin, doxorubicin, or actinomycin or dactinomycin), bleomycin, clofarabine, nelarabine, cladribine, ginase, methotrexate, or pralatrexate; or other anti-cancer agents or chemotherapeutic agents, such as, e.g., fludarabine, ibrutinib, fostamatinib, lenalidomide, thalidomide, mab, cyclophosphamide, doxorubicin, vincristine, prednisone, or R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin or ydaunomycin, Vincristine or Oncovin, Prednisone). Additional embodiments of second active agents are provided herein elsewhere.

Without being limited by a particular theory, in one embodiment, the cancer or disease being treated or prevented, such as a blood disorder or hematologic malignancy, has a high expression level of one or more PI3K isoform(s) (e.g., PI3K-α, PI3K-β, PI3K-δ, or PI3K-γ, or a combination thereof). In one embodiment, the cancer or disease that can be treated or prevented by methods, itions, or kits provided herein includes a blood disorder or a hematologic malignancy, ing, but not d to, myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), among others. In one embodiment, the blood disorder or the logic malignancy includes, but is not limited to, acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL), B-cell ALL (B-ALL), acute d leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), blast phase CML, small cytic lymphoma (SLL), CLL/SLL, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL (iNHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), sive B-cell NHL, B-cell lymphoma (BCL), Richter’s syndrome (RS), T-cell lymphoma (TCL), eral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), transformed mycosis fungoides, Sézary syndrome, anaplastic large-cell lymphoma (ALCL), follicular lymphoma (FL), Waldenström macroglobulinemia (WM), lymphoplasmacytic lymphoma, Burkitt lymphoma, le myeloma (MM), amyloidosis, MPD, essential thrombocytosis (ET), myelofibrosis (MF), polycythemia vera (PV), c myelomonocytic leukemia , myelodysplastic syndrome (MDS), high-risk MDS, and low-risk MDS. In one embodiment, the hematologic malignancy is relapsed. In one embodiment, the hematologic malignancy is refractory. In one embodiment, the cancer or disease is in a pediatric patient (including an infantile patient). In one embodiment, the cancer or disease is in an adult patient. Additional ments of a cancer or disease being treated or prevented by methods, compositions, or kits provided herein are bed herein elsewhere.

In one embodiment, the cancer or disease being d or prevented, such as a blood disorder or hematologic malignancy, has a high expression level of PI3K-δ and/or PI3K-γ, which includes, but is not limited to, CLL, CLL/SLL, blast phase CLL, CML, DLBCL, MCL, B-ALL, T-ALL, multiple myeloma, B-cell lymphoma, CTCL (e.g., mycosis fungoides or Sézary syndrome), AML, Burkitt lymphoma, follicular lymphoma (FL), Hodgkin lymphoma, ALCL, or MDS.

In one embodiment, provided herein is a PI3K modulator, as a single agent or in ation with one or more additional therapies, for use in a method, composition, or kit provided herein, to ameliorate cancer or hematologic disease, such as a hematologic malignancy (e.g., by sing one or more symptoms associated with the cancer or hematologic disease) in a subject, e.g., a ian subject.

Symptoms of cancer or hematologic disease that can be ameliorated include any one or combination of symptoms of cancer or hematologic disease, as known the art and/or as sed . Experimental conditions for evaluating the effects of a PI3K modulator in ameliorating cancer or hematologic disease in animal models of cancer or hematologic disease are provided herein or are known in the art.

In one embodiment, provided herein is a method of reducing a symptom associated with cancer or hematologic disease, such as a hematologic malignancy, in a biological sample, comprising contacting the biological sample with a PI3K modulator, e.g., a compound provided herein (e.g., a compound of a I, e.g., Compound 292) or a pharmaceutically acceptable form thereof (e.g., an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, cocrystal , ate, or polymorph thereof), in an amount sufficient to reduce the symptom associated with cancer or hematologic disease.

In one embodiment, provided herein is a method of treating or preventing cancer or hematologic disease (e.g., a hematologic malignancy) in a subject, comprising administering an effective amount of a PI3K modulator, e.g., a compound provided herein (e.g., a compound of Formula I, e.g., Compound 292), or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof.

In one embodiment, the nd is a compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: Formula I wherein Wd is heterocycloalkyl, aryl or heteroaryl; B is alkyl or a moiety of Formula II; (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; X is absent or –(CH(R9))z–, and z is an integer of 1; Y is absent, or -N(R9)-; R1 is hydrogen, alkyl, alkenyl, alkynyl, , amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy, or nitro; R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, carbonyl sulfonamido, halo, cyano, hydroxy, or nitro; R5, R6, R7, and R8 are each independently en, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxy, or nitro; and each instance of R9 is independently en, alkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments, when both X and Y are present then Y is –NH–.

In some embodiments, X is absent or is –(CH(R9))z–, and z is ndently an integer of 1, 2, 3, or 4; and Y is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z-, -, - N(R9)(C=O)-, -N(R9)(C=O)NH-, 9)C(R9)2-.

In some embodiments, -X- is -CH2-, -CH(CH2CH3)-, or -CH(CH3)-.

In some ments, -X-Y- is -CH2-N(CH3)-, -CH2-N(CH2CH3)-, -CH(CH2CH3)-NH-, or -CH(CH3)-NH-.

In some embodiments, Wd is a pyrazolopyrimidine of Formula III(a), or a purine of Formula III(b), Formula III(c) or Formula III(d): N R12 N N N NH NH R12 N N N N N N N R11 N R12 Ra' Formula III(a) a III(b) Formula III(c) Formula III(d) wherein Ra’ of Formula III(d) is hydrogen, halo, phosphate, urea, a carbonate, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl; R11 of Formula III(a) is H, alkyl, halo, amino, amido, hydroxy, or alkoxy; and R12 of Formula III(a), Formula III(c) or Formula III(d) is H, alkyl, l, alkenyl, halo, aryl, heteroaryl, cycloalkyl, or cycloalkyl. In some embodiments, Wd is a lopyrimidine of Formula III(a), wherein R11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R12 is cyano, amino, carboxylic acid, or amido.

In some embodiments, a compound of Formula I has the structure of Formula IV: R3 O R5 B R6 H R7 R8 N N N R12 N Formula IV wherein R11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, aryl, heterocycloalkyl, or cycloalkyl. In some embodiments, the nd of Formula I has the structure of Formula IV wherein R11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R12 is cyano, amino, carboxylic acid, or amido.

In some embodiments, R11 is amino. In some embodiments, R12 is alkyl, alkenyl, alkynyl, heteroaryl, aryl, or heterocycloalkyl. In some embodiments, R12 is cyano, amino, carboxylic acid, amido, monocyclic heteroaryl, or bicyclic heteroaryl.

In some embodiments of a compound of Formula I, the compound has the structure of Formula V: R3 O R5 B R7 R8 NR9 N N N N .

Formula V In some embodiments, -NR9- is -N(CH2CH3)CH2- or )CH2-.

In some embodiments of a compound of Formula I, the compound has a structure of Formula VI: R1R3 R5 B R6 N R7 R8R3 N N N N .

Formula VI In some ments, R3 is -H, -CH3, -Cl, or -F, and R5, R6, R7, and R8 are ndently hydrogen.

In some embodiments, B is a moiety of Formula II; (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4.

In one embodiment, the PI3 kinase modulator is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I-1: a I-1 n B is a moiety of a II; wherein Wc in B is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; X is absent or –(CH(R9))z–, and z is an integer of 1; Y is absent, or -; N N N R12 N N N when Y is absent, Wd is: H2N H , or when Y is present, Wd is: N ; R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy, or nitro; R3 is hydrogen, alkyl, l, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido, halo, cyano, hydroxy, or nitro; each instance of R9 is independently hydrogen, C1-C10 alkyl, cycloalkyl, or heterocycloalkyl; and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.

In some embodiments, a compound of Formula I or Formula I-1 has the structure of Formula IV-A: R3 O H B H H H H N N N R12 N H2N .

Formula IV-A In some embodiments, R12 is substituted benzoxazole.

In some embodiments, a compound of Formula I or Formula I-1 has the structure of Formula V-A: R3 O H B H H HN N N N N . a V-A In some embodiments, a compound of Formula I or Formula I-1 has the structure of Formula IV-A or Formula V-A.

In some embodiments, a compound of Formula I or Formula I-1 has the structure of Formula V-B: R3 O H B H H NR9 N N N N .

Formula V-B In some embodiments, a compound of Formula I or Formula I-1 has the structure of Formula VI-A: R3R O H B H NH H H N N N N .

Formula VI-A In some embodiments, a compound of Formula I or a I-1 is a compound wherein B is a moiety of Formula II: (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; q is an integer of 0 or 1; R1 is hydrogen, alkyl, or halo; R2 is alkyl or halo; and R3 is hydrogen, alkyl, or halo. In some embodiments, when both X and Y are present then Y is –NH–. In other embodiments, R3 is -H, -CH3, -CH2CH3, -CF3, -Cl or -F. In other embodiments, R3 is methyl or chloro.

In some ments, X is –(CH(R9))z–, n R9 is methyl and z is 1; and Wd is N N N .

In some embodiments of a compound of Formula I or Formula I-1, the compound is predominately in an (S)- stereochemical configuration.

In some embodiments of a compound of Formula I or Formula I-1, the compound has a structure of Formula V-A2: R3 O H B H H HN N N N N . a V-A2 In some ments, R12 is a monocyclic heteroaryl, bicyclic heteroaryl, or heterocycloalkyl.

In some embodiments, B is a moiety of Formula II: (R2)q Formula II wherein Wc is aryl or cycloalkyl.

In some embodiments, the compound of Formula I is a polymorph Form C of Compound 292 as sed herein.

In some embodiments, the compound inhibits or reduces the activity of a class I PI3K. In n embodiments, the class I PI3K is p110 α, p110 β, p110 γ, or p110 δ.

In some embodiments, the compound inhibits one or more class I PI3K isoforms ed from the group consisting of PI3 kinase-α, PI3 -β, PI3 kinase-γ, and PI3 -δ.

In some embodiments, the compound selectively inhibits a class I PI3 kinase-δ isoform, as ed with other class I PI3 kinase isoforms. In some embodiments, the nd selectively inhibits a class I PI3 kinase-γ isoform, as compared with other class I PI3 kinase isoforms. In some embodiments, the compound selectively ts a class I PI3 kinase-δ and a PI3 kinase-γ isoform, as ed with other class I PI3 kinase isoforms.

In some embodiments, a pharmaceutical composition is used, wherein the ition comprises a pharmaceutically acceptable excipient and one or more compounds of any formulae provided herein, including but not limited to Formula I, I-1, and IV to XVIII (including IV-A, V, V-A, V-A2, V-B, VI, and VI-A, among others). In some embodiments, the composition is a liquid, solid, semi-solid, gel, or an aerosol form.

In some embodiments, two or more PI3K modulators (e.g., two or more PI3K modulators described ) are administered in combination. In one embodiment, the PI3K modulators are administered concurrently. In another embodiment the modulators are administered sequentially. For example, a combination of e.g., nd 292 and a second PI3K modulator, can be administered concurrently or sequentially. In one embodiment, the second PI3K modulator, is administered first, followed, with or without a period of overlap, by administration of Compound 292. In another embodiment, Compound 292 is administered first, followed, with or without a period of overlap, by administration of the second PI3K modulator.

In other embodiments, a PI3K modulator (e.g., one or more PI3K modulators described ) are administered in combination with one or more than one additional therapeutic agent, such as a cancer eutic agent described herein. In one ment, the PI3K modulator and the second agent are administered concurrently. In another embodiment the PI3K modulator and the second agent are administered sequentially. For example, a combination of e.g., Compound 292 and a second agent, can be administered concurrently or sequentially. In one embodiment, the second agent, is administered first, followed, with or without a period of overlap, by administration of Compound 292. In another embodiment, Compound 292 is administered first, followed, with or without a period of overlap, by administration of the second agent.

In one embodiment, the t treated is a mammal, e.g., a primate, typically a human (e.g., a patient having, or at risk of having, cancer or hematologic disorder, such as hematologic malignancy, as described herein). In some embodiments, the subject treated is in need of PI3 kinase inhibition (e.g., has been evaluated to show elevated PI3K levels or alterations in another component of the PI3K pathway). In one embodiment, the subject previously received other treatment (e.g., a treatment for cancer or a ent for hematologic disorder).

In some embodiments, the PI3K modulator is administered as a pharmaceutical composition comprising the PI3K modulator, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain ments, the PI3K modulator is administered or is present in the composition, e.g., the pharmaceutical composition.

The PI3K modulators described herein can be administered to the subject systemically (e.g., orally, parenterally, aneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or avitary installation). Typically, the PI3K tors are administered .

In one embodiment, the PI3K modulator is Compound 292, as disclosed in Table 4, or a pharmaceutically acceptable salt thereof. nd 292, or a pharmaceutically acceptable salt f, can be administered orally. Other routes of administration are also provided herein.

The methods and compositions provided herein can, optionally, be used in combination with other therapies (e.g., one or more , surgical procedures, or radiation procedures). Any combination of one or more PI3K modulator(s) and one or more other agents or therapies can be used. The PI3K modulator(s) and other therapies can be administered before treatment, concurrently with treatment, post-treatment, or during remission of the disease. In one embodiment, a second agent is administered simultaneously or sequentially with the PI3K modulator.

In one embodiment, ed herein is a biomarker (e.g., a diagnostic biomarker, a predictive ker, or a stic biomarker), for use in treating or preventing a cancer or disease (e.g., a hematologic malignancy) described herein. In one embodiment, the ker provided herein include, but are not limited to: a target biomarker, a signaling pathway biomarker, a protein mutation biomarker, a protein expression biomarker, a gene mutation biomarker, a gene sion biomarker, a cytokine biomarker, a chemokine biomarker, or a biomarker for particular cancer cells. In one embodiment, the biomarker can be used to evaluate a particular type of cancer or disease, or a particular t or group of patients. In one embodiment, the biomarker involves immunohistochemistry (IHC) of a particular protein target. In one ment, the ker involves the RNA (e.g., mRNA) (e.g., in situ hybridization (ISH) of mRNA) of a ular protein target. In one embodiment, the biomarker involves the DNA of a particular protein target, including c alteration such as somatic mutation, copy number alterations such as amplification or deletion, and chromosomal translocation as well as epigenetic alteration such as methylation and histone modification. In one embodiment, the ker involves micro-RNA (miRNA) which regulates sion of a particular protein target. In one embodiment, the ker involves measurement of a protein/protein modification. In one embodiment, the biomarker involves measurement of a non-protein marker, such as, e.g., metabolomics. In one embodiment, the biomarker is measured by ELISA, n blot, or mass spectroscopy. In one embodiment, the biomarker is a serum biomarker. In one embodiment, the biomarker is a blood biomarker. In one embodiment, the biomarker is a bone marrow biomarker. In one embodiment, the biomarker is a sputum biomarker. In one embodiment, the biomarker is a urine biomarker. In one embodiment, the biomarker involves trixes, ing, but not limited to, serum, blood, bone marrow, sputum, or urine.

In exemplary embodiments, the biomarker provided herein is a target biomarker, such as, e.g., a biomarker to determine the protein and/or RNA expression of one or more particular PI3K isoform; e.g., a biomarker for PI3K-α sion, for PI3K-β expression, for PI3K-δ expression, or for PI3K-γ expression, or combinations thereof. In other embodiments, the biomarker could be DNA alteration of one or more particular PI3K ms (e.g., mutation, copy number variation, or etic modification).

In exemplary embodiments, the biomarker provided herein is a signaling y ker, such as, e.g., a PTEN pathway biomarker and/or a biomarker of signaling pathway activation such as pAKT, pS6, and/or pPRAS40 (e.g., an IHC biomarker, a DNA alteration biomarker, a DNA deletion biomarker, or a DNA on biomarker). In exemplary embodiments, the biomarker provided herein is a mutation biomarker, such as, a protein on biomarker or a gene mutation biomarker, to assess the mutation of one or more targets, such as, e.g., IGH7, KRAS, NRAS, A20, CARD11, CD79B, TP53, CARD11, MYD88, GNA13, MEF2B, TNFRSF14, MLL2, BTG1, EZH2, NOTCH1, JAK1, JAK2, PTEN, FBW7, PHF6, IDH1, IDH2, TET2, FLT3, KIT, NPM1, CEBPA, DNMT3A, BAALC, RUNX1, ASXL1, IRF8, POU2F2, WIF1, ARID1A, MEF2B, TNFAIP3, PIK3R1, MTOR, PIK3CA, PI3Kδ, and/or PI3Kγ. In exemplary embodiments, the ker provided herein is an expression biomarker, such as, a n expression biomarker, a gene expression biomarker, to assess the expression of one or more targets, or the upregulation or downregulation of a pathway, such as, e.g., pERK IHC biomarker or pERK sion biomarker, for example, to assess RAS or PI3K pathway activation.

In exemplary embodiments, the biomarker provided herein is a cytokine biomarker (e.g., serum cytokine biomarkers or other cytokine biomarkers provided herein). In exemplary embodiments, the biomarker provided herein is a chemokine biomarker (e.g., serum chemokine biomarkers or other chemokine biomarkers provided herein).

In exemplary embodiments, the biomarker provided herein is a biomarker for cancer cells (e.g., a particular cancer cell line, a particular cancer cell type, a particular cell cycle profile).

In exemplary embodiments, the biomarker provided herein relates to gene expression profiling of a patient or group of patients, e.g., as a predictive biomarker for PI3Kδ and/or PI3Kγ pathway activation, or as a predictive ker for response to a treatment described herein. In exemplary embodiments, the biomarker provided herein relates to a gene sion classifier, e.g., as a predictive biomarker for PI3Kδ and/or PI3Kγ expression or activation (e.g., differential expression or activation in the ABC, GCB, oxidative orylation (Ox Phos), B-cell receptor/proliferation (BCR), or host response (HR) subtypes of DLBCL).

In one embodiment, the methods provided herein can further include the step of evaluating a subject, e.g., for one or more signs or symptoms or biological concomitants of cancer or hematologic disorder, as disclosed , e.g., evaluate a biomarker described herein in the subject. In some embodiments, one or more of these biological itants or biomarkers correlate with improved likelihood of response of a subject to a particular therapy. In some ments, one or more of these biological concomitants or biomarkers ate with reduced side effect in a subject to a particular therapy.

In one embodiment, the methods provided herein can further include the step of monitoring the subject, e.g., for a change (e.g., an increase or decrease) in levels of one or more signs or symptoms or biological itants of cancer or hematologic disorder, as disclosed herein, e.g., a biomarker bed herein. In some ments, one or more of these biological concomitants or biomarkers correlate with a decrease in one or more clinical ms associated with cancer or hematologic disorder. In some embodiments, one or more of these biological concomitants or biomarkers correlate with improved likelihood of se in a subject to a particular y. In some embodiments, one or more of these ical itants or biomarkers correlate with reduced side effect in a subject to a particular therapy.

In some embodiments, a normalization or change (e.g., a decrease in an ed level or increase in a diminished level) of a biological concomitant or biomarker is indicative of treatment efficacy and/or is tive of improvement in clinical symptoms. In some embodiments, the subject is monitored for a change in a biological concomitant or biomarker (e.g., a decrease or increase of a biological concomitant or biomarker, which can be indicative of treatment efficacy).

In one embodiment, the subject can be evaluated or monitored in one or more of the ing periods: prior to beginning of treatment; during the treatment; or after one or more elements of the ent have been administered. Evaluation and monitoring can be used to determine the need for further treatment with the same PI3K modulator, alone or in combination with, another agent, or for additional treatment with additional agents, or for adjusted dosing regimen of the same PI3K modulator.

] In one embodiment, the methods provided herein can r include the step of analyzing a nucleic acid or protein from the subject, e.g., analyzing the genotype of the subject. In one embodiment, a PI3K protein, or a nucleic acid encoding a PI3K protein, and/or an upstream or downstream component(s) of a PI3K signaling pathway is analyzed. The nucleic acid or protein can be detected in any biological sample (e.g., blood, urine, ating cells, a tissue biopsy or a bone marrow biopsy) using any method disclosed herein or known in the art. For example, the PI3K protein can be detected by systemic administration of a d form of an antibody to PI3K followed by imaging.

] The is can be used, e.g., to te the suitability of, or to choose between alternative treatments, e.g., a particular dosage, mode of delivery, time of delivery, inclusion of adjunctive therapy, e.g., administration in combination with a second agent, or lly to determine the subject’s probable drug response phenotype or pe. The nucleic acid or protein can be analyzed at any stage of treatment. In one embodiment, the nucleic acid or protein can be analyzed at least prior to administration of the PI3K modulator and/or agent, to thereby determine appropriate dosage(s) and treatment regimen(s) of the PI3K modulator (e.g., amount per treatment or frequency of treatments) for prophylactic or therapeutic treatment of the subject.

In certain embodiments, the methods provided herein further include the step of detecting an altered PI3K level in a patient, prior to, or after, administering a PI3K modulator to the patient. The PI3K level can be assessed in any biological sample, e.g., blood, urine, circulating cells, or a tissue biopsy.

In some embodiments, the PI3K level is assessed by ic administration of a labeled form of an antibody to PI3K followed by imaging.

] In r embodiment, provided herein is a composition, e.g., a pharmaceutical composition, that includes one or more PI3K tors, e.g., a PI3K modulator as described herein, and one or more agents (e.g., a second active agent as disclosed herein). The ition can further include a pharmaceutically-acceptable carrier or excipient.

In another ment, provided herein is a composition for use, or the use, of a PI3K modulator, alone or in combination with a second agent or a therapeutic modality described herein for the treatment of a cancer or disorder, such as a hematologic ancy, as described herein.

In another embodiment, ed herein are therapeutic kits that include a PI3K modulator, alone or in combination with one or more additional agents, and instructions for use in the treatment of a cancer or disorder, such as a hematologic malignancy, as described herein.

INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be orated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS depicts the PK/PD onship of mean drug plasma concentration and mean % reduction from pre-dose for basophil activation over time, following single dose administration of Compound 292 in human. s the PK/PD relationship of mean drug plasma concentration and mean % reduction from pre-dose for basophil activation over time, following multiple dose administration of Compound 292 in human. depicts the pharmacodynamic response versus concentration of Compound 292 in human. depicts the steady state (C2D1) plasma trations over time after administration of Compound 292 in human. depicts AKT phosphorylation in CLL/SLL cells of Compound 292. s changes in tumor size after administration of Compound 292 in human. depicts rapid onset of clinical activity of Compound 292 in CLL/SLL patients. depicts clinical activity of Compound 292 in T-cell lymphoma patients. depicts clinical ty of Compound 292 in a T-cell lymphoma patient. s percent changes in measurable e in patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell ma. depicts percent changes in measurable disease in patients with aggressive NHL (aNHL), Hodgkin’s ma and mantle cell lymphoma (MCL). depicts percent changes in measurable disease in ts with indolent NHL (iNHL). iNHL patients included patients with follicular lymphoma, Waldenstrom macroglobulinemia (lymphoplasmacytic ma) and marginal zone lymphoma (MZL). depicts months on study by subject and sis for patients treated with Compound 292. depicts that Compound 292 inhibits TNF-α and IL-10 productions from diluted whole blood stimulated with LPS. depicts the effects of Compound 292 treatment on serum tration of CXCL13 in CLL/SLL and iNHL/MCL/FL patients. depicts the effects of Compound 292 treatment on serum tration of CCL4 in CLL/SLL and iNHL/MCL/FL patients. depicts the effects of Compound 292 treatment on serum concentration of CCL17 in L and iNHL/MCL/FL patients. depicts the effects of Compound 292 treatment on serum concentration of CCL22 in CLL/SLL and iNHL/MCL/FL patients. ] depicts the effects of Compound 292 treatment on serum concentration of TNF- α in CLL/SLL and iNHL/MCL/FL patients. depicts the effects of Compound 292 ent on serum tration of MMP9 in some non-CLL/iNHL patients. depicts a possible ism of actions for certain chemokines in patients with hematologic malignancies. depicts steady state plasma concentrations of Compound 292 on cycle 2, day 1 of 28 day cycles, 25 mg and 75 mg BID administration. depicts decrease in levels of CLL kers in serum at various time points following 28 day cycles, 25 mg BID administration of Compound 292. ] depicts decrease in levels of CLL biomarkers in serum at various time points following 28 day cycles, 25 mg or 75 mg BID administration of Compound 292. ] depicts median Absolute Lymphocyte Count (ALC) at various time points following 28 day cycles, 25 mg BID administration in ts with higher than 10x103/μl baseline ALC (darker line) and lower than 10x103/μl baseline ALC (lighter line). depicts median ALC at various time points following 28 day cycles, 25 mg BID administration and changes in tumor measurement.

A depicts decrease in levels of lymphoma biomarkers in serum at various time points following 28 day cycles, 25 mg BID administration of nd 292.

] B depicts decrease in levels of iNHL biomarkers in serum at various time points following 28 day cycles, 25 mg BID administration of Compound 292. depicts decrease in levels of T-cell ma biomarkers in serum at various time points following 28 day cycles, 25 mg BID administration of Compound 292. depicts decrease in levels of iNHL biomarkers in serum at various time points following 28 day cycles, 25 mg or 75 mg BID administration of Compound 292.

] A depicts number of Sézary cells per microliter of peripheral blood at various time points ing 28 day cycles, 25 mg BID administration of Compound 292.

B depicts CT response shown in terms of Sum of Product Diameters (SPD) at various time points following 28 day cycles, 25 mg BID administration of Compound 292.

C depicts mSWAT score at s time points following 28 day cycles, 25 mg BID administration of Compound 292. depicts correlation between growth inhibition and pharmacodynamic se in DLBCL cell lines DHL-6, DHL-4, Ri-1 and U2932, as ed by western blot of various proteins. depicts sensitivity of Loucy ALL cell line to different PI3K isoform inhibitors. depicts decrease in level of pPRAS40 upon treatment by Compound 292, as compared to the administration of GS-1101, and that the level of pERK1/2 is much lower in HH cells than MJ or HuT78 cells. depicts increase of Ki-67/pAKT ve CLL cells at 30 minutes, 4 hours, 24 hours and 72 hours after the treatment by a cytokine cocktail consisting of CD40L, IL-2 and Il-10. depicts reduction in Ki-67/pAKT positive CLL cells treated by cytokine cocktail upon treatment by 100 nM Compound 292. depicts percent inhibition of CLL cell proliferation by Compound 292 in comparison with CAL-101.

A depicts absolute cyte counts in CLL patients treated by 25 mg BID Compound 292.

B depicts reduction in CD38 positive circulating CLL cells in CLL patients treated by 25 mg BID Compound 292.

C depicts ion in CD69 positive circulating CLL cells in CLL patients treated by 25 mg BID Compound 292.

D depicts reduction in CD38/CD69 double positive ating CLL cells in CLL patients treated by 25 mg BID Compound 292. depicts the effects of Compound 292/ibrutinib combination on viability of DLBCL cells as compared with the monotherapy. depicts the s of Compound 292 on pATK in CLL ts who previously progressed on ibrutinib treatment. shows an ogram depicting the synergistic effect of the combination of Compound 292 and ibrutinib in TMD-8 line. shows an isobologram depicting the synergistic effect of the combination of Compound 292 and ibrutinib in L cell line. shows an isobologram depicting the synergistic effect of the combination of Compound 292 and nib in Farage cell line.

DETAILED DESCRIPTION While specific embodiments have been discussed, the specification is illustrative only and not restrictive. Many ions of this disclosure will become apparent to those skilled in the art upon review of this specification.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly tood by one of skill in the art. All patents and publications referred to herein are incorporated by nce.

As used in the specification and , the singular form “a”, “an” and “the” includes plural references unless the context y dictates otherwise.

As used herein, and unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term ” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

As used herein, the term nt” or “subject” refers to an , typically a human (e.g., a male or female of any age group, e.g., a pediatric patient (e.g., infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or senior adult) or other mammal, such as a primate (e.g., cynomolgus monkey, rhesus monkey); other mammals such as rodents (mice, rats), cattle, pigs, horses, sheep, goats, cats, dogs; and/or birds, that will be or has been the object of treatment, observation, and/or experiment. When the term is used in conjunction with administration of a compound or drug, then the patient has been the object of treatment, ation, and/or administration of the compound or drug.

A “therapeutic effect,” as that term is used , encompasses a therapeutic benefit and/or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a e or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The term “effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. An effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and e condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells. The specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, r it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

As used , the terms “treatment”, “treating”, “palliating” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological ms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the t can still be afflicted with the ying disorder. For prophylactic benefit, the ceutical compositions can be administered to a t at risk of developing a ular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. In one embodiment, these terms also refer to partially or completely inhibiting or reducing the condition from which the subject is suffering. In one embodiment, these terms refer to an action that occurs while a t is suffering from, or is diagnosed with, the condition, which reduces the severity of the condition, or retards or slows the progression of the condition. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the condition is assed by this term. ent is intended to ass prevention or prophylaxis.

“Therapeutically effective amount,” as used herein, refers to a minimal amount or concentration of a compound, such as aPI3K modulator, that, when administered alone or in combination, is ient to provide a eutic benefit in the treatment of the condition, or to delay or minimize one or more symptoms associated with the condition. The term “therapeutically effective amount” can ass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. The therapeutic amount need not result in a complete cure of the condition; partial inhibition or reduction of the condition is encompassed by this term.

The therapeutically effective amount can also encompass a prophylactically effective amount.

As used herein, unless otherwise specified, the terms "prevent," "preventing" and "prevention" refers to an action that occurs before the subject begins to suffer from the condition, or relapse of the condition. The prevention need not result in a complete prevention of the ion; partial prevention or reduction of the condition or a symptom of the condition, or reduction of the risk of ping the condition, is encompassed by this term.

As used herein, unless ise specified, a “prophylactically effective amount” of a compound, such as a PI3K modulator, that, when administered alone or in combination, prevents or reduces the risk of ping the condition, or one or more symptoms associated with the condition, or prevents its recurrence. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the lactic efficacy of another prophylactic agent. The prophylactic amount need not result in a complete prevention of the condition; l prevention or reduction of the condition is assed by this term.

As used herein, to “decrease”, “ameliorate,” “reduce,” “treat” (or the like) a condition or symptoms associated with the condition includes reducing the severity and/or frequency of symptoms of the condition, as well as preventing the condition and/or symptoms of the condition (e.g., by reducing the severity and/or frequency of flares of symptoms). In some embodiments, the symptom is d by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% relative to a control level. The control level includes any appropriate control as known in the art. For example, the control level can be the pre-treatment level in the sample or subject treated, or it can be the level in a l population (e.g., the level in subjects who do not have the condition or the level in samples derived from subjects who do not have the condition). In some embodiments, the decrease is tically icant, for example, as assessed using an appropriate parametric or non-parametric statistical comparison.

As used herein, ” or gically active agent” or d active agent” refers to a biological, pharmaceutical, or chemical compound or other . Non-limiting examples include simple or complex organic or inorganic molecules, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, an antibody fragment, a vitamin, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound, and metabolites thereof. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for ing, such as plant or animal extracts, and the like. A skilled artisan can y recognize that there is no limit as to the structural nature of the agents of this disclosure.

The term “agonist” as used herein refers to a compound or agent having the ability to initiate or enhance a biological function of a target protein or polypeptide, such as increasing the activity or expression of the target protein or polypeptide. Accordingly, the term “agonist” is d in the t of the biological role of the target protein or ptide. While some agonists herein ically interact with (e.g., bind to) the target, compounds and/or agents that initiate or enhance a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

The terms “antagonist” and itor” are used interchangeably, and they refer to a nd or agent having the ability to inhibit a biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. While some antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a ical activity of the target protein or polypeptide by interacting with other members of the signal uction pathway of which the target protein or ptide are also specifically included within this definition. Non-limiting examples of biological activity inhibited by an antagonist include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in mune disease.

] An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic ion. One class of anti-cancer agents comprises herapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, uscular, intraperitoneal, intravesical, subcutaneous, transdermal, or buccal administration, or inhalation, or in the form of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to subject so that both agents and/or their metabolites are present in the subject at the same time. Co-administration es simultaneous administration in separate itions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

As used herein, unless ise specified, a “phosphoinositide 3-kinase (PI3K) modulator” or “PI3K modulator” refers to a modulator of a PI3K, including an inhibitor of PI3K. PI3Ks are members of a unique and conserved family of intracellular lipid kinases that orylate the 3’-OH group on phosphatidylinositols or phosphoinositides. The PI3K family includes kinases with ct substrate specificities, expression patterns, and modes of regulation (see, e.g., Katso et al., 2001, Annu. Rev. Cell Dev.

Biol. 17, 615 -675; Foster, F.M. et al., 2003, J Cell Sci 116, 3037-3040). The class I PI3Ks (e.g., p110 α, p110 β, p110 γ, and p110 δ) are typically activated by tyrosine kinases or G-protein d receptors to generate PIP3, which engages downstream mediators such as those in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rho family GTPases. The class II PI3Ks (e.g., PI3K-C2α, PI3K-C2β, PI3KC2γ ) and III PI3Ks (e.g., Vps34) play a key role in intracellular cking through the synthesis of PI(3)P and PI(3,4)P2. Specific exemplary PI3K modulators and inhibitors are disclosed herein.

The class I PI3Ks comprise a p110 catalytic subunit and a regulatory adapter subunit.

See, e.g., Cantrell, D.A. (2001) Journal of Cell e 114: 1439-1445. Four isoforms of the p110 subunit (including PI3K-α (alpha), PI3K-β , PI3K-γ (gamma), and PI3K-δ (delta) isoforms) have been implicated in various biological functions. Class I PI3Kα is involved, for example, in insulin signaling, and has been found to be d in solid tumors. Class I PI3K-β is involved, for example, in platelet activation and insulin signaling. Class I PI3K-γ plays a role in mast cell activation, innate immune function, and immune cell trafficking (chemokines). Class I PI3K-δ is involved, for example, in B-cell and T-cell activation and on and in Fc receptor signaling in mast cells. In some embodiments provided herein, the PI3K modulator is a class I PI3K modulator (e.g., an inhibitor). In some such embodiments, the PI3K modulator inhibits or reduces the activity of a PI3K-α (alpha), a PI3K-β (beta), a PI3K-γ (gamma), or a PI3K-δ (delta) isoform, or a ation thereof.

Downstream mediators of PI3K signal transduction include Akt and mammalian target of rapamycin (mTOR). Akt ses a pleckstrin homology (PH) domain that binds PIP3, leading to Akt kinase activation. Akt phosphorylates many substrates and is a central downstream effector of PI3K for diverse ar responses. One function of Akt is to augment the activity of mTOR, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine-threonine kinase related to the lipid kinases of the PI3K family.

“Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular se. A “modulator” of a signal transduction pathway refers to a nd which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator can augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

] Unless otherwise specified, the term “selective inhibition” or “selectively inhibit” or “selective toward” as applied to a biologically active agent refers to the agent’s ability to ively reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target. For example, a compound that selectively inhibits one isoform of PI3K over r isoform of PI3K has an activity of at least 2X t a first m relative to the compound’s activity against the second isoform (e.g., at least about 3X, 5X, 10X, 20X, 50X, 100X, 200X, 500X, or 1000X).

The term “in vivo” refers to an event that takes place in a subject’s body.

The term “in vitro” refers to an event that takes places outside of a subject’s body. For example, an in vitro assay asses any assay conducted outside of a subject. In vitro assays encompass cell-based assays in which cells, alive or dead, are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed “Radiation therapy” means exposing a t, using routine methods and compositions known to the practitioner, to radiation emitters such as, but not limited to, alpha-particle emitting radionuclides (e.g., actinium and thorium uclides), low linear energy transfer (LET) radiation emitters (e.g., beta rs), conversion electron emitters (e.g., strontium-89 and samariumEDTMP), or highenergy ion, including without limitation , gamma rays, and neutrons.

“Therapeutic modality” referes to any agent applied to produce therapeutic changes to biologic tissues; includes but not limited to thermal, acoustic, light, mechanical, or electric . For example, the agent can be any of the agents bed herein.

“Pharmaceutically acceptable r” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, gs, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for ceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.

Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, es, isomers, prodrugs, and isotopically labeled derivatives of sed compounds. In one embodiment, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and ically d derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For e, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19.

Pharmaceutically acceptable salts of the nds provided herein include those derived from suitable nic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts e adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, ophosphate, gluconate, lfate, heptanoate, hexanoate, odide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, e, pectinate, fate, 3– phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, ne earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. r pharmaceutically able salts include, when riate, nontoxic ammonium, nary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts can be derived e, for example, primary, secondary, and tertiary amines, substituted amines ing lly occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base on salt is chosen from ammonium, ium, sodium, calcium, and magnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate”. Pharmaceutically acceptable solvates and hydrates are complexes that, for e, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, t or water les.

It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures f.

In certain ments, the pharmaceutically acceptable form is a g. As used herein, the term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The prodrug nd often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., rd, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, dam). A discussion of prodrugs is ed in Higuchi, T., et al., “Pro drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are orated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it es absorption from the digestive tract, or it can enhance drug stability for long–term storage.

The term “prodrug” is also meant to include any covalently bonded carriers, which release the active nd in vivo when such prodrug is stered to a subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. gs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a t, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide tives of an amine functional group in the active nd and the like. Other examples of prodrugs include nds that comprise -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those bed in Burger’s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of gs (H.

Bundgaard ed., Elsevier, New York, 1985).

] For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, a prodrug can comprise a ceutically acceptable ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-C8)alkyl, (C2–C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl- 1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, oxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolactonyl, di-N,N-(C1–C2)alkylamino(C2–C3)alkyl (such as hylaminoethyl ), carbamoyl-(C1–C2)alkyl, N,N-di(C1–C2)alkylcarbamoyl-(C1–C2)alkyl and piperidino-, pyrrolidino- or lino(C2–C3)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1–C6)alkanoyloxymethyl, 1-((C1– C6)alkanoyloxy)ethyl, 1-methyl((C1-C6)alkanoyloxy)ethyl (C1–C6)alkoxycarbonyloxymethyl, N- (C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1–C6)alkanoyl, α-amino(C1–C4)alkanoyl, arylacyl and α- aminoacyl, or oacyl-α-aminoacyl, where each α-aminoacyl group is ndently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2, and glycosyl (the l resulting from the l of a yl group of the hemiacetal form of a carbohydrate).

If a sed nd or a ceutically acceptable form of the compound incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, a natural α-aminoacyl or natural α-aminoacylnatural α-aminoacyl, –C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N– or di-N,N–(C1- C6)alkylaminoalkyl, –C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N– or di-N,N–(C1-C6)alkylamino, morpholino, piperidinyl or idinyl.

In certain embodiments, the pharmaceutically acceptable form is an isomer. “Isomers” are different nds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. As used herein, the term r” includes any and all geometric s and stereoisomers. For example, rs” include geometric double bond cis– and trans–isomers, also termed E– and Z– isomers; R– and S–enantiomers; diastereomers, (d)–isomers and (l)– isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

In one ment, provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of tuents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring, and the term ” represents substituents on opposite sides of the plane of the ring.

Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of the plane of the ring are designated “cis/trans.” “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any tion can be known as a “racemic” mixture.

The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute chemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.

Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric s and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to e all such possible s, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a composition can be calculated using the equation shown below. In the example shown below, a composition ns 90% of one enantiomer, e.g., an S enantiomer, and 10% of the other enantiomer, e.g., an R enantiomer. ee = (90-10)/100 = 80%.

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. Some compositions described herein contain an enantiomeric excess of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 75%, about 90%, about 95%, or about 99% of the S enantiomer. In other words, the compositions contain an omeric excess of the S enantiomer over the R enantiomer. In other ments, some compositions described herein n an omeric excess of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 75%, about 90%, about 95%, or about 99% of the R enantiomer. In other words, the compositions contain an omeric excess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some ments, be provided substantially free of the corresponding enantiomer, and can also be referred to as ally enriched,” “enantiomerically enriched,” “enantiomerically pure” and “non-racemic,” as used interchangeably herein. These terms refer to compositions in which the amount of one enantiomer is greater than the amount of that one omer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer, means a preparation of the compound having greater than about 50% by weight of the S enantiomer relative to the total weight of the preparation (e.g., total weight of S and R rs), such as at least about 75% by weight, further such as at least about 80% by weight. In some embodiments, the enrichment can be much greater than about 80% by weight, providing a “substantially enantiomerically enriched,” “substantially enantiomerically pure” or a "substantially non-racemic" preparation, which refers to preparations of compositions which have at least about 85% by weight of one enantiomer relative to the total weight of the preparation, such as at least about 90% by weight, and further such as at least about 95% by weight. In certain embodiments, the compound provided herein is made up of at least about 90% by weight of one enantiomer. In other embodiments, the compound is made up of at least about 95%, about 98%, or about 99% by weight of one enantiomer ] In some embodiments, the nd is a racemic mixture of (S)- and (R)- isomers. In other ments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)- isomeric configuration. For example, in some embodiments, the compound mixture has an (S)-enantiomeric excess of greater than about 10%, r than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (S)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the compound mixture has an (S)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound e has an (R)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, r than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, r than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, r than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (R)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the nd mixture has an (R)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound e contains identical chemical entities except for their stereochemical orientations, namely (S)- or (R)-isomers. For example, if a compound disclosed herein has –CH(R)– unit, and R is not en, then the –CH(R)– is in an (S)- or (R)- stereochemical orientation for each of the identical al entities (i.e., (S)- or (R)-stereoisomers). In some embodiments, the mixture of identical chemical entities (i.e., mixture of stereoisomers) is a racemic mixture of (S)- and (R)- isomers. In r embodiment, the mixture of the cal chemical entities (i.e., e of stereoisomers) contains predominately (S)-isomer or predominately (R)-isomer. For example, in some embodiments, the (S)-isomer in the mixture of identical chemical entities (i.e., e of stereoisomers) is present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of (S)- and (R)-isomers. In some embodiments, the (S)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at an (S)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the (R)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of (S)- and (R)-isomers. In some embodiments, the (R)-isomers in the e of identical chemical entities (i.e., mixture of stereoisomers) is present at an antiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid tography (HPLC), the formation and crystallization of chiral salts, or ed by asymmetric syntheses. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley cience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (E.L. Eliel, Ed., McGraw–Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertable nds ing from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). “Tautomerization” es prototropic or -shift erization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, t, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of ers can be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base, or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypentenone tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of nol and pyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant to e compounds which differ only in the presence of one or more isotopically ed atoms. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium, or the replacement or ment of a carbon by 13C or 14C, are within the scope of this disclosure.

The disclosure also embraces ically labeled compounds which are cal to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, , fluorine, and chlorine, such as, e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Certain isotopically-labeled sed compounds (e.g., those labeled with 3H and/or 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can allow for ease of ation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage ements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that can also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. All isotopic variations of the compounds as disclosed herein, r radioactive or not, are encompassed within the scope of the present disclosure.

When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when ing to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental ility (or within statistical experimental error), and thus the number or numerical range can vary from, for example, between 1% and 15% of the stated number or numerical range. When a range of values is listed, it is intended to encompass each value and nge within the range. For example “C1– 6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3– 6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are fied in accordance with the Periodic Table of the Elements, CAS n, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, sity Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic try, 5th ed., John Wiley & Sons, Inc., New York, 2001; , Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., dge University Press, Cambridge, 1987.

Abbreviations used herein have their conventional meaning within the chemical and biological arts. The following abbreviations and terms have the indicated meanings throughout: PI3K = Phosphoinositide 3-kinase; PI = phosphatidylinositol; PDK = Phosphoinositide Dependent Kinase; DNAPK = Deoxyribose Nucleic Acid Dependent Protein Kinase; PTEN = Phosphatase and Tensin homolog deleted on some Ten; PIKK = Phosphoinositide Kinase Like Kinase; AIDS = Acquired Immuno Deficiency Syndrome; HIV = Human Immunodeficiency Virus; MeI = Methyl Iodide; POCl3 = Phosphorous Oxychloride; KCNS = Potassium IsoThiocyanate; TLC = Thin Layer Chromatography; MeOH = Methanol; and CHCl3 = Chloroform.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no ration, having from one to ten carbon atoms (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each r in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present tion also covers the occurrence of the term ” where no numerical range is designated. In some embodiments, it is a C1-C4 alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, tyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the le by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, yl, 1,1-dimethylethyl (t-butyl), ylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, l, alkynyl, cycloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O )Ra, - N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, yclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

“Alkylheteroaryl” refers to an -(alkyl)heteroaryl radical where hetaryl and alkyl are as sed herein and which are optionally substituted by one or more of the substituents bed as suitable substituents for heteroaryl and alkyl tively.

“Alkylheterocycloalkyl” refers to an –(alkyl)heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable tuents for heterocycloalkyl and alkyl respectively.

An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, can be branched, straight chain, or cyclic.

] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group ting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (ie. C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon In n embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C2-C5 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which ndently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, kyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, hylsilanyl, -ORa, - SRa, -Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)R a, - N(Ra)C(O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical where alkenyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.

“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (ie.

C2-C10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (e.g., C2-C5 alkynyl).

The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, yl, butynyl, pentynyl, hexynyl, and the like. Unless stated ise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, lkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, 2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)R a, - (O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, l, heterocycloalkyl, cycloalkylalkyl, heteroaryl or arylalkyl.

“Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical where alkynyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents bed as le substituents for alkynyl and cycloalkyl respectively.

“Carboxaldehyde” refers to a –(C=O)H radical.

“Carboxyl” refers to a OH radical.

“Cyano” refers to a –CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated, or partially unsaturated. lkyl groups include groups having from 3 to 10 ring atoms (ie. C2-C10 cycloalkyl). Whenever it appears herein, a cal range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C3-C8 cycloalkyl radical. In some embodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, exyl,cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, aryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, oromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, C(O)R a, - (O)N(Ra) a)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, cycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a –(cycloalkyl) alkenyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are ally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.

“Cycloalkyl-heterocycloalkyl” refers to a –(cycloalkyl) heterocycyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are ally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.

“Cycloalkyl-heteroaryl” refers to a –(cycloalkyl) heteroaryl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and lkyl respectively.

The term “alkoxy” refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic uration and combinations thereof attached to the parent ure through an oxygen.

Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

“Lower alkoxy” refers to alkoxy groups ning one to six carbons. In some embodiments, C1-C4 alkyl, is an alkyl group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.

The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)). Unless stated otherwise specifically in the ication, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, kyl, heteroaryl, arylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O) Ra, - N(Ra)C(O)N(Ra)2, (NRa)N(Ra)2, S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is ndently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term ycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the yl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a C1-C6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached h its oxygen to a carbonyl linker. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group. In some embodiments, C1-C4 alkoxy, is an alkoxy group which encompasses both straight and branched chain alkoxy groups of from 1 to 4 carbon atoms.

The term “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure h the carbonyl functionality. Unless stated otherwise ically in the specification, the alkyl moiety of an carbonyl group is optionally substituted by one or more substituents which independently are: alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O) Ra, - N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyl” refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. In some embodiments, it is a C1-C10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e three other ring or chain atoms plus yl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.

Unless stated otherwise specifically in the ication, the “R” of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, C(O) Ra, - N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently en, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyloxy” refers to a R(C=O)O- radical wherein “R” is alkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, which are as described herein. In some embodiments, it is a C1-C4 acyloxy radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e three other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, – SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, Ra, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, C(O)R a, - N(Ra)C(O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2-S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, yclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a -N(Ra)2 radical group, where each Ra is ndently hydrogen, alkyl, fluoroalkyl, yclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or arylalkyl, unless stated otherwise specifically in the specification. When a -N(Ra)2 group has two Ra other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -N(Ra)2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. Unless stated otherwise ically in the specification, an amino group is ally substituted by one or more tuents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)R a, - N(Ra)C(O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, cycloalkylalkyl, aryl or heteroarylalkyl and each of these moieties can be ally substituted as defined herein.

The term “substituted amino” also refers to N-oxides of the groups -NHRd, and NRdRd each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with on conditions for ng out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula –C(O)N(R)2 or –NRC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic d through a ring ), each of which moiety can itself be optionally substituted. In some embodiments it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. The R2 of - N(R)2 of the amide can ally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally tuted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide can be an amino acid or a peptide molecule ed to a compound of Formula (I), thereby forming a prodrug. Any amine, y, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is orated herein by reference in its entirety. tic” or “aryl” refers to an aromatic radical with six to up to fourteen ring atoms (e.g., C6- C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from tuted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.

Bivalent radicals d from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding ent l, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share nt pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, oromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)R a, - N(Ra)C(O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

] “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl— radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

“Ester” refers to a chemical radical of formula –COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring ). Any amine, hydroxy, or yl side chain on the compounds described herein can be fied. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, a, Ra, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)R a, - N(Ra)C(O)N(Ra) a)C(NRa)N(Ra) a)S(O) a (where t is 1 or 2), -S(O) a (where t is 1 or 2, N(R 2, -N(R tR tOR 2), N(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or arylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethylfluoroethyl, and the like. The alkyl part of the fluoroalkyl l can be optionally substituted as d above for an alkyl group.

“Halo”, “halide”, or, alternatively, “halogen” means , chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

“Heteroalkyl” “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, l and alkynyl radicals and which have one or more al chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range can be given, e.g. C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.

For example, a –CH2OCH2CH3 radical is referred to as a “C4” heteroalkyl, which includes the heteroatom center in the atom chain length description. Connection to the rest of the molecule can be through either a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl group can be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, lkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as le substituents for alkyl and aryl respectively.

] “Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl tively.

“Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where alkyl and heteroaryl are as disclosed herein and which are optionally tuted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl respectively “Heteroalkylcycloalkyl” refers to an -(heteroalkyl) cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are ally tuted by one or more of the substituents described as le substituents for heteroalkyl and cycloalkyl respectively.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from ent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the al atoms of the ring is a en atom. The polycyclic heteroaryl group can be fused or sed. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl thiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, 4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, ,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, ,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, nyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, azinyl, pteridinyl, purinyl, l, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, yl, quinazolinyl, quinoxalinyl, quinolinyl, nolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, ,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the ication, a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, 2, -C(O)Ra, -C(O)ORa, (Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), ORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or )2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

“Heteroarylalkyl” refers to a moiety having an aryl moiety, as described herein, ted to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is h the alkylene group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and . er it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group can consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl. In some embodiments, it is a C3-C10 heterocycloalkyl. Unless stated otherwise specifically in the ication, the heterocycloalkyl radical is a monocyclic, bicyclic, lic or tetracyclic ring system, which can include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical can be ally oxidized. One or more nitrogen atoms, if present, are ally quaternized. The cycloalkyl radical is partially or fully saturated. The heterocycloalkyl can be attached to the rest of the le through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, ydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the ication, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, aryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, l, heterocycloalkyl, aryl or heteroarylalkyl.

“Heterocycloalkyl” also includes ic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from , sulfur, and nitrogen and is not aromatic.

“Moiety” refers to a specific segment or onal group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

“Nitro” refers to the –NO2 radical.

“Oxa” refers to the -O- radical.

“Oxo” refers to the =O radical.

A “leaving group or atom” is any group or atom that will, under the reaction conditions, leave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy .

“Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of ting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For e, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups can similarly be protected.

“Solvate” refers to a nd (e.g., a compound selected from Formula I or a ceutically acceptable salt thereof) in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that “a compound of Formula I” ass the compound of Formula I and solvates of the compound, as well as mixtures thereof.

“Substituted” means that the referenced group can be substituted with one or more onal group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, , aryloxy, mercapto, alkylthio, arylthio, cyano, halo, yl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Disubstituted amino groups encompass those which form a ring together with the nitrogen of the amino group, such as for instance, morpholino. The tuents themselves can be substituted, for example, a kyl substituent can have a halide substituted at one or more ring carbons, and the like. The protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in nces such as Greene and Wuts, above.

“Sulfanyl” refers to the groups: tionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocycloalkyl).

] “Sulfinyl” refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)-(optionally substituted aryl), and -S(O)-(optionally substituted cycloalkyl).

“Sulfonyl” refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

“Sulfonamidyl” or namido” refers to a –S(=O)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, lkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in –NRR of the –S(=O)2- NRR l can be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7- membered ring. In some embodiments, it is a C1-C10 sulfonamido, wherein each R in sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4 carbons total. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively ] “Sulfoxyl” refers to a –S(=O)2OH radical.

“Sulfonate” refers to a –S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl tively.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they y encompass the ally identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is lent to -OCH2-.

Compounds that can be used as described herein also include crystalline and amorphous forms of compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof As used herein, and unless otherwise specified, “polymorph” can be used herein to describe a crystalline material, e.g., a crystalline form. In n embodiments, “polymorph” as used herein are also meant to include all lline and amorphous forms of a compound or a salt thereof, ing, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs ding anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, ing, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, ated polymorphs (including anhydrates), conformational rphs, tautomeric forms, disordered crystalline forms, and amorphous forms of the compounds or a salt thereof, as well as mixtures Chemical entities include, but are not limited to, compounds of Formula I, I-1, IV, IV-A, V, V-A, V-A2, V-B, VI or VI-A, and all pharmaceutically able forms f. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Hence, the terms “chemical entity” and “chemical entities” also ass ceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures.

In addition, if the compound of Formula I is obtained as an acid addition salt, the free base can be obtained by basifying a on of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by ving the free base in a suitable organic solvent and ng the solution with an acid, in accordance with conventional procedures for ing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

Compounds The compounds ed below are exemplary PI3K modulators that can be used in the pharmaceutical compositions, methods and kits disclosed herein.

In some aspects, the PI3K modulator is a compound of Formula I: Formula I or its pharmaceutically acceptable salt thereof, n Wd is cycloalkyl, aryl or heteroaryl; B is alkyl, amino, heteroalkyl, or a moiety of Formula II; (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; X is absent or is –(CH(R9))z-and z is an integer of 1, 2, 3, or 4; Y is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z-, -C(=O)-, -N(R9)-C(=O)-, or -N(R9)- C(=O)NH-,-N(R9)C(R9)2-, or -C(=O)-(CHR9)z-; R1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, kyl, heteroaryl, arylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, kyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, y, alkoxycarbonyl, amido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, carbonyl, sulfonamido, halo, cyano, y, nitro, aryl, or heteroaryl; R5, R6, R7, and R8 are independently hydrogen, C1-C4alkyl, C2-C5alkenyl, C2-C5alkynyl, C3-C5cycloalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4amido, amino, acyl, C1-C4acyloxy, C1-C4sulfonamido, halo, cyano, hydroxy or nitro; and each instance of R9 is ndently hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heterocycloalkyl, or C2- C10heteroalkyl.

In some embodiments, B is tituted or substituted alkyl, including but not limited to – -NRaRa ,wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or arylalkyl, or NRaRa are combined together to form a cyclic moiety, which includes but is not limited to piperidinyl, piperazinyl, and morpholinyl. In some embodiments, B is unsubstituted or substituted amino. In some embodiments, B is unsubstituted or substituted heteroalkyl.

(R2)q Formula II In some embodiments, B is a moiety of Formula II and wherein Wc is a member ed from the group consisting of unsubstituted or substituted aryl, substituted phenyl, unsubstituted or substituted heteroaryl including but not limited to pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, dinyl, pyrimidinyl, or pyrazinyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, a heteroaryl comprising two heteroatoms as ring atoms, unsubstituted or tuted heteroaryl comprising a nitrogen ring atom, heteroaryl comprising two nitrogen ring atoms, aryl comprising a nitrogen and a sulfur as ring atoms, unsubstituted or substituted heterocycloalkyl including but not limited to morpholinyl, tetrahydropyranyl, piperazinyl, and piperidinyl, unsubstituted or substituted cycloalkyl including but not limted to cyclopentyl and cyclohexyl.

In some embodiments, B is one of the ing moieties: -CH3 -CH2CH3 -CH(CH3)2 N O CH3 N H3C Cl H3C OCH3 N N F O N N Cl N N N O N NH2 O N N N N N N CN O N NH2 O N N N N O NH2 CF3 N N OH F CN N O H N N N Cl N O N NH2 N N N N N N N N N N N N N N N N N N N N N O N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N O N N N N N N N N CN N O S S S S N N N N N N N N N N N N N N N N N N N N N Cl N N N N O N S S S N N N N N N N N N N [F F CH3 F HO MeO CH3 F H3C CH2CH3 N O H3C OH N N CH3 F SO2ME H N N In some embodiments, B is substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl , amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, alkyl, alkenyl, l, cycloalkyl, cycloalkyl, aryl, heteroaryl, , amido, amino, acyl, acyloxy,or sulfonamido, can itself be substituted.

In some ments, R1 is a member selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, tituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1 is unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or tuted heteroaryl, or unsubstituted or substituted heteroarylalkyl.

In some embodiments, R1 is unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some embodiments, R1 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, tituted or substituted alkoxycarbonyl, or unsubstituted or substituted sulfonamido. In some ments, R1 is halo which includes –Cl, -F, -I, and -Br. In some embodiments, R1 is selected from the group consisting of cyano, hydroxy, nitro, unsubstituted or substituted ate, unsubstituted or substituted urea, and carbonate.

In some embodiments, when R1 is alkyl, R1 is methyl, ethyl, propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl.

] In some embodiments, when R1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, or hydroxy, R1 is substituted by phosphate, or unsubstituted urea, or tuted urea, or carbonic acid, or carbonate.

] In some embodiments, when R1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, R1 is substituted by one or more of alkyl, heteroalkyl, alkenyl, l, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or amido can itself be substituted.

In some embodiments, R2 is a member selected from the group consisting of unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, and unsubstituted or substituted heterocycloalkyl. In some embodiments, R2 is unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, tituted or substituted heteroaryl, or unsubstituted or substituted heteroarylalkyl. In some embodiments, R2 is unsubstituted or tuted alkoxy, unsubstituted or substituted amido, unsubstituted or tuted amino. In some embodiments, R2 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, or unsubstituted or substituted amido. In some embodiments, R2 is halo, which is –I, -F, -Cl, or -Br. In some embodiments, R2 is ed from the group ting of cyano, hydroxy, nitro, a carbonic acid, and a carbonate. In some embodiments, R2 is unsubstituted or substituted phosphate. In some embodiments, R2 is unsubstituted or substituted urea. In some embodiments, when R2 is alkyl, R2 is methyl, ethyl, propyl, pyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, or hydroxy, it is substituted by phosphate, substituted by urea, or substituted by ate.

In some ments, when R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, y, alkoxycarbonyl, or sulfonamido, it is substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, y, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments, q is an integer of 0. In some embodiments, q is an integer of 1. In some embodiments, q is an integer of 2. In some embodiments, q is an integer of 3. In some embodiments, q is an integer of 4.

In some embodiments of the compound of a I, R3 is a member ed from the group consisting of en, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, and unsubstituted or substituted alkynyl. In some embodiments, R3 is unsubstituted or substituted aryl, unsubstituted or tuted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R3 is unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some ments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, or tituted or tuted sulfonamido. In some ments, R3 is halo, which is –I, -F, -Cl, or -Br.

In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, and nitro. In some embodiments, when R3 is alkyl, R3 is methyl, ethyl, propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl. In some embodiments, R3 is -CF3.

In some embodiments, when R3 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido, it is substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments of the compound of a I, R5 is en, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted lkyl). In some embodiments, R5 is unsubstituted or substituted alkenyl including but not limited to unsubstituted or substituted C2-C5alkenyl.

In some embodiments, R5 is unsubstituted or substituted l ing but not limited to unsubstituted or substituted C2-C5alkynyl. In some embodiments, R5 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or tuted C3-C5cycloalkyl. In some embodiments, R5 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R5 is unsubstituted or substituted heteroalkyl including but not d to unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R5 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C1-C4alkoxy. In some embodiments, R5 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted C1-C4amido. In some embodiments, R5 is unsubstituted or substituted amino. In some embodiments, R5 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or tuted C1-C4sulfonamido. In some embodiments, R5 is halo, which is –I, -F, -Cl, or -Br. In some embodiments, R5 is selected from the group consisting of cyano, hydroxy, and nitro. In some other ments, R5 is -CH3, -CH2CH3, n-propyl, isopropyl, -OCH3, -OCH2CH3, or -CF3.

In some embodiments, when R5 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R5 is optionally substituted with one or more of alkyl, heteroalkyl, l, l, cycloalkyl, heterocycloalkyl, aryl, aryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, , amido, amino, acyl, y, alkoxycarbonyl, or amido can itself be substituted.

In some embodiments of the compound of Formula I, R6 is hydrogen, tituted or tuted alkyl (including but not limited to unsubstituted or substituted C1-C4alkyl). In some embodiments, R6 is unsubstituted or substituted alkenyl including but not d to unsubstituted or substituted C2-C5alkenyl.

In some embodiments, R6 is unsubstituted or tuted alkynyl including but not limited to unsubstituted or substituted C2-C5alkynyl. In some embodiments, R6 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C3-C5cycloalkyl. In some embodiments, R6 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R6 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R6 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C1-C4alkoxy. In some embodiments, R6 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted C1-C4amido. In some embodiments, R6 is unsubstituted or substituted amino. In some embodiments, R6 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted carbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C1-C4sulfonamido. In some embodiments, R6 is halo, which is –I, -F, -Cl, or -Br. In some embodiments, R6 is selected from the group consisting of cyano, hydroxy, and nitro. In some other embodiments, R6 is -CH3, -CH2CH3, n-propyl, isopropyl, -OCH3, -OCH2CH3, or -CF3.

] In some embodiments, when R6 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, y, alkoxycarbonyl, or sulfonamido, R6 is ally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, aryl, aryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments of the compound of Formula I, R7 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted C1-C4alkyl). In some embodiments, R7 is tituted or substituted alkenyl including but not limited to unsubstituted or substituted C2-C5alkenyl.

In some embodiments, R7 is tituted or substituted alkynyl including but not limited to unsubstituted or substituted C2-C5alkynyl. In some embodiments, R7 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C3-C5cycloalkyl. In some embodiments, R7 is unsubstituted or tuted heterocycloalkyl. In some embodiments, R7 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R7 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C1-C4alkoxy. In some embodiments, R7 is unsubstituted or substituted amido including but not limited to tituted or substituted C1-C4amido. In some embodiments, R7 is unsubstituted or substituted amino. In some embodiments, R7 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or tuted C1-C4acyloxy, unsubstituted or tuted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C1-C4sulfonamido. In some embodiments, R7 is halo, which is –I, -F, -Cl, or -Br. In some ments, R7 is selected from the group ting of cyano, y, and nitro. In some other embodiments, R7 is -CH3, -CH2CH3, n-propyl, isopropyl, -OCH3, -OCH2CH3, or -CF3.

In some embodiments, when R7 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R7 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments of the compound of Formula I, R8 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or tuted C1-C4alkyl). In some embodiments, R8 is unsubstituted or substituted l including but not d to unsubstituted or substituted C2-C5alkenyl.

In some embodiments, R8 is unsubstituted or substituted alkynyl including but not limited to unsubstituted or substituted C2-C5alkynyl. In some embodiments, R8 is unsubstituted or substituted lkyl including but not limited to unsubstituted or substituted C3-C5cycloalkyl. In some embodiments, R8 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R8 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R8 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C1-C4alkoxy. In some embodiments, R8 is unsubstituted or substituted amido including but not limited to tituted or substituted mido. In some embodiments, R8 is unsubstituted or substituted amino. In some embodiments, R8 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted cyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or tuted sulfonamido, or tituted or substituted C1-C4sulfonamido. In some embodiments, R8 is halo, which is –I, -F, -Cl, or -Br. In some embodiments, R8 is selected from the group consisting of cyano, hydroxy, and nitro. In some other ments, R8 is -CH3, -CH2CH3, n-propyl, isopropyl, -OCH3, -OCH2CH3, or -CF3.

In some embodiments, when R8 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R8 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, , amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments of the compound of a I, R5, R6, R7, and R8 are H and the compound has a structure of Formula I-1: Formula I-1.

In some embodiments of the compound of Formula I, X is absent. In some ments, X is – (CH(R9))z, and z is an integer of 1, 2, 3 or 4.

In some embodiments, R9 is unsubstituted or substituted alkyl including but not limited to unsubstituted or substituted C1-C10alkyl. In some embodiments, R9 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C3-C7cycloalkyl. In some ments, R9 is ethyl, methyl or hydrogen. In some embodiments, R9 is unsubstituted or substituted heterocycloalkyl including but not limited to unsubstituted or substituted C2-C10heteroalkyl. In some embodiments, R9 is tituted or substituted heteroalkyl ing but not limited to unsubstituted or substituted C2- C10heteroalkyl.

] Also provided herein is a compound of Formula I wherein R9 is hydrogen, and X is -CH2-, - CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, or -CH(CH2CH3)-. In other embodiments, X is –(CH(R9))z , R9 is not hydrogen, and z is an integer of 1. When X is-CH(R9)- and R9 is not hydrogen, then the compound can adopt either an (S)- or (R)-stereochemical configuration with respect to carbon X. In some embodiments, the compound is a racemic mixture of (S)- and (R) s with respect to carbon X. In other embodiments, provided herein is a mixture of compounds of Formula I wherein individual nds of the mixture exist predominately in an (S)- or (R)- isomeric configuration. For example, the compound mixture has an (S)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at the X carbon. In other embodiments, the compound mixture has an (S)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, r than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

] In other embodiments, the nd mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at the X carbon. In some other embodiments, the nd mixture has an (R)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

] In other embodiments, the compound e contains identical chemical entities except for their stereochemical orientations, namely (S)- or (R)- isomers. For instance, in the compounds of Formula I, when X is -CH(R9)-, and R9 is not hydrogen, then the -CH(R9)- is in an (S)- or (R)- sterochemical orientation for each of the identical chemical entities. In some embodiments, the mixture of identical al entities of a I is a racemic mixture of (S)- and (R)- isomers at the carbon represented by X.

In another embodiment, the e of the identical chemical entities (except for their stereochemical orientations),contain predominately (S)-isomers or predominately (R)- isomers. For example, the (S)- isomers in the mixture of identical chemical entities are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% ,or more, relative to the (R)- isomers. In some embodiments, the (S)- isomers in the mixture of identical chemical entities are present at an (S)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

In another embodiment, the (R)- isomers in the mixture of identical chemical entities (except for their stereochemical orientations),are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more, relative to the (S)- isomers. In some embodiments, the (R)- s in the mixture of identical chemical entities (except for their stereochemical orientations), are present at a (R)- enantiomeric purity greater than about 55% to about 99.5%, r than about about 60% to about 99.5%, greater than about 65% to about 99.5%, r than about 70% to about 99.5%, r than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

] In some embodiments, the compound of Formula I, X is -CH(R9)-, R9 is methyl or ethyl, and the compound is the (S)- isomer.

In some embodiments of the compound of Fornula I, Y is absent. In some ments, Y is -O- , -S-, -S(=O)-, -S(=O)2-, -, -N(R9)(C=O)-, -N(R9)(C=O)NH-, C(R9)2- (such as-N(R9)CH2-, specifically -N(CH3)CH2-, N(CH(CH3)2)CH2 - or N(CH2CH3)CH2-), -N(R9)-, –N(CH3)-, –N(CH2CH3)-, or – N(CH(CH3)2)-. In some ments, Y is -C(=O)-(CHR9)z- and z is an integer of 1, 2, 3, or 4.

In some embodiments, at least one of X and Y is present. In some embodiments of the compound of Formula I, -XY- is -CH2-, -CH2-N(CH3), -CH2-N(CH2CH3), -CH(CH3)-NH-, (S) 3)-NH-, or (R) -CH(CH3)-NH-. In other embodiments, X-Y is -N(CH3)-CH2-, N(CH2CH3) CH2-, -N(CH(CH3)2)CH2-, or -NHCH2-. Provided herein are other compounds of Formula I wherein when X-Y is X is – (CH(R9))zN(R9)-, z is an integer of 1, 2, 3 or 4, and -N(R9)- is not –NH-, then -XY- is not connected to purinyl.

In some embodiments, Wd in a formula disclosed herein (including but not d to I, I-1, IV, IV-A, V, V-A, V-A2, V-B, VI and VI-A), is a member selected from the group consisting of unsubstituted or substituted heterocycloalkyl, unsubstituted or tuted aryl, and unsubstituted or tuted heteroaryl.

In various embodiments, Wd is tituted or substituted monocyclic heteroaryl (including but not limited to pyrimidinyl, pyrrolyl, pyrazinyl, triazinyl, or pyridazinyl) or unsubstituted or substituted bicyclic aryl.

In some embodiments, Wd is a monocyclic aryl of the following formula: N N R12 N Ra' N N Ra' , Ra' or R12 wherein Ra’ is hydrogen, halo, phosphate, urea, a carbonate, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, or tituted or substituted heterocycloalkyl; and R12 is H, unsubstituted or substituted alkyl, unsubstituted or substituted cyano, unsubstituted or substituted alkynyl, unsubstituted or substituted alkenyl, halo, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or tuted heterocycloalkyl, unsubstituted or tuted cycloalkyl, unsubstituted or substituted amino, carboxylic acid, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, unsubstituted or substituted acyl, or unsubstituted or tuted sulfonamido.

Also included herein are compounds having monocyclic heteroaryl Wd including but not limited to one of the following formulae: F Cl CF3 CN N N N N N N N N H2N H2N H2N H2N O O NH2 NHMe N N N NH2 N NH2 N N N H2N H2N Cl CF3 .

In some embodiments, Wd in a formula disclosed herein (including but not limited to I, I-1, IV, IV-A, V, V-A, V-A2, V-B, VI and VI-A), is a bicyclic heteroaryl having at least one heteroatom, e.g., a bicyclic aryl having at least one nitrogen ring atom. In some embodiments, Wd is a bicyclic heteroaryl having at least two heteroatoms, e.g., a bicyclic aryl having at least two nitrogen ring atoms. In some embodiments, Wd is a bicyclic heteroaryl having two heteroatoms in the ring which is connected to XY. In some embodiments, Wd is a bicyclic aryl having two nitrogen ring atoms in the ring to which XY is connected. In some embodiments, Wd is a bicyclic heteroaryl having four heteroatoms, e.g, a bicyclic heteroaryl having four nitrogen ring atoms. In some embodiments, Wd is unsubstituted or substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidinyl, unsubstituted or substituted 7-aminomethyl-2H-pyrazolo[4,3-d]pyrimidinyl. unsubstituted or tuted 6-methylenyl- 9H-purinyl, or unsubstituted or substituted 6-amino-9H-purinyl.

In some embodiments Wd is one of the following: Ra N N N N Ra' N N N N Ra' NH N R12 N N Ra' R12 N N N N Ra' R11 N N R11 R12 N R11 H R12 R11 R11 H N N N N R12 R12 N N Ra' N NH N N N Ra' N Ra' Ra' Ra' N N N N N N R12 N N N N R11 H H Ra' H H N R11 N N N N HN N R11 NH R12 N N N N R12 N N N N Ra' N R11 R11 R11 H wherein Ra’ is en, halo, phosphate, urea, a carbonate, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or tuted alkenyl, unsubstituted or tuted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, or tituted or substituted heterocycloalkyl; R11 is hydrogen, unsubstituted or substituted alkyl, halo (which includes –I, -F, -Cl, or –Br), unsubstituted or substituted amino, unsubstituted or substituted amido, hydroxy, or unsubstituted or substituted alkoxy, phosphate, unsubstituted or substituted urea, or ate; and R12 is H, tituted or substituted alkyl, unsubstituted or substituted cyano, unsubstituted or substituted alkynyl, unsubstituted or tuted alkenyl, halo, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted lkyl, unsubstituted or substituted amino, carboxylic acid, unsubstituted or substituted alkoxycarbonyl, unsubstituted or tuted amido, unsubstituted or substituted acyl, or unsubstituted or substituted sulfonamido.

In some embodiments of Wd of the compounds of Formula I, when Ra’ is alkyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl, it is substituted by phosphate, urea, or carbonate.

In some embodiments of Wd of the compounds of Formula I, when R11 is alkyl, amino, amido, hydroxy, or alkoxy, it is substituted by phosphate, urea, or ate.

In some embodiments of the compound of Formula I,-X-Y-Wd is one of the following moieties: O CH3 CH3 CH3 Et N N N H N N N N H N N N N N N N N N N N H H N H H H R12 N N R12 N H2N R12 N R12 R12 N R12 N H2N H2N H2N H2N H2N H2N Et Et N N N N H N N N N N H H N N R12 N R12 N R12 N R12 N H2N H2N H2N H2N CH3 CH3 CH3 N N N N N N N N N O CH3 N N N N R12 N R12 N N R12 N R12 H2N H2N H2N H2N O CH3 CH3 N N N CH3 N N N N CH3 N N N N N CH3 CH3 R12 N N R12 N H2N R12 H2N H2N H2N O CH3 CH3 N N N N N N N N N N N N R12 N N N H2N R12 R12 H2N H2N H2N O CH3 CH3 N N N N N N N N N N N R12 N N R12 N H2N H2N H2N O CH3 CH3 N N O N N N N N N O O N N N N N O N N R12 N N N R12 R12 H2N H2N H2N S N O N NH N N NH NH NH HN NH N N N N N N N N R12 R12 R12 R12 CH3 Et HN N R12 HN N R12 HN N R12 N N N N N N NH NH NH CH3 Et HN N H HN N H HN N H N N N N N N NH NH NH CH3 Et CH3 Et HN N R12 NH N R12 HN N R12 HN N R12 NH N R12 HN N R12 N N N N N N N N N NH N N NH N NH NH NH NH CH3 Et CH3 Et HN N H HN N H HN N H HN N H HN N H HN N H N N N N N N N N N N N N NH NH NH NH NH NH CH3 Et CH3 Et HN N F HN N F HN N F HN N Cl HN N Cl HN N Cl N N N N N N N N N N N N NH NH NH NH NH NH CH3 Et CH3 Et HN N F HN N F HN N F HN N F HN N F HN N F N N N N N N N N N N N N NH NH NH NH NH NH CH3 Et CH3 Et HN N Cl HN N Cl HN N Cl HN N Cl HN N Cl HN N Cl N N N N N N N N N N N N NH NH NH NH NH NH CH3 Et HN N NH2 HN N NH2 HN N NH2 N N N N N N NH NH NH CH3 Et HN N NH2 HN N NH2 HN N NH2 N N N N N N NH NH NH CH3 Et HN N NH2 HN N NH2 HN N NH2 N N N N N N NH NH NH CH3 R12 Et R12 R12 N N N HN NH HN NH HN NH N N N N N N Ra' Ra' Ra' CH3 R12 Et R12 R12 N N N HN NH HN NH HN NH N N N N N N Ra' Ra' Ra' CH3 R12 Et R12 R12 N N N HN NH HN NH HN NH N N N N N N Ra' Ra' Ra' CH3 F Et F F N N N HN NH HN NH HN NH N N N N N N CH3 F Et F F N N N HN NH HN NH HN NH N N N N N N CH3 F Et F F N N N HN NH HN NH HN NH N N N N N N N Et N N N R12 N R12 N R12 N N N N N N NH NH NH CH3 Et N N N N H N H N H N N N N N N NH NH NH CH3 CH3 CH3 CH3 N N N N N N N H CH3 N N N N N N N N H2N H2N H2N H2N CH3 CH3 N N O N N N O R12 N N H2N H2N CH3 CH3 CH3 CH3 N N N N N N N N N N H H CH3 N N H CH3 N CH3 N N N N N N N N N N H2N H2N H2N H2N H2N H2N CH3 CH3 CH3 CH3 N N N N N N N N N N N N N N N N N N N N N N N H2N H2N H2N H2N H2N H2N N N N N O O N N O N N N N N N N N H2N H2N HN HN HN R12 N R12 N R12 N N N N N N N N N H H H HN HN HN HN R12 N R12 N R12 N R12 N N N N N N N N N N N N H H H H HN HN R12 N R12 N N NH2 N N NH2 N N N H H HN HN HN HN R12 N R12 N R12 N R12 N N NH2 NH2 N NH2 N NH2 N N N N N N N N H H H H HN HN HN HN HN HN R12 N R12 N R12 N R12 N R12 N R12 N NH2 NH2 NH2 N N N N N N N N N N N N H H H H H H HN HN HN HN HN HN R12 N R12 N R12 N R12 N R12 N R12 N N N N N N N N N N N N N H H H H H H HN HN HN HN HN HN R12 N R12 N R12 N R12 N R12 N R12 N NH2 NH2 NH2 NH2 NH2 NH2 N N N N N N N N N N N N H H H H H H HN R12 HN R12 HN F HN F HN Cl HN Cl HN CF3 N N N N N N N N N N N N N N H2N H2N H2N H2N H2N H2N H2N HN CF3 HN CN HN CN N N N N N N H2N H2N H2N O O O O HN NH2 HN NH2 HN NH2 HN NH2 N N N N N N N N H2N H2N MeHN MeHN HN R12 HN R12 HN F HN F HN Cl HN Cl HN CF3 N N N N N N N N N N N N N N H2N H2N H2N H2N H2N H2N H2N HN CF3 HN CN HN CN N N N N N N H2N H2N H2N O O O O HN NH2 HN NH2 HN NH2 HN NH2 N N N N N N N N H2N H2N MeHN MeHN HN R12 HN R12 HN F HN F HN Cl HN Cl HN CF3 N N N N N N N N N N N N N N H2N H2N H2N H2N H2N H2N H2N HN CF3 HN CN HN CN N N N N N N H2N H2N H2N O O O O HN NH2 HN NH2 HN NH2 HN NH2 N N N N N N N N H2N H2N MeHN MeHN CH3 Et CH3 Et HN HN HN HN HN HN N NH2 N NH2 N NH2 N NH2 N NH2 N NH2 N N N N N N Cl Cl Cl Cl Cl Cl CH3 Et HN HN HN N NH2 N NH2 N NH2 N N N Cl Cl Cl CH3 Et HN HN HN N N N N NH2 N NH2 N NH2 CF3 CF3 CF3 CH3 Et HN HN HN N N N N NH2 N NH2 N NH2 CF3 CF3 CF3 CH3 Et HN HN HN N N N N NH2 N NH2 N NH2 CF3 CF3 CF3 In some embodiments of the compound of Formula I, R12 is a member of the group ting of en, cyano, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, and unsubstituted or substituted alkenyl. In some embodiments, R12 is tituted or substituted aryl. In some embodiments, R12 is unsubstituted or substituted heteroaryl, which includes but is not limited to heteroaryl having a 5 membered ring, heteroaryl having a six membered ring, aryl with at least one nitrogen ring atom, heteroaryl with two en ring atoms, monocylic heteroaryl, and bicylic heteroaryl.

In some embodiments, R12 is unsubstituted or tuted heterocycloalkyl, which includes but is not limited to heterocycloalkyl with one nitrogen ring atom, heterocycloalkyl with one oxygen ring atom, R12 is heterocycloalkyl with one sulfur ring atom, 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, saturated heterocycloalkyl, unsaturated heterocycloalkyl, heterocycloalkyl having an unsaturated moiety connected to the heterocycloalkyl ring, heterocycloalkyl substituted by oxo, and heterocycloalkyl substituted by two oxo. In some embodiments, R12 is unsubstituted or substituted cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl substituted by one oxo, lkyl having an unsaturated moiety connected to the cycloalkyl ring. In some embodiments, R12 is unsubstituted or substituted amido, carboxylic acid, unsubstituted or substituted acyloxy, unsubstituted or tuted alkoxycarbonyl, unsubstituted or substituted acyl, or unsubstituted or substituted sulfonamido.

In some embodiments, when R12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, it is substituted with phosphate. In some embodiments, when R12 is alkyl, l, alkenyl, aryl, heteroaryl, heterocycloalkyl, or lkyl, it is substituted with urea. In some ments, when R12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, it is substituted with carbonate.

In some embodiments, when R12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substituted with one or more of alkyl, heteroalkyl, l, alkynyl, cycloalkyl, cycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, aloxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments of the compound of Formula I, R12 of Wd is one of the following moieties: N N O N S S N N NH2 NH H CONH2 O CH3 H CH3 F F N N N N N N NH2 NH2 NH2 NH2 F OCH3 NH Cl NH N NH N NH F OH N N NH NH CH3 OH OH Et CH3 N F OH OH OCH3 OCH3 OCH3 OCH3 Cl F N(Et)2 F OCH3 H2N H2N COOH NH2 O S S N N O N N N N N N O H2N H H H2N H2N NH2 HN Ac O O HN S S N N N HN -CN, -Br, -Cl, -I, -H, -Me, -Et, -i-Pr, H3C O H2N H2N N N N N N N N O N N N N N N N N N N N N NH2 OH H H H F H H H N N NH N O S O N O N O N O N H2N HN H H H H H NC O O H N O O O N N HN O H3C O H2N O F NHMe H N O HO F .

In some ments of the compound of Formula I, Wd is a pyrazolopyrimidine of Formula III: Formula III n R11 is H, alkyl, halo, amino, amido, hydroxy, or , and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, cycloalkyl, or cycloalkyl. In some embodiments, R11 is amino and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl. In some embodiments, R11 is amino and R12 is alkyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl. In some embodiments, R11 is amino and R12 is monocyclic heteroaryl. In some embodiments, R11 is amino and R12 is bicyclic heteroaryl. In some embodiments, R11 is amino and and R12 is cyano, amino, carboxylic acid, acyloxy, carbonyl,or amido.

In some embodiments, the compound of Formula I is a compound having a structure of Formula R5 BB R6 H R7 R8 N R11 .

Formula IV In some embodiments of the compound of Formula IV, R11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, cycloalkyl, or cycloalkyl. In another ment, R11 is amino and R12 is alkyl, alkenyl, heteroaryl, aryl, or heterocycloalkyl. In some embodiments, R11 is amino and and R12 is cyano, amino, carboxylic acid, alkoxycarbonyl, or amido.

] In some embodiments, the compound of Formula IV is a compound of Formula IV-A: R3 O H B H H H H N N N R12 N H2N .

Formula IV-A Also provided herein are compounds of Formula I having a structure of any of Formulae V, V- A1, V-A2, V-B, VI, VI-A, VII-A1, VII-A2, VIII-A1, VIII-A2, IX-A1, IX-A2, X-A1, X-A2, XI-A1, XI-A2, XII-A, XII-A1, XII-A2, XIII-A, XIII-A1, XIII-A2, XIV-A, , XIV-A2, XV-A, XV-A1, XV-A2, XVI-A, XVI-A1, XVI-A2, XVII-A, XVII-A1, XVII-A2, XVIII-A, XVIII-A1, or XVIII-A2: R3 O B R3 R5 R3 O O N R3 H B N H B H B N N R6 R9 H R9 R9 H H R7 R8 NR9 N H H HN N H H HN N H H HN N N N N N H N N N N N H H H N N N a V Formula V-A Formula V-A1 Formula V-A2 R3 O RR3 O H B O N R3R H B H R5 N H N H R9 R9 H N R6 N H H NR9 N H H R7 R8 N N N N H N N N N H H N N Formula V-B Formula VI Formula VI-A R3 O O R3 O H B N H B H B N N R9 R9 R9 H H H H H HN N H H HN N H H HN N N N N N N N H H H N N N R12 R12 R12 Formula VII-A Formula VII-A1 Formula VII-A2 R3 O R3 O R3 H H B H B B N N N R9 R9 R9 H H H H H HN H H HN N H H HN N N N N N N N N H H H N N N Ra' Ra' Ra' Formula VIII-A Formula VIII-A1 Formula VIII-A2 R3 O R3 O R3 O H B H N H B B N N R9 R9 R9 H R12 H R12 H R12 H H HN H H HN H H HN N N N N N N H H H N N N Formula IX-A Formula IX-A1 Formula IX-A2 O R3 O O R3 R3 H B H B H B N N N R9 R9 R9 H H H H H HN N H H HN N H H HN N N N N N N N H H H N N N Ra' Ra' Ra' Formula X-A a X-A1 Formula X-A2 O R3 O R3 O R3 H H B H B B N N N R9 R9 R9 H H R12 H R12 R12 H H HN H H HN H H HN N N N N N N N N N H H H N N N Formula XI-A Formula XI-A1 Formula XI-A2 R3 O R3 O H B R3 O H B N H B N R9 R9 H R9 H H H HN H HN H H HN H N N N N N N N H H N N R12 R12 R12 Formula XII-A Formula XII-A1 Formula XII-A2 R3 O R3 O R3 O H B H B H B N N R9 R9 R9 H H H HN H H HN H HN H H N N N N N N H H H N N N Ra' Ra' Ra' Formula XIII-A Formula XIII-A1 Formula XIII-A2 R3 O O R3 O H B N H B H B N N R9 R9 R9 H H H H H HN R12 H H HN R12 H H HN R12 N N N N N N Ra' Ra' Ra' Formula XIV-A Formula XIV-A1 Formula XIV-A2 R3 O R3 O R3 O B B N B N N R9 R9 R9 NH NH NH N N N N N N R12 R12 R12 Ra' N Ra' N N N H Ra' N N H H Formula XV-A Formula XV-A1 Formula XV-A2 R3 O R3 O R3 O B B B N N N R9 R9 R9 NH NH NH R12 R12 R12 N N N Ra' N N Ra' N N Ra' N N H H H Formula XVI-A Formula XVI-A1 Formula XVI-A2 R3 O R3 O R3 O B B N N N R9 R9 R9 NH NH NH N N N N R12 Ra' N R12 Ra' Ra' N R12 Formula XVII-A Formula 1 Formula XVII-A2 R3 O R3 O R3 O B B B N N N R9 R9 R9 NH NH NH N N N N N N Ra' Ra' Ra' R12 R12 R12 Formula XVIII-A Formula XVIII-A1 Formula XVIII-A2 Any of the disclosed elements and their substituents for the compounds of a I can be used in any combination.

In one aspect, for the compounds of Formula I, R3 is H, CH3, CF3, Cl, or F; and B is a moiety of Formula II: (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, or nitro; q is an integer of 0, 1, 2, 3, or 4; R5, R6, R7, and R8 are H; X is absent or ; z is 1; Y is absent or –N(R9)-; R9 is hydrogen, C1-C10alkyl, C3- C7cycloalkyl, or C2-C10heteroalkyl; at least one of X and Y is present; and Wd is pyrazolopyrimidine or purine. In some embodiments, when X and Y are t and Wd is purine, then –N(R9)- is –NH-.

In another aspect, for the compounds of a I, R3 is H, CH3, CF3, Cl, or F; B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, or nitro; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent or (CH2)z; z is 1; Y is absent or –N(R9)-; R9 is hydrogen, methyl, or ethyl; at least one of X N N R12 N N N H and Y is present; Wd is: R11 or N ; R11 is amino; and R12 is H, alkyl, alkynyl, l, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl. In some embodiments, when X and Y are present and Wd is , then –N(R9)- is –NH-.

In another aspect, for the compounds of Formula I, R3 is H, CH3, CF3, Cl, or F; B is a moiety of Formula II, which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, or nitro; q is 0, 1 or 2; X is (CH2)z; z is 1; R5, R6, R7, and R8 are H; Y is absent and Wd is: R11 ; R11 is amino; and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.

In another , R3 is H, CH3, CF3, Cl, or F; B is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, y, cyano, or nitro; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is (CH2)z; z is 1; X is (CH2)z; z is 1; Y is–N(R9)-; N N R9 is hydrogen, methyl, or ethyl; and Wd is N . In some embodiments, Y is –NH-.

In another aspect, for the compounds of Formula I R3 is aryl, heteroaryl, H, CH3, CF3, Cl, or F; B is alkyl or a moiety of Formula II; wherein Wc is aryl, heteroaryl, cycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, nitro, or ate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent or ))z; z is an integer of 1, 2, 3, or 4; Y is absent, –N(R9)-, or –N(R9) CH(R9)-; R9 is hydrogen, alkyl, lkyl, or heteroalkyl; at least one of X and Y is present; and Wd is pyrazolopyrimidine or purine. In some embodiments, when X is present, Y is –N(R9)-, and Wd is purine, then Y is –NH-.

In another , for the compounds of Formula I, R3 is aryl, heteroaryl, H, CH3, CF3, Cl, or F; B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or lkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent or (CH(R9))z; z is an integer of 1, 2, 3, or 4; Y is absent, – N(R9)-, or –N(R9) CH(R9)-; R9 is hydrogen, methyl, or ethyl; at least one of X and Y is present; Wd is: N N R12 N N N R11 or N ; R11 is amino; and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, arbonyl, or amido . In some embodiments, when X is present, Y is –N(R9)-, and Wd is purine, then Y is –NH-.

] In r aspect, for the compounds of Formula I, R3 is H, CH3, CF3, Cl, or F; B is alkyl or a moiety of Formula II which is aryl, heteroaryl, cycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is (CH(R9))z; z is an integer of 1; Y is absent–; R9 is hydrogen, methyl, or ethyl; Wd is: R11 ; R11 is amino; and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, cycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido.

In another aspect, for the nds of Formula I, R3 is aryl, heteroaryl, H, CH3, CF3, Cl, or F; B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, - CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent or (CH(R9))z; z is an integer of 1; Y is absent, –N(R9)-, or –N(R9) N N CH(R9)-; R9 is hydrogen, methyl, or ethyl; at least one of X and Y is present, and Wd is: N . In some embodiments, when X is present, Y is –N(R9)-, and Wd is purine, then Y is –NH-.

In another aspect, for the compounds of Formula I, R3 is aryl, heteroaryl, H, CH3, CF3, Cl, or F; B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, - CH3, isopropyl, -CF3, -OCH3, nitro, or ate; R2 is halo, hydroxy, cyano, nitro, or ate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent; Y is–N(R9) CH(R9)-; R9 is hydrogen, methyl, or ethyl; and Wd is: N N N .

In another aspect, for the compounds of Formula I, R3 is aryl, heteroaryl, H, CH3, CF3, Cl, or F; B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R1 is H, –F, -Cl, -CN, -CH3, isopropyl, -CF3, -OCH3, nitro, or phosphate; R2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7, and R8 are H; X is absent or (CH(R9))z; z is an r of 1, 2, 3, or 4; Y is absent, – N(R9)-, or –N(R9) CH(R9)-; R9 is hydrogen, , or ethyl; at least one of X and Y is present; Wd is: R12 N N R12 N NH Ra' Ra' N N N N N N H , H , or Ra' ; Ra’ is hydrogen, halo, or amino; and R12 is H, alkyl, alkynyl, alkenyl, halo, aryl, aryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, arbonyl, or amido . In some embodiments, when X is present, Y is –N(R9)-, and Wd is purine, then Y is –NH-.

Additional exemplary nds have a sub-structure of Formula IV-A.

R3 O H B H H H H N N N R12 N Formula IV-A Some illustrative compounds of the present disclosure having a structure of Formula IV-A e those in which R3 is –H, -Cl, -F, or –CH3 in combination with any B moiety described in Table 1, and any R12 as described in Table 2. A compound of Formula IV-A includes any combination of R3, B, and R12. Additional exemplary compounds of Formula IV-A are illustrated in Table 4.

Table 1. Illustrative B moieties of the compounds of Formula I.

Sub- B Sub- B Sub- B class class class # # # B-1 B-2 B-3 -CH(CH3)2 B-4 F3C B-5 B-6 B-7 H3C B-8 H3C B-9 B-10 B-11 CH3 B-12 Sub- B Sub- B Sub- B class class class # # # B-13 MeO B-14 B-15 HO B-16 B-17 B-18 CN B-19 B-20 B-21 H3C OCH3 B-22 B-23 B-24 N NO2 N B-25 B-26 CH3 B-27 O N N N B-28 B-29 B-30 N Cl N N B-31 B-32 B-33 N N O CF3 B-34 N B-35 B-36 NH2 N N B-37 B-38 B-39 O N NH2 N CN O B-40 N Cl B-41 B-42 N O O N N O O B-43 N B-44 N B-45 CN N O Sub- B Sub- B Sub- B class class class # # # B-46 OH B-47 F B-48 N N N NH2 B-49 N O B-50 N NH2 B-51 N N N N B-52 B-53 B-54 N N N N N N N N B-55 N B-56 B-57 N N N N N N N N B-58 O B-59 B-60 N N N N N N N N N B-61 B-62 N B-63 N N N N N N N N N B-64 N B-65 N B-66 N N N N N N N N N B-67 B-68 O B-69 N N N N N N CN B-70 N B-71 N B-72 N N O N N N N B-73 N B-74 N B-75 N N N N Cl N N Sub- B Sub- B Sub- B class class class # # # B-76 N B-77 N B-78 N N N N N N B-79 S B-80 S B-81 S N N N B-82 B-83 B-84 O S S S N N N N N N B-85 S B-86 B-87 -CH3 B-88 -CH2CH3 B-89 B-90 H3C B-91 B-92 CH3 B-93 F CH3 F B-94 H3C B-95 F B-96 CH2CH3 CH3 F B-97 H B-98 O B-99 OH N N B- SO2ME B-101 CN B- F 100 N 102 Table 2. rative R12 of compounds of Formula I.

Sub- R12 Sub- R12 Sub- R12 class class # class # # 12-1 -CN 12-2 -Br 12-3 -Cl Sub- R12 Sub- R12 Sub- R12 class class # class # # 12-4 3 12-5 -CH3 12-6 -CH(CH3)2 12-7 12-8 12-9 12-10 OH 12-11 12-12 12-13 12-14 12-15 N O N S H NH CONH2 CH3 12-16 12-17 12-18 N S N S NH2 H CH3 NH2 12-19 F 12-20 12-21 F N N N N N NH2 NH2 12-22 12-23 12-24 F NH N NH N 12-25 12-26 12-27 F N N OCH3 NH 12-28 OH 12-29 12-30 Et 12-31 OCH3 12-32 OH 12-33 Cl Cl 12-34 F 12-35 -H 12-36 OH OH Sub- R12 Sub- R12 Sub- R12 class class # class # # 12-37 12-38 12-39 F OH OH 12-40 12-41 12-42 OCH3 OCH3 Cl F 12-43 12-44 F 12-45 OCH3 H2N H2N 12-46 12-47 12-48 OCH3 NH2 COOH 12-49 OCH3 12-50 12-51 O S N N N F H2N H H 12-52 12-53 12-54 N O N N N H2N H2N NH2 12-55 12-56 12-57 N O N N N NH2 N H3C 12-58 12-59 O 12-60 O N N HN S HN OH O 12-61 -I 12-62 OH 12-63 OH Sub- R12 Sub- R12 Sub- R12 class class # class # # 12-64 OH 12-65 CH3 12-66 N F CH3 N(Et)2 12-67 12-68 12-69 S N N N H H 12-70 12-71 12-72 N N N H F N N H H 12-73 12-74 12-75 NH N O O N O N O N H H H 12-76 12-77 12-78 NC H2N S O O N 12-79 12-80 12-81 O O N NHMe O 12-82 12-83 12-84 O O HN H3C O H O HO O 12-85 H 12-86 H 12-87 N N H2N HN N F N O F 12-88 12-89 12-90 N N N N O H CH3 NH2 12-91 12-92 12-93 O O N O N N HN Ac O Sub- R12 Sub- R12 Sub- R12 class class # class # # 12-94 12-95 12-96 N N N N O N N N NH2 H H 12-97 -F 12-98 O O 12-99 O O S S NH2 NHCH3 12- O O 12- 12- 100 S 101 102 N(CH3)2 Other illustrative nds of the present disclosure have a structure of Formula V-A, V-A1, or V-A2, wherein B is a moiety bed in Table 1, in combination with R3, which is –H, -Cl, -F, or d R9 , which is –H, -CH3, or -CH2CH3. A compound of Formula V-A, V-A1, or V-A2 includes any combination of R3, B, and R9.

R3 O R3 O R3 O H B N H B H B N N H R9 R9 H H H H HN N H H HN N H H HN N N N N N N N N H H N N Formula V-A Formula V-A1 Formula V-A2 Yet other illustrative compounds of the present disclosure have a structure of Formula V-B, wherein B is a moiety described in Table 1, in combination with R3, which is –H, -Cl, -F, or CH3,and R9 , which is –H, -CH3, or -CH2CH3. A compound of a V-B includes any combination of R3, B, and R9.

R3 O H B H H NR9 N N N Formula V-B Some other illustrative compounds of the present disclosure have a structure of Formula VI-A, wherein B is a moiety bed in Table 1, in combination with R3, which is –H, -Cl, -F, or CH3,and R9 , which is –H, -CH3, or -CH2CH3. A compound of Formula VI-A includes any combination of R3, B, and R9.

R3R O H B H NH H H N N N Formula VI-A Further illustrative compounds that can be employed as described herein have a structure of one of Formulae VII-A1, VII-A2, VIII-A1, VIII-A2, IX-A1, IX-A2, X-A1, X-A2, XI-A1, XI-A2, XII-A, XIIA1 , XII-A2, XIII-A, XIII-A1, XIII-A2, XIV-A, XIV-A1, or XIV-A2: wherein B is a moiety described in Table 1, any R12 as described in Table 2, in combination with R3, which is –H, -Cl, -F, or CH3, R9 which is –H, -CH3, or -CH2CH3, and Ra’ which is –H, -Cl, -F, or –NH2. A compound of Formulae VII-A1, , VIII-A1, VIII-A2, IX-A1, IX-A2, X-A1, X-A2, XI-A1, XI-A2, XII-A, XII-A1, XII-A2, XIII-A, XIII-A1, XIII-A2, XIV-A, XIV-A1, or : includes any ation of Ra, R3, B, R9and R12.

Additional exemplary compounds include but are not d to the following: O O O N N N N N N N N N N N N N H2N N N N H2N N AcHN H2N F H2N O N N N N N N N N N N N O N N N N N O N N H2N N N HO N H2N N H2N O HO H2N O N N O N N N O O N N N N N N N N N O N N O N N N O S N N HN O N H2N H2N H2N O NMe O N O N O N N N N N N N N N N N N N N N N N N N N H2N H2N H2N H2N O N O N O N O N NH2 NH2 NH2 NH2 O N O N O N O N N N N N N N N H2N NH N N N N N N O N N N N N N N N N N N HN H2N NH2 H H H N O NMe O N O O N N N N N N N H2N N N N N N N NH N N N N N N O N N N H2N H2N H2N NH2 HN N HN N N N HN N H2N H Cl O Cl O Cl O Cl O Cl O Cl O N N N N N N NH NH NH NH NH NH N N F N N N N N N N N Cl N N F N N F H H N N N N N N N N H H2N H H H Cl O Cl O NH CN N N N N H Cl O Cl O Cl O Cl O N N N NH O NH O NH NH NH2 NH Cl CN N N N N N N N N N N N N N H H H H Cl O Cl O Cl O Cl O N N N N NH O NH2 NH O NH NH N CN N N F N N N N N N H N H2N N H H2N N Cl O Cl O N N NH NH N CF3 N H2N N Cl N NH2 Cl O Cl O Cl O Cl O N N N N NH NH O NH O N Cl N N N NH2 N NH H2N N NH2 H2N N H2N N CH3 CF3 Cl O Cl O Cl O Cl O Cl O Cl O N N N N N N NH NH NH NH NH NH N N N N N N N N N N N F Cl N N F N H H N N N N N N N N H H2N H H H Cl O Cl O NH CN N N N Cl O Cl O Cl O Cl O N N N N NH O NH O NH NH NH2 NH Cl CN N N N N N N N N N N N N N N H H H H Cl O Cl O Cl O Cl O N N N N NH O NH2 NH O NH NH N N CN N N N F N N N N H N H H2N N H2N Cl O Cl O N N NH NH N CF3 N N Cl N H2N NH2 Cl O Cl O Cl O Cl O N N N N NH NH NH O NH O N Cl N N N NH2 N NH H2N N NH2 H2N N H2N N CH3 CF3 In some embodiments, the PI3K modulator is a compound of Formula I-1: a I-1 or its pharmaceutically acceptable salt thereof, wherein B is a moiety of Formula II: (R2)q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; X is a bond or –(CH(R9))z-, and z is an r of 1; Y is -N(R9)-; N N Wd is: N ; R1 is hydrogen, alkyl, l, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, , amino, halo, cyano, hydroxy or nitro; R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl amido, halo, cyano, hydroxy or nitro; and each instance of R9 is independently hydrogen, alkyl, or heterocycloalkyl.

In some embodiments, the compound is predominately in an (S)- stereochemical configuration In some embodiments, X is –(CH(R9))z-, and Y is -NH-.

In some embodiments, R3 is -H, -CH3, -CH2CH3, -CF3, -Cl or –F.

In some embodiments, B is a moiety of Formula II: (R2)q Formula II wherein Wc is aryl, aryl, heterocycloalkyl, or cycloalkyl; q is an integer of 0 or 1; R1 is en, alkyl, or halo; R2 is alkyl or halo; R3 is hydrogen, alkyl, or halo; and, optionally wherein the compound has one or more of the following features: N N (i) X is –(CH(R9))z-, n R9 is methyl and z = 1; and Wd is N ; and/or (ii) R3 is methyl or chloro.

In some embodiments, the compound has a structure of Formula V-A2: R3 O H B H H HN N N N N , optionally wherein (i) B is a moiety of Formula II: (R2)q Formula II and Wc is aryl or cycloalkyl, and/or (ii) R3 is methyl or chloro and further, optionally wherein one or more of the following also applies: (a) R9 is methyl or ethyl, (b) B is substituted or unsubstituted phenyl, (c) B is substituted or unsubstituted cycloalkyl. In some embodiments where B is substituted phenyl, B is substituted with fluoro. In some embodiments, B is phenyl that is substituted with one fluoro in the ortho or meta position of the phenyl ring.

] In some ments, a compound used as described herein is selected from O O O O N N N N NH N N NH N N N N N N N N N N N N N N N N H , H , H , H , CH3 O CH3 O CH3 O CH3 O CH3 O N N N N N CH3 CH3 CH3 CH3 CH3 NH NH NH NH NH N N N N N N N N N N N N N N N N N N H , N H , H , H , H , CH3 O N O CH3 N N N N N N N , , N N H , H , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some ments, the compound is selected from F CH3 O O O CH3 O N N N CH3 CH3 NH NH NH NH N N N N N N N N N N , N , N N H H N N H , H , CH3 O CH3 N N N N N N N N N H , , H , , , , , , , , , , and .

In some embodiments, the compound is selected from , , , , , N N N N H , and .

In some embodiments, the PI3K inhibitor has a formula selected from the group consisting of: , , , and .

] In some embodiments, the compound is the S-enantiomer having an omeric purity selected from greater than about 55%, greater than about 80%, greater than about 90%, and greater than about 95%.

In some such embodiments, the compound is selected from: , , , , , , and .

In some embodiments, the PI3K inhibitor has a formula selected from the group consisting of: , , and .

In n such embodiments, the compound is In other such embodiments, the compound is ] In yet other such embodiments, the compound is In some embodiments, the compound has the following structure: which is also referred to herein as Compound 292.

In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ’568 publication”), which is hereby incorporated by reference in its entirety.

In one ment, the compound is Form A of Compound 292, as described in the ’568 publication. In another ment, the nd is Form B of nd 292, as described in the ’568 publication. In yet another ment, the compound is Form C of Compound 292, as described in the ’568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ’568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ’568 ation. In yet another embodiment, the compound is Form F of nd 292, as described in the ’568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ’568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ’568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ’568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ’568 publication.

In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ’568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ’568 application.

Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, s, prodrugs, isotopically d derivatives, or mixtures thereof.

Chemical es described herein can be synthesized according to exemplary methods disclosed in U.S. Patent ation No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby orated by reference in its ty, and/or according to methods known in the art.

Pharmaceutical Compositions In some embodiments, provided herein are pharmaceutical compositions comprising a compound as disclosed herein, or an enantiomer, a mixture of enantiomers, or a e of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives), and a ceutically acceptable excipient, diluent, or carrier, including inert solid diluents and fillers, sterile s solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In some embodiments, a pharmaceutical composition described herein es a second active agent such as an additional therapeutic agent, (e.g., a chemotherapeutic . 1. Formulations Pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, es (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), capsules, boluses, powders, es, pastes for application to the tongue, and intraduodenal routes; parenteral administration, including intravenous, intraarterial, subcutaneous, uscular, intravascular, intraperitoneal or on as, for example, a sterile solution or suspension, or nedrelease formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; intravaginally or intrarectally, for example, as a pessary, cream, stent or foam; sublingually; ocularly; pulmonarily; local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, ble oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

] These compositions can also contain adjuvants such as preservatives, g agents, fying , dispersing agents, lubricants, and/or antioxidants. tion of the action of microorganisms upon the compounds described herein can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the itions. In addition, ged tion of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay tion such as aluminum monostearate and gelatin.

Methods of preparing these ations or compositions include the step of bringing into association a compound described herein and/or the chemotherapeutic with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and tely bringing into association a compound as disclosed herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., ples of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, h Edition, McGraw Hill, 2011; Goodman and Gilman, eds., The Pharmacological Basis of eutics, Tenth Edition, McGraw Hill, 2001; Remingtons ceutical Sciences, 20th Ed., Lippincott Williams & s., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second n (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. Except insofar as any conventional excipient medium is incompatible with the compounds provided herein, such as by producing any undesirable biological effect or otherwise interacting in a rious manner with any other component(s) of the pharmaceutically able composition, the excipient’s use is contemplated to be within the scope of this disclosure.

In some embodiments, the concentration of one or more of the compounds provided in the disclosed pharmaceutical compositions is equal to or less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about , about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about , about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about %, about 0.0002%, or about 0.0001%, w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compounds as disclosed herein is greater than about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about , about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%, about 10.75%, about .50%, about 10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about %, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001%, w/w, w/v, or v/v.

In some embodiments, the concentration of one or more of the compounds as disclosed herein is in the range from approximately 0.0001% to approximately 50%, imately 0.001% to approximately 40%, approximately 0.01% to imately 30%, approximately 0.02% to approximately 29%, imately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to imately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, or approximately 1% to approximately 10%, w/w, w/v or v/v.

In some embodiments, the tration of one or more of the compounds as disclosed herein is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately %, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, imately 0.08% to approximately 1.5%, imately 0.09% to approximately 1%, or approximately 0.1% to imately 0.9%, w/w, w/v or v/v.

In some embodiments, the amount of one or more of the compounds as disclosed herein is equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about 0.0001 g.

In some embodiments, the amount of one or more of the compounds as sed herein is more than about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the nds as disclosed herein is in the range of about 0.0001 to about 10 g, about 0.0005 to about 5 g, about 0.001 to about 1 g, about 0.002 to about 0.5 g, 0.005 to about 0.5 g, about 0.01 to about 0.1 g, about 0.01 to about 0.05 g, or about 0.05 to about 0.1 g. 1A. Formulations for oral administration In some embodiments, provided herein are pharmaceutical compositions for oral administration containing a compound as disclosed herein, and a pharmaceutical excipient suitable for oral administration.

In some embodiments, provided herein are pharmaceutical compositions for oral administration ning: (i) an effective amount of a sed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for oral administration. In some embodiments, the pharmaceutical ition further contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquid ceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or s or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a on, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.

Such dosage forms can be prepared by any of the s of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more ory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a lowing form such as powder or granules, optionally mixed with an excipient such as, but not d to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded s can be made by molding in a le e a mixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous ceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the ation of some compounds. For example, water can be added (e.g., about 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of ations over time.

Anhydrous pharmaceutical compositions and dosage forms can be ed using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. For example, pharmaceutical compositions and dosage forms which contain lactose can be made anhydrous if ntial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained.

Accordingly, anhydrous ceutical compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with a ceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation d for administration. In preparing the pharmaceutical compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring , and the like in the case of oral liquid ations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, s, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers e powders, capsules, and tablets, with the solid oral preparations. In some embodiments, tablets can be coated by standard aqueous or nonaqueous techniques.

Binders le for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other tes, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl idone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium ate (e.g., granules or powder), microcrystalline cellulose, ed cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. egrants can be used in the pharmaceutical compositions as provided herein to provide tablets that disintegrate when d to an aqueous environment. Too much of a disintegrant can produce tablets which can disintegrate in the bottle. Too little can be insufficient for egration to occur and can thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to entally alter the release of the active ingredient(s) can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based upon the type of formulation and mode of administration, and can be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. egrants that can be used to form ceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose , crospovidone, polacrilin potassium, sodium starch glycolate, potato or a starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof. ants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium te, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, ol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a ated aerosol of synthetic silica, or mixtures thereof. A lubricant can ally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral stration, the active ient therein can be combined with various sweetening or flavoring agents, coloring matter or dyes and, for example, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The s can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For e, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

] Surfactant which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hilic surfactants can be employed, a mixture of lipophilic surfactants can be employed, or a e of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of at least about 10, while suitable lipophilic surfactants can lly have an HLB value of or less than about 10. An cal parameter used to characterize the ve hydrophilicity and hydrophobicity of nic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. hilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, ic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hobic) surfactants are compounds having an HLB value equal to or less than about . However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionic tants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; ins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides ; and mixtures thereof.

] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, olipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides ; and mixtures thereof.

Ionic surfactants can be the d forms of lecithin, lysolecithin, phosphatidylcholine, atidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyllactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, te, lauroyl carnitines, palmitoyl carnitines, myristoyl ines, and salts and mixtures f. hilic non-ionic surfactants can include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; yalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as hylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; yethylene sterols, derivatives, and ues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Other hilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 , PEG-15 , PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 te, PEG-100 stearate, PEG-20 ate, PEG-25 glyceryl trioleate, PEG-32 te, PEG-20 glyceryl laurate, PEG-30 yl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan , PEG-80 sorbitan e, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

Suitable ilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid ; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; s and sterol derivatives; polyoxyethylated s and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid tives of mono- and di-glycerides; hobic transesterification products of a polyol with at least one member of ides, vegetable oils, hydrogenated ble oils, fatty acids and sterols; oilsoluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, non-limiting examples of lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification ts of a polyol with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include a solubilizer to ensure good lization and/or dissolution of a compound as ed herein and to minimize precipitation of the compound. This can be especially important for pharmaceutical compositions for al use, e.g., pharmaceutical compositions for injection. A solubilizer can also be added to increase the solubility of the hydrophilic drug and/or other ents, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers f, glycerol, rythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene s having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N- alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, ylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, εcaprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers f; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl bide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but not limited to, triacetin, ylcitrate, ethyl oleate, ethyl caprylate, ylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. In some embodiments, solubilizers include ol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

The amount of lizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a bioacceptable amount, which can be y determined by one of skill in the art. In some circumstances, it can be advantageous to include amounts of solubilizers far in excess of eptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to ing the pharmaceutical composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of about 10%, %, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer can also be used, such as about 5%, 2%, 1% or even less. Typically, the solubilizer can be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

The pharmaceutical ition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, antifoaming agents, buffering agents, rs, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents, antimicrobial vatives, antifungal vatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, ium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, ic acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium de, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, ea, , phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not d to, butyl paraben, methyl n, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. ary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, nol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. ary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, arotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In n embodiments, the preservative is an anti–oxidant. In other embodiments, the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot , avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, y, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, , olive, orange, orange roughy, palm, palm kernel, peach , peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, i, vetiver, walnut, and wheat germ oils. Exemplary oils also include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, l te, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

In addition, an acid or a base can be orated into the pharmaceutical composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium ide, potassium hydroxide, sodium ide, sodium hydrogen carbonate, aluminum hydroxide, m ate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, hylamine, tris(hydroxymethyl)-aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, nic acid, p-toluenesulfonic acid, lic acid, stearic acid, succinic acid, tannic acid, tartaric acid, ycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of otic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can e, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. es of le inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, c acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. 1B. Formulations for Parenteral Administration In some embodiments, provided herein are pharmaceutical compositions for parenteral administration containing a compound as disclosed herein, and a pharmaceutical excipient suitable for parenteral administration. In some embodiments, provided herein are pharmaceutical compositions for parenteral administration containing: (i) an effective amount of a disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for parenteral administration. In some embodiments, the pharmaceutical composition further contains: (iv) an effective amount of a third agent.

The forms in which the sed pharmaceutical compositions can be incorporated for administration by injection include aqueous or oil sions, or ons, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, se, or a sterile aqueous solution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection. l, glycerol, propylene glycol, liquid hylene , and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be employed.

Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and ble oils can also be employed. The proper fluidity can be maintained, for e, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal , for example, parabens, butanol, , sorbic acid, thimerosal, and the like. e injectable solutions are prepared by incorporating a compound as disclosed herein in the required amount in the appropriate solvent with various other ients as enumerated above, as riate, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the appropriate other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile able solutions, certain s of ation are vacuum-drying and freezedrying techniques which yield a powder of the active ingredient plus any additional ingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for e, by filtration h a bacterial– ing filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile able medium prior to use. Injectable compositions can contain from about 0.1 to about 5% w/w of a nd as sed herein. 1C. Formulations for Topical Administration In some embodiments, provided herein are pharmaceutical compositions for l (e.g., ermal) administration containing a compound as disclosed herein, and a pharmaceutical excipient suitable for topical administration. In some embodiments, provided herein are pharmaceutical compositions for topical administration containing: (i) an effective amount of a disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for topical administration. In some embodiments, the pharmaceutical composition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions provided herein can be formulated into preparations in solid, semi- solid, or liquid forms suitable for local or l stration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, nts, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation can e more immediate exposure of the active ingredient to the chosen area.

The pharmaceutical compositions also can comprise le solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic les across the stratum corneum permeability r of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Another ary formulation for use in the disclosed methods employs ermal delivery s (“patches”). Such transdermal patches can be used to provide continuous or discontinuous infusion of a compound as provided herein in controlled amounts, either with or without another agent.

The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on demand ry of pharmaceutical agents.

Suitable devices for use in delivering intradermal pharmaceutically acceptable compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal itions can be stered by devices which limit the ive penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and onal equivalents thereof. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Patents 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; ,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 05 and WO 97/13537. Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are le. Alternatively or additionally, conventional syringes can be used in the cal x method of intradermal administration.

Topically–administrable formulations can, for example, comprise from about 1% to about 10% (w/w) of a compound provided herein relative to the total weight of the formulation, although the concentration of the compound provided herein in the ation can be as high as the solubility limit of the compound in the solvent. In some embodiments, topically–administrable ations can, for example, comprise from about 1% to about 9% (w/w) of a compound provided herein, such as from about 1% to about 8% (w/w), further such as from about 1% to about 7% (w/w), further such as from about 1% to about 6% (w/w), further such as from about 1% to about 5% (w/w), further such as from about 1% to about 4% (w/w), r such as from about 1% to about 3% (w/w), and further such as from about 1% to about 2% (w/w) of a compound provided herein. Formulations for topical administration can further comprise one or more of the additional pharmaceutically acceptable excipients described . 1D. Formulations for Inhalation Administration In some embodiments, provided herein are pharmaceutical compositions for inhalation administration containing a nd as disclosed herein, and a pharmaceutical excipient suitable for topical administration. In some embodiments, provided herein are pharmaceutical itions for inhalation administration containing: (i) an effective amount of a sed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for inhalation administration. In some embodiments, the pharmaceutical composition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions for inhalation or insufflation e solutions and suspensions in pharmaceutically acceptable, aqueous or c solvents, or es thereof, and powders. The liquid or solid pharmaceutical compositions can n suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect. Pharmaceutical compositions in ceutically acceptable solvents can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, sion, or powder pharmaceutical compositions can be administered, e.g., orally or nasally, from devices that deliver the formulation in an appropriate manner. 1E. Formulations for Ocular Administration In some embodiments, the disclosure provides a pharmaceutical composition for treating ophthalmic disorders. The pharmaceutical composition can contain an ive amount of a compound as disclosed herein and a pharmaceutical excipient le for ocular administration. Pharmaceutical compositions suitable for ocular administration can be ted as discrete dosage forms, such as drops or sprays each containing a predetermined amount of an active ient a on, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Other administration foms include intraocular injection, intravitreal injection, topically, or through the use of a drug eluting device, microcapsule, t, or microfluidic device. In some cases, the compounds as disclosed herein are stered with a carrier or excipient that increases the intraocular penetrance of the compound such as an oil and water emulsion with colloid particles having an oily core surrounded by an interfacial film. It is contemplated that all local routes to the eye can be used including topical, subconjunctival, periocular, retrobulbar, subtenon, intracameral, intravitreal, cular, inal, juxtascleral and suprachoroidal administration. Systemic or parenteral administration can be feasible including, but not limited to intravenous, subcutaneous, and oral delivery. An exemplary method of administration will be itreal or subtenon injection of solutions or suspensions, or intravitreal or subtenon placement of bioerodible or non-bioerodible devices, or by topical ocular administration of solutions or suspensions, or posterior juxtascleral administration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in a sterile aqueous solution such as physiological saline, buffering solution, etc., or by ing powder compositions to be dissolved before use. Other vehicles can be chosen, as is known in the art, including, but not limited to: balance salt solution, saline solution, water soluble polyethers such as polyethyene , polyvinyls, such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as l oil and white petrolatum, animal fats such as lanolin, rs of acrylic acid such as ypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate. In some embodiments, additives ordinarily used in the eye drops can be added. Such additives include isotonizing agents (e.g., sodium chloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.), thickeners (e.g., ride such as lactose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salt such as sodium hyaluronate, ium hyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinked rylate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art).

In some cases, the colloid particles include at least one cationic agent and at least one non-ionic sufactant such as a poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a yl stearate. In some cases, the cationic agent is an mine, a tertiary alkyl amine, a quarternary um compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound or a e thereof. In some cases, the cationic agent is a biguanidine salt such as exidine, polyaminopropyl biguanidine, phenformin, iguanidine, or a mixture thereof. In some cases, the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, cetrimide, cyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl amine halide, rnyristylalkonium halide, stearalkonium halide or a e of two or more thereof. In some cases, cationic agent is a konium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; enated oils comprising enated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 enated castor oil or polyoxyl-100 enated castor oil. 1F. Formulations for Controlled Release Administration In some ments, provided herein are pharmaceutical compositions for controlled release administration containing a compound as sed herein, and a pharmaceutical excipient suitable for controlled release administration. In some embodiments, provided herein are pharmaceutical compositions for controlled release administration containing: (i) an effective amount of a disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients le for controlled release administration. In some embodiments, the pharmaceutical composition further ns: (iv) an effective amount of a third agent.

Active agents such as the compounds ed herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; ,733,566; 5,739,108; 474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 548; 6,613,358; 6,699,500 each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled e of one or more active agents using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic s, multilayer coatings, microparticles, liposomes, microspheres, or a combination f to provide the desired e profile in varying proportions. le controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein. Thus, the ceutical compositions provided encompass single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal of improving drug therapy over that ed by their non controlled counterparts. In some embodiments, the use of a controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the e, disorder, or condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In on, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed to lly release an amount of a compound as disclosed herein that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of the nd to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of the compound in the body, the compound should be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active agent can be stimulated by s conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or nds.

In certain embodiments, the pharmaceutical composition can be administered using intravenous infusion, an table osmotic pump, a transdermal patch, mes, or other modes of administration.

In one embodiment, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); ld et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in a t at an appropriate site determined by a practitioner of skill, e.g., thus requiring only a on of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, 115-138 (vol. 2, 1984). Other controlled e systems are discussed in the review by Langer, Science 249:1527- 1533 (1990). The one or more active agents can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, cized nylon, cized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ne-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, methyl siloxanes, neoprene rubber, nated polyethylene, polyvinylchloride, vinylchloride mers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ne/vinyl acetate/vinyl alcohol terpolymer, and ne/vinyloxyethanol copolymer, that is insoluble in body fluids. The one or more active agents then e through the outer ric membrane in a release rate controlling step. The percentage of active agent in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. 2. Dosages A compound described herein can be delivered in the form of pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more compounds described herein and/or one or more additional therapeutic agents such as a chemotherapeutic, formulated together with one or more pharmaceutically acceptable excipients. In some ces, the compound bed herein and the additional therapeutic agent are administered in separate pharmaceutical compositions and can (e.g., because of different physical and/or chemical characteristics) be administered by different routes (e.g., one therapeutic is administered orally, while the other is stered intravenously). In other instances, the compound described herein and the onal therapeutic agent can be administered separately, but via the same route (e.g., both orally or both intravenously). In still other instances, the compound described herein and the additional therapeutic agent can be administered in the same pharmaceutical composition.

] The selected dosage level will depend upon a variety of s including, for example, the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the l arts.

In general, a suitable daily dose of a compound described herein and/or a herapeutic will be that amount of the nd which, in some embodiments, can be the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described herein. lly, doses of the compounds described herein for a patient, when used for the indicated effects, can range from about 1 mg to about 1000 mg, about 0.01 mg to about 500 mg per day, about 0.1 mg to about 500 mg per day, about 1 mg to about 500 mg per day, about 5 mg to about 500 mg per day, about 0.01 mg to about 200 mg per day, about 0.1 mg to about 200 mg per day, about 1 mg to about 200 mg per day, about mg to about 200 mg per day, about 0.01 mg to about 100 mg per day, about 0.1 mg to about 100 mg per day, about 1 mg to about 100 mg per day, about 5 mg to about 100 mg per day, about 0.01 mg to about 50 mg per day, about 0.1 mg to about 50 mg per day, about 1 mg to about 50 mg per day, about 5 mg to about 50 mg per day, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, or about 5 mg to about 20 mg per day. An exemplary dosage is about 0.1 to 100 mg per day. Actual dosage levels of the active ingredients in the ceutical compositions described herein can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, ition, and mode of administration, without being toxic to the patient. In some instances, dosage levels below the lower limit of the aforesaid range can be more than te, while in other cases still larger doses can be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.

In some embodiments, the compounds can be administered daily, every other day, three times a week, twice a week, weekly, or kly. The dosing le can include a “drug holiday,” e.g., the drug can be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday. The compounds can be stered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day.

Dosing can be about once a month, about once every two weeks, about once a week, or about once every other day. In another embodiment, a compound as disclosed herein and another agent are administered together from about once per day to about 6 times per day. In another embodiment, the administration of a compound as provided herein and an agent continues for less than about 7 days. In yet another embodiment, the stration continues for more than about 6 days, about 10 days, about 14 days, about 28 days, about two months, about six , or about one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

Administration of the pharmaceutical itions as disclosed herein can continue as long as necessary. In some ments, an agent as disclosed herein is administered for more than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, about 21, or about 28 days. In some ments, an agent as disclosed herein is administered for less than about 28, about 21, about 14, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 day. In some embodiments, an agent as disclosed herein is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, about 21, or about 28 days. In some embodiments, an agent as disclosed herein is stered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

Since the compounds described herein can be administered in combination with other treatments (such as onal chemotherapeutics, radiation or surgery), the doses of each agent or therapy can be lower than the corresponding dose for -agent therapy. The dose for single-agent y can range from, for example, about 0.0001 to about 200 mg, or about 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1 to about 100 mg, or about 1 to about 50 mg per day.

When a compound provided herein, is administered in a ceutical composition that comprises one or more agents, and the agent has a shorter half-life than the compound provided herein unit dose forms of the agent and the compound provided herein can be adjusted ingly.

In specific embodiments, provided herein is a pharmaceutical composition (e.g., a tablet or a capsule) sing a PI3K modulator provided herein (e.g., nd 292, or a pharmaceutically acceptable form thereof), wherein the PI3K modulator is in the amount of about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, or about 100 mg. In exemplary embodiments, a pharmaceutical composition (e.g., a tablet or a capsule) comprising a PI3K modulator provided herein (e.g., Compound 292, or a pharmaceutically acceptable form thereof) is administered once daily. In exemplary embodiments, a pharmaceutical composition (e.g., a tablet or a capsule) comprising a PI3K modulator provided herein (e.g., Compound 292, or a pharmaceutically acceptable form thereof) is administered twice daily. In exemplary embodiments, a pharmaceutical composition (e.g., a tablet or a capsule) comprising a PI3K modulator provided herein (e.g., Compound 292, or a pharmaceutically acceptable form thereof) is administered in a 28-day cycle.

In ic ments, provided herein is a pharmaceutical composition (e.g., a tablet or a capsule) comprising a PI3K modulator provided herein (e.g., Compound 292, or a pharmaceutically acceptable form thereof), which is prepared for oral delivery.

In specific embodiments, ed herein is a pharmaceutical composition (e.g., a tablet or a capsule) comprising a PI3K modulator provided herein (e.g., Compound 292, or a pharmaceutically acceptable form thereof), and a pharmaceutically acceptable excipient or carrier. In exemplary embodiments, the pharmaceutically acceptable excipient or carrier in the composition is one or more of microcrystalline cellulose (e.g., silicified microcrystalline cellulose), crospovidone, and/or magnesium stearate.

Methods of ent and Prevention Without being limited to a particular theory, PI3Ks are regulators of signal transduction that mediate cell proliferation, differentiation, survival, and migration. PI3K-δ and PI3K-γ are expressed in hematopoietic cells and play roles in hematologic ancies. For example, PI3K-δ and PI3K-γ have roles in the establishment and nance of the tumor nvironment. PI3K-δ and PI3K-γ are highly expressed in the heme compartment, and can be useful in treating hematologic cancers. Class I PI3Ks, ing PI3K-δ and PI3K-γ isoforms, are also associated with cancers (reviewed, e.g., in Vogt, PK et al. (2010) Curr Top Microbiol Immunol. 347:79-104; Fresno Vara, JA et al. (2004) Cancer Treat Rev. (2):193-204; Zhao, L and Vogt, PK. (2008) Oncogene 27(41):5486-96). Inhibitors of PI3K, e.g., PI3K-δ and/or PI3K-γ, have been shown to have anti-cancer activity (e.g., Courtney, KD et al. (2010) J Clin Oncol. 28(6):1075-1083); Markman, B et al. (2010) Ann Oncol. 21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem. 16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s ; abstr 3542); Flinn, IW et al. (2009) J Clin Oncol. 27:156s (suppl; abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. s (suppl; abstr 3500); Wagner, AJ et al. (2009) J Clin Oncol. 27:146s (suppl; abstr 3501); Vogt, PK et al. (2006) Virology 344(1):131-8; Ward, S et al. (2003) Chem Biol. 10(3):207-13; ; US 2010/0029693; US 2010/0305096; US 2010/0305084; each incorporated herein by reference). PI3K-δ and PI3K-γ are expressed in some solid tumors, including prostate, breast, and astomas (Chen J.S. et al. (2008) Mol Cancer Ther. 7(4):841-50; Ikeda H. et al. (2010) Blood 116(9):1460-8). Without being limited to a particular theory, tion of PI3K can have an effect on tumor inflammation and progression.

In one embodiment, provided herein is a method for treating or preventing a specific type of cancer or disease, such as, a specific type of hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K. The PI3K isoforms include one or more of PI3K-α, , PI3K-δ, or PI3K-γ, or a combination thereof. In one ment, the specific type of cancer or disease, such as, a specific type of hematologic malignancy, has a high expression level of PI3K-δ, or PI3K-γ, or both PI3K-δ and PI3K-γ.

In one embodiment, provided herein is a method for treating or preventing a specific sub-type of cancer or disease, such as, a specific sub-type of hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K. The PI3K isoforms include one or more of PI3K-α, PI3K-β, PI3K- δ, or PI3K-γ, or a ation thereof. In one embodiment, the specific sub-type of cancer or disease, such as, a specific sub-type of logic malignancy, has a high expression level of PI3K-δ, or PI3K-γ, or both PI3K-δ and PI3K-γ.

In one embodiment, provided herein is a method for treating or preventing a specific patient or group of patients, having a cancer or disease, such as, a hematologic malignancy, wherein the ular patient or group of patients has(ve) a high expression level of one or more isoform(s) of PI3K. The PI3K isoforms e one or more of PI3K-α, PI3K-β, PI3K-δ, or PI3K-γ, or a ation thereof. In one embodiment, the specific patient or group of patients has(v) a high expression level of PI3K-δ, or PI3K-γ, or both PI3K-δ and PI3K-γ.

In one embodiment, ed herein is a method of treating or managing cancer or hematologic malignancy in a subject who developed resistance to a prior ent comprising identifying a subject who received prior treatment and administering to the subject a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, alone or in combination with one or more other therapeutic agents.

In one embodiment, the prior treatment is a treatment with one or more BTK inhibitors, anti-CD20 antibodies, proteasome inhibitors, or alkylating agents. In one embodiment, the prior treatment is treatment with one or more BTK inhibitors.

In one embodiment, the BTK inhibitor is nib R)[4-Amino(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl]piperidinyl]propenone) or AVL-292 (N-(3-((5- fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide). In one embodiment, the BTK tor is RN-486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5- (4-methyl-piperazinyl)-pyridinylamino]oxo-1,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolin one), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5- dihydropyrazinyl)methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 ( N- [3-(8-anilinoimidazo[1,2-a]pyrazinyl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2- methyl(4-methyl((4-(morpholinecarbonyl)phenyl)amino)oxo-4,5-dihydropyrazin nyl)benzamide), HM-71224, ONO-4059, ACP-196, CNX-774 (4-(4-((4-((3- midophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), or LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide).

In one embodiment, the method ed herein further comprises obtaining a biological sample from the subject and detecting the presence of one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of ma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on e 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on e 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene ), and WHIM-like CXCR4 mutation in the sample.

In one embodiment, the mutation is one mutation ed from residue 481 of BTK ) and cysteine to alanine mutation on residue 481 of BTK (C481F).

In another embodiment, the mutation is at least one mutation selected from arginine to phan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to ne mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to alanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), and histidine to ne mutation on residue 244 of the ma2 gene (H244R). For example, the mutation can be two mutations on the PLCgamma2 gene such as M1141R and S707F.

In one embodiment, the mutation is one mutation selected from from residue 481 of BTK (C481S) and cysteine to phenylalanine mutation on residue 481 of BTK (C481F), and at least one mutation selected from arginine to tryptophan mutation on residue 665 of PLCgamma2 gene ), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), nine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R).

In one ment, the prior treatment is treatment with one or more proteasome inhibitors. In one embodiment, the proteasome inhibitor is bortezomib. In one embodiment, the prior ent is treatment with one or more alkylating agents. In one embodiment, the alkylating agent is nitrogen mustard. In one ment, the prior treatment is treatment with one or more anti-CD20 antibodies. In one embodiment, wherein the anti-CD20 antibody is rituximab, obinutuzumab, momab,131I tositumomab, 90Y momab, 111I ibritumomab, or ofatumumab.

In one embodiment, provided herein is a method of treating a subject with a cancer or hematologic malignancy comprising: identifying a subject with one or more ons selected from cysteine to serine mutation on residue 481 of BTK ), cysteine to phenylalanine mutation on e 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to alanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to ne mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), and WHIM-like CXCR4 on; and administering a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, to the subject identified with one or more of the mutations.

In one embodiment, the mutation is one mutation selected from residue 481 of BTK (C481S) and cysteine to phenylalanine mutation on e 481 of BTK (C481F).

In another ment, the mutation is at least one mutation selected from arginine to tryptophan on on residue 665 of ma2 gene (R665W), histidine to e on on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the ma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine on on residue 707 of the ma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R). For example, the mutation can be two mutations on the PLCgamma2 gene such as M1141R and S707F.

In one embodiment, the mutation is one mutation selected from from residue 481 of BTK (C481S) and cysteine to phenylalanine on on residue 481 of BTK (C481F), and at least one mutation selected from arginine to tryptophan mutation on residue 665 of ma2 gene ), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on e 707 of the PLCgamma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R).

In another embodiment, the administration further comprises combining with one or more other therapeutic agents to the subject identified with one or more of the mutations.

In one embodiment, the identifying comprises obtaining a biological sample from the subject and detecting one or more mutations selected from ne to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on e 481 of BTK ), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on e 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of ma2 gene (M1141R), serine to alanine mutation on residue 707 of the PLCgamma2 gene ), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), and WHIM-like CXCR4 on in the sample. In one embodiment, the detecting comprises performing polymerase chain reaction (PCR) or hybridization to detect one or more of the mutations.

In one embodiment, the mutation is one mutation selected from residue 481 of BTK (C481S) and cysteine to phenylalanine mutation on residue 481 of BTK (C481F).

In another embodiment, the mutation is at least one mutation selected from arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on e 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the ma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene ). For example, the mutation can be two mutations on the PLCgamma2 gene such as M1141R and S707F.

In one ment, the mutation is one mutation selected from from residue 481 of BTK (C481S) and cysteine to phenylalanine mutation on e 481 of BTK (C481F), and at least one on selected from arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of ma2 gene (H257L), methionine to arginine mutation on residue 1141 of ma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine on on residue 707 of the PLCgamma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R).

In one ment, provided herein is a method of selecting a s ubject diagnosed with a cancer or hematologic malignancy as a candidate for treatment w ith a eutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof, comprising: (a) detecting the presence or absence of one or more mutations selected from cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to alanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), ine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine on on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on e 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene ), and WHIM-like CXCR4 mutation in a sample obtained from the subject, wherein the presence of one or more of the mutations indicates that the subject is a candidate for treatment with a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable form thereof; and (b) administering to the subject a therapeutically effective amount of a PI3K tor, or a pharmaceutically acceptable form thereof, when one or more of t he ons are present in the sample.

In one embodiment, the mutation is one mutation selected from residue 481 of BTK (C481S) and cysteine to phenylalanine mutation on residue 481 of BTK (C481F).

In another embodiment, the mutation is at least one mutation ed from arginine to phan mutation on residue 665 of PLCgamma2 gene (R665W), ine to leucine mutation on residue 257 of PLCgamma2 gene ), nine to arginine mutation on e 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), and histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R). For example, the mutation can be two mutations on the ma2 gene such as M1141R and S707F.

In one embodiment, the mutation is one on selected from from residue 481 of BTK (C481S) and cysteine to phenylalanine on on residue 481 of BTK (C481F), and at least one mutation selected from arginine to tryptophan mutation on residue 665 of PLCgamma2 gene ), histidine to leucine mutation on residue 257 of ma2 gene (H257L), nine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the ma2 gene (S707Y), and ine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R).

In one embodiment, the administration further comprises combining with one or more other therapeutic agents to the subject identified with one or more of the mutations.

In one embodiment, the PI3K modulator is Compound 292. In another embodiment, the PI3K modulator is or CAL-101 (GS-1101, isib, (S)(1-(9H-purinylamino)propyl)fluoro phenylquinazolin-4(3H)-one).

In one embodiment, the PI3K modultors include, but are not limited to, GDC-0032 (2-[4-[2-(2- Isopropylmethyl-1,2,4-triazolyl)-5,6-dihydroimidazo[1,2- d][1,4]benzoxazepinyl]pyrazolyl] methylpropanamide), MLN-1117/ INK1117, and BYL-719 ((2S)-N1-[4-Methyl[2-(2,2,2-trifluoro-1,1- dimethylethyl)pyridinyl]thiazolyl]-1,2-pyrrolidinedicarboxamide).

In one embodiment, the PI3K tors include, but are not limited to, GSK2126458 (2,4- Difluoro-N-{2-(methyloxy)[4-(4-pyridazinyl)quinolinyl]pyridinyl}benzenesulfonamide).

In one embodiment, the PI3K modulators include, but are not limited to, TGX-221 ((±)Methyl- pholinyl)(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidinone), GSK2636771 (2-Methyl(2- methyl(trifluoromethyl)benzyl)morpholino-1H-benzo[d]imidazolecarboxylic acid dihydrochloride), and KIN-193 ((R)((1-(7-methylmorpholinooxo-4H-pyrido[1,2-a]pyrimidin yl)ethyl)amino)benzoic acid).

In one embodiment, the PI3K modulators include, but are not limited to, TGR-1202/RP5264 (((S)(l-(4-amino(3-fluoroisopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)fluoro(3- fluorophenyl)-4H-chromenone)), GS-9820 (CAL-120, (S)(1-((9H-purinyl)amino)ethyl)fluoro phenylquinazolin-4(3H)-one), GS-1101 (5-fluorophenyl([S)][9H-purinylamino]-propyl)-3H- quinazolinone), AMG-319, GSK-2269557 (2-(6-(1H-indolyl)-1H-indazolyl)((4- isopropylpiperazinyl)methyl)oxazole), 409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), INCB040093, and BAY80-6946 (2-amino-N-(7-methoxy(3-morpholinopropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl)pyrimidinecarboxamide).

] In one embodiment, the PI3K tors include, but are not limited to, AS 252424 (5-[1-[5-(4- Fluorohydroxy-phenyl)-furanyl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), and CZ 24832 (5-(2- aminofluoro-[1,2,4]triazolo[1,5-a]pyridinyl)-N-tert-butylpyridinesulfonamide).

In one embodiment, the PI3K modulators include, but are not limited to, Buparlisib 6-Di(4- morpholinyl)pyrimidinyl](trifluoromethyl)pyridinamine), SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), and GDC- 0941 (2-(1H-Indazolyl)[[4-(methylsulfonyl)piperazinyl]methyl](4-morpholinyl)thieno[3,2- midine).

In one embodiment, the PI3K modulators include, but are not limited to, GDC-0980 ((S)(4-((2- (2-aminopyrimidinyl)methylmorpholinothieno[3,2-d]pyrimidinyl)methyl)piperazinyl) hydroxypropanone (also known as RG7422)), SF1126 ((8S,14S,17S)(carboxymethyl)(3- guanidinopropyl)(hydroxymethyl)-3,6,9,12,15-pentaoxo(4-(4-oxophenyl-4H-chromen yl)morpholinoium)oxa-7,10,13,16-tetraazaoctadecanoate), PF-05212384 (N-[4-[[4- (Dimethylamino)piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-dimorpholinyl-1,3,5-triazin yl)phenyl]urea), 414, BEZ235 hyl{4-[3-methyloxo(quinolinyl)-2,3-dihydro-1H- imidazo[4,5-c]quinolinyl]phenyl}propanenitrile), XL-765 (N-(3-(N-(3-(3,5- oxyphenylamino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)quinolinyl]methylene]-2,4-thiazolidenedione).

In one embodiment, the PI3K modulators include, but are not limited to, PX886, PX866 ([(3aR,6E,9S,9aR,10R,11aS)[[bis(propenyl)amino]methylidene]hydroxy(methoxymethyl)- 9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5-h]isochromenyl] acetate (also known as sonolisib)).

In one embodiment, the PI3K modulator is a modulator as described in WO 13556, the entirety of which is incorporated herein by reference. In one embodiment, the PI3K modulator is Compound Nos. 113 or 107 as described in WO2005/113556.

In one ment, the PI3K modulator is a modulator as described in WO2014/006572, the entirety of which is incorporated herein by reference. In one embodiment, the PI3K modulator is Compound Nos. A1, A2, B, B1, or B2 as described in /006572.

In one embodiment, the PI3K modulator is a modulator as described in , the entirety of which is incorporated herein by reference. In one embodiment, the PI3K modulator is a compound of a (I) as described in . In one embodiment, the PI3K modulator is a modulator as described in with a IC50 (nM) for the PI3K delta isoform of less than 100 nM and a IC50 (nM) for the PI3K alpha, beta, or gamma of greater than about 100 nM, r than about 1μM, or r than about 10 μM. In one embodiment, the PI3K tor is a modulator that has an delta selectivity ratio, a beta/delta selectivity ratio, or a gamma/delta selectivity ratio of greater than 1, greater than about 10, or greater than about 100. In one embodiment, the PI3K modulator is Compound No. 359 as described in .

In one embodiment, the PI3K modulator is a modulator as described in WO2011/146882, WO2013/012915, or WO2013/012918 the entireties of which are incorporated herein by reference.

In one embodiment, the PI3K modulators e, but are not limited to RP6503, , IC87114, Palomid 529, ZSTK474, PWT33597, TG100-115, GNE-477, CUDC-907, and AEZS-136.

In one embodiment, the other therapeutic agent is a chemotherapeutic agent or a therapeutic antibody. In one embodiment, the chemotherapeutic agent is selected from mitotic inhibitors, alkylating , anti-metabolites, some inhibitor, intercalating antibiotics, growth factor tors, cell cycle inhibitors, s, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. In one embodiment, the other therapeutic agent is a steroid. In another ment, the steroid is a glucocorticoid. In another embodiment, the glucocorticoid is aldosterone, beclometasone, betamethasone, cortisol (hydrocortisone), cortisone, deoxycorticosterone acetate (DOCA), dexamethasone, fludrocortisone acetate, methylprednisolone, prednisolone, prednisone, or triamcinolone. In another embodiment, glucocorticoid is dexamethasone.

In one embodiment, the therapeutic antibody is selected from anti-CD37 antibody, anti- CD20 antibody, and anti-CD52 antibody. In one embodiment, the therapeutic antibody is anti-CD20 antibody. In one embodiment, the anti-CD20 antibody is mab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or umab. In one embodiment, the anti-CD20 antibody is uzumab.

In one embodiment, the molar ratio of the PI3K modulator to the other therapeutic agent is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1.In one embodiment, the PI3K modulator is stered at a daily dosage of about 0.1 mg to about 150 mg, about 1 mg to about 100 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 10 mg, about 20 mg, or about 50 mg; or at a twice daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, about 20 mg, about mg, or about 50 mg; and the other therapeutic agent is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 1000.

] . In one embodiment, the PI3K modulator is administered at a daily dosage of about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg; obinutuzumab is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg.

In one embodiment, the PI3K modulator is administered at an amount to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and the other agent is administered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, the PI3K modulator is administered at an amount to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr, about 7500 ng/mL*hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr; the other agent is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr.

In one embodiment, the PI3K modulator is Compound 292, or a pharmaceutically acceptable form thereof, and the other eutic agent is obinutuzumab.

In another embodiment, the PI3K modulator is CAL-101, or a pharmaceutically acceptable form thereof, and the other therapeutic agent is obinutuzumab.

] In one embodiment, the molar ratio of nd 292 to obinutuzumab is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one embodiment, the molar ratio is 25:1 to about 1:1. In one embodiment, the molar ratio is about 20:1 to about 5:1. In one embodiment, the molar ratio is about 20:1 to about 10:1. In one embodiment, the molar ratio is about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, or about :1. In one ment, the molar ratio is about 16:1. In one embodiment, the molar ratio is about 17:1.

In one embodiment, the molar ratio of 1 to obinutuzumab is about 500:1, about 250:1, about 100:1, about 50:1, about 25:1, about 20:1, about 19:1, about 18: 1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In one embodiment, the molar ratio is about 150:1 to about 50:1. In one embodiment, the molar ratio is about 150:1 to about 75:1. In one embodiment, the molar ratio is about 125:1 to about 75:1. In one embodiment, the molar ratio is about 110:1 to about 90:1. In one embodiment, the molar ratio is about 100:1. In one embodiment, Compound 292 is administered at a daily dosage of about 0.1 mg to about 150 mg, about 1 mg to about 100 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 10 mg, about 20 mg, or about 50 mg; or at a twice daily dosage of about 0.1 mg to about 75 mg, about 1 mg to about 75 mg, about 5 mg to about 75 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, or about 50 mg; and obinutuzumab is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 1000 mg.

In one embodiment, Compound 292 is administered at a daily dosage of about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg. In one ment, Compound 292 is administered at a daily dosage of about 50 mg. In one embodiment, Compound 292 is administered at a twice daily at a dosage of about 5 mg to about 30 mg, about 15 mg to about 30 mg, or about 20 mg to about 30 mg. In one embodiment, Compound 292 is administered at twice daily at a dosage of about 25 mg. In one embodiment, obinutuzumab is administered at a daily dosage of about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one embodiment, obinutuzumab is administered at a daily dosage of about 1000 mg.

In one embodiment, CAL-101 is administered at a daily dosage of about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg; and obinutuzumab is administered at a daily dosage of about 0.1 mg to about 10,000 mg, about 0.1 mg to about 7500 mg, about 0.1 mg to about 5000 mg, about 1 mg to about 2500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one embodiment, CAL- 101 is administered at a daily dosage of about 200 mg to about 500 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg. In one embodiment, 1 is administered at a daily dosage of about 300 mg. In one embodiment, CAL-101 is administered at twice daily at a dosage of about 10 mg to about 250 mg, about 75 mg to about 200 mg, about 100 mg to about 200 mg, or about 125 mg to about 1750 mg.

In one embodiment, CAL-101 is administered twice daily at a dosage of about 150 mg. In one embodiment, obinutuzumab is administered at a daily dosage of about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. In one ment, obinutuzumab is administered at a daily dosage of about 1000 mg.

] In one embodiment, Compound 292 is stered at an amount to reach is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and obinutuzumab is administered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, Compound 292 is administered at an amount to reach Cmaxss at about 1500 ng/mL to about 1000 ng/mL, about 1500 ng/mL to about 1200 ng/mL, about 1500 ng/mL to about 1300 ng/mL, or about 1500 ng/mL to about 1400 ng/mL. In one embodiment, Compound 292 is administered at an amount to reach Cmaxss at about 1487 ng/mL. In one embodiment, Cmaxss is at least 700 ng/mL, at least 1000 ng/mL, at least 1200 ng/mL, at least 1400 ng/mL, at least 1450 ng/mL, at least 1480 ng/mL, or at least 1490 ng/mL, or at least 1500 ng/mL. In one embodiment, uzumab is administered at an amount to reach Cmaxss at about 750 ng/mL to about 900 ng/mL, about 750 ng/mL to about 850 ng/mL, or about 750 ng/mL to about 800 ng/mL. In one embodiment, uzumab is administered at an amount to reach Cmaxss at about 741 ng/mL. In one embodiment, Cmaxss is at least 200 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 720 ng/mL, at least 730 ng/mL, or at least 740 ng/mL.

In one embodiment, CAL-101 is administered at an amount to reach is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 5000 ng/mL, about 1000 ng/mL to about 4000 ng/mL, about 1000 ng/mL to about 3000 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 1400 ng/mL to about 2200 ng/mL; and obinutuzumab is stered at an amount to reach Cmaxss at about 100 ng/mL to about 1000 ng/mL, about 250 ng/mL to about 1000 ng/mL, about 500 ng/mL to about 1000 ng/mL, about 600 ng/mL to about 1000 ng/mL, about 700 ng/mL to about 1000 ng/mL, about 740 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 1000 ng/mL, about 750 ng/mL to about 900 ng/mL, or about 750 ng/mL to about 800 ng/mL.

In one embodiment, CAL-101 is administered at an amount to reach Cmaxss at about 1000 ng/mL to about 2500 ng/mL, 1500 ng/mL to about 2500, or about 2000 ng/mL to about 2500 ng/mL.

In one embodiment, CAL-101 is administered at an amount to reach Cmaxss at about 2200 ng/mL. In one embodiment, the Cmaxss is at least 1000 ng/mL, at least 1500 ng/mL, at least 1750 ng/mL, at least 2000 ng/mL, at least 2100 ng/mL, at least 2150 ng/mL, at least 2175 ng/mL, or at least 2200 ng/mL. In one embodiment, obinutuzumab is administered at an amount to reach Cmaxss at about 750 ng/mL to about 900 ng/mL, about 750 ng/mL to about 850 ng/mL, or about 750 ng/mL to about 800 ng/mL. In one embodiment, obinutuzumab is administered at an amount to reach Cmaxss at about 741 ng/mL. In one embodiment, Cmaxss is at least 300 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 720 ng/mL, at least 730 ng/mL, or at least 740 ng/mL.

In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr, about 7500 ng/mL*hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr; and obinutuzumab is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 ng/mL*hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 hr to about 4500 ng/mL*hr.

In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 7000 ng/mL*hr to about 9000 ng/mL*hr or about 8000 ng/mL*hr to about 8500 ng/mL*hr. In one embodiment, nd 292 is administered at an amount to reach an AUCss at about 8600 ng/mL*hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr. In one embodiment, Compound 292 is administered at an amount to reach an AUCss at about 8787 ng/mL*hr. In one embodiment, obinutuzumab is stered at an amount to reach an AUCss at about 3000 ng/mL*hr to about 5000 hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr. In one embodiment, obinutuzumab is stered at an amount to reach an AUCss at about 4044 ng/mL*hr.

In one embodiment, CAL-101 is administered at an amount to reach an AUCss at about 5000 ng/mL*hr to about 10000 ng/mL*hr, about 5000 ng/mL*hr to about 9000 ng/mL*hr, about 6000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr to about 9000 ng/mL*hr, about 7000 ng/mL*hr, about 7500 hr, about 8000 ng/mL*hr, about 8500 ng/mL*hr , about 8600 hr, about 8700 ng/mL*hr, or about 8800 ng/mL*hr; and obinutuzumab is administered at an amount to reach an AUCss at about 1000 ng/mL*hr to about 5000 hr, about 2000 ng/mL*hr to about 5000 ng/mL*hr, about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr.

In one embodiment, CAL-101 is administered at an amount to reach AUCss at about 6000 ng/mL*hr to about 9000 hr, about 6000 ng/mL*hr to about 8000 ng/mL*hr, about 6000 ng/mL*hr to about 7500 ng/mL*hr, or about 6500 ng/mL*hr to about 7500 ng/mL*hr. In one embodiment, CAL-101 is administered at an amount to reach AUCss at about 7000 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 3000 ng/mL*hr to about 5000 ng/mL*hr, about 4000 ng/mL*hr to about 5000 ng/mL*hr, or about 4000 ng/mL*hr to about 4500 ng/mL*hr. In one embodiment, obinutuzumab is administered at an amount to reach an AUCss at about 4044 ng/mL*hr.

In one embodiment, the cancer or logic malignancy is CLL, Waldenström macroglobulinemia (WM), mantle cell, NHL, iNHL, diffuse large B-cell lymphoma, or T-cell lymphoma.

In another embodiment, the cancer or hematologic malignancy is follicular lymphoma.

In one embodiment, the methods provided herein se administering a PI3K modulator (e.g., a compound that selectively reduces the activity of one or more PI3K m(s)), alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human. In one embodiment, the PI3K modulator is selective for one or more m(s) of PI3K over the other isoform(s) of PI3K (e.g., PI3K-δ selective, PI3K-γ selective, or PI3K-δ and PI3K-γ selective).

Exemplary PI3K-α selective inhibitors include, but are not limited to, GDC-0032 (2-[4-[2-(2- Isopropylmethyl-1,2,4-triazolyl)-5,6-dihydroimidazo[1,2- d][1,4]benzoxazepinyl]pyrazolyl] methylpropanamide), MLN-1117/ INK1117, and BYL-719 ((2S)-N1-[4-Methyl[2-(2,2,2-trifluoro-1,1- dimethylethyl)pyridinyl]thiazolyl]-1,2-pyrrolidinedicarboxamide).

] Exemplary PI3K-α/m-TOR tors include, but are not limited to, GSK2126458 (2,4-Difluoro- N-{2-(methyloxy)[4-(4-pyridazinyl)quinolinyl]pyridinyl}benzenesulfonamide).

Exemplary PI3K-β selective inhibitors include, but are not limited to, TGX-221 ((±)Methyl (morpholinyl)(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidinone), GSK2636771 (2-Methyl(2- methyl(trifluoromethyl)benzyl)morpholino-1H-benzo[d]imidazolecarboxylic acid dihydrochloride), and 3 -((1-(7-methylmorpholinooxo-4H-pyrido[1,2-a]pyrimidin yl)ethyl)amino)benzoic acid).

] Exemplary PI3K-δ selective inhibitors include, but are not limited to, TGR-1202/RP5264 (((S) (l-(4-amino(3-fluoroisopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)fluoro(3- fluorophenyl)-4H-chromenone)), GS-9820 (CAL-120, (S)(1-((9H-purinyl)amino)ethyl)fluoro phenylquinazolin-4(3H)-one), GS-1101 (5-fluorophenyl([S)][9H-purinylamino]-propyl)-3H- quinazolinone), AMG-319, GSK-2269557 (2-(6-(1H-indolyl)-1H-indazolyl)((4- isopropylpiperazinyl)methyl)oxazole), SAR245409 (N-(4-(N-(3-((3,5- oxyphenyl)amino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), INCB040093, and BAY80-6946 (2-amino-N-(7-methoxy(3-morpholinopropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl)pyrimidinecarboxamide).

Exemplary PI3K-γ ive inhibitors include, but are not limited to, AS 252424 (5-[1-[5-(4- hydroxy-phenyl)-furanyl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), and CZ 24832 (5-(2- aminofluoro-[1,2,4]triazolo[1,5-a]pyridinyl)-N-tert-butylpyridinesulfonamide).

Exemplary 3K inhibitors include, but are not limited to, Buparlisib (5-[2,6-Di(4- morpholinyl)pyrimidinyl](trifluoromethyl)pyridinamine), 409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), and GDC- 0941 (2-(1H-Indazolyl)[[4-(methylsulfonyl)piperazinyl]methyl](4-morpholinyl)thieno[3,2- d]pyrimidine).

Exemplary pan-PI3K/mTOR inhibitors include, but are not limited to, GDC-0980 ((S)(4-((2- (2-aminopyrimidinyl)methylmorpholinothieno[3,2-d]pyrimidinyl)methyl)piperazinyl) hydroxypropanone (also known as RG7422)), SF1126 ((8S,14S,17S)(carboxymethyl)(3- guanidinopropyl)(hydroxymethyl)-3,6,9,12,15-pentaoxo(4-(4-oxophenyl-4H-chromen yl)morpholinoium)oxa-7,10,13,16-tetraazaoctadecanoate), PF-05212384 (N-[4-[[4- (Dimethylamino)piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-dimorpholinyl-1,3,5-triazin yl)phenyl]urea), LY3023414, BEZ235 (2-Methyl{4-[3-methyloxo(quinolinyl)-2,3-dihydro-1H- imidazo[4,5-c]quinolinyl]phenyl}propanenitrile), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalinyl)sulfamoyl)phenyl)methoxymethylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)quinolinyl]methylene]-2,4-thiazolidenedione).

] Exemplary beta-sparing α/δ/γ) inhibitors include, but are not limited to, PX886, PX866 ([(3aR,6E,9S,9aR,10R,11aS)[[bis(propenyl)amino]methylidene]hydroxy(methoxymethyl)- 9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5-h]isochromenyl] acetate (also known as sonolisib)).

In one embodiment, the PI3K inhibitor is a PI3K tor as described in , the entirety of which is incorporated herein by reference. In one embodiment, the PI3K inhibitor is Compound Nos. 113 or 107 as described in WO2005/113556.

In one embodiment, the PI3K inhibitor is a PI3K inhibitor as bed in WO2014/006572, the entirety of which is incorporated herein by reference. In one embodiment, the PI3K inhibitor is nd Nos. A1, A2, B, B1, or B2 as described in WO2014/006572.

In one embodiment, the PI3K inhibitor is a PI3K inhibitor as described in , the entirety of which is incorporated herein by reference. In one embodiment, the PI3K inhibitor is a compound of a (I) as described in . In one embodiment, the PI3K delta selective inhibitor is a compound described in with a IC50 (nM) for the PI3K delta isoform of less than 100 nM and a IC50 (nM) for the PI3K alpha, beta, or gamma of r than about 100 nM, r than about 1μM, or greater than about 10 μM. In one embodiment, the PI3K delta selective inhibitor has an alpha/delta selectivity ratio, a beta/delta selectivity ratio, or a gamma/delta selectivity ratio of greater than 1, greater than about 10, or greater than about 100. In one embodiment, the PI3K inhibitor is Compound No. 359 as described in .

In one embodiment, the PI3K inhibitor is a PI3K inhibitor as described in WO2011/146882, WO2013/012915, or WO2013/012918 the entireties of which are incorporated herein by reference.

In one embodiment, the PI3K inhibitor is selected from RP6503, RP6530, IC87114, Palomid 529, ZSTK474, PWT33597, TG100-115, 7, CUDC-907, and AEZS-136.

Without being limited to a particular theory, in one embodiment, as used herein, and unless otherwise indicated, high expression of a particular PI3K isoform can be an increased DNA copy number of the PI3K isoform or a receptor or target ng to the PI3K isoform, a high expression of RNA of the PI3K isoform or a receptor or target relating to the PI3K isoform, a high expression of the protein of the PI3K isoform or a receptor or target relating to the PI3K isoform, ication of the PI3K isoform or a or or target relating to the PI3K isoform, deletion of a receptor or target relating to the PI3K isoform, downregulation of a receptor or target ng to the PI3K isoform, mutation of the PI3K isoform or a or or target relating to the PI3K isoform, and/or pathway activation of the PI3K isoform or a receptor or target relating to the PI3K isoform. Without being limited to a particular theory, in one embodiment, provided herein are kers of pathway activation and methods of use thereof, which are predictive of response to treatment described herein (e.g., a biomarker relating to pAKT, pS6, pPRAS40, or other proteins or transcriptionally regulated genes downstream of PI3Kδ and/or PI3Kγ).

] In certain embodiments, the expression level of one or more than one particular PI3K isoform in a cancer or a disease, or a patient or a group of patients, can be determined by detecting the expression level of a ular PI3K m protein, or RNA of a particular PI3K isoform, or the increased DNA copy number of a particular PI3K isoform, for example, using a method provided herein or a method known in the art. In other embodiments, the sion level of one or more than one particular PI3K isoform in a cancer or a disease, or a patient or a group of patients, can be determined by measuring a biomarker ed herein (e.g., a signaling pathway biomarker, a protein mutation biomarker, a protein expression biomarker, a gene mutation biomarker, a gene expression biomarker, a cytokine biomarker, a ine biomarker, a matrix metalloproteinase biomarker, or a biomarker for particular cancer cells, among others).

In yet another embodiment, the expression level of one or more than one particular PI3K isoform in a cancer or a disease, or a patient or a group of patients, can be determined based on information known in the art or based on prior studies on the cancer or disease, or prior testing of the patient or group of patients.

In n embodiments, the selectivity of a PI3K modulator (e.g., a compound provided herein) toward one or more PI3K isoform(s) over other PI3K m(s) can be ined by measuring the activity of the PI3K modulator toward PI3K ms (e.g., PI3K-α, PI3K-β, PI3K-δ, and/or ), for example, using a method ed herein or a method known in the art.

PI3K-γ is a Class 1B PI3K that associates with the p101 and p84 (p87PIKAP) r proteins, and canonically signals through GPCRs. Non-cononical activation through tyrosine kinase receptors and RAS can occur. Activated PI3K-γ leads to production of PIP3, which serves as a docking site for downstream effector proteins including AKT and BTK, bringing these enzymes to the cell membrane where they may be activated. A scaffolding role for PI3k-γ has been proposed and may contribute to the tion of the RAS/MEK/ERK pathway. The interaction with the RAS pathway explains ties attributed to kinase dead PI3K-γ in cells or in animals. PI3K-γ is essential for function of a y of immune cells and pathways. Production of chemokines that attract neutrophil or monocyte cell migration is mediated by PI3K- γ upon inflammatory stimulants (including IL8, fMLP, and C5a) (HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049- 1053 (2000); SASAKI et al., ion of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040-1046 (2000); LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049 (2000)). The requirement for PI3K-γ-dependent neutrophil migration is demonstrated by failure of arthritis development in the K/BXN serum transfer arthritis model in PI3K-γ knockout mice (Randis et al., Eur. J. Immunol., 2008, 38(5), 1215– 24). Similarly, the mice fail to develop cellular inflammation and airway hyper-responsiveness in the ovalbumin induced asthma model (Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805–12). PI3K-γ deficient mice also have defects in er cell on. T-cell cytokine production and proliferation in response to tion is reduced, and T helper dependent viral clearance is defective i et al., Science, 2000, 287, 1040–46). T-cell dependent inflammatory disease models including EAE also do not develop in PI3K-γ deficient mice, and both the T-cell activation defect and cellular migration defects may contribute to efficacy in this model (Comerfold, PLOS One, 2012, 7, e45095). The imiquimod psoriasis model has also been used to demonstrate the importance of PI3K- γ in the matory response. Using PI3K-γ deficient mice in this model, the accumulation of γδ T cells in the skin is blocked, as well as dendritic cell maturation and migration (ROLLER et al., “Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL- 17 and Ameliorates Imiquimod-Induced Psoriasis-like itis,” J. Immunol. 189:4612-4620 (2012)).

The role of PI3K-γ in cellular trafficking can also be trated in gy models where tumor mation is important for growth and metastasis of cancers. In the Lewis Lung Carcinoma model, monocyte activation, migration, and differentiation in tumors are defective. This defect results in a reduction in tumor growth and extended al in PI3K-γ deficient mice (Schmid et al., Cancer Cell, 2011, 19, 715–27) or upon treatment with inhibitors that target PI3K-γ. In pancreatic cancer, PI3K-γ can be inappropriately expressed, and in this solid tumor cancer or others where PI3K-γ plays a functional role, inhibition of PI3K-γ can be beneficial. Inhibition of PI3K-γ shows promise for the treatment of hematologic malignancies. In a T-ALL model employing a T cell directed knockout of PTEN, PI3K-δ and PI3K-γ are both essential for the appropriate development of disease, as shown with c deletion of both genes (Subramaniam et al. Cancer Cell 21, 2, 2012). In addition, in this T-ALL model, treatment with a small molecule inhibitor of both kinases leads to extended survival of these mice. In CLL, chemokine networks support a pseudo-follicular microenvironment that includes nurse-like cells, stromal cells and T-helper cells. The roles of PI3K-γ in normal chemokine signaling and T cell biology suggest the value of inhibiting this target in CLL (BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012)). Accordingly, PI3K-γ inhibitors are therapeutically interesting for diseases of the immune system where cell trafficking and T-cell or myeloid cell function is important. In oncology, solid tumors that are dependent on tumor inflammation, or tumors with high levels of PI3K-γ expression, may be targeted. For logical cancers a l role for PI3K-γ and PI3K-δ isoforms in T-ALL and potentially in CLL suggests there could be benefit from targeting these PI3Ks in these diseases.

The role of PI3K-γ pathway in promoting myeloid cell cking to tumors and the role of de of p110γ in suppression of tumor inflammation and growth in breast cancer, pancreatic cancer, and lung cancer are reported in Schmid et al. (2011) Cancer Cell 19, 715–727, the entirety of which is incorporated herein by reference. In one embodiment, provided herein is a method of treating or preventing pancreatic cancer with a PI3K inhibitor. In another embodiment, provided herein is a method of treating or preventing breast cancer with a PI3K inhibitor. In yet another embodiment, provided herein is a method of treating or preventing lung cancer with a PI3K inhibitor. In one ment, the PI3K inhibitor is a PI3K- γ inhibitor, selective or non-selective over one or more other PI3K isoform(s). In one embodiment, the PI3K inhibitor is a PI3K-γ selective inhibitor.

] PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes where they have distinct and non-overlapping roles in immune cell development and function. See, e.g., PURI and GOLD, “Selective tors of phosphoinositide 3-kinase delta: tors of B-cell function with potential for ng autoimmune inflammatory disease and B-cell malignancies,” Front. Immunol. 3:256 ; BUITENHUIS et al., “The role of the PI3k-PKB signaling module in regulation of hematopoiesis,” Cell Cycle 8(4):560-566 (2009); HOELLENRIEGEL and BURGER, “Phosphoinositide 3'-kinase delta: turning off BCR signaling in Chronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738 (2011); HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049- 1053 (2000); LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040-1046 ; CUSHING et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem. 55:8559- 8581 ; L et al., uation of phosphoinositide se δ signaling restrains autoimmune e,” J. Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives the pathogenesis of experimental mune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation,” J. Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cell ne production during primary and secondary immune responses in mice and ,” Blood 115(11):2203-2213 (2010); ROLLER et al., ade of Phosphatidylinositol se (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced sis-like Dermatitis,” J. Immunol. 189:4612-4620 (2012); CAMPS et al., “Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid tis,” Nat. Med. 11(9):936-943 (2005). As key enzymes in yte signaling, PI3K-δ and PI3K-γ facilitate normal B-cell, T-cell and myeloid cell functions including differentiation, activation, and migration. See, e.g., HOELLENRIEGEL and BURGER, “Phosphoinositide 3'-kinase delta: turning off BCR signaling in Chronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738 (2011); CUSHING et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem. 55:8559-8581 (2012). PI3K-δ or PI3K-γ activity is critical for preclinical models of autoimmune and inflammatory diseases. See, e.g., HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049-1053 ; LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049 ; SASAKI et al., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040- 1046 (2000); G et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem. 55:8559-8581 (2012); L et al., “Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J. Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell sis and promoting Th17 differentiation,” J. Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans,” Blood 115(11):2203-2213 (2010); ROLLER et al., “Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates mod-Induced Psoriasis-like Dermatitis,” J.

Immunol. 12-4620 (2012); CAMPS et al., ade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid tis,” Nat. Med. 11(9):936-943 (2005). Given the key role for PI3K-δ and PI3K-γ in immune function, inhibitors of the PI3K-δ and/or γ have therapeutic potential in immune-related inflammatory or neoplastic diseases.

PI3K-δ and PI3K-γ are central to the growth and survival of B- and T-cell malignancies and inhibition of these isoforms may effectively limit these diseases. See, e.g., SUBRAMANIAM et al., “Targeting ssical Oncogenes for Therapy in T-ALL,” Cancer Cell 21:459-472 (2012); LANNUTTI et al., “CAL-101 a p110δ selective phosphatidylinositolkinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability,” Blood 117(2):591-594 (2011). PI3K-δ and PI3K-γ support the growth and survival of certain B-cell malignancies by mediating ellular BCR signaling and interactions between the tumor cells and their microenvironment. See, e.g., PURI and GOLD, tive inhibitors of phosphoinositide 3-kinase delta: tors of B-cell function with potential for treating autoimmune inflammatory disease and B-cell ancies,” Front. Immunol. 3:256 (2012); HOELLENRIEGEL et al., “The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leuckemia,” Blood 118(13):3603-3612 (2011); BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012). Increased BCR signaling is a central pathologic mechanism of B-cell ancies and PI3K activation is a direct consequence of BCR y activation. See, e.g., BURGER, “Inhibiting B-Cell Receptor Signaling ys in c Lymphocytic Leukemia,” Curr.

Mematol. Malig. Rep. 7:26-33 (2012); HERISHANU et al., “The lymph node microenvironment promotes B-cell receptor ing, NF-κB activation, and tumor proliferation in c lymphocytic leukemia,” Blood 117(2):563-574 (2011); DAVIS et al., “Chronic active B-cell-receptor signaling in diffuse large B- cell lymphoma,” Nature 463:88-92 (2010); PIGHI et al., “Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling,” Cell Oncol. (Dordr) 34(2):141- 153 (2011); RIZZATTI et al., “Gene expression ing of mantle cell lymphoma cells reveals aberrant sion of genes from the PI3K-AKT, WNT and TGFβ signaling pathways,” Brit. J. Haematol. 130:516- 526 (2005); MARTINEZ et al., “The Molecular ure of Mantle Cell Lymphoma Reveals Multiple Signals Favoring Cell Survival,” Cancer Res. 63:8226-8232 (2003). Interactions between malignant B-cells and ting cells (eg, stromal cells, nurse-like cells) in the tumor microenvironment are important for tumor cell survival, proliferation, homing, and tissue ion. See, e.g., BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 3 (2012); HERISHANU et al., “The lymph node microenvironment es B-cell receptor ing, NF- κB activation, and tumor proliferation in chronic lymphocytic leukemia,” Blood 117(2):563-574 (2011); KURTOVA et al., “Diverse marrow stromal cells protect CLL cells from spontaneous and drig-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance,” Blood ): 4441-4450 (2009); BURGER et al., “High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR ation,” Blood 113(13) 3050-3058 (2009); A et al., “B-cell antigen receptor signaling enhances c lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406,” Blood 114(5):1029-1037 (2009). Inhibiting PI3K-δ,γ with an inhibitor in certain malignant B-cells can block the BCR-mediated intracellular survival and proliferation signals as well as key interactions with their microenvironment that are critical for their growth.

PI3K-δ and PI3K-γ also play a direct role in the survival and proliferation of certain T-cell malignancies. See, e.g., SUBRAMANIAM et al., “Targeting Nonclassical Oncogenes for Therapy in TALL ,” Cancer Cell 21:459-472 (2012). Aberrant PI3K-δ and PI3K-γ activity provides the signals necessary for the development and growth of certain T-cell malignancies. While BTK is expressed in B- cells, it is not expressed in T-cells, and therefore BTK is not a viable target for the ent of T-cell malignancies. See, e.g., NISITANI et al., “Posttranscriptional regulation of Bruton’s tyrosine kinase expression in antigen receptor-stimulated splenic B cells,” PNAS 97(6):2737-2742 (2000); DE WEERS et al., “The Bruton’s ne kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages,” Eur. J. Immunol. 23:3109-3114 (1993); SMITH et al., “Expression of ’s Agammaglobulinemia Tyrosine Kinase Gene, BTK, Is Selectively Down-Regulated in T Lymphocytes and Plasma Cells,” J. Immunol. 152:557-565 (1994). PI3K-δ and/or γ tors can have unique therapeutic potential in T-cell malignancies.

In certain embodiments, provided herein is a method of treating cancer or hematologic malignancy comprising administering a PI3K δ/γ selective inhibitor. Without being limited by a particular theory, selectively inhibiting δ/γ isoform(s) can provide a treatment regimen where adverse effects associated with administration of a non-selective PI3K inhibitor are zed or reduced. Without being d by a particular theory, it is believed that the e effects can be reduced by avoiding the inhibition of other isoforms (e.g., α or β) of PI3K.

In one embodiment, the adverse effect is hyperglycemia. In r embodiment, the adverse effect is rash. In another embodiment, the adverse effect is impaired male fertility that may result from inhibition of β isoform of PI3K (see, e.g., Ciraolo et al., Molecular Biology of the Cell, 21: 704-711 (2010)). In another embodiment, the e effect is testicular toxicity that may result from inhibition of PI3K-β (see, e.g., Wisler et al., Amgen SOT, Abstract ID # 2334 (2012)). In another embodiment, the adverse effect is embryonic lethality (see, e.g., Bi et al., J Biol Chem, 274: 10968 (1999)). In another ment, the adverse effect is ive platelet aggregation (see, e.g., Kulkarni et al., Science, 287: 1049-1053 ). In another embodiment, the adverse effect is functionally defective neutrophil (id.).

In one embodiment, provided herein is a method of ng or preventing a specific cancer or disease, such as, a hematologic malignancy, which has a high expression level of one or more isoform(s) of PI3K, wherein the method comprises: (1) determining the expression level of one or more PI3K isoform(s) in the cancer or e; (2) selecting a treatment agent (e.g., a PI3K modulator having a particular selectivity profile for one or more PI3K isoform(s)) based on the expression levels of PI3K isoforms in the cancer or disease to be treated; and (3) administering the treatment agent to a patient having the cancer or disease, alone or in combination with one or more other agents or therapeutic modalities. In one embodiment, the expression level of one or more PI3K isoform(s) in the cancer or disease can be measured by determining the expression level of PI3K isoform n, RNA; and/or DNA copy number, or by measuring one or more biomarkers ed herein (e.g., a signaling y biomarker, a n mutation biomarker, a protein expression biomarker, a gene mutation biomarker, a gene expression ker, a cytokine biomarker, a chemokine biomarker, a matrix metalloproteinase biomarker, or a biomarker for particular cancer cells, among ). In other embodiments, the expression level of one or more PI3K isoform(s) in the cancer or disease can be determined based on information known in the art or information ed in prior studies on the cancer or disease.

Certain cancer or disorder, e.g., a hematologic malignancy, can exhibit geneity in PI3K isoform expression among t populations. In one embodiment, provided herein is a method of treating or preventing a specific patient or group of patients, having a cancer or disease, such as, a hematologic malignancy, wherein the method ses: (1) determining the expression levels of one or more PI3K isoform(s) in the patient or group of patients having the cancer or disease; (2) selecting a treatment agent (e.g., a PI3K modulator having a particular selectivity profile for one or more PI3K isoform(s)) based on the expression levels of PI3K isoforms in the patient(s) to be treated; and (3) administering the treatment agent to the patient(s), alone or in ation with one or more other agents or therapeutic modalities. In one embodiment, the expression level of one or more PI3K isoform(s) in the patient or group of patients can be measured by ining the expression level of PI3K isoform protein, RNA, and/or DNA copy number in the patient or group of patients; or by measuring one or more biomarkers provided herein in the patient or group of patients (e.g., a signaling pathway biomarker, a protein on biomarker, a protein sion biomarker, a gene mutation biomarker, a gene expression ker, a cytokine biomarker, a chemokine biomarker, a matrix metalloproteinase biomarker, or a biomarker for particular cancer cells, among others).

In other embodiments, the sion level of one or more PI3K isoform(s) in the patient or group of patients can be determined based on information known in the art or information obtained in prior testing of the patient or group of patient(s).

] In one embodiment, the methods provided herein comprise administering a PI3K modulator, alone or in combination with one or more other agents or therapeutic modalities, to a subject, e.g., a ian subject, e.g., a human; wherein the PI3K modulator is selective for one or more PI3K isoform(s) over the other isoforms of PI3K (e.g., selective for PI3K-δ, selective for PI3K-γ, or selective for both PI3K-δ and PI3K-γ); and the subject being treated has a high expression level of the particular PI3K isoform(s) (e.g., high expression of PI3K-δ, high expression of PI3K-γ, or high expression of both PI3K-δ and PI3K-γ).

In one embodiment, provided herein is a method of ining whether a subject having a cancer or hematologic malignancy is more or less likely to respond to a treatment with a PI3K modulator that selectively reduces the activity of one or more isoform(s) of PI3K over other ms of PI3K, wherein the method comprises (1) administering the PI3K modulator to the t; and (2) determining the response of the subject to treatment after about 7, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days, or about 1, 2, 3, 4, or 5 months after first treatment with the PI3K modulator.

] Without being limited by a particular theory, as provided herein, treating a ic cancer or hematologic malignancy, or a specific sub-type of cancer or hematologic ancy, or a specific patient having a cancer or hematologic malignancy, that has a high expression of a particular PI3K isoform, with a PI3K inhibitor that selectively inhibits that particular PI3K isoform, allows the use of a lower dose of the therapeutic agent and/or reduced off-target effect (e.g., effects on other PI3K ms), thereby zing the potential for adverse effects. Without being limited by a particular theory, the methods provided herein can provide reduced side effects and/or improved efficacy. In one embodiment, provided herein is a method of treating or preventing a cancer or disease, such as a hematologic malignancy, having a high expression level of one or more m(s) of PI3K, wherein the adverse effects associated with administration of a PI3K inhibitor are reduced. In one ment, provided herein is a method of treating or preventing a cancer or e, such as hematologic malignancy, or a specific type or sub-type of cancer or disease, such as a specific type or sub-type of hematologic malignancy, with a PI3K-γ selective tor, wherein the adverse effects associated with administration of inhibitors for other isoform(s) of PI3K (e.g., PI3K-α or PI3K-β) are reduced. In one embodiment, provided herein is a method of treating or preventing a cancer or disease, such as hematologic malignancy, or a specific type or sub-type of cancer or disease, such as a specific type or sub-type of hematologic malignancy, with a PI3K-γ selective inhibitor, at a lower (e.g., by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, or by about 80%) dose as compared to treatment with a PI3K-γ non-selective or less selective inhibitor (e.g., a PI3K pan inhibitor (e.g., PI3K-α, β, γ, δ)). Such adverse effects can include, but not be limited to, nausea, diarrhea, constipation, fatigue, a, chills, vomiting, sed appetite, rash, elevated ASL, elevated ALT, increased blood urea, increased alanine aminotransferase, increased aspartate aminotransferase, sed blood alkaline phosphatase, neutropenia, thrombocytopenia, anaemia, lycemia, hypercholesterolemia, hypertrigliceridemia, hosphataemia, hypomagnesaemia, pain, back pain, muscle pain, cough, and dyspnoea. The term “reduction” of one or more adverse effects means a se of the occurrence and/or the severity of one or more of the adverse effects provided herein or known in the art that are lly ated with administration of a PI3K inhibitor, e.g., by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about 90%, by about 95%, by about 100% as compared to treatment with another PI3K inhibitor (e.g., a non-selective or less selective inhibitor).

In one embodiment, described herein is a method of treating or preventing cancer, or a specific type or a specific pe of cancer provided herein. Examples of cancer that can be treated or prevented with a tor of PI3K (e.g., PI3K-δ and/or PI3K-γ), e.g., a compound provided herein, include, e.g., leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia (e.g., Salmena, L et al. (2008) Cell 133:403-414; Chapuis, N et al. (2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A (2010) Curr Top Microbiol Immunol. 347:169-88); lymphoma, e.g., non-Hodgkin lymphoma (e.g., Salmena, L et al. (2008) Cell 133:403-414); lung cancer, e.g., non-small cell lung cancer, small cell lung cancer (e.g., Herrera, VA et al. (2011) Anticancer Res. 31(3):849-54); ma (e.g., Haluska, F et al. (2007) Semin Oncol. 34(6):546-54); te cancer (e.g., Sarker, D et al. (2009) Clin Cancer Res. (15):4799-805); glioblastoma (e.g., Chen, JS et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer (e.g., Bansal, N et al. (2009) Cancer Control. 16(1):8-13); pancreatic cancer (e.g., Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renal cell carcinoma (e.g., Porta, C and Figlin, RA (2009) J Urol. 182(6):2569-77); colorectal cancer (e.g., Saif, MW and Chu, E (2010) Cancer J. 16(3):196-201); breast cancer (e.g., Torbett, NE et al. (2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brzezianska, E and Pastuszak-Lewandoska, D (2011) Front Biosci. 16:422-39); and ovarian cancer (e.g., etti, M and Broggini, M (2010) Curr Med Chem. 17(36):4433-47). In some embodiments, said method relates to the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, , liver, ovarian, prostate, ctal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi’s sarcoma) or other viralinduced cancers. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or te (e.g., benign tic hypertrophy (BPH)).

Patients that can be treated with a compound ed , or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, es, solvates, isomers, prodrugs, and ically labeled derivatives) thereof, or a pharmaceutical composition as provided herein, according to the methods as provided herein include, for example, but not limited to, patients that have been diagnosed as having breast cancer such as a ductal oma , lobular carcinoma, medullary omas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal ; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial ing or squamous cell carcinoma; te cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarcinoma that has migrated to the bone; atic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a atic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphoblastic ia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, , myeloproliferative disorders, NK cell leukemia (e.g., blastic plasmacytoid dendritic cell neoplasm), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone ; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung ; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer; kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK cell lymphoma (e.g., blastic plasmacytoid dendritic cell neoplasm), and Burkitt lymphoma; Kaposi’s Sarcoma; viralinduced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and cellular carcinoma; human lymphotropic type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical ; central nervous system cancers (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, and medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas, malignant ytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Müllerian tumor; oral cavity and oropharyngeal cancers such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular s such as germ cell tumors (GCTs), which include seminomas and nonseminomas, and gonadal stromal , which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as to thymomas, thymic carcinomas, n lymphoma, dgkin lymphomas, carcinoids or carcinoid ; rectal cancer; and colon .

In one embodiment, described herein is a method of treating or ting a hematologic malignancy (or a specific type or a specific subtype of the logic ancy provided herein), ing, but not limited to, myeloid disorder, id er, leukemia, lymphoma, ysplastic syndrome (MDS), myeloproliferative e (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), among others. In one embodiment, the hematologic malignancy includes, but is not limited to, acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL), B-cell ALL (B-ALL), acute T-cell leukemia, acute B-cell leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), blast phase CML, small lymphocytic ma (SLL), CLL/SLL, blast phase CLL, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL , diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), aggressive B-cell NHL, B-cell lymphoma (BCL), Richter’s syndrome (RS), T-cell ma (TCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), transformed mycosis fungoides, Sézary syndrome, anaplastic large-cell lymphoma (ALCL), follicular lymphoma, Waldenström macroglobulinemia (WM), lymphoplasmacytic lymphoma, Burkitt lymphoma, le myeloma (MM), amyloidosis, MPD, essential thrombocytosis (ET), ibrosis (MF), polycythemia vera (PV), chronic myelomonocytic leukemia (CMML), MDS, high-risk MDS, and low-risk MDS.

In exemplary embodiments, the cancer or hematologic malignancy is CLL. In exemplary embodiments, the cancer or logic malignancy is CLL/SLL. In exemplary embodiments, the cancer or hematologic malignancy is blast phase CLL. In exemplary ments, the cancer or hematologic malignancy is SLL.

In further embodiments, the cancer or hematologic malignancy is CLL, and a compound provided herein promotes apoptosis of CLL cells. Without being limited by a particular theory, it was found that the treatment by a compound provided herein (e.g., Compound 292) sensitizes CLL cells. In some instances, without being limited by a particular theory, the protective effects induced by anti-IgM crosslinking or stromal cells can be mitigated by a nd provided herein. Accordingly, provided herein is a method of promoting apoptosis of CLL cells comprising stering to a patient a therapeutically effective amount of a compound ed herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292. Also provided herein is a method of mitigating protective effects on CLL cells induced by anti-IgM crosslinking comprising administering to a patient a therapeutically effective amount of a compound provided , or a pharmaceutically acceptable derivative (e.g., salt or solvate) f. In one embodiment, the compound is Compound 292. In another embodiment, provided herein is a method of mitigating protective effects on CLL induced by stromal cells comprising administering to a t a therapeutically effective amount of a compound provided herein, or a pharmaceutically able tive (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292.

In another embodiment, provided herein is a method of inhibiting proliferation of CLL cells in the lymph nodes comprising administering to a patient a eutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292. In another ment, provided herein is a method of ing a rapid onset of response in CLL ts administering to a patient a therapeutically effective amount of a compound provided , or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292.

Without being limited by a particular theory, as provided herein, a compound provided herein inhibits chemotaxis of leukocyte in response to stimulation of a chemokine/cytokine (e.g., CXCL12 SDF-1). Thus, without being limited by a particular theory, the methods provided herein can interfere with the homing and migration capabilities of immune cells that support cancer cell growth to the tumor microenvironment. In another embodiement, the methods provided herein ly inhibit the migration of a cancer cell to the protective nvironment. In one embodiment, provided herein is a method of preventing or controlling metastasis or dissemination of a cancer or hematologic malignancy comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) f. In one embodiment, the cancer or hematologic malignancy is CLL. In one embodiment, the compound is nd 292.

Without being limited by a ular theory, as provided herein, a compound provided herein does not exhibit significant cytotoxicity in normal immune cells. Thus, without being limited by a particular theory, the methods provided herein can minimize the potential for adverse effects associated with cytotoxicity in normal immune cells. In one embodiment, the normal immune cell is a T-cell (e.g., a CD3+ T-cell), a B-cell (e.g., a CD19+ B-cell), or a NK cell (e.g., a CD56+ NK cell). In one embodiment, the nd is Compound 292.

In ary embodiments, the cancer or hematologic malignancy is iNHL. In exemplary ments, the cancer or hematologic malignancy is DLBCL. In ary embodiments, the cancer or hematologic malignancy is B-cell NHL (e.g., aggressive B-cell NHL). In exemplary embodiments, the cancer or hematologic malignancy is MCL. In exemplary embodiments, the cancer or hematologic malignancy is RS. In exemplary embodiments, the cancer or hematologic malignancy is AML. In exemplary embodiments, the cancer or hematologic ancy is MM. In exemplary embodiments, the cancer or hematologic malignancy is ALL. In ary embodiments, the cancer or logic malignancy is T-ALL. In exemplary embodiments, the cancer or hematologic malignancy is B-ALL. In exemplary embodiments, the cancer or hematologic malignancy is TCL. In exemplary embodiments, the cancer or hematologic malignancy is ALCL. In exemplary ments, the cancer or hematologic malignancy is leukemia. In exemplary embodiments, the cancer or hematologic malignancy is lymphoma.

In exemplary embodiments, the cancer or logic malignancy is T-cell lymphoma. In exemplary ments, the cancer or hematologic malignancy is MDS (e.g., low grade MDS). In exemplary embodiments, the cancer or hematologic malignancy is MPD. In exemplary embodiments, the cancer or hematologic malignancy is a mast cell disorder. In exemplary embodiments, the cancer or hematologic malignancy is Hodgkin lymphoma (HL). In exemplary embodiments, the cancer or hematologic malignancy is non-Hodgkin lymphoma. In exemplary embodiments, the cancer or hematologic malignancy is PTCL. In exemplary embodiments, the cancer or hematologic malignancy is CTCL (e.g., mycosis des or Sézary syndrome). In exemplary embodiments, the cancer or hematologic ancy is WM.

In exemplary embodiments, the cancer or hematologic malignancy is CML. In exemplary embodiments, the cancer or hematologic malignancy is FL. In ary embodiments, the cancer or hematologic malignancy is transformed mycosis fungoides. In exemplary embodiments, the cancer or hematologic malignancy is Sézary syndrome. In exemplary embodiments, the cancer or hematologic malignancy is acute T-cell leukemia. In exemplary embodiments, the cancer or hematologic malignancy is acute B-cell leukemia. In exemplary embodiments, the cancer or logic malignancy is Burkitt lymphoma. In exemplary embodiments, the cancer or hematologic malignancy is roliferative neoplasms. In exemplary embodiments, the cancer or hematologic malignancy is splenic marginal zone. In exemplary embodiments, the cancer or hematologic malignancy is nodal marginal zone. In exemplary ments, the cancer or hematologic malignancy is extranodal marginal zone.

In one embodiment, the cancer or hematologic malignancy is a B cell lymphoma. In a specific ment, provided herein is a method of treating or managing a B cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one ment, the compound is Compound 292. Also provided herein is a method of treating or lessening one or more of the symptoms associated with a B cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof.

In one embodiment, the B cell ma is iNHL. In another embodiment, the B cell lymphoma is follicular lymphoma. In another embodiment, the B cell lymphoma is Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma). In another embodiment, the B cell lymphoma is marginal zone lymphoma (MZL). In another embodiment, the B cell lymphoma is MCL. In another embodiment, the B cell lymphoma is HL. In another embodiment, the B cell lymphoma is aNHL. In another embodiment, the B cell lymphoma is DLBCL. In another embodiment, the B cell lymphoma is Richters lymphoma.

In one embodiment, the cancer or hematologic ancy is a T cell lymphoma. In a specific embodiment, provided herein is a method of treating or managing a T cell lymphoma comprising administering to a patient a therapeutically effective amount of a nd provided herein, or a pharmaceutically acceptable tive (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292. Also provided herein is a method of treating or ing one or more of the symptoms associated with a T cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound ed herein, or a ceutically acceptable derivative (e.g., salt or e) thereof.

In one embodiment, the T cell lymphoma is peripheral T cell ma (PTCL). In another embodiment, the T cell lymphoma is cutaneous T cell lymphoma (CTCL).

In one embodiment, the cancer or hematologic malignancy is Sézary syndrome. In a specific embodiment, provided herein is a method of treating or managing Sézary syndrome comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the compound is Compound 292. Also provided herein is a method of treating or lessening one or more of the symptoms associated with Sézary syndrome comprising stering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or e) thereof.

The symptoms associated with Sézary syndrome include, but are not limited to, epidermotropism by neoplastic CD4+ lymphocytes, Pautrier’s microabscesses, erythroderma, lymphadenopathy, al T cells in the peripheral blood, and hepatosplenomegaly. In one embodiment, the compound is Compound 292. In one embodiment, the therapeutically effective amount for treating or managing Sézary syndrome is from about 25 mg to 75 mg, administered twice daily. In other embodiments, the eutically effective amount is from about 50 mg to about 75 mg, from about 30 mg to about 65 mg, from about 45 mg to about 60 mg, from about 30 mg to about 50 mg, or from about 55 mg to about 65 mg, each of which is administered twice daily. In one embodiment, the effective amount is about 25 mg, administered twice daily. In one embodiment, the effective amount is about 50 mg, administered twice daily.

In one embodiment, the cancer or hematologic ancy is relapsed. In one embodiment, the cancer or hematologic malignancy is refractory. In certain embodiments, the cancer being d or prevented is a specific sub-type of cancer described herein. In certain embodiments, the hematologic malignancy being treated or prevented is a specific pe of hematologic ancy described herein.

Certain classifications of type or sub-type of a cancer or hematologic malignancy provided herein is known in the art. t being limited by a particular theory, it is believed that many of the cancers that become relapsed or refractory develop resistance to the ular prior therapy administered to treat the cancers.

Thus, without being limited by a particular theory, a compound provided herein can provide a second line therapy by providing an alternative ism to treat cancers different from those mechanisms utilized by certain prior therapies. Accordingly, in one embodiment, provided herein is a method of treating or managing cancer or logic ancy comprising administering to a patient a therapeutically effective amount of a compound ed herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, wherein the cancer or hematologic malignancy is relapsed after, or refractory to, a prior therapy.

In exemplary embodiments, the cancer or logic malignancy is refractory iNHL. In exemplary embodiments, the cancer or hematologic ancy is tory CLL. In exemplary ments, the cancer or hematologic malignancy is tory SLL. In exemplary embodiments, the cancer or hematologic malignancy is refractory to rituximab therapy. In exemplary embodiments, the cancer or hematologic malignancy is refractory to herapy. In ary embodiments, the cancer or hematologic malignancy is tory to mmunotherapy (RIT). In exemplary embodiments, the cancer or hematologic malignancy is iNHL, FL, splenic marginal zone, nodal marginal zone, odal marginal zone, or SLL, the cancer or hematologic malignancy is refractory to rituximab y, chemotherapy, and/or RIT.

BTK inhibitors, such as ibrutinib, can be used to treat some patients with relapsed CLL (J. A. Woyach, et al., N Engl J Med, “Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib,” published online on May 28, 2014). r, it has been shown that some patients can develop resistance to treatment with ibrutinib. Thus, it is important to develop therapies that can treat patients who developed such resistance. nib is an irreversible inhibitor of BTK through its ability to bind to the C481 site, guishing it from other reversible kinase inhibitors. The development of mutations in genes that reactivate downstream B-cell–receptor signaling or other pathways can be responsible for the development of resistance, because clonal evolution is common in previously treated CLL (D.A. Landau, Cell, 2013; 4-26). There exist needs to treat subjects who have developed resistance to prior treatments, e.g., prior treatment with a BTK inhibitor such as ibrutinib. The methods ed herein address these needs.

In another exemplary embodiment, the cancer or hematologic ancy is lymphoma, and the cancer is relapsed after, or refractory to, the treatment by a BTK inhibitor such as, but not limited to, ibrutinib, RN-486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5-(4-methyl-piperazin- 1-yl)-pyridinylamino]oxo-1,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolinone), GDC-0834 ([RN- (3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl) methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 ( N-[3-(8- anilinoimidazo[1,2-a]pyrazinyl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl- 3-(4-methyl((4-(morpholinecarbonyl)phenyl)amino)oxo-4,5-dihydropyrazin yl)phenyl)benzamide), HM-71224(Hammi Pharmaceticals), ONO-4059 (Ono ceuticals Co., LTD), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N- methylpicolinamide), LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide) and AVL-292 (N-(3-((5-fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide), which can also be referred to as CC-292. ONO-4059 is an oral Btk inhibitor that is being used to treat patients with a hematologic malignancy. ONO-4059 is described, for example, in Blood November 15, 2013 vol. 122 no. 21, p.4397, which is hereby orated by reference. In another exemplary embodiment, the cancer or hematologic malignancy is CLL, and the cancer is relapsed after, or refractory to, the treatment by a BTK tor such as, but not limited to, ibrutinib and AVL-292 or other BTK inhibitor described herein.

In some embodiments, the cancer or hematologic malignancy is Waldenström lobulinemia (WM), mantle cell, NHL, iNHL, follicular lymphoma, diffuse large B-cell lymphoma, or T-cell lymphoma and the cancer is relapsed after, or refractory to, the treatment by a BTK inhibitor such as, but not limited to, ibrutinib and AVL-292 or other BTK inhibitor described herein. In one embodiment, provided herein is a method for treating or managing cancer or hematologic malignancy comprising administering to a subject who develops resistance to a BTK inhibitor treatment a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, alone or in combination with one or more other agents or therapeutic modalities. In one embodiment, a nd provided herein (e.g., Compound 292) is the only therapeutic agent that is administered. In one embodiment, the other agent is a chemotherapeutic agent or a therapeutic antibody. In one ment, the herapeutic agent is selected from mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, s, omerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. In one embodiment, the other therapeutic agent is a steroid. In another embodiment, the steroid is a glucocorticoid. In another embodiment, the glucocorticoid is aldosterone, beclometasone, betamethasone, cortisol (hydrocortisone), cortisone, deoxycorticosterone acetate , dexamethasone, fludrocortisone acetate, methylprednisolone, prednisolone, sone, or inolone. In another embodiment, the steroid is dexamethasone. In one embodiment, the therapeutic antibody is selected from anti-CD37 antibody, anti- CD20 antibody, and anti-CD52 antibody. In one embodiment, the therapeutic antibody is anti-CD20 antibody. In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab. In one embodiment, a compound provided herein (e.g., Compound 292) is administered in combination with a BTK inhibitor (e.g., ibrutinib or 2). In one embodiment, Compound 292 is administered in ation with ibrutinib. In one embodiment, a compound provided herein (e.g., Compound 292) is stered in combination with an anti-CD20 antibody (e.g., rituximab or obinutuzumab). In one ment, Compound 292 is administered in combination with obinutuzumab. In one embodiment, the subject has a cysteine to serine mutation on residue 481 of BTK (C481S), a cysteine to phenylalanine on on residue 481 of BTK (C481F), or a arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W). In some embodiments, the subject has a a histidine to e mutation on residue 257, leucine to phenylalanine mutation on residue 845, serine to tyrosine mutation on residue 707, histidine to arginine mutation on residue 244, a methionine to ne mutation on residue 1141, or a serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene. In one embodiment, provided herein is a method of preventing BTK resistance in a subject comprising stering to the t a therapeutically ive amount of a PI3K modulator, or a pharmaceutically acceptable form f, in ation with a BTK inhibitor, or a pharmaceutically able form thereof. In some embodiments, the combination includes an anti-CD20 antibody. es of such an antibody e, but are not limited to, GA101.

Without being limited by a particular theory, it was found that patients who p resistance to a BTK inhibitor treatment often has a ne to serine mutation on residue 481 of BTK (C481S) or a cysteine to phenylalanine mutation on residue 481 of BTK (C481F). The mutation could also be C481A.

Accordingly, also provided herein is a method for treating or ng cancer or hematologic ancy sing administering to a patient having cysteine to serine, cysteine to alanine, or cysteine to phenylalanine mutation on residue 481 of BTK of BTK, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, alone or in combination with one or more other agents or therapeutic modalities, wherein the cancer or hematologic malignancy is relapsed after, or refractory to, a prior y. In another embodiment, provided herein is a method of treating or ng cancer or hematologic malignancy comprising: (1) identifying a patient who has a mutation in BTK, such as but not limited to, cysteine to serine, cysteine to alanine, or ne to phenylalanine mutation on e 481 of BTK; and (2) administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, alone or in combination with one or more other agents or therapeutic ties. In one embodiment, the patient is a CLL patient. In another embodiment, the patient is an ibrutinib-resistant CLL patient. In one embodiment, a compound provided herein (e.g., Compound 292) is the only therapeutic agent that is administered. In one embodiment, a compound provided herein (e.g., Compound 292) is administered in combination with a BTK inhibitor (e.g., ibrutinib, RN-486 (6-cyclopropylfluoro(2- hydroxymethyl{1-methyl[5-(4-methyl-piperazinyl)-pyridinylamino]oxo-1,6-dihydro-pyridin- 3-yl}-phenyl)-2H-isoquinolinone), GDC-0834 (3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl)methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophenecarboxamide]), 0 ( N-[3-(8-anilinoimidazo[1,2-a]pyrazin yl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl(4-methyl((4-(morpholine carbonyl)phenyl)amino)oxo-4,5-dihydropyrazinyl)phenyl)benzamide), HM-71224(Hammi Pharmaceticals), ONO-4059 (Ono ceuticals Co., LTD), CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), LFM-A13 (2Z- cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide) or AVL-292 (N-(3-((5-fluoro((4-(2- methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide), which can also be referred to as CC-292.) In one embodiment, Compound 292 is administered in combination with ibrutinib. In one embodiment, a compound provided herein (e.g., Compound 292) is administered in combination with an anti-CD20 antibody (e.g., mab or obinutuzumab (GA101)). In one embodiment, Compound 292 is administered in combination with obinutuzumab. In some embodiments, the refractory patient is administered with the combination of one or more BTK inhibitors with an anti-CD20 antibody and a nd provided herein (e.g., Compound 292). In some embodiments, the refractory patient is not administered a BTK inhibitor.

In another exemplary embodiment, the cancer or hematologic malignancy is relapsed after, or refractory to, the treatment by an anti-CD20 dy (e.g. rituximab or uzumab). In one embodiment, a compound provided herein (e.g., Compound 292) is administered to a subject with a cancer that is relapsed after, or refractory to, the treatment by an anti-CD20 antibody (e.g. rituximab or obinutuzumab). In some ments, the compound is administered in combination with the D20 antibody. In some embodiments, the compound is Compound 292. In some embodiments, the subject with a cancer or hematologic malignancy is relapsed after, or tory to, the treatment by an anti-CD20 antibody has a WHIM-like CXCR4 mutation. (Proc ASH bstract 251). In one embodiment, a compound provided herein, (e.g. Compound 292) is administered in combination with obinutuzumab. In some embodiments, the cancer or logic malignancy is CLL, Waldenström macroglobulinemia (WM), mantle cell, NHL, iNHL, follicular lymphoma, diffuse large B-cell ma, or T-cell lymphoma.

In another exemplary embodiment, the cancer or hematologic malignancy is relapsed after, or refractory to, the treatment by a proteasome inhibitor (e.g. bortezomib). In one embodiment, a compound provided herein (e.g., Compound 292) is administered to a subject with a cancer that is relapsed after, or tory to, the treatment by a proteasome inhibitor (e.g. omib). In some embodiments, the compound is stered in combination with the proteasome inhibitor. In some embodiments, the compound is Compound 292. In some embodiments, the subject with a cancer or hematologic malignancy is relapsed after, or refractory to, the treatment by proteasome inhibitor has a on identified herein in the BTK gene or protein, the CXCR4 gene or protein, or the PLCgamma2 gene. In one ment, a compound provided herein, (e.g. Compound 292) is administered in combination with bortezomib. In some embodiments, the cancer or hematologic malignancy is CLL, ström macroglobulinemia (WM), mantle cell, NHL, iNHL, follicular lymphoma, diffuse large B-cell lymphoma, or T-cell lymphoma.

In some embodiments, a compound provided herein (e.g. Compound 292) is administered to a t in combination with an alkylating agent. In some embodiments, the alkylating agent is a nitrogen mustard. In some embodiments, the subject has a cancer or hematologic malignancy that is relapsed after, or refractory to, the treatment by a alkylating agent (e.g. nitrogen mustard). In one embodiment, a compound provided herein (e.g., Compound 292) is administered to a t with a cancer that is relapsed after, or refractory to, the ent by a alkylating agent (e.g. nitrogen mustard). In some embodiments, the compound is administered in combination with the ting agent. In some embodiments, the compound is Compound 292. In some embodiments, the subject with a cancer or hematologic malignancy is relapsed after, or refractory to, the treatment by alkylating agent (nitrogen mustard) has a mutation identified herein in the BTK gene or protein, the CXCR4 gene or n, or the PLCgamma2 gene. In one embodiment, a compound ed herein, (e.g. Compound 292) is administered in combination with nitrogen mustard. In some embodiments, the cancer or hematologic malignancy is CLL, Waldenström macroglobulinemia (WM), mantle cell, NHL, iNHL, follicular lymphoma, diffuse large B-cell lymphoma, or T-cell lymphoma.

Without being limited by a particular theory, it was found that ts who develop resistance to a BTK inhibitor treatment also can have a argnine to phan on on residue 665 of PLCgamma2 gene (R665W). Other mutations in the PLCgamma2 gene have also been found in patients who develop resistance to BTK inhibitor treatment. Examples of mutations include, but are not limited to, H257L, , and S707F. Patients who p resistant or who are resistant to BTK inhibitor treatment may also have mutations in the BTK protein. Examples of ons include, but are not limited to C481S, C481A, and C481F. Patients with mutations in other genes or proteins have also been identified as one that will p resistance or not respond as well to a particular treatment. Examples of other mutations include, but are not limited to, WHIM-like CXCR4 mutations (Proc ASH 2013;Abstract 251). ingly, also provided herein is a method for treating or managing cancer or hematologic ancy comprising administering to a patient having a mutation in the PLCgamma2 gene, ing those described above, such as but not limited to, an arginine to tryptophan on on residue 665, a histidine to leucine mutation on residue 257, e to phenylalanine mutation on residue 845, serine to tyrosine mutation on residue 707, histidine to arginine mutation on residue 244, a nine to arginine mutation on residue 1141, or a serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene or a WHIM-like CXCR4 mutation, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, alone or in combination with one or more other agents or therapeutic ties, wherein the cancer or hematologic malignancy is relapsed after, or refractory to, a prior therapy. In some embodiments, the patient has a mutation in the BTK protein, such as those described above, and . The combination therapy can be any combination described herein. In another embodiment, provided herein is a method of treating or managing cancer or hematologic ancy comprising: (1) identifying a patient who has a mutation in the PLCgamma2 that results in a mutation in the ma2 gene product, including, but not limited to a arginine to tryptophan mutation on residue 665, a histidine to leucine mutation on residue 257, , leucine to phenylalanine mutation on residue 845, serine to tyrosine mutation on e 707, histidine to arginine mutation on residue 244, a methionine to arginine mutation on residue 1141, or a serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene or a mutation in the Btk protein or a WHIM-like CXCR4 mutation; and (2) administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, alone or in combination with one or more other agents or therapeutic modalities.

] In one embodiment, the patient is a CLL patient. In another embodiment, the patient is an ibrutinib-resistant CLL patient. In one embodiment, a compound provided herein (e.g., Compound 292) is the only therapeutic agent that is administered. In one embodiment, a compound provided herein (e.g., Compound 292) is stered in combination with a BTK inhibitor (e.g., ibrutinib , RN-486 (6- ropylfluoro(2-hydroxymethyl{1-methyl[5-(4-methyl-piperazinyl)-pyridinylamino]- 6-oxo-1,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolinone), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl- 3-oxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl)methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophenecarboxamide]), 0 ( N-[3-(8-anilinoimidazo[1,2-a]pyrazin yl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl(4-methyl((4-(morpholine carbonyl)phenyl)amino)oxo-4,5-dihydropyrazinyl)phenyl)benzamide), HM-71224(Hammi Pharmaceticals), ONO-4059 (Ono Pharmaceuticals Co., LTD), CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), LFM-A13 (2Z- cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide) or 2 (N-(3-((5-fluoro((4-(2- methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide), which can also be referred to as CC-292.). In one embodiment, Compound 292 is administered in combination with ibrutinib. In one embodiment, a compound provided herein (e.g., Compound 292) is administered in combination with an anti-CD20 dy (e.g., rituximab or obinutuzumab). In one embodiment, Compound 292 is administered in combination with obinutuzumab. In some embodiments, the fied patient is administered with the combination of one or more Btk inhibitors with an D20 antibody.

In some embodiments, methods of treating a subject with a cancer or hematologic malignancy are provided, wherein the method ses identifying a subject with a cysteine to serine mutation on residue 481 of BTK (C481S), ne to phenylalanine mutation on residue 481 of BTK (C481F), ne to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on residue 845 of the PLCgamma2 gene ), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine on on residue 244 of the PLCgamma2 gene (H244R), or WHIM-like CXCR4 on; and administering a therapeutically effective amount of a PI3K modulator, or a pharmaceutically acceptable derivative thereof, alone or in combination with one or more other agents or therapeutic modalities to the subject fied with the cysteine to serine mutation on residue 481 of BTK (C481S), ne to phenylalanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on residue 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine mutation on e 845 of the ma2 gene (L845F), serine to tyrosine mutation on residue 707 of the PLCgamma2 gene (S707Y), histidine to arginine mutation on residue 244 of the ma2 gene ), or WHIM-like CXCR4 mutation. In some ments, the PI3K modulator is Compound 292. In some embodiments, the other agent is a chemotherapeutic agent or a therapeutic antibody. In some embodiments, the chemotherapeutic agent is selected from mitotic inhibitors, alkylating agents, anti-metabolites, proteasome inhibitor, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. In one embodiment, the other therapeutic agent is a steroid. In another ment, the steroid is a glucocorticoid.

In another embodiment, the glucocorticoid is aldosterone, beclometasone, betamethasone, cortisol (hydrocortisone), cortisone, deoxycorticosterone acetate (DOCA), dexamethasone, fludrocortisone acetate, methylprednisolone, prednisolone, prednisone, or triamcinolone. In another ment, the steroid is dexamethasone.In some embodiments, the therapeutic antibody is selected from D37 antobidy, anti- CD20 antibody, and anti-CD52 antibody. In some embodiments, the therapeutic antibody is anti-CD20 antibody. In some embodiments, the anti-CD20 dy is rituximab, obinutuzumab, tositumomab,131I momab, 90Y momab, 111I ibritumomab, or ofatumumab. In some ments, the anti-CD20 dy is obinutuzumab. In some embodiments, the PI3K modulator is administered in combination with an anti-CD20 antibody. In some embodiments, the method further comprises administering a BTK inhibitor. The BTK inhibitor can be any inhibitor described . In some embodiments, the PI3K modulator is administered in combination with an a BTK inhibitor. In some embodiments, the BTK tor is AVL-292. In some embodiments, the PI3K modulator is administered in combination with a proteasome tor (e.g. bortezomib). In some embodiments, the combination of the PI3K modulator and the proteasome inhibitor is also administered with an anti-CD20 dy and/or a BTK inhibitor. In some embodiments, the PI3K modulator is administered in combination with a alkylating agent. In some ments, the alkylating agent is nitrogen mustard. In some embodiments, the combination of the PI3K modulator and the alkylating agent is administered with an anti-CD20 antibody and/or a BTK inhibitor. As discussed herein, the cancer or hematologic malignancy is CLL, Waldenström macroglobulinemia (WM), mantle cell, NHL, iNHL, ular lymphoma, diffuse large B-cell lymphoma, or T-cell lymphoma.

The mutation can be identified or detected by any method and detecting or identifying a mutation in a sample from a subject is e to one of skill in the art. In some embodiments, identifying comprises detecting the cysteine to serine mutation on residue 481 of BTK (C481S), cysteine to phenylalanine mutation on residue 481 of BTK (C481F), arginine to tryptophan mutation on residue 665 of PLCgamma2 gene (R665W), histidine to leucine mutation on residue 257 of PLCgamma2 gene (H257L), methionine to arginine mutation on e 1141 of PLCgamma2 gene (M1141R), serine to phenylalanine mutation on residue 707 of the PLCgamma2 gene (S707F), leucine to phenylalanine on on residue 845 of the PLCgamma2 gene (L845F), serine to tyrosine mutation on residue 707 of the ma2 gene (S707Y), histidine to arginine mutation on residue 244 of the PLCgamma2 gene (H244R), or WHIM-like CXCR4 mutation in a sample obtained from the subject. The sample can be a sample as described herein ing, but not d to, a biopsy, blood, urine, and the like. In some embodiments, the mutation is detected by PCR, which includes RT-PCR, or hybridization (e.g. use of gene chips and the like).

In another embodiment, a method of treating or managing cancer or hematologic malignancy comprising: administering a therapeutically effective amount of a nd provided herein, or a pharmaceutically able derivative (e.g., salt or solvate) and a therapeutically ive amount of a BTK inhibitor is disclosed. Exemplary BTK inhibitors include, but are not d to, ibrutinib (1-[(3R) [4-Amino(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinyl]propenone), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyloxopiperazinyl)phenylamino)methyloxo-4,5-dihydropyrazinyl)- 2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 rt-butyl)-N-(3-(8- (phenylamino)imidazo[1,2-a]pyrazinyl)phenyl)benzamide), CGI-1746 (4-tert-butyl-N-[2-methyl[4- methyl[4-(morpholinecarbonyl)anilino]oxopyrazinyl]phenyl]benzamide), 24, AVL-292 (CC-292) ((5-fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidin yl)amino)phenyl)acrylamide), ONO-4059, CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino) fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), and LFM-A13 (2-Cyano-N-(2,5- ophenyl)hydroxybutenamide), and those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. In one ment the compound is compound 292 and the BTK tor is selected from ibrutinib and AVL- 292. In some embodiments, the cancer is a lymphoma or leukemia. In one embodiment the lymphoma is non-Hodgkin lymphoma. In one embodiment, the leukemia is B-cell chronic lymphocytic leukemia.

In n ments, without being limited by a particular theory, it was found that certain subtypes of a particular cancer are more susceptible to the treatment by a compound provided herein than the others. For example, while it was found that the sensitivity exists in both ABC and GCB subtypes of DLBCL, it was found that cells with BCR-dependent signaling have higher sensitivity to a compound provided herein than those without. Without being limited by a particular theory, additional factors, such as dependencies on other signaling pathways, anti-apoptotic characteristics (e.g., Bcl-2, HRK), and/or mutations status (e.g., IgH-BCL2, CD79b, MYD-88), can contribute to the differential sensitivities exhibited by various subtypes. Accordingly, in some embodiments, provided herein is a method of treating a particular subtype of a cancer by a compound ed herein, wherein the subtype comprises of cells having BCR-dependent signaling. In one embodiment, the subtype is Ri-1, WSU-DLCL2, Toledo, OCILY8 , SU-DHL-4, or SU-DHL-6. In another embodiment, the subtype is Ri-1, -4 or SU-DHL-6.

In one embodiment, provided herein are methods of modulating a PI3K kinase activity (e.g., selectively modulating) by contacting the kinase with an effective amount of a compound as provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical composition as provided herein. Modulation can be inhibition (e.g., reduction) or activation (e.g., enhancement) of kinase activity.

In one ment, provided herein are s of inhibiting kinase activity by contacting the kinase with an effective amount of a compound as provided herein in solution. In some embodiments, provided herein are methods of inhibiting the kinase activity by ting a cell, tissue, organ that s the kinase of interest, with a nd provided herein. In some embodiments, provided herein are methods of inhibiting kinase activity in a subject by administering into the subject an effective amount of a compound as provided herein, or a pharmaceutically acceptable form thereof. In some embodiments, the kinase activity is ted (e.g., reduced) by more than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, when contacted with a compound provided herein as compared to the kinase activity without such contact. In some ments, provided herein are methods of inhibiting PI3 kinase activity in a subject (including mammals such as humans) by contacting said subject with an amount of a compound as provided herein sufficient to inhibit or reduce the activity of the PI3 kinase in said subject. In some embodiments, the kinase is a lipid kinase or a protein kinase. In some embodiments, the kinase is selected from a PI3 kinase including different isoforms, such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3 kinase δ; DNAPK ; mTOR; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3); Platelet derived growth factor receptor ); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor (IR); and IGFR.

] In one embodiment, provided herein is a method of reducing a symptom associated with cancer or disorder such as a hematologic ancy, in a biological sample, sing contacting the biological sample with a compound provided herein (e.g., a nd of a I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal , clathrate, or rph thereof), in an amount ient to reduce the symptom. In one embodiment, the method is carried out in vivo, for example, in a mammalian subject, e.g., an animal model or as part of eutic protocol. In one embodiment, the compound is used as a single agent or in ation with another agent or therapeutic modality.

As used herein, and unless otherwise specified, “contacting” can be direct (e.g., by direct application of the compound provided herein to a ical sample, e.g., in vitro) or indirect (e.g., by administering the compound provided herein to a subject (e.g., by any known administration route, e.g., orally), such that the nd provided herein s an affected biological sample within the body.

As used herein, and unless otherwise specified, a “biological ” includes, for example, a cell or group of cells (e.g., PBMCs, or plasmacytoid dendritic cell(s)), a tissue, or a fluid (e.g., whole blood or serum) that comes into contact with a compound ed herein, e.g., a PI3K modulator, thereby resulting in a se or inhibition of cancer or hematologic malignancy, or associated symptoms. In some embodiments, the biological sample is present within or derived from a subject who has cancer or hematologic malignancy, or from a subject at risk for developing cancer or hematologic malignancy. In some embodiments, the biological sample can be contacted with the compound provided herein outside the body and then introduced into the body of a subject (e.g., into the body of the subject from whom the biological sample was derived or into the body of a ent subject). In some embodiments, the biological sample includes cells that express one or more isoforms of PI3K.

] In certain embodiments, the method, or assay, further includes the step of obtaining the , e.g., a biological sample, from the subject. In one ment, the method, or assay, includes the step of obtaining a predominantly llular fraction from the subject. The non-cellular fraction can be plasma, serum, or other non-cellular bodily fluid. In one embodiment, the sample is a serum or plasma sample. In other embodiments, the body fluid from which the sample is obtained from an individual comprises blood (e.g., whole . In certain embodiments, the blood can be further processed to obtain plasma or serum.

In another embodiment, the sample contains a tissue, or cells (e.g., tumor cells). For e, the sample can be a fine needle biopsy sample; an archival sample (e.g., an archived sample with a known diagnosis and/or ent history); a histological section (e.g., a frozen or formalin-fixed section, e.g., after long term storage), among others. A sample can include any material obtained and/or derived from a biological sample, ing a polypeptide, and nucleic acid (e.g., genomic DNA, cDNA, RNA) purified or processed from the sample. Purification and/or processing of the sample can e one or more of extraction, concentration, dy isolation, sorting, concentration, fixation, addition of reagents and the like. In one embodiment, the biological sample includes a sample containing tissue, whole blood, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow, In one embodiment, the detection methods provide herein includes, but not limited to, polymerase chain reaction (PCR) or antibody-based detection techniques, such as -based immunoabsorbent assay (e.g., ELISA), immunofluorescence cell sorting (FACS), immunohistochemistry, immunofluorescence (IF), western blot, affinity purification, fluorescence resonance energy transfer (FRET) imaging, n retrieval and/or microarray detection methods. In other embodiments, detection method includes mass spectrometry. In one embodiment, the detection method es labeling the sample with a detectable label (e.g., a fluorescent or a radioactive label, biotin-avidin detection). The activity or level of a marker protein can also be detected and/or fied by detecting or quantifying the expressed polypeptide. The polypeptide can be detected and quantified by any of a number of means well known to those of skill in the art. These can include ic biochemical methods such as ophoresis, ary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitin reactions, immunodiffusion (single or double), immunoelectrophoresis, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, Western blotting, immunohistochemistry and the like. A skilled artisan can readily adapt known protein/antibody ion methods for use in determining whether cells express a marker of the present invention.

In one embodiment, provided herein is a method of treating, ting, and/or managing cancer or hematologic malignancy in a subject, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof) to a subject in need thereof. In one embodiment, the compound is administered as a single agent. In another embodiment, the nd is administered in combination with another agent or therapeutic modality.

As used herein, and unless otherwise specified, hematologic malignancy or a symptom associated with hematologic malignancy encompasses all types of manifestation of hematologic malignancy as disclosed herein or as known in the art. As used herein, and unless ise ied, cancer or a m associated with cancer encompasses all types of manifestation of cancer as disclosed herein or as known in the art. Symptoms can be assessed using assays and scales disclosed and/or exemplified herein and/or as known in the art.

In some embodiments, the symptom is reduced by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% relative to a l level. The control level includes any appropriate control as known in the art. For example, the control level can be the pre-treatment level in the sample or subject treated, or it can be the level in a control population (e.g., the level in subjects who do not have cancer or hematologic malignancy or the level in samples derived from ts who do not have cancer or hematologic malignancy). In some embodiments, the decrease is statistically significant, for example, as assessed using an riate tric or non-parametric statistical comparison.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

In certain ments, the t is an animal model of cancer or hematologic malignancy, a human with cancer or hematologic malignancy, or a subject (e.g., a human) at risk for developing cancer or hematologic malignancy. In some ments, the subject is a human who has a family history of cancer or hematologic malignancy, who carries a gene associated with cancer or hematologic malignancy, who is positive for a biomarker associated with cancer or hematologic malignancy (e.g., a ker provided herein), or a combination thereof. In some embodiments, the t has been diagnosed with cancer or hematologic malignancy. In some embodiments, the subject has one or more signs or symptoms associated with cancer or hematologic malignancy. In some embodiments, the subject is at risk for developing cancer or logic malignancy (e.g., the subject carries a gene that, individually, or in combination with other genes or environmental factors, is associated with development of cancer or hematologic ancy).

In some embodiments, the subject ts elevated level of one or more PI3K isoform(s) (e.g., PI3K-δ and/or PI3K-γ, which can be indicative of increased likelihood of responding to, or better efficacy of, a particular treatment or therapeutic agent, as compared to another t with lower level of the PI3K m(s). The levels of PI3K isoforms can be assessed using methods known in the art.

In some embodiments, the t exhibits one or more biomarkers provided herein, which can be indicative of increased likelihood of responding to, or better efficacy of, a particular treatment or therapeutic agent.

In some embodiments, the subject has a mutation (e.g., an SNP) in a gene ated with cancer or hematologic ancy. In one embodiment, the gene is selected from CXCR4, IGH7, KRAS, NRAS, A20, CARD11, CD79B, TP53, , MYD88, GNA13, MEF2B, TNFRSF14, MLL2, BTG1, EZH2, NOTCH1, JAK1, JAK2, PTEN, FBW7, PHF6, IDH1, IDH2, TET2, FLT3, KIT, NPM1, CEBPA, DNMT3A, BAALC, RUNX1, ASXL1, IRF8, POU2F2, WIF1, ARID1A, MEF2B, TNFAIP3, , MTOR, PIK3CA, PI3Kδ, and/or PI3Kγ, or a combination thereof. In one embodiment, the disorder to be d, prevented and/or managed is WM and the subject has a PTEN deficiency.

In some embodiments, the subject exhibits excessive PI3K activity or abnormal activity (e.g., excessive or reduced activity) of one or more components of the PI3K signaling pathway (e.g., Akt (PKB), mTOR, a Tec kinase (e.g., Btk, Itk, Tec), phospholipase C, PDK1, PKCs, NFκB, Rac GEF (e.g., Vav-1), or Rac).

In certain embodiments, provided herein is a method of treating or managing a hematologic malignancy comprising administering to a patient who has one or more mutations selected from MYD88 (L265P), CXCR4, ARID1A, MUC16, TRAF2, TRRAP, and MYBBP1A mutations a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the patient has MYD88 (L265P) and/or N- terminal domain of CXCR4 mutation. In one ment, the hematologic malignancy is Waldenström's macroglobulinemia (WM). In one embodiment, the hematologic malignancy is DLBCL. In one embodiment, the hematologic malignancy is CLL. In one embodiment, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents described herein below.

In certain ments, provided herein is a method of treating or managing WM sing administering to a patient who has CXCR4 mutation a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the CXCR4 mutation occurs at the N-terminal domain of CXCR4. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in ation with one or more other eutic agents bed herein below.

In certain embodiments, provided herein is a method of treating or managing DLBCL comprising administering to a patient who has CXCR4 on a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the CXCR4 mutation occurs at the N-terminal domain of CXCR4. In other embodiments, a nd provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents described herein below.

In certain embodiments, ed herein is a method of treating or ng CLL comprising administering to a patient who has CXCR4 mutation a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In one embodiment, the CXCR4 mutation occurs at the N-terminal domain of CXCR4. In other embodiments, a compound provided herein (e.g., nd 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents described herein below.

] In certain embodiments, provided herein is a method of treating or managing CLL sing administering to a patient who has CD38 positive cancer cells a eutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically able derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents described herein below.

In n embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient who has CD69 positive cancer cells a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) f, can be used in combination with one or more other therapeutic agents described herein below.

In certain embodiments, provided herein is a method of ng or managing CLL comprising administering to a patient who has CD38/CD69 double ve cancer cells a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in ation with one or more other therapeutic agents described herein below.

In certain ments, provided herein is a method of ng or managing CLL comprising stering to a patient who has Ki67 positive cancer cells a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or e) thereof, can be used in combination with one or more other therapeutic agents bed herein below.

In certain embodiments, provided herein is a method of treating or managing CLL sing administering to a patient who has pAKT positive cancer cells a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a ceutically able tive (e.g., salt or solvate) thereof. In other embodiments, a nd provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents described herein below.

In certain embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient who has Ki67/pAKT double positive cancer cells a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof. In other embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically able derivative (e.g., salt or solvate) thereof, can be used in combination with one or more other therapeutic agents bed herein below.

] In some embodiments, the subject has been previously treated for cancer or hematologic malignancy. In some embodiments, the subject has been previously treated for cancer or hematologic malignancy but are non-responsive to standard therapies. Thus, in one embodiment, provided herein is a method of treating, preventing, and/or managing cancer or hematologic malignancy in a subject, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) to a t in need thereof, wherein the subject has been usly administered a therapy for cancer or hematologic malignancy.

In one embodiment, the t has been previously administered a therapy for cancer or hematologic malignancy at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before a compound provided herein (e.g., a compound of a I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof) is administered. In one embodiment, the subject has been usly administered a therapy for cancer or hematologic malignancy at least 1 week, 2 weeks, 1 month, 2 months, 3 months, or 4 months before a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or rph thereof) is administered.

In one embodiment, the subject has been administered a stable dose of a therapy for cancer or hematologic malignancy before a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof) is administered. In one embodiment, the subject has been administered a stable dose of a therapy for cancer or hematologic malignancy for at least 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered. In one embodiment, the subject has been administered a stable dose of a therapy for cancer or hematologic malignancy for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof) is administered.

In one embodiment, the subject has been previously administered a therapy for cancer or hematologic malignancy at least 5 s, 15 s, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before, and the subject has been administered a stable dose of the same therapy for cancer or hematologic malignancy for at least 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof) is administered.

In one embodiment, the stable dose of the previously stered therapy is from about 0.005 to about 1,000 mg per week, from about 0.01 to about 500 mg per week, from about 0.1 to about 250 mg per week, from about 1 to about 100 mg per week, from about 2 to about 75 mg per week, from about 3 to about 50 mg per week, from about 5 to about 50 mg per week, from about 7.5 to about 25 mg per week, from about 10 to about 25 mg per week, from about 12.5 to about 25 mg per week, from about 15 to about mg per week, or from about 15 to about 20 mg per week. The total dose per week can be administered once or administered among split doses.

In some embodiments, the t has not been previously treated for cancer or hematologic malignancy.

In certain embodiments, a therapeutically or prophylactically effective amount of a compound provided herein (e.g., a compound of Formula I (e.g., nd 292), or an enantiomer or a mixture of omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 2 to about 25 mg per day, or from about 5 to about 10 mg per day.

In certain embodiments, the therapeutically or lactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

In one embodiment, the recommended daily dose range of a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 100 mg per day, or from about 0.5 mg to about 50 mg per day, preferably given as a single -day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 25 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, , 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 100 mg per day.

In a specific embodiment, the recommended starting dosage can be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, , 50, or 100 mg per day. In another embodiment, the ended ng dosage can be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose can be escalated to 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100 .

In n embodiments, the eutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 to about 1 mg/kg/day.

The administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ry skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m2/day.

In one embodiment, the amount of the compound stered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.005 to about 100 μM, from about 0.005 to about 10 μM, from about 0.01 to about 10 μM, from about 0.01 to about 5 μM, from about 0.005 to about 1 μM, from about 0.005 to about 0.5 μM, from about 0.005 to about 0.5 μM, from about 0.01 to about 0.2 μM, or from about 0.01 to about 0.1 μM. In one embodiment, the amount of the compound administered is sufficient to provide a plasma concentration at steady state, of about 0.005 to about 100 μM.

In another embodiment, the amount of the compound administered is sufficient to provide a plasma concentration at steady state, of about 0.005 to about 10 μM. In yet r embodiment, the amount of the compound stered is sufficient to provide a plasma concentration at steady state, of about 0.01 to about 10 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a plasma concentration at steady state, of about 0.01 to about 5 μM. In yet r embodiment, the amount of the compound administered is sufficient to provide a plasma concentration at steady state, of about 0.005 to about 1 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a plasma concentration at steady state, of about 0.005 to about 0.5 μM. In yet r embodiment, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, of about 0.01 to about 0.2 μM. In still another embodiment, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, of about 0.01 to about 0.1 μM.

As explained in more detail herein below, following 25 mg or 75 mg BID administration of Compound 292, it was found that the compound is rapidly absorbed, with maximal plasma concentrations typically observed around 1 hour following dosing. It was also found that AUC increases proportionally with doses through 75 mg BID, but ation half-life (about 4-5 hours for both 25 mg and 75 mg BID) is independent of dose. The mean predose steady state plasma concentration following 25 mg BID was about 390 ng/ml, indicating complete suppression of PI3K-δ (IC90 = 361 ng/ml) with inhibition of PI3K-γ (IC50 = 429 ng/ml) throughout the dosing interval.

In another embodiment, the amount of the compound administered is sufficient to e a plasma concentration of the compound at steady state at a level higher than IC50 for a particular isoform of PI3K. In another embodiment, the amount of the compound stered is sufficient to provide a plasma concentration of the compound at steady state at a level higher than IC90 for a particular isoform of PI3K.

In one embodiment, the PI3K isoform is PI3K-δ for which IC90 is about 361 mg/ml. In another embodiment, the PI3K isoform is PI3K-γ for which IC50 is about 429 ng/ml.

In one embodiment, the nd is Compound 292, and the PI3K isoform is PI3K-δ. In another embodiment, the compound is Compound 292, and the PI3K isoform is PI3K-γ. In another embodiment wherein the compound is Compound 292, the amount of Compound 292 administered is sufficient to provide a plasma concentration of the compound at steady state of about 300 ng/ml to about 500 ng/ml, about 350 ng/ml to about 450 ng/ml, or from about 380 ng/ml to about 420 ng/ml. In another embodiment, wherein the compound is Compound 292, the amount of Compound 292 administered is sufficient to provide a plasma concentration of the compound at steady state of about 390 ng/ml. As used herein, the term “plasma concentration at steady state” is the concentration reached after a period of administration of a compound. Once steady state is reached, there are minor peaks and s on the time dependent curve of the plasma concentration of the compound.

In one embodiment, the amount administered is sufficient to provide a maximum plasma tration (peak concentration) of the nd, ranging from about 0.005 to about 100 μM, from about 0.005 to about 10 μM, from about 0.01 to about 10 μM, from about 0.01 to about 5 μM, from about 0.005 to about 1 μM, from about 0.005 to about 0.5 μM, from about 0.01 to about 0.2 μM, or from about 0.01 to about 0.1 μM. In one embodiment, the amount of the compound administered is sufficient to provide a maximum plasma concentration of the compound of about 0.005 to about 100 μM. In another embodiment, the amount of the compound administered is sufficient to e a maximum plasma concentration of the compound of about 0.005 to about 10 μM. In yet another ment, the amount of the compound administered is ient to provide a maximum plasma concentration of the nd of about 0.01 to about 10 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a maximum plasma tration of the nd of about 0.01 to about 5 μM. In yet another embodiment, the amount of the compound administered is sufficient to e a maximum plasma concentration of the compound of about 0.005 to about 1 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a maximum plasma concentration of the compound of about 0.005 to about 0.5 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a maximum plasma concentration of the compound of about 0.01 to about 0.2 μM. In still another embodiment, the amount of the compound administered is sufficient to provide a maximum plasma concentration of the compound of about 0.01 to about 0.1 μM.

In one embodiment, the amount administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.005 to about 100 μM, from about 0.005 to about 10 μM, from about 0.01 to about 10 μM, from about 0.01 to about 5 μM, from about 0.005 to about 1 μM, about 0.005 to about 0.5 μM, from about 0.01 to about 0.2 μM, or from about 0.01 to about 0.1 μM, when more than one doses are administered. In one embodiment, the amount of the compound administered is sufficient to provide a minimum plasma tration of the compound of about 0.005 to about 100 μM. In another embodiment, the amount of the nd administered is sufficient to provide a minimum plasma concentration of the compound of about 0.005 to about 10 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a minimum plasma concentration of the compound of about 0.01 to about 10 μM. In yet r embodiment, the amount of the compound administered is ient to provide a minimum plasma concentration of the compound of about 0.01 to about 5 μM. In yet another embodiment, the amount of the compound stered is sufficient to provide a minimum plasma concentration of the compound of about 0.005 to about 1 μM. In yet another embodiment, the amount of the nd administered is sufficient to provide a minimum plasma concentration of the compound of about 0.005 to about 0.5 μM. In yet another embodiment, the amount of the compound administered is sufficient to provide a minimum plasma concentration of the compound of about 0.01 to about 0.2 μM. In still another embodiment, the amount of the nd administered is sufficient to provide a minimum plasma concentration of the compound of about 0.01 to about 0.1 μM.

In one embodiment, the amount stered is ient to provide an area under the curve (AUC) of the compound, ranging from about 50 to about 10,000 ng*hr/mL, about 100 to about 50,000 ng*hr/mL, from about 100 to 25,000 ng*hr/mL, or from about 10,000 to 25,000 ng*hr/mL. t being d by a particular theory, it was found that administration of a compound provided herein to a patient having cancer or hematologic malignancy results in rapid onset of response in patients. Accordingly, in one embodiment, provided herein is a method of achieving rapid onset of response in patients having cancer or hematologic malignancy comprising administering to the patient a nd provided herein, or a pharmaceutically acceptable tive (e.g., salt or solvate) thereof. In some embodiments, the onset of response is achieved within about 4 , 3 months, 2 months, or 1 month from the date of first administration of a nd provided herein. In one embodiment, the compound is Compound 292, or a pharmaceutically acceptable derivative thereof. In one embodiment where the compound is Compound 292, or a ceutically acceptable derivative thereof, the cancer or hematologic malignancy is a T cell lymphoma and the onset of response is achieved within about 2 months of first administration of the compound. In another embodiment where the compound is Compound 292, or a pharmaceutically acceptable derivative f, the cancer or hematologic malignancy is a T cell lymphoma and the onset of response is achieved within about 1.9 months of first administration of the compound. In one embodiment where the compound is nd 292, or a pharmaceutically acceptable tive thereof, the cancer or hematologic malignancy is a B cell lymphoma and the onset of response is achieved within about 2 months of first administration of the compound. In another embodiment where the nd is Compound 292, or a pharmaceutically acceptable derivative thereof, the cancer or hematologic malignancy is a B cell lymphoma and the onset of response is achieved within about 1.8 months of first administration of the compound.

The compound provided herein (e.g., a compound of a I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal , ate, or polymorph thereof) can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of stration.

In one embodiment, the compound is administered orally. In another embodiment, the compound is administered parenterally. In yet another embodiment, the compound is administered intravenously.

A compound provided herein (e.g., a compound of a I (e.g., Compound 292), or an enantiomer or a mixture of omers thereof, or a ceutically acceptable salt, solvate, hydrate, cocrystal , clathrate, or polymorph thereof) can be administered once daily (QD), or divided into le daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), ittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used , the term “daily” is intended to mean that a therapeutic compound, such as a compound of Formula I, is administered once or more than once each day, for example, for a period of time. The term “continuous” is ed to mean that a therapeutic compound, such as a compound of Formula I, is stered daily for an uninterrupted period of at least 10 days to 52 weeks. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound of Formula I is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a therapeutic compound, such as a nd of Formula I, is administered daily or uously but with a rest period (e.g., after dosing for 7, 14, 21, or 28 days).

In some embodiments, the frequency of stration is in the range of about a daily dose to about a monthly dose. In certain embodiments, stration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound provided herein is administered once a day. In another embodiment, the compound ed herein is administered twice a day. In yet another embodiment, the compound provided herein is administered three times a day. In still another embodiment, the compound ed herein is administered four times a day.

In one embodiment, a nd provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, ate, or polymorph f) is stered about 0.1, 0.2, 0.25, 0.5, 1, 2, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 mg, or 75 mg BID. In one embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof) is administered about 0.5 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof) is administered about 1 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered about 5 mg BID. In another ment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered about 8 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, stal, clathrate, or polymorph thereof) is administered about 15 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered about 25 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is stered about 35 mg BID. In another embodiment, a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered about 50 mg BID. In another embodiment, a compound ed herein (e.g., a compound of Formula I (e.g., nd 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof) is administered about 75 mg BID.

] In certain embodiments, the compound provided herein (e.g., a compound of Formula I (e.g., nd 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein is administered once per day for one week. In another embodiment, the compound provided herein is stered once per day for two weeks. In yet another embodiment, the compound provided herein is administered once per day for three weeks. In still another embodiment, the compound provided herein is administered once per day for four weeks. In still another embodiment, the compound provided herein is administered once per day for more than four weeks.

In n embodiments, the compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) is administered twice per day from one day to six , from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein is administered twice per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein is administered twice per day for one week. In another embodiment, the compound ed herein is stered twice per day for two weeks. In yet another embodiment, the compound ed herein is administered twice per day for three weeks. In still another embodiment, the nd ed herein is administered twice per day for four weeks. In still another embodiment, the compound provided herein is administered twice per day for more than four weeks.

The compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal , clathrate, or polymorph thereof) can be red as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.

Combination Therapy In some embodiments, the compound provided herein is administered in combination with one or more other therapies. In one embodiment, provided herein are s for combination therapies in which an agent known to modulate other pathways, or other components of the same y, or even overlapping sets of target enzymes are used in combination with a compound provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, es, es, s, prodrugs, and isotopically labeled derivatives) thereof. In one aspect, such therapy includes, but is not limited to, the combination of the subject compound with chemotherapeutic agents, therapeutic antibodies, and/or ion treatment, to provide a istic or additive therapeutic effect.

By “in combination with,” it is not intended to imply that the other therapy and the PI3K tor must be administered at the same time and/or formulated for delivery together, gh these methods of delivery are within the scope of this disclosure. The compound provided herein can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 s, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 s, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more other therapies (e.g., one or more other additional agents). In general, each therapeutic agent will be administered at a dose and/or on a time schedule determined for that particular agent. The other therapeutic agent can be administered with the compound provided herein in a single composition or separately in a different composition. Triple therapy is also contemplated herein.

In l, it is expected that additional therapeutic agents employed in ation be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

In some embodiments, the nd provided herein is a first line treatment for cancer or hematologic malignancy, i.e., it is used in a subject who has not been previously administered r drug or therapy intended to treat cancer or hematologic malignancy or one or more symptoms thereof.

In other embodiments, the compound provided herein is a second line treatment for cancer or hematologic malignancy, i.e., it is used in a subject who has been previously administered another drug or therapy intended to treat cancer or hematologic malignancy or one or more symptoms thereof.

In other embodiments, the nd provided herein is a third or fourth line treatment for cancer or hematologic malignancy, i.e., it is used in a subject who has been previously administered two or three other drugs or therapies intended to treat cancer or hematologic malignancy or one or more symptoms thereof.

In embodiments where two agents are administered, the agents can be administered in any order.

For example, the two agents can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two). In some embodiments, the nd provided herein is administered tially (i.e., after the first therapeutic).

In one embodiment, provided herein is a combination therapy for inhibiting abnormal cell growth in a subject which ses administering a nd provided , or a pharmaceutically acceptable form (e.g., pharmaceutically able salts, hydrates, es, isomers, prodrugs, and isotopically labeled derivatives) thereof, in combination with an amount of an anti-cancer agent (e.g., a chemotherapeutic agent). Many chemotherapeutics are presently known in the art and can be used in combination with a compound ed herein.

In some embodiments, the herapeutic is selected from mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, enesis inhibitors, and antiandrogens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), CasodexTM (bicalutamide), Iressa® inib), Tarceva® (erlotinib), and Adriamycin® (doxorubicin) as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl ates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, lenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; BTK tors such as ibrutinib (PCI-32765), AVL-292 (N-(3-((5-fluoro((4-(2-methoxyethoxy)phenyl)amino)pyrimidin yl)amino)phenyl)acrylamide), which can also be referred to as CC-292, Dasatinib, LFM-A13(2Z-cyano-N- ibromophenyl)3-hydroxybutenamide), ONO-WG-307, GDC-0834, RN-486 (6-cyclopropyl fluoro(2-hydroxymethyl{1-methyl[5-(4-methyl-piperazinyl)-pyridinylamino]oxo-1,6- dihydro-pyridinyl}-phenyl)-2H-isoquinolinone), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl oxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl)methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophenecarboxamide]), CGI-560 ( N-[3-(8-anilinoimidazo[1,2-a]pyrazin nyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl(4-methyl((4-(morpholine carbonyl)phenyl)amino)oxo-4,5-dihydropyrazinyl)phenyl)benzamide), HM-71224(Hammi Pharmaceticals), ONO-4059 (Ono Pharmaceuticals Co., LTD), and CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide); HDAC inhibitors such as vorinostat, romidepsin, panobinostat, ic acid, belinostat, mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat, CUDC-101, AR-42, CHR-2845, 96, 4SC-202, CG200745, ACY-1215 and kevetrin; EZH2 inhibitors such as, but not limited to, EPZ-6438 (N-((4,6- yloxo-1,2-dihydropyridinyl)methyl)(ethyl(tetrahydro-2H-pyranyl)amino)methyl-4'- (morpholinomethyl)-[1,1'-biphenyl]carboxamide), GSK-126 ((S)(sec-butyl)-N-((4,6-dimethyloxo- 1,2-dihydropyridinyl)methyl)methyl(6-(piperazinyl)pyridinyl)-1H-indolecarboxamide), GSK-343 (1-Isopropyl-N-((6-methyloxopropyl-1,2-dihydropyridinyl)methyl)(2-(4- methylpiperazinyl)pyridineyl)-1H-indazolecarboxamide), El1, 3-deazaneplanocin A (DNNep, 5R- (4-amino-1H-imidazo[4,5-c]pyridinyl)(hydroxymethyl)cyclopentene-1S,2R-diol), small interfering RNA ) es targeted against EZH2 (S. M. Elbashir et al., Nature 411:494-498 (2001)), isoliquiritigenin, and those provided in, for example, U.S. Publication Nos. 2009/0012031, 203010, 2010/0222420, 2011/0251216, 2011/0286990, 2012/0014962, 2012/0071418, 2013/0040906, and 2013/0195843, all of which are incorporated herein by reference; AT inhibitors such as lestaurtinib, tofacitinib, ruxolitinib, pacritinib, CYT387, baricitinib, GLPG0636, TG101348, 562, CP-690550, and AZD1480; PKC-β inhibitor such as Enzastaurin; SYK inhibitors such as, but not limited to, GS-9973, R788 matinib), PRT 062607, R406, (S)(2-((3,5-dimethylphenyl)amino)pyrimidinyl)-N-(1- hydroxypropanyl)methylthiazolecarboxamide, R112, GSK143, BAY61-3606, PP2, PRT 060318, R348, and those provided in, for example, U.S. Publication Nos. 113828, 158195, 2003/0229090, 2005/0075306, 2005/0232969, 267059, 2006/0205731, 2006/0247262, 2007/0219152, 2007/0219195, 2008/0114024, 2009/0171089, 2009/0306214, 2010/0048567, 2010/0152159, 2010/0152182, 2010/0316649, 2011/0053897, 2011/0112098, 2011/0245205, 2011/0275655, 2012/0027834, 2012/0093913, 2012/0101275, 2012/0130073, 2012/0142671, 2012/0184526, 2012/0220582, 2012/0277192, 2012/0309735, 2013/0040984, 2013/0090309, 116260, and 2013/0165431, all of which are incorporated herein by reference; SYK/JAK dual inhibitor such as PRT2070; nitrogen mustards such as bendamustine, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, terine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as tine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as nomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazooxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, cin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil ; folic acid analogues such as denopterin, methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, idine, androgens such as erone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid isher such as folinic acid; tone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; mine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; ’’-trichlorotriethyla- mine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; ctol; pipobroman; sine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel (e.g., TAXOLTM) and docetaxel (e.g., TAXOTERETM) and ABRAXANE® (paclitaxel protein-bound particles); retinoic acid; micins; capecitabine; and pharmaceutically acceptable forms (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) of any of the above. Also included as suitable chemotherapeutic cell ioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as strogens including for example tamoxifen (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, fene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; guanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; rone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; thecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Where desired, the compounds or pharmaceutical ition as provided herein can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, , Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, ne carboxamide, adecatumumab, 17-N-allylaminodemethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridinecarboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic, antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV therapy), calyculin, inib, cell-cycle nonspecific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, abine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, mod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, zan, vinflunine, ZD6126, and zosuquidar.

In some embodiments, the herapeutic is selected from hedgehog inhibitors including, but not limited to IPI-926 (See U.S. Patent 7,812,164). Other suitable hedgehog inhibitors include, for example, those described and disclosed in U.S. Patent 7,230,004, U.S. Patent Application Publication No. 293754, U.S. Patent ation Publication No. 2008/0287420, and U.S. Patent Application Publication No. 2008/0293755, the entire disclosures of which are incorporated by reference herein.

Examples of other suitable hedgehog inhibitors include those described in U.S. Patent Application Publication Nos. US 2002/0006931, US 2007/0021493 and US 2007/0060546, and International Application Publication Nos. , , , , WO 2001/74344, , , , , WO 2005/033288, , , , , WO 2006/078283, , , , WO 31201, WO 70357, , WO 12913, and , each orated herein by reference. onal es of hedgehog inhibitors include, but are not limited to, 49 (also known as RG3616 or egib) described in, e.g., Von Hoff D. et al., N. Engl. J. Med. 2009; ):1164-72; Robarge K.D. et al., Bioorg Med Chem Lett. 2009; 19(19):5576-81; Yauch, R. L. et al. (2009) Science 326: 572-574; Sciencexpress: 1-3 (10.1126/science.1179386); Rudin, C. et al. (2009) New England J of Medicine 361-366 (10.1056/nejma0902903); BMS-833923 (also known as XL139) described in, e.g., in Siu L. et al., J. Clin. Oncol. 2010; 28:15s (suppl; abstr 2501); and National Institute of Health Clinical Trial fier No. NCT00670189l; LDE-225 described, e.g., in Pan S. et al., ACS Med. Chem.

Lett., 2010; 1(3): 130–134; LEQ-506 described, e.g., in National Institute of Health al Trial Identifier No. NCT01106508; PF-04449913 described, e.g., in National Institute of Health al Trial Identifier No. NCT00953758; Hedgehog pathway antagonists disclosed in U.S. Patent Application Publication No. 2010/0286114; SMOi2-17 described, e.g., U.S. Patent Application Publication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., in Rominger C.M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005; 1- piperazinylarylphthalazines or analogues thereof, described in Lucas B.S. et al., Bioorg. Med. Chem.

Lett. 2010; 20(12):3618-22.

Other hormonal therapy and chemotherapeutic agents e, but are not limited to, anti- ens (e.g. tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g. goserelin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BADMHA)), nitrogen mustards (e.g. cyclophosphamide, mide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine ), alkylsulphonates (e.g. busulfan and treosulfan), nes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids or taxanes (e.g. axel or a axel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel aclitaxel, Taxoprexin), polyglutamate boundpaclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2- glucopyranosyl ate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), antimetabolites , DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. enolic acid, tiazofurin, rin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and xamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C, cytosine arabinoside), and fludarabine), purine s (e.g. mercaptopurine and thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methylphenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, cin B2, peplomycin), anthracyclines (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), omide, lenalidomide (REVLIMID®), tyrosine kinase inhibitors (e.g., axitinib (AG013736), nib (SKI-606), cediranib (RECENTINTM, AZD2171), nib (SPRYCEL®, BMS- 354825), erlotinib (TARCEVA®), gefitinib A®), ib (Gleevec®, CGP57148B, STI-571), lapatinib B®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), nib (SUTENT®, SU11248), toceranib (PALLADIA®), anib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), zumab (Lucentis®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), 076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF- 04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, 5, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI- 930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR tors (e.g., rapamycin, temsirolimus (CCI-779), imus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, omycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, omycin,, aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, -stimulants and/or immuno-modulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar (tositumomab), or Perjeta (pertuzumab)).

In one embodiment, the rapeutic agent is an anti-CD37 antibody such as, but not limited to, IMGN529, K7153A and TRU-016. In another embodiment, the rapeutic agent is an anti-CD20 antibody such as, but not limited to, 131I tositumomab, 90Y ibritumomab, 111I ibritumomab, obinutuzumab and umab. In another embodiment, the biotherapeutic agent is an anti-CD52 antibody such as, but not limited to, zumab.

In some embodiments, the chemotherapeutic is ed from HSP90 inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g., a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g., IPI-493 and/or IPI-504). Non-limiting examples of HSP90 inhibitors include IPI-493, IPI- 504, 17-AAG (also known as tanespimycin or CNF-1010), BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as 009), SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17- DMAG, CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, CCT-129397, , or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3K inhibitors (e.g., including those PI3K inhibitors provided herein and those PI3K inhibitors not provided ). In some embodiment, the PI3K tor is an inhibitor of delta and gamma isoforms of PI3K. In some embodiment, the PI3K inhibitor is an inhibitor of delta m of PI3K. In some embodiment, the PI3K inhibitor is an inhibitor of gamma isoform of PI3K. In some embodiments, the PI3K inhibitor is an inhibitor of alpha isoform of PI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one or more alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can be used in combination are described in, e.g., WO 09/088990, WO 09/088086, , , , WO 09/114870, WO 05/113556; US 312310, and US 2011/0046165, each incorporated herein by reference. Additional PI3K inhibitors that can be used in combination with the pharmaceutical compositions, include but are not limited to, AMG-319, GSK 2126458, GDC-0980, GDC- 0941, Sanofi XL147, XL499, XL756, XL147, PF-4691502, BKM 120, GA-101 tuzumab), CAL-101 (GS-1101), CAL 263, SF1126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235). In one embodiment, the PI3K inhibitor is an isoquinolinone.

In some embodiments, the chemotherapeutic is selected from polo-like kinase 1 (PLK1) inhibitors such as, but not limited to, volasertib (BI6727; N-((1S,4S)(4-(cyclopropylmethyl)piperazin yl)cyclohexyl)(((R)ethylisopropylmethyloxo-5,6,7,8-tetrahydropteridinyl)amino) methoxybenzamide), BI2536 ((R)[(8-Cyclopentylethyl-5,6,7,8-tetrahydromethyloxo pteridinyl)amino]methoxy-N-(1-methylpiperidinyl)benzamide), ZK-Thiazolidone ((2-imidazolyl- 1-oxidanylphosphono-ethyl)phosphonic acid), TAK-960 (4-((9-cyclopentyl-7,7-difluoromethyl oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepinyl)amino)fluoromethoxy-N-(1- methylpiperidinyl)benzamide), MLN0905 (2-((5-(3-(dimethylamino)propyl)methylpyridin yl)amino)(trifluoromethyl)-5H-benzo[b]pyrimido[4,5-d]azepine-6(7H)-thione), GSK461364 ((R)(6- thylpiperazinyl)methyl)-1H-benzo[d]imidazolyl)(1-(2- (trifluoromethyl)phenyl)ethoxy)thiophenecarboxamide), rigosertib (ON-01910; sodium (E)((2- methoxy(((2,4,6-trimethoxystyryl)sulfonyl)methyl)phenyl)amino)acetate) and HMN-214 ((E)(2-(N- ((4-methoxyphenyl)sulfonyl)acetamido)styryl)pyridine 1-oxide).

In some embodiments, the chemotherapeutic is selected from IRAK inhibitors. Inhibitors of the IRAK protein kinase family refer to compounds which inhibit the function of IRAK protein kinases and more preferably nds which inhibit the on of IRAK-4 and/or IRAK-1. Exemplary IRAK inhibitors include, but are not limited to, IRAK4 tors such as ND-2110 and ND-2158; the IRAK inhibitors disclosed in WO2003/030902, WO2004/041285, WO2008/030579, and Buckley et al. (IRAK-4 inhibitors. Part 1: a series of amides. In Bioorganic & medicinal chemistry letters 2008, :3211-3214; IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1 ,2-a]pyridine g. In anic & nal chemistry s 2008, 18(11):3291-3295; IRAK-4 inhibitors. Part III: a series of imidazo[1 ,2- dines. In Bioorganic & medicinal chemistry letters 2008, 18(11):3656-3660), the entireties of which are incorporated herein by reference; RO6245, RO0884, N-acyl 2-aminobenzimidazoles 1-(2-(4- Morpholinyl)ethyl)(3- nitrobenzoylamino)benzimidazole, and/or N-(2-Morpholinylethyl)(3- nitrobenzoylamido)-benzimidazole.

In some embodiments, provided herein is a method for using the a compound provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical ition as provided herein, in combination with radiation therapy in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the subject. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination y described herein. The administration of a compound provided herein in this combination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation, external-beam therapy, internal radiation therapy, t radiation, stereotactic radiosurgery, systemic ion therapy, radiotherapy and permanent or ary interstitial brachytherapy. The term ytherapy,” as used herein, refers to radiation therapy delivered by a spatially ed radioactive material inserted into the body at or near a tumor or other proliferative tissue e site. The term is intended without limitation to include exposure to radioactive isotopes (e.g., At- 211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell ioner as provided herein include both solids and liquids. By way of non-limiting example, the ion source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a ctive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, a compound provided herein, or a pharmaceutically acceptable form (e.g., ceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) f, or a pharmaceutical composition as ed herein, can render abnormal cells more sensitive to treatment with radiation for purposes of g and/or inhibiting the growth of such cells. Accordingly, provided herein is a method for izing abnormal cells in a subject to treatment with radiation which comprises administering to the subject an amount of a compound provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, es, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, which amount is effective in sensitizing abnormal cells to treatment with radiation. The amount of the compound used in this method can be determined according to the means for ascertaining effective s of such compounds described herein.

] In some embodiments, provided herein is a method for using the a compound provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, es, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical composition as provided herein, in combination with hormonal therapy in inhibiting abnormal cell growth or treating hyperproliferative disorder in the subject.

In some embodiments, provided herein is a method for using the a compound provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical ition as provided herein, in combination with surgery in inhibiting abnormal cell growth or treating hyperproliferative disorder in the subject.

In one embodiment, a compound as provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, gs, and isotopically labeled derivatives) thereof, or a ceutical composition as ed herein, can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.

Other therapeutic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 x-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) tors, can be used in conjunction with a compound provided herein, or a ceutically acceptable form thereof, or a pharmaceutical composition described herein. Such therapeutic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. es of useful COX-II inhibitors include EXTM (alecoxib), oxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent ation No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 15 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931, 788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 89 shed October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent ,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein in their entireties by reference. In some embodiments, MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. Other embodiments include those that selectively inhibit MMP-2 and/or AMP-9 relative to the other -metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, , MMP-12, and MMP-13). Some non-limiting examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830. agy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-aminoimidazole carboxamide riboside (AICAR), c acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6- mercaptopurine riboside, and stine. In addition, antisense or siRNAs that t expression of ns including, but not limited to ATG5 (which are implicated in autophagy), can also be used.

] Other exemplary therapeutic agents useful for a ation therapy include, but are not limited to, agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the sis and actions of adrenocortical hormones, n, oral hypoglycemic agents, and the cology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, ns A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and nists; olinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or nists; and 5- hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, oxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective ysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal antiinflammatory agents, analgesic-antipyretic agents, agents that inhibit the sis of prostaglandins and thromboxanes, ive inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, n, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and riene inhibitors. es of therapeutic antibodies that can be combined with a compound provided herein include but are not limited to anti-receptor tyrosine kinase dies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immuno-modulation, such as immuno-modulators, immuno-suppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein. In addition, therapeutic agents acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and anti-platelet drugs are also contemplated by the methods herein.

In exemplary embodiments, for ng renal carcinoma, one can combine a compound provided herein, or a ceutically acceptable form (e.g., ceutically acceptable salts, es, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical composition as provided herein, with sorafenib and/or avastin. For treating an trial disorder, one can combine a compound provided herein with doxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). For treating ovarian cancer, one can combine a nd provided herein with cisplatin, carboplatin, docetaxel, doxorubincin, can, and/or tamoxifen. For ng breast cancer, one can combine a compound provided herein with paclitaxel or docetaxel, gemcitabine, capecitabine, tamoxifen, letrozole, erlotinib, lapatinib, PD0325901, bevacizumab, trastuzumab, OSI-906, and/or OSI-930. For treating lung cancer, one can combine a compound as provided herein with paclitaxel, xel, gemcitabine, cisplatin, pemetrexed, erlotinib, PD0325901, and/or bevacizumab.

In some embodiments, the disorder to be d, prevented and/or managed is a hematological cancer, e.g., lymphoma (e.g., T-cell lymphoma; NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g., CLL), and a compound provided herein (e.g., Compound 292) is used in combination with: HDAC inhibitors such as vorinostat, romidepsin and ACY-1215; mTOR inhibitors such as everolimus; anti-folates such as pralatrexate; nitrogen mustard such as bendamustine; gemcitabine, optionally in further ation with oxaliplatin; rituximab-cyclophosphamide ation; PI3K inhibitors such as GS-1101, XL 499, 41, and AMG-319; angiogenesis tors such as pomalidomide or BTK inhibitors such as ibrutinib, AVL-292, Dasatinib, LFM-AI3, ONO-WG-307, and GDC-0834.

In some embodiments, the disorder to be treated, prevented and/or managed is DLBCL, and a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) f, is used in combination with HDAC inhibitors provided herein. In one particular embodiment, the HDAC inhibitor is ACY-1215.

In some embodiments, the disorder to be d, prevented and/or managed is DLBCL, and a compound provided herein (e.g., nd 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with BTK inhibitors provided herein. In one ular embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is AVL-292.

In some embodiments, the disorder to be treated, ted and/or managed is DLBCL, and a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with IRAK inhibitors provided herein. In one particular embodiment, the IRAK4 inhibitor is ND-2110 or ND-2158.

In some embodiments, the disorder to be treated, prevented and/or managed is WM, and a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with BTK inhibitors provided herein. In one ular embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is 2.

In some embodiments, the disorder to be treated, prevented and/or managed is WM, and a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with IRAK4 inhibitors provided herein. In one ular ment, the IRAK4 inhibitor is ND-2110 or ND-2158.

In some ments, the disorder to be treated, prevented and/or managed is T-ALL, the subject/patient has a PTEN deficiency, and a nd provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or e) thereof, is used in ation with doxorubicin and/or vincristine.

Further therapeutic agents that can be combined with a compound ed herein can be found in Goodman and ’s “The Pharmacological Basis of eutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician’s Desk Reference, both of which are incorporated herein by reference in their entirety.

In one embodiment, the nds described herein can be used in combination with the agents provided herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments, a compound ed herein, or a pharmaceutically acceptable form thereof, will be coadministered with other agents as described above. When used in combination therapy, a compound described herein, or a pharmaceutically acceptable form thereof, can be administered with a second agent aneously or separately. This administration in combination can include simultaneous stration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and te administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound provided herein and any of the agents described above can be simultaneously administered, wherein both agents are present in separate formulations. In another alternative, a compound provided herein can be administered just followed by any of the agents described above, or vice versa. In the separate administration protocol, a compound provided herein and any of the agents described above can be administered a few minutes apart, or a few hours apart, or a few days apart.

Administration of a compound provided herein, or a pharmaceutically acceptable form thereof, can be effected by any method that enables delivery of the compound to the site of action. An effective amount of a compound provided herein, or a pharmaceutically acceptable form thereof, can be administered in either single or le doses by any of the accepted modes of administration of agents having similar utilities, ing rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenously, eritoneally, erally, uscularly, subcutaneously, orally, topically, as an inhalant, or via an nated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

When a compound provided herein, or a pharmaceutically acceptable form thereof, is administered in a pharmaceutical composition that comprises one or more agents, and the agent has a shorter half-life than the compound provided herein, unit dose forms of the agent and the compound as provided herein can be adjusted accordingly.

In some embodiments, the compound provided herein and the second agent are administered as te compositions, e.g., pharmaceutical compositions. In some embodiments, the PI3K modulator and the agent are administered separately, but via the same route (e.g., both orally or both intravenously). In other embodiments, the PI3K modulator and the agent are administered in the same composition, e.g., pharmaceutical composition.

In some embodiments, a compound ed herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with an HDAC inhibitor, such as, e.g., stat, vorinostat, panobinostat, ACY-1215, or romidepsin.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically able derivative (e.g., salt or solvate) thereof, is used in combination with an mTOR inhibitor, such as, e.g., everolimus (RAD 001).

In some embodiments, a compound ed herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with a proteasome inhibitor, such as, e.g., bortezomib or carfilzomib.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with a PKC-β inhibitor, such as, e.g., Enzastaurin (LY317615)..

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with a JAK/STAT inhibitor, such as, e.g., 562 or AZD1480.

In some embodiments, a compound provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) f, is used in combination with an anti-folate, such as, e.g., pralatrexate.

In some embodiments, a nd provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) f, is used in combination with a farnesyl transferase inhibitor, such as, e.g., tipifarnib.

In some embodiments, a compound provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination bendamustine and one additional active agent. In one embodiment, the cancer or hematological malignancy is iNHL.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination rituximab and one additional active agent. In one embodiment, the cancer or hematological malignancy is iNHL.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination bendamustine and rituximab. In one embodiment, the cancer or hematological malignancy is iNHL.

In some embodiments, a compound provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination fludarabine, cyclophosphamide, and rituximab. In one ment, the cancer or hematological malignancy is CLL.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or e) thereof, is used in combination with an antibody or a biologic agent, such as, e.g., alemtuzumab, rituximab, ofatumumab, or brentuximab vedotin (SGN-035). In one ment, the second agent is rituximab. In one ment, the second agent is rituximab and the combination therapy is for treating, preventing, and/or managing iNHL, FL, splenic al zone, nodal al zone, extranodal marginal zone, and/or SLL.

In some embodiments, a nd provided herein (e.g., Compound 292), or a pharmaceutically able derivative (e.g., salt or e) thereof, is used in combination with an antibody-drug conjugate, such as, e.g., umab ozogamicin, or brentuximab vedotin.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with a cytotoxic agent, such as, e.g., bendamustine, gemcitabine, oxaliplatin, cyclophosphamide, stine, vinblastine, anthracycline (e.g., daunorubicin or ycin, doxorubicin), actinomycin, dactinomycin, bleomycin, clofarabine, nelarabine, cladribine, asparaginase, methotrexate, or pralatrexate.

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with one or more other anticancer agents or chemotherapeutic agents, such as, e.g., fludarabine, ibrutinib, fostamatinib, lenalidomide, thalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, sone, or R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin or Hydroxydaunomycin, Vincristine or Oncovin, Prednisone).

In some embodiments, a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, is used in combination with an antibody for a cytokine (e.g., an IL-15 antibody, an IL-21 dy, an IL-4 antibody, an IL-7 antibody, an IL-2 antibody, an IL-9 dy). In some embodiments, the second agent is a JAK1 inhibitor, a JAK3 inhibitor, a K inhibitor, a BTK inhibitor, an SYK inhibitor, or a PI3K delta inhibitor. In some ments, the second agent is an antibody for a chemokine. ] t being limited to a particular theory, a targeted combination therapy described herein has reduced side effect and/or enhanced efficacy. For example, in one embodiment, provided herein is a combination therapy for treating CLL with a compound described herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, and a second active agent (e.g., IL-15 antibodies, IL-21 antibodies, IL-4 antibodies, IL-7 antibodies, IL-2 antibodies, IL-9 antibodies, JAK1 inhibitors, JAK3 inhibitors, K inhibitors, BTK inhibitors, SYK inhibitors, and/or PI3K delta inhibitors).

Further t being limited by a particular theory, it was found that a compound provided herein (e.g., Compound 292) does not affect BTK or MEK pathway. Accordingly, in some embodiments, provided herein is a method of treating or managing cancer or hematological ancy comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with a BTK tor. In one ment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is AVL-292. In one ment, the cancer or hematological malignancy is DLBCL. In another embodiment, the cancer or hematological malignancy is iNHL. In another embodiment, the cancer or hematological malignancy is CLL.

In other embodiments, provided herein is a method of treating or managing cancer or hematological malignancy comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in ation with a MEK tor. In one embodiment, the MEK inhibitor is tametinib/GSK1120212 (N-(3-{3-Cyclopropyl[(2-fluoroiodophenyl)amino]-6,8-dimethyl-2,4,7- -3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide), selumetinob (6-(4-bromo chloroanilino)fluoro-N-(2-hydroxyethoxy)methylbenzimidazolecarboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)((2-fluoro iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (1-({3,4-difluoro[(2-fluoro iodophenyl)amino]phenyl}carbonyl)[(2S)-piperidinyl]azetidinol), refametinib/BAY869766/RDEA119 (N-(3,4-difluoro(2-fluoroiodophenylamino)methoxyphenyl)- 1-(2,3-dihydroxypropyl)cyclopropanesulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4- difluoro[(2-fluoroiodophenyl)amino]-benzamide), TAK733 ((R)(2,3-Dihydroxypropyl)fluoro (2-fluoroiodophenylamino)methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-Bromofluorophenyl)amino]fluoro-N-(2-hydroxyethoxy)methyl-1H- benzimidazolecarboxamide), RO5126766 (3-[[3-Fluoro(methylsulfamoylamino)pyridyl]methyl] methylpyrimidinyloxychromenone), WX-554, RO4987655/CH4987655 ifluoro((2-fluoro- 4-iodophenyl)amino)-N-(2-hydroxyethoxy)((3-oxo-1,2-oxazinanyl)methyl)benzamide), or AZD8330 (2-((2-fluoroiodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyloxo-1,6-dihydropyridine carboxamide). In one embodiment, the cancer or hematological malignancy is DLBCL. In another embodiment, the cancer or hematological malignancy is ALL. In another embodiment, the cancer or hematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating or managing cancer or hematological ancy comprising administering to a patient a eutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with an EZH2 inhibitor. In one embodiment, the EZH2 inhibitor is EPZ- 6438, GSK-126, GSK-343, El1, or 3-deazaneplanocin A (DNNep). In one embodiment, the cancer or hematological malignancy is DLBCL. In r embodiment, the cancer or hematological malignancy is iNHL. In another embodiment, the cancer or hematological malignancy is ALL. In another embodiment, the cancer or hematological malignancy is CTCL.

In other embodiments, ed herein is a method of treating or managing cancer or hematological malignancy comprising administering to a patient a therapeutically ive amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in ation with a bcl-2 tor. In one embodiment, the BCL2 inhibitor is ABT-199 [[2-(4-Chlorophenyl)-4,4-dimethylcyclohexen yl]methyl]piperazinyl]-N-[[3-nitro [[(tetrahydro-2H- 4-yl)methyl]amino]phenyl]sulfonyl][(1H- o[2,3-b]pyridin ]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazinyl]-N-[4-[[(2R) (dimethylamino)phenylsulfanylbutanyl]amino]nitrophenyl]sulfonylbenzamide), ABT-263 ((R) (4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]yl)methyl)piperazinyl)-N-((4-((4- lino(phenylthio)butanyl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)[(5Z)[(3,5-dimethyl-1H-pyrrolyl)methylidene] methoxypyrrolylidene]indole; methanesulfonic acid))), or G3139 (Oblimersen). In one embodiment, the cancer or hematological malignancy is DLBCL. In another embodiment, the cancer or hematological malignancy is iNHL. In another embodiment, the cancer or hematological malignancy is CLL. In another embodiment, the cancer or hematological malignancy is ALL. In another embodiment, the cancer or hematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating or managing iNHL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab. In one embodiment, the patient is an elderly patient. In another embodiment, iNHL is relapsed or refractory.

In other embodiments, ed herein is a method of treating or managing iNHL comprising administering to a patient a therapeutically effective amount of a nd provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with bendamustine. In one embodiment, iNHL is relapsed or refractory.

] In other embodiments, provided herein is a method of ng or ng iNHL comprising administering to a t a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab, and in further combination with ustine. In one embodiment, iNHL is relapsed or refractory.

] In other embodiments, provided herein is a method of treating or managing iNHL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with lenalidomide. In one embodiment, iNHL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or e) f, in combination with rituximab. In one embodiment, the patient is an y patient. In another embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient a therapeutically effective amount of a compound ed herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in ation with bendamustine. In one embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in ation with rituximab, and in further combination with bendamustine. In one embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing CLL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with lenalidomide. In one embodiment, CLL is ed or refractory.

In other embodiments, provided herein is a method of treating or managing DLBCL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab. In one embodiment, the patient is an elderly patient. In another embodiment, DLBCL is relapsed or refractory.

In other ments, ed herein is a method of treating or managing DLBCL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or e) thereof, in combination with bendamustine. In one embodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing DLBCL comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., nd 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab, and in further combination with bendamustine. In one embodiment, DLBCL is relapsed or refractory.

In other ments, provided herein is a method of treating or managing DLBCL comprising stering to a patient a therapeutically effective amount of a compound ed herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in ation with R-GDP (rituximab, cyclophosphamide, vincristine and prednisone). In one embodiment, DLBCL is relapsed or refractory. In another embodiment, the treatment is done subsequent to treatment by R-CHOP.

] In other embodiments, provided herein is a method of treating or managing DLBCL comprising administering to a patient a eutically effective amount of a compound provided herein (e.g., Compound 292), or a ceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with ibrutinib. In one embodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing T-cell lymphoma (PTCL or CTCL) sing administering to a t a eutically effective amount of a compound ed herein (e.g., Compound 292), or a pharmaceutically acceptable tive (e.g., salt or solvate) thereof, in combination with rituximab. In one embodiment, T-cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing T-cell lymphoma (PTCL or CTCL) comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically able derivative (e.g., salt or solvate) thereof, in ation with bendamustine. In one embodiment, T-cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing T-cell lymphoma (PTCL or CTCL) comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab, and in further combination with bendamustine. In one embodiment, T-cell lymphoma is ed or refractory.

In other embodiments, ed herein is a method of treating or ng T-cell lymphoma (PTCL or CTCL) comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or e) thereof, in combination with romidepsin. In one embodiment, T-cell lymphoma is relapsed or refractory.

] In other embodiments, provided herein is a method of treating or managing mantle cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) f, in combination with rituximab. In one embodiment, mantle cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing mantle cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound ed herein (e.g., Compound 292), or a pharmaceutically acceptable tive (e.g., salt or solvate) thereof, in combination with bendamustine. In one embodiment, mantle cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating or managing mantle cell lymphoma comprising administering to a t a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with rituximab, an din further combination with ustine. In one embodiment, mantle cell ma is relapsed or refractory.

] In other embodiments, provided herein is a method of treating or managing mantle cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 292), or a pharmaceutically acceptable tive (e.g., salt or solvate) thereof, in combination with ibrutinib. In one embodiment, mantle cell lymphoma is relapsed or refractory.

] Further, t being limited by a particular theory, it was found that cancer cells exhibit differential sensitivity profiles to doxorubicin and compounds provided herein. Thus, ed herein is a method of treating or managing cancer or logical malignancy comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., nd 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with a doxorubicin. In one embodiment, the cancer or hematological malignancy is ALL.

In some embodiments, provided herein is a method of treating or managing cancer or hematological malignancy comprising administering to a patient a therapeutically effective amount of a nd provided herein (e.g., Compound 292), or a pharmaceutically acceptable derivative (e.g., salt or solvate) thereof, in combination with a AraC. In one embodiment, the cancer or hematological malignancy is AML.

In specific embodiments, Compound 292 or a pharmaceutically acceptable form thereof, is used in combination with one or more second agent or second y provided herein.

Combinations of PI3K inhibitors and BTK inhibitors Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a PI3K tor, or a pharmaceutically acceptable form thereof, and a BTK inhibitor, or a pharmaceutically acceptable form thereof.

Also provided herein are s of treating, managing, or preventing a cancer or hematologic malignancy in a subject comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor, or a pharmaceutically acceptable form f, in combination with a BTK inhibitor, or a ceutically acceptable form thereof.

BTK inhibitors that can be used in the compositions and methods provided herein are provided herein and elsewhere. In one embodiment, the BTK inhibitor is ibrutinib. In another embodiment, the BTK tor is AVL-292. In some embodiments, the BTK tor is RN-486 (6-cyclopropylfluoro(2- hydroxymethyl{1-methyl[5-(4-methyl-piperazinyl)-pyridinylamino]oxo-1,6-dihydro-pyridin- 3-yl}-phenyl)-2H-isoquinolinone), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyloxopiperazinyl) phenylamino)methyloxo-4,5-dihydropyrazinyl)methylphenyl)-4,5,6,7- ydrobenzo[b]thiophenecarboxamide]), CGI-560 ( N-[3-(8-anilinoimidazo[1,2-a]pyrazin yl)phenyl]tert-butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl(4-methyl((4-(morpholine carbonyl)phenyl)amino)oxo-4,5-dihydropyrazinyl)phenyl)benzamide), HM-71224(Hammi ceticals), ONO-4059 (Ono Pharmaceuticals Co., LTD), CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)fluoropyrimidinyl)amino)phenoxy)-N-methylpicolinamide), LFM-A13 (2Z- cyano-N-(2,5-dibromophenyl)3-hydroxybutenamide) or AVL-292 (N-(3-((5-fluoro((4-(2- methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide), which can also be referred to as CC-292.

In certain embodiments, provided herein is a pharmaceutical composition comprising a eutically effective amount of a PI3K delta selective inhibitor, or a ceutically acceptable form thereof, and a BTK inhibitor, or a pharmaceutically acceptable form thereof. In one embodiment, the PI3K delta selective inhibitor is GS1101 (CAL-101). In one ment, the BTK inhibitor is ibrutinib, GDC- 0834, CGI-560, CGI-1746, HM-71224, AVL-292, ONO-4059, CNX-774, or LFM-A13, or a e thereof. In one embodiment, the BTK inhibitor is ibrutinib. In another embodiment, the BTK inhibitor is AVL-292. In another embodiment, the BTK inhibitor is a BTK inhibitor described herein. In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of GS1101, or a pharmaceutically acceptable form thereof, and ibrutinib, or a pharmaceutically acceptable form thereof. In another ment, ed herein is a pharmaceutical composition comprising a therapeutically effective amount of GS1101, or a pharmaceutically acceptable form thereof, and AVL-292, or a pharmaceutically acceptable form thereof.

In one embodiment of the compositions and methods described herein, the molar ratio of the PI3K delta selective inhibitor (e.g., ), or a pharmaceutically acceptable form thereof, to the BTK inhibitor (e.g., ibrutinib or 2 or other BTK inhibitor described herein), or a pharmaceutically able form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about :1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.

In one embodiment, the ition comprises the PI3K delta selective tor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.

In one ment, the composition comprises the PI3K delta ive inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.

In certain ments, provided herein is a method of treating, managing, or preventing a cancer or hematologic ancy in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, in combination with a BTK tor (e.g., ibrutinib or AVL-292), or a pharmaceutically acceptable form thereof, wherein the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B- cell lymphoma (germinal center B-cell-like), follicular lymphoma, indolent non-Hodgkin lymphoma, T-cell lymphoma, mantle cell lymphoma, or multiple myeloma.

In some embodiments of the methods described herein, the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, and the BTK tor (e.g., ibrutinib or AVL- 292), or a pharmaceutically acceptable form thereof, are stered at certain dosages. In one embodiment, provided herein is a method of treating, managing, or preventing a cancer in a subject sing administering to the subject a therapeutically effective amount of a PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically able form thereof, in combination with a BTK inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K delta ive inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the BTK inhibitor (e.g., ibrutinib or AVL-292), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about mg to about 25 mg, or from about 10 mg to about 20 mg daily.

In one ment, the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.

] In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form f, and a BTK inhibitor, or a pharmaceutically acceptable form thereof. In one embodiment, the BTK inhibitor is ibrutinib, GDC-0834, 0, CGI-1746, HM-71224, AVL-292, ONO-4059, CNX-774, or LFM-A13, or a mixture thereof. In one embodiment, the BTK inhibitor is ibrutinib. In another embodiment, the BTK inhibitor is AVL-292. The BTK inhibitor can also be another BTK inhibitor described herein. In some ments, a BTK inhibitor is not combined with the PI3K delta/gamma dual inhibitor.

In one embodiment of the compositions and methods described herein, the molar ratio of the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, to the BTK inhibitor (e.g., ibrutinib or 2), or a pharmaceutically acceptable form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5. In one embodiment, the molar ratio of the PI3K delta/gamma dual inhibitor, or a pharmaceutically able form thereof, to the BTK inhibitor (e.g., nib or AVL-292), or a pharmaceutically acceptable form thereof, is about 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1: 5, 1:4, 1:3, 1:2, or 1:1. In another embodiment, the molar ratio is about 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, or 1:6.

In one embodiment, the molar ratio of the PI3K delta/gamma dual inhibitor to the BTK inhibitor is from about 0.05 to about 3. In another embodiment, the molar ratio is from about 0.1 to about 2.5. In another embodiment, the molar ratio is from about 0.1 to about 2. In another embodiment, the molar ratio is from about 0.1 to about 1.5.

In one ment, the composition comprises the PI3K delta/gamma dual tor, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about mg to about 25 mg, or from about 10 mg to about 20 mg.

In one embodiment, the composition comprises the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.

In certain embodiments, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, in combination with a BTK inhibitor (e.g., ibrutinib or AVL-292), or a ceutically able form thereof, wherein the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B- cell-like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma, or le myeloma.

In some embodiments of the methods described herein, the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., ibrutinib or AVL-292), or a pharmaceutically acceptable form f, are administered at certain dosages. In one embodiment, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta/gamma dual tor, or a pharmaceutically acceptable form thereof, in combination with a BTK inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K gamma dual inhibitor, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the BTK tor (e.g., ibrutinib or AVL-292), or a ceutically acceptable form thereof, is stered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, the PI3K delta/gamma dual tor, or a pharmaceutically able form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about mg, or from about 10 mg to about 20 mg daily.

In one embodiment, the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.

In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form f, and a BTK inhibitor, or a pharmaceutically acceptable form thereof. In one embodiment, the BTK inhibitor is ibrutinib, GDC-0834, CGI-560, CGI-1746, HM-71224, 2, ONO-4059, CNX-774, or LFM-A13, or a mixture thereof. In one embodiment, the BTK inhibitor is ibrutinib. In r embodiment, the BTK inhibitor is AVL-292.

In certain embodiments, provided herein is a method of treating, managing, or preventing a cancer or hematologic malignancy in a t comprising administering to the subject a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form thereof, in combination with a BTK inhibitor, or a ceutically acceptable form thereof. In one embodiment, the BTK tor is ibrutinib, 34, CGI-560, CGI- 1746, HM-71224, AVL-292, ONO-4059, CNX-774, or LFM-A13, or a mixture thereof. In one embodiment, the BTK inhibitor is ibrutinib. In another embodiment, the BTK inhibitor is AVL-292. In one ment, the BTK inhibitor is a BTK inhibitor described herein.

In some embodiments of the compositions and methods described herein, Compound 292, or a pharmaceutically acceptable form thereof, is used in combination with a BTK inhibitor (e.g., ibrutinib or 2 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, at certain molar ratios. In one ment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form thereof, and a BTK inhibitor, or a pharmaceutically acceptable form thereof, wherein the molar ratio of Compound 292, or a ceutically acceptable form thereof, to the BTK inhibitor (e.g., ibrutinib or AVL-292), or a pharmaceutically acceptable form thereof, is in the range of from about 1000:1 to about 1:1000.

] In one embodiment of the compositions and methods described herein, the molar ratio of Compound 292, or a pharmaceutically acceptable form thereof, to the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK tor described ), or a pharmaceutically acceptable form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about :1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5. In one embodiment, the molar ratio of the Compound 292, or a pharmaceutically acceptable form thereof, to the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described ), or a pharmaceutically acceptable form f, is about 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1: 5, 1:4, 1:3, 1:2, or 1:1. In r embodiment, the molar ratio is about 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, or 1:6.

In one embodiment, the molar ratio of Compound e BTK inhibitor is from about 0.05 to about 3. In another embodiment, the molar ratio is from about 0.1 to about 2.5. In another embodiment, the molar ratio is from about 0.1 to about 2. In another embodiment, the molar ratio is from about 0.1 to about In one embodiment of the itions and methods described herein, the weight ratio of Compound 292, or a pharmaceutically able form thereof, to ibrutinib, or a pharmaceutically acceptable form thereof, is in the range of from about 7.5–37.5 of Compound 292 to from 42–210 of ibrutinib. In one embodiment, the weight ratio is in the range of from about 1:1.1 to about 1:28. In one embodiment, the weight ratio is in the range of from about 1:2.2 to about 1:14. In one embodiment, the weight ratio is in the range of from about 1:3.3 to about 1:9.3.

In one embodiment of the compositions and methods described herein, the weight ratio of Compound 292, or a pharmaceutically acceptable form thereof, to AVL-292 (or other BTK tor described herein), or a pharmaceutically acceptable form thereof, is in the range of from about 7.5–37.5 of Compound 292 to from 20–100 of AVL-292. In one embodiment, the weight ratio is in the range of from about 1.9:1 to about 1:13.3. In one embodiment, the weight ratio is in the range of from about 1:1.1 to about 1:6.7. In one embodiment, the weight ratio is in the range of from about 1:1.6 to about 1:4.4.

In some embodiments of the compositions and methods described herein, the composition ses Compound 292, or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., nib or AVL-292 or other BTK tor described herein), or a pharmaceutically acceptable form thereof, at certain amounts. In one embodiment, provided herein is a pharmaceutical composition sing a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically able form thereof, and a BTK inhibitor, or a pharmaceutically acceptable form thereof, wherein the composition comprises Compound 292, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.01 mg to about 75 mg and the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically able form thereof, at an amount of in the range of from about 0.01 mg to about 1100 mg.

In one embodiment, the composition comprises nd 292, or a pharmaceutically acceptable form f, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg. In one embodiment, the composition comprises Compound 292, or a pharmaceutically acceptable form f, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg. In one ment, the ition comprises Compound 292, or a pharmaceutically acceptable form thereof, at an amount of about 50 mg, about 37.5 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, or about 1 mg.

In one embodiment, the composition comprises the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 50 mg to about 250 mg. In one embodiment, the composition comprises the BTK inhibitor (e.g., ibrutinib or AVL-292), or a pharmaceutically acceptable form thereof, at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg.

In one embodiment, the composition comprises ibrutinib, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 210 mg, from about 1 mg to about 150 mg, from about 5 mg to about 100 mg, from about 10 mg to about 80 mg, from about 20 mg to about 60 mg, or from about 30 mg to about 50 mg. In one embodiment, the composition comprises ibrutinib, or a pharmaceutically acceptable form f, at an amount of less than about 210 mg, less than about 150 mg, less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 50 mg, less than about mg, less than about 20 mg, or less than about 10 mg. In one embodiment, the composition comprises nib, or a ceutically acceptable form thereof, at an amount of about 210 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, or about 10 mg.

In one embodiment, the composition comprises AVL-292, or a ceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 100 mg, from about 0.5 mg to about 80 mg, from about 1 mg to about 60 mg, from about 5 mg to about 50 mg, from about 10 mg to about 40 mg, or from about 20 mg to about 30 mg. In one embodiment, the composition comprises AVL-292, or a pharmaceutically acceptable form thereof, at an amount of less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about mg, less than about 10 mg, or less than about 5 mg. In one embodiment, the composition comprises AVL-292, or a pharmaceutically acceptable form thereof, at an amount of about 100 mg, about 80 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 10 mg, or about 5 mg.

In certain embodiments, provided herein is a method of treating, managing, or preventing a cancer or hematologic malignancy in a subject comprising administering to the subject a therapeutically effective amount of Compound 292, or a pharmaceutically able form thereof, in combination with a BTK inhibitor, or a pharmaceutically acceptable form f, n the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma nal center -like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma, or multiple myeloma. In one embodiment, the BTK inhibitor is ibrutinib. In r embodiment, the BTK inhibitor is AVL-292.

In some embodiments of the methods described herein, Compound 292, or a pharmaceutically acceptable form f, and the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, are administered at certain s. In one embodiment, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a eutically effective amount of Compound 292: nd 292, or a pharmaceutically acceptable form thereof, in combination with a BTK inhibitor, or a pharmaceutically acceptable form thereof, wherein Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the BTK inhibitor (e.g., ibrutinib or AVL-292), or a ceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily. In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily. In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is stered at a dosage of about 50 mg, about 37.5 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, or about 1 mg daily.

In one embodiment, the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 50 mg to about 250 mg daily. In one embodiment, the BTK inhibitor (e.g., ibrutinib or AVL-292), or a ceutically acceptable form thereof, is administered at a dosage of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.

In one embodiment, ibrutinib, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 210 mg, from about 1 mg to about 150 mg, from about mg to about 100 mg, from about 10 mg to about 80 mg, from about 20 mg to about 60 mg, or from about mg to about 50 mg daily. In one embodiment, ibrutinib, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 210 mg, less than about 150 mg, less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 50 mg, less than about 30 mg, less than about 20 mg, or less than about 10 mg daily. In one embodiment, nib, or a pharmaceutically acceptable form f, is administered at a dosage of about 210 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, or about 10 mg daily.

In one ment, AVL-292, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 100 mg, from about 0.5 mg to about 80 mg, from about 1 mg to about 60 mg, from about 5 mg to about 50 mg, from about 10 mg to about 40 mg, or from about 20 mg to about 30 mg daily. In one embodiment, AVL-292, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about mg, or less than about 5 mg daily. In one embodiment, AVL-292, or a ceutically acceptable form thereof, is administered at a dosage of about 100 mg, about 80 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 10 mg, or about 5 mg daily.

In one embodiment, the BTK inhibitor (e.g., nib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before the PI3K inhibitor (e.g., Compound 292), or a ceutically acceptable form f, is administered. In another embodiment, the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, is administered concurrently with the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, in a single dosage form or separate dosage forms. In yet another embodiment, the BTK inhibitor (e.g., nib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form f, is administered to the subject at least 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, is administered. In one embodiment, the BTK inhibitor is ibrutinib. In another embodiment, the BTK inhibitor is AVL-292.

In certain embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, are in a single dosage form. In other embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., ibrutinib or AVL-292), or a pharmaceutically able form thereof, are in separate dosage forms.

In certain ments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), are administered via a same route, e.g., both are administered . In other embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described ), are administered via different routes, e.g., one is stered orally and the other is administered enously. In one embodiment, nd 292 is stered orally once per day and ibrutinib is administered orally once per day. In one embodiment, Compound 292 is administered orally once per day and AVL-292 is administered orally once per day.

In certain embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the BTK tor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein), or a pharmaceutically acceptable form thereof, are the only therapeutically active ients of the compositions and methods provided herein. In other embodiments, the itions provided herein comprise and the methods provided herein use at least one more therapeutically active ingredient. In one embodiment, the compositions provided herein comprise and the methods provided herein use a PI3K delta selective inhibitor (e.g., GS1101), a PI3K gamma dual inhibitor, and a BTK inhibitor (e.g., ibrutinib or AVL-292 or other BTK inhibitor described herein).

Combinations of PI3K inhibitors and Anti-CD20 dies ] Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and an anti-CD20 antibody, or a pharmaceutically acceptable form thereof.

Also provided herein are methods of treating, managing, or preventing a cancer or hematologic malignancy in a subject comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, in combination with an anti-CD20 antibody, or a pharmaceutically acceptable form thereof.

Anti-CD20 antibodies that can be used in the compositions and methods ed herein are provided herein and elsewhere. In one embodiment, the anti-CD20 antibody is obinutuzumab (GA101). In another embodiment, the anti-CD20 antibody is rituximab.

] In certain embodiments, provided herein is a pharmaceutical ition comprising a therapeutically ive amount of a PI3K delta selective inhibitor, or a pharmaceutically able form thereof, and an anti-CD20 antibody, or a pharmaceutically acceptable form thereof. In one embodiment, the PI3K delta selective inhibitor is GS1101 (CAL-101). In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab, or a mixture thereof. In one embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is rituximab. In one ment, provided herein is a pharmaceutical composition comprising a therapeutically ive amount of GS1101, or a pharmaceutically able form thereof, and obinutuzumab, or a pharmaceutically acceptable form thereof. In another embodiment, provided herein is a pharmaceutical ition comprising a eutically effective amount of GS1101, or a pharmaceutically acceptable form thereof, and rituximab, or a pharmaceutically acceptable form thereof.

In one embodiment of the compositions and methods described herein, the molar ratio of the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, to the anti- CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about :1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.

In one ment, the composition comprises the PI3K delta selective inhibitor (e.g., ), or a pharmaceutically able form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg.

In one embodiment, the composition comprises the PI3K delta ive tor (e.g., GS1101), or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.

In certain embodiments, provided herein is a method of treating, managing, or preventing a cancer or logic malignancy in a subject comprising stering to the subject a therapeutically effective amount of a PI3K delta selective tor (e.g., GS1101), or a pharmaceutically acceptable form thereof, in combination with an anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, wherein the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), follicular lymphoma, indolent non-Hodgkin lymphoma, T-cell lymphoma, mantle cell lymphoma, or multiple myeloma.

In some embodiments of the methods described herein, the PI3K delta selective inhibitor (e.g., GS1101), or a ceutically acceptable form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form f, are administered at certain s. In one embodiment, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, in combination with an anti-CD20 antibody, or a pharmaceutically acceptable form thereof, wherein the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically able form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the anti-CD20 dy (e.g., obinutuzumab or rituximab), or a pharmaceutically able form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, the PI3K delta ive inhibitor (e.g., GS1101), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about mg to about 25 mg, or from about 10 mg to about 20 mg daily.

In one embodiment, the PI3K delta selective inhibitor (e.g., GS1101), or a pharmaceutically acceptable form f, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.

In n ments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and an anti-CD20 antibody, or a ceutically acceptable form thereof. In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab, or a mixture thereof. In one embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is rituximab.

In one embodiment of the compositions and methods described herein, the molar ratio of the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form f, to the D20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.

In one ment, the composition comprises the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about mg to about 25 mg, or from about 10 mg to about 20 mg.

In one embodiment, the composition comprises the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg.

] In certain embodiments, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the t a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, in combination with an anti- CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, wherein the cancer is diffuse large B-cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), ular ma, T-cell lymphoma, mantle cell lymphoma, or multiple myeloma.

In some embodiments of the s described herein, the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically able form thereof, are administered at n dosages. In one embodiment, provided herein is a method of ng, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of a PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, in combination with an D20 antibody, or a pharmaceutically acceptable form thereof, wherein the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the D20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, the PI3K gamma dual tor, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about mg, or from about 10 mg to about 20 mg daily.

In one embodiment, the PI3K delta/gamma dual inhibitor, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily.

In one embodiment, the anti-CD20 dy (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered at a dosage amount in the range of from about 0.1 mg to about 10,000 mg, from about 0.1 mg to about 7500 mg, from about 0.1 mg to about 5000 mg, from about 1 mg to about 2500 mg, from about 1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 750 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 900 mg to about 1000 mg. In one embodiment, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered at a dosage amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg.

In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form thereof, and an anti-CD20 antibody, or a pharmaceutically acceptable form thereof. In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab, or a mixture thereof.

In one embodiment, the D20 antibody is obinutuzumab. In r embodiment, the D20 antibody is rituximab.

In certain embodiments, provided herein is a method of treating, ng, or preventing a cancer or hematologic ancy in a subject comprising administering to the subject a therapeutically ive amount of Compound 292: Compound 292, or a pharmaceutically acceptable form f, in combination with an anti-CD20 antibody, or a pharmaceutically acceptable form thereof. In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, tositumomab,131I tositumomab, 90Y ibritumomab, 111I ibritumomab, or ofatumumab, or a mixture thereof. In one embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is rituximab.

In some embodiments of the compositions and s described herein, Compound 292, or a pharmaceutically able form thereof, is used in combination with an anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically able form thereof, at certain molar ratios. In one embodiment, provided herein is a pharmaceutical ition comprising a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically able form thereof, and an anti-CD20 antibody, or a pharmaceutically acceptable form f, wherein the molar ratio of Compound 292, or a pharmaceutically acceptable form f, to the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically able form thereof, is in the range of from about 1000:1 to about 1:1000.

In one embodiment of the compositions and methods described herein, the molar ratio of Compound 292, or a pharmaceutically acceptable form thereof, to the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is in the range of from about 500:1 to about 1:500, from about 400:1 to about 1:400, from about 300:1 to about 1:300, from about 200:1 to about 1:200, from about 100:1 to about 1:100, from about 75:1 to about 1:75, from about 50:1 to about 1:50, from about 40:1 to about 1:40, from about 30:1 to about 1:30, from about 20:1 to about 1:20, from about 10:1 to about 1:10, or from about 5:1 to about 1:5.

In some embodiments of the compositions and methods described herein, the composition ses Compound 292, or a pharmaceutically acceptable form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, at certain amounts. In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form thereof, and an D20 antibody, or a pharmaceutically acceptable form thereof, wherein the composition comprises Compound 292, or a pharmaceutically acceptable form f, at an amount in the range of from about 0.01 mg to about 75 mg and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, at an amount of in the range of from about 0.01 mg to about 1100 mg.

In one embodiment, the composition ses Compound 292, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg. In one ment, the composition comprises Compound 292, or a pharmaceutically acceptable form thereof, at an amount of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg. In one embodiment, the composition ses Compound 292, or a pharmaceutically acceptable form thereof, at an amount of about 50 mg, about 37.5 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, or about 1 mg.

In one embodiment, the composition comprises the anti-CD20 antibody (e.g., obinutuzumab or mab), or a pharmaceutically able form thereof, at an amount in the range of from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 50 mg to about 250 mg. In one embodiment, the composition comprises the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, at an amount of less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 In one embodiment, the ition comprises the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically able form thereof, at an amount in the range of from about 0.1 mg to about 10,000 mg, from about 0.1 mg to about 7500 mg, from about 0.1 mg to about 5000 mg, from about 1 mg to about 2500 mg, from about 1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 750 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 900 mg to about 1000 mg.

In certain embodiments, provided herein is a method of ng, managing, or preventing a cancer or hematologic malignancy in a subject sing administering to the subject a therapeutically effective amount of Compound 292, or a pharmaceutically acceptable form thereof, in combination with an anti-CD20 antibody, or a pharmaceutically acceptable form thereof, wherein the cancer is diffuse large B- cell lymphoma (activated B-cell-like), diffuse large B-cell lymphoma (germinal center B-cell-like), follicular lymphoma, T-cell lymphoma, mantle cell lymphoma, or le myeloma. In one ment, the anti-CD20 antibody is obinutuzumab. In r embodiment, the anti-CD20 antibody is rituximab.

In some embodiments of the methods described herein, Compound 292, or a pharmaceutically acceptable form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, are administered at n dosages. In one embodiment, provided herein is a method of treating, managing, or preventing a cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound 292: Compound 292, or a pharmaceutically acceptable form f, in combination with an anti-CD20 antibody, or a pharmaceutically acceptable form thereof, wherein Compound 292, or a pharmaceutically acceptable form f, is stered at a dosage of in the range of from about 0.01 mg to about 75 mg daily and the anti- CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.01 mg to about 1100 mg daily.

In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 75 mg, from about 1 mg to about 75 mg, from about 5 mg to about 75 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 25 mg, or from about 10 mg to about 20 mg daily. In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 25 mg, less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, or less than about 10 mg daily. In one embodiment, Compound 292, or a pharmaceutically acceptable form thereof, is administered at a dosage of about 50 mg, about 37.5 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, or about 1 mg daily.

In one embodiment, the anti-CD20 antibody (e.g., obinutuzumab or mab), or a pharmaceutically acceptable form thereof, is administered at a dosage of in the range of from about 0.1 mg to about 1500 mg, from about 0.1 mg to about 1000 mg, from about 0.1 mg to about 800 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 50 mg to about 250 mg daily. In one embodiment, the anti-CD20 antibody (e.g., uzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered at a dosage of less than about 1500 mg, less than about 1000 mg, less than about 800 mg, less than about 750 mg, less than about 500 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 75 mg, less than about 50 mg, or less than about 25 mg daily.

In one embodiment, the D20 antibody (e.g., obinutuzumab or rituximab), or a ceutically acceptable form thereof, is administered to the subject at least 5 s, 15 s, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, is administered. In another embodiment, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered concurrently with the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, in a single dosage form or te dosage forms. In yet another embodiment, the anti-CD20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, is administered to the subject at least 5 s, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after the PI3K tor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, is administered. In one embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is rituximab.

In certain embodiments, the PI3K inhibitor (e.g., Compound 292), or a ceutically acceptable form thereof, and the anti-CD20 dy (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, are in a single dosage form. In other embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the D20 antibody (e.g., obinutuzumab or rituximab), or a pharmaceutically acceptable form thereof, are in separate dosage forms.

In certain embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically able form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), are administered via a same route. In other embodiments, the PI3K inhibitor (e.g., nd 292), or a pharmaceutically acceptable form thereof, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab), are administered via different routes, e.g., one is administered orally and the other is administered intravenously. In one embodiment, Compound 292 is administered orally once per day and obinutuzumab is administered enously. In one embodiment, Compound 292 is administered orally once per day and rituximab is administered intravenously.

In certain embodiments, the PI3K inhibitor (e.g., Compound 292), or a pharmaceutically acceptable form thereof, and the anti-CD20 antibody (e.g., uzumab or rituximab), or a pharmaceutically acceptable form thereof, are the only therapeutically active ingredients of the compositions and methods provided herein. In other ments, the compositions provided herein comprise and the methods ed herein use at least one more therapeutically active ient. In one embodiment, the compositions provided herein comprise and the s provided herein use a PI3K delta selective inhibitor (e.g., GS1101), a PI3K delta/gamma dual inhibitor, and an anti-CD20 antibody (e.g., obinutuzumab or mab).

Biomarkers and Screening Methods In one embodiment, provided herein is a biomarker (e.g., a diagnostic biomarker, a predictive biomarker, or a stic biomarker), for use in a method provided herein, or for use in treating or preventing a cancer or disease provided herein (e.g., a hematologic malignancy). In one embodiment, the biomarker provided herein include, but are not limited to: a target biomarker, a signaling pathway biomarker, a protein on ker, a protein expression biomarker, a gene mutation biomarker, a DNA copy number biomarker, a gene expression ker, a cytokine biomarker, a chemokine biomarker, a matrix metalloproteinase biomarker, or a biomarker for particular cancer cells. In one embodiment, the biomarker can be used to evaluate the prognosis, and/or sensitivity to a treatment agent, of a particular type of cancer or disease, or of a particular patient or group of patients.

] In one embodiment, the biomarker provided herein is a target biomarker, such as, e.g., a biomarker to determine the protein and/or RNA expression of one or more particular PI3K isoform; e.g., a biomarker for PI3K-α expression, for PI3K-β expression, for PI3K-δ expression, or for PI3K-γ expression, or combinations thereof. In other embodiments, the target biomarker is DNA alteration of one or more particular PI3K isoforms (e.g., mutation, copy number variation, or etic modification). In one embodiment, the biomarker es IHC of a particular protein target. In one embodiment, the biomarker involves the RNA (e.g., mRNA) (e.g., ISH of mRNA) of a particular protein target. In one embodiment, the biomarker involves the DNA of a particular protein target including genetic alteration such as somatic mutation, copy number alterations such as amplification or deletion, and chromosomal translocation as well as epigenetic alteration such as methylation and histone cation. In one embodiment, the biomarker es miRNA which regulates expression of a ular n target.

In one embodiment, the biomarker provided herein is a signaling pathway biomarker, such as, e.g., a PTEN pathway biomarker and/or a biomarker of signaling pathway activation such as pAKT, pS6, and/or 0 (e.g., an IHC biomarker, a DNA tion biomarker, a DNA deletion biomarker, a DNA copy number biomarker, or a DNA mutation biomarker). In one embodiment, the ker provided herein is a mutation biomarker, such as, a protein mutation biomarker or a gene mutation biomarker, to assess the mutation of one or more s, such as, e.g., CXCR4, IGH7, KRAS, NRAS, A20, , CD79B, TP53, CARD11, MYD88, GNA13, MEF2B, TNFRSF14, MLL2, BTG1, EZH2, NOTCH1, JAK1, JAK2, PTEN, FBW7, PHF6, IDH1, IDH2, TET2, FLT3, KIT, NPM1, CEBPA, DNMT3A, BAALC, RUNX1, ASXL1, IRF8, POU2F2, WIF1, ARID1A, MEF2B, TNFAIP3, PIK3R1, MTOR, PIK3CA, PI3Kδ, and/or PI3Kγ. In one embodiment, the biomarker provided herein is an expression biomarker, such as, a protein expression biomarker, a gene expression ker, to assess the expression of one or more targets, or the upregulation or downregulation of a pathway, such as, e.g., pERK IHC biomarker or pERK expression biomarker, for example, to assess RAS or PI3K pathway activation.

In one embodiment, the biomarker ed herein is a cytokine biomarker, including, but not limited to, IL-2, IL-4, IL-7, IL-9, IL-10, IL-12 (p40), IL-15, IL-16, IL-21, TNFα and TGFα. In one embodiment, the biomarker provided herein is a chemokine biomarker, ing, but not limited to, CCL1, CXCL10, CXCL12, CXCL13, CCL2, and CCL3. In one embodiment, the biomarker provided herein is a serum cytokine biomarker. In one embodiment, the biomarker provided herein is a serum chemokine biomarker. In one embodiment, the biomarker provided herein relates to gene expression patterns of one or more cytokines, cytokine receptors, ines, and/or chemokine receptors. In one embodiment, the biomarker provided herein is at least one, at least two, or at least three of CXCL13, CCL3, CCL4, CCL17, CCL22, IL-2, IFN-γ, GM-CSF or TNF-α, or a combination f. In another embodiment, the biomarker provided herein is a matrix metalloproteinases. In one embodiment, the matrix oproteinase is MMP- 9. In another embodiment, the matrix metalloproteinase is MMP-12. In another embodiment, the biomarker is CCL3 and/or CCL4.

] In one embodiment, the biomarkers provided herein can be used to identify, diagnose, predict efficacy, predict long term clinical outcome, predict prognosis, and/or select patients for a treatment described herein. In one embodiment, the biomarkers provided herein can be used for subsets of ts with different prognostic s, such as, e.g., Rai stages, β2-microglobulin, diverse cytogenetics including trisomy 12, del13q, 17p, PTEN, and 11q mutations or deletions, ZAP-70 status, CD38 status, CD49d status, and/or IgHV gene mutations. In one embodiment, the biomarker is 11q deletion. In another embodiment, the biomarker is PTEN deletion and/or decreased PTEN expression. In another embodiment, the biomarker is 17p deletion. In some embodiments, a method of determining a subject’s tibility to treatment comprising detecting the ce of a biomarker in a sample from the subject is sed. In some embodiments, the presence of one or more of Rai stages, β2-microglobulin, e cytogenetics including trisomy 12, del13q, 17p, PTEN, and 11q mutations or ons, ZAP-70 status, CD38 , CD49d status, and/or IgHV gene mutations indicates that the subject has an increased susceptibility to treatment with a PI3K inhibitor. In some embodiments, the presence of 11q deletion indicates that the subject has an increased tibility to treatment with a PI3K inhibitor. In some embodiments, the presence of 17p deletion indicates that the subject has an increased susceptibility to treatment with a PI3K inhibitor. In some embodiments, the presence of PTEN deletion and/or decreased PTEN expression indicates that the subject has an sed susceptibility to ent with a PI3K inhibitor. In some embodiments, the presence of pS6 indicates that the subject has a decreased susceptibility to treatment with a PI3K inhibitor.

In some embodiments, the method further comprises administering a PI3K tor to a subject identified as having an increased susceptibility to treatment. In some embodiments, the PI3K inhibitor is compound 292. In some embodiments, the method further comprises using the information to stratify subjects have increased likelihood of response to a treatment from those with a decreased likelihood of response to a treatment.

In one embodiment, a method for predicting the likelihood that a subject will d therapeutically to a method of treating cancer is disclosed comprising administering a PI3K tor (e.g., compound 292), said method comprises: (a) measuring the expression level of a biomarker in a biological cancer sample of said subject; (b) ining the presence of or level of said biomarker in said cancer sample relative to a ermined level of said biomarker, (c) classifying said subject as having an increased or decreased likelihood of responding therapeutically to said method of treating cancer if said patient has a biomarker, and (d) stering a PI3K inhibitor to said patient classified as having an increased hood of responding. For example, detection of one of more of Rai stages, β2-microglobulin, diverse cytogenetics including trisomy 12, del13q, 17p, PTEN, and 11q mutations or deletions, ZAP-70 status, CD38 status, CD49d status, and/or IgHV gene mutations can be classified as having an increased likelihood of se. For example, detection of one of more of pS6 can be classified as having a decreased hood of response. In one embodiment, detection of 11q deletion can be classified as having an increased likelihood of response. In another embodiment, detection of 17p deletion can be classified as having an increased likelihood of response. In another embodiment, ion of PTEN deletion and/or decreased PTEN expression can be classified as having an increased likelihood of response. In one embodiment, the PI3K inhibitor is administered at a ermined dosage for a predetermined period of time.

In some embodiments, once the treatment begins with patients with an increased likelihood of response (e.g., patients identified based on the ion of ), the actual efficacy of the treatment can also be monitored by assessing the modulation of a second set of biomarkers such as pAKT, c-MYC, NOTCH1, CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, IL-16, MMP-9, CCL17, CCL22, CCL1, CXCL10, MMP- 12, and combinations thereof.

In one specific embodiment, provided herein is a method of monitoring the efficacy of a compound ed herein (e.g., nd 292) in a cancer patient having 11q deletion comprising: (a) obtaining a first biological sample from the t; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, , CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, IL-16, MMP-9, CCL17, CCL22, CCL1, CXCL10, MMP-12, or a ation thereof; (c) administering the treatment compound to the patient; (d) thereafter obtaining a second biological sample from the t; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; wherein the patient is responsive to the treatment if the level of the biomarker in the second biological sample of the patient is decreased as compared to the level of the biomarker in the first biological sample of the patient. In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a ma or a leukemia. In another embodiment, the cancer is T cell lymphoma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In another embodiment, the cancer is CTCL. In r embodiment, the cancer is CLL. In r embodiment, the cancer is SLL. In one embodiment, the treatment compound is administered at a predetermined dosage for a ermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the responsive patient at a predetermined dosage for a predetermined period of time.

In another specific embodiment, provided herein is a method of monitoring the efficacy of a compound provided herein (e.g., Compound 292) in a cancer patient having 17p deletion comprising: (a) obtaining a first biological sample from the patient; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, NOTCH1, CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, IL-16, MMP-9, CCL17, CCL22, CCL1, , MMP-12, or a combination thereof; (c) administering the treatment compound to the patient; (d) thereafter obtaining a second biological sample from the patient; (e) determining the level of the biomarker in the second ical sample; and (f) comparing the levels of the biomarker in the first and second biological samples; wherein the patient is responsive to the treatment if the level of the biomarker in the second biological sample of the patient is decreased as compared to the level of the ker in the first biological sample of the t. In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a lymphoma or a leukemia. In another embodiment, the cancer is T cell lymphoma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In r embodiment, the cancer is CTCL. In another embodiment, the cancer is CLL. In another ment, the cancer is SLL. In one embodiment, the treatment compound is stered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of stering the treatment compound to the sive patient at a predetermined dosage for a predetermined period of time.

In another specific embodiment, provided herein is a method of monitoring the efficacy of a compound provided herein (e.g., nd 292) in a cancer patient having PTEN deletion and/or decreased PTEN expression comprising: (a) obtaining a first biological sample from the patient; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, , CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, IL-16, MMP-9, CCL17, CCL22, CCL1, CXCL10, MMP-12, or a combination thereof; (c) administering the treatment compound to the patient; (d) fter ing a second biological sample from the patient; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; wherein the patient is responsive to the treatment if the level of the biomarker in the second biological sample of the patient is decreased as compared to the level of the biomarker in the first biological sample of the patient. In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a ma or a leukemia. In another embodiment, the cancer is T cell lymphoma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In another embodiment, the cancer is CTCL. In another embodiment, the cancer is CLL. In r embodiment, the cancer is SLL. In one embodiment, the treatment nd is administered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the responsive patient at a predetermined dosage for a predetermined period of time.

In another ic embodiment, provided herein is a method of monitoring the efficacy of a compound provided herein (e.g., Compound 292) in a cancer patient having 13q deletion sing: (a) obtaining a first biological sample from the patient; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, NOTCH1, CXCL13, CCL3, CCL4, IL-10, TNFα, 40, IL-16, MMP-9, CCL17, CCL22, CCL1, , MMP-12, or a combination thereof; (c) administering the treatment compound to the patient; (d) thereafter obtaining a second biological sample from the patient; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second ical samples; wherein the patient is responsive to the treatment if the level of the biomarker in the second biological sample of the patient is decreased as compared to the level of the biomarker in the first biological sample of the patient. In one embodiment, the cancer is a logical cancer. In one embodiment, the cancer is a lymphoma or a leukemia. In another embodiment, the cancer is T cell lymphoma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In r embodiment, the cancer is CTCL. In another embodiment, the cancer is CLL. In r embodiment, the cancer is SLL. In one embodiment, the treatment compound is stered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further ses a step of administering the treatment compound to the responsive patient at a predetermined dosage for a predetermined period of time.

In another specific ment, provided herein is a method of monitoring the efficacy of a compound provided herein (e.g., Compound 292) in a cancer patient having y 12 deletion comprising: (a) ing a first biological sample from the patient; (b) determining the level of a biomarker in the first biological sample, n the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, NOTCH1, CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, IL-16, MMP-9, CCL17, CCL22, CCL1, CXCL10, MMP-12, or a combination thereof; (c) administering the treatment compound to the patient; (d) thereafter obtaining a second biological sample from the patient; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; n the patient is responsive to the treatment if the level of the biomarker in the second biological sample of the t is decreased as compared to the level of the biomarker in the first biological sample of the patient. In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a lymphoma or a leukemia. In r embodiment, the cancer is T cell lymphoma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In another ment, the cancer is CTCL. In another embodiment, the cancer is CLL. In another embodiment, the cancer is SLL. In one embodiment, the treatment compound is administered at a predetermined dosage for a predetermined period of time. In one ment, the method further comprises a step of administering the treatment compound to the responsive t at a predetermined dosage for a predetermined period of time.

In another specific embodiment, ed herein is a method of monitoring the efficacy of a compound provided herein (e.g., Compound 292) in a cancer patient having IgHV gene mutation comprising: (a) obtaining a first biological sample from the patient; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is at least one, at least two, or at least three of pAKT, c-MYC, NOTCH1, CXCL13, CCL3, CCL4, IL-10, TNFα, 40, IL-16, MMP-9, CCL17, CCL22, CCL1, CXCL10, MMP-12, or a combination thereof; (c) administering the treatment compound to the patient; (d) thereafter ing a second biological sample from the patient; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; n the patient is responsive to the ent if the level of the biomarker in the second biological sample of the patient is decreased as compared to the level of the biomarker in the first biological sample of the patient. In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a lymphoma or a leukemia. In another embodiment, the cancer is T cell ma. In another embodiment, the cancer is NHL. In another embodiment, the cancer is iNHL. In another embodiment, the cancer is CTCL. In another embodiment, the cancer is CLL. In another embodiment, the cancer is SLL. In one embodiment, the treatment compound is stered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the responsive patient at a predetermined dosage for a predetermined period of time.

In one embodiment, the biomarker provided herein is a biomarker for cancer cells (e.g., a particular cancer cell line, a particular cancer cell type, a particular cell cycle profile).

] In exemplary embodiments, the biomarker provided herein relates to gene expression profiling of a patient or group of ts, e.g., as a predictive biomarker for PI3Kδ and/or PI3Kγ pathway activation, or as a predictive ker for response to a treatment described herein. In ary embodiments, the biomarker provided herein relates to a gene expression classifier, e.g., as a predictive biomarker for PI3Kδ and/or PI3Kγ expression or activation (e.g., differential expression or tion in the ABC, GCB, oxidative phosphorylation (Ox Phos), B-cell receptor/proliferation (BCR), or host response (HR) subtypes of DLBCL).

] In one embodiment, provided herein are methods ng to the use of mRNAs or proteins as biomarkers to ascertain the effectiveness of a therapy provided herein. In one embodiment, mRNA or protein levels can be used to determine whether a particular agent is likely to be successful in the treatment of a particular cancer or hematologic malignancy.

As used herein, and unless otherwise specified, a ical marker or biomarker is a substance whose detection indicates a particular ical state, such as, for example, the presence of cancer or logic malignancy. In some embodiments, kers can either be determined dually, or several biomarkers can be measured simultaneously.

In some embodiments, a biomarker indicates a change in the level of mRNA expression that can correlate with the risk or progression of a disease, or with the susceptibility of the e to a given treatment. In some embodiments, the biomarker is a c acid, such as a mRNA, miRNA or cDNA.

In additional embodiments, a biomarker indicates a change in the level of polypeptide or protein expression that can correlate with the risk, susceptibility to treatment, or progression of a disease. In some embodiments, the biomarker can be a polypeptide or protein, or a fragment thereof. The relative level of specific proteins can be determined by methods known in the art. For example, antibody based methods, such as an immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods can be used.

In one embodiment, the methods ed herein encompass methods for screening or identifying patients having a cancer or hematologic malignancy, for treatment with a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof). In one ment, the method comprises obtaining a biological sample from a subject, and measuring the level of at least one, at least two, or at least three biomarker in the biological sample, where an abnormal baseline level (e.g., higher or lower than the level in a control group) of the biomarker indicates a higher hood that the subject has a cancer or hematologic malignancy that can be treated with a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof).

In one embodiment, the method optionally ses isolating or purifying mRNA from the biological sample, amplifying the mRNA ripts (e.g., by RT-PCR). In one embodiment, the level of a biomarker is the level of an mRNA or a protein. In one ment, the method further comprises a step of stering the treatment compound to the patient having a higher likelihood at a predetermined dosage for a predetermined period of time.

In some embodiments, provided herein are methods of predicting the sensitivity to treatment with a compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof) in a t having a cancer or hematologic malignancy. The method ses obtaining a biological sample from the patient, and measuring the level of at least one, at least two, or at least three ker in the biological sample, where an abnormal baseline level (e.g., higher or lower than the level in a control group) of the biomarker indicates a higher hood that the patient will be sensitive to treatment with a compound provided herein (e.g., a compound of Formula I (e.g., nd 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal , clathrate, or polymorph thereof). In one embodiment, the method optionally comprises isolating or ing mRNA from the biological sample, amplifying the mRNA transcripts (e.g., by RT-PCR). In one embodiment, the level of a biomarker is the level of an mRNA or a protein. In one embodiment, the method further comprises a step of administering the treatment nd to the patient having a higher likelihood at a predetermined dosage for a predetermined period of time.

In one embodiment, provided herein is a method for treating or managing cancer or hematologic malignancy in a patient, comprising: (i) obtaining a biological sample from the patient and measuring the level of at least one, at least two, or at least three biomarker in the biological sample; and (ii) administering to the patient with an abnormal baseline level of at least one, at least two, or at least three biomarker (e.g., higher or lower than the level in a control group) a therapeutically effective amount of a compound ed herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers f, or a pharmaceutically able salt, solvate, hydrate, co-crystal, ate, or polymorph thereof). In one embodiment, step (i) optionally comprises isolating or purifying mRNA from the biological sample, amplifying the mRNA transcripts (e.g., by RT-PCR). In one embodiment, the level of a biomarker is the level of an mRNA or a protein. In one embodiment, the treatment compound is administered at a predetermined dosage for a predetermined period of time.

In another embodiment, provided herein is a method of monitoring se to treatment with a compound provided herein (e.g., a nd of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof) in a patient having a cancer or hematologic malignancy. In one embodiment, the method comprises obtaining a biological sample from the patient, measuring the level of at least one, at least two, or at least three biomarker in the biological sample, stering a compound provided herein (e.g., a nd of Formula I (e.g., Compound 292), or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, ate, or polymorph thereof) to the patient, thereafter obtaining a second biological sample from the patient, measuring the level of the biomarker(s) in the second biological sample, and comparing the two levels of the biomarker(s), where an altered (e.g., increased or decreased) level of the biomarker after treatment indicates the likelihood of an effective tumor response. In one ment, a sed level of biomarker after treatment indicates the likelihood of effective tumor response. In another embodiment, an increased level of biomarker after treatment indicates the likelihood of effective tumor response. The level of biomarker can be, for example, the level of an mRNA or a protein. The expression in the treated sample can increase, for example, by about 1.5X, 2.0X, 3X, 5X, or more. In one embodiment, the ent compound is administered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further ses a step of administering the treatment compound to the patient having likelihood of effective tumor response at a predetermined dosage for a predetermined period of time.

] In yet another embodiment, a method for monitoring patient compliance with a drug treatment protocol is provided. In one embodiment, the method comprises obtaining a biological sample from the patient, ing the level of at least one, at least two, or at least three biomarker in the sample, and determining if the level is increased or decreased in the patient sample compared to the level in a control untreated sample, wherein an increased or decreased level indicates patient compliance with the drug treatment protocol. In one embodiment, the level of at least one biomarker is increased. The biomarker level monitored can be, for example, mRNA level or protein level. The expression in the treated sample can increase, for example, by about 1.5X, 2.0X, 3X, 5X, or more. In one ment, the method further comprises a step of administering the ent nd to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

A gene expression signature characteristic of a ular type of cancer or hematologic malignancy can also be evaluated. The gene expression signature can e analysis of the level (e.g., expression) of one or more genes involved in the cancer or hematologic malignancy.

A gene ation signature characteristic of a particular type of cancer or hematologic malignancy can also be evaluated. The gene methylation signature can include analysis of the level (e.g., expression) of one or more genes involved in the cancer or hematologic ancy.

Any combination of the biomarkers provided herein can be used to te a subject.

In one embodiment, the ker used in the methods provided herein is the expression level of PI3K-δ. In one embodiment, the biomarker used in the methods provided herein is the sion level of PI3K-γ. In one embodiment, the biomarker used in the methods provided herein is the expression level of . In one embodiment, the biomarker used in the methods provided herein is the expression level of PI3K-α.

In one embodiment, the biomarker used in the methods provided herein is the expression level of mRNA of . In one embodiment, the biomarker used in the methods provided herein is the expression level of mRNA of PI3K-γ. In one embodiment, the biomarker used in the methods provided herein is the expression level of mRNA of PI3K-β. In one embodiment, the biomarker used in the methods provided herein is the expression level of mRNA of PI3K-α. In some embodiments, the expression level of mRNA for a PI3K isoform is determined from a whole blood sample from the subject. In one embodiment, the expression level of mRNA for a PI3K isoform is determined by techniques known in the art (e.g., RNA expression).

In one embodiment, the biomarker used in the methods provided herein is the sion level of PI3K-δ protein. In one embodiment, the biomarker used in the methods provided herein is the expression level of PI3K-γ protein. In one embodiment, the biomarker used in the methods provided herein is the expression level of PI3K-β n. In one embodiment, the biomarker used in the methods ed herein is the expression level of PI3K-α protein.

In one embodiment, the biomarker used in the methods provided herein is high level of expression, increased DNA amplification, and/or ion of gene on of PI3K-δ. In one embodiment, the biomarker used in the methods provided herein is high level of expression, increased DNA ication, and/or detection of gene mutation of PI3K-γ. In one embodiment, the biomarker used in the methods provided herein is high level of expression, increased DNA amplification, and/or detection of gene on of PI3K-β. In one embodiment, the biomarker used in the methods provided herein is high level of expression, increased DNA amplification, and/or ion of gene mutation of PI3K-α.

In certain embodiments, the biomarker used in the methods provided herein is the detection of the normal level of expression of a PI3K isoform in certain cell types. In one embodiment, the biomarker used in the methods provided herein is the detection of the normal level of expression of PI3K-γ and/or PI3K-δ in normal immune cells.

In one embodiment, the ker used in the methods provided herein is a germline SNP that has been previously linked to susceptibility to cancer or hematologic ancy.

In one embodiment, the biomarker used in the methods provided herein is a ne SNP that has been previously linked to pathways of drug metabolism or transport (e.g., CYP3A family and/or other drug metabolizing enzymes that have been associated with metabolism of a nd provided herein).

] In specific embodiments, provided herein is a method of identifying a subject who is likely to be sive to a treatment of a cancer or disease, e.g., a hematologic malignancy, with a treatment compound (e.g., a nd provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is described herein (e.g., a ker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a ation thereof)); and (b) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered (e.g., high or low) as compared to the reference level of the biomarker. In one ment, the method further comprises a step of administering the treatment compound to the patient having a higher hood at a predetermined dosage for a predetermined period of time.

In some embodiments, provided herein is a method for predicting the likelihood that a subject will respond therapeutically to a method of ng cancer comprising administering a PI3K inhibitor (e.g., compound 292), said method comprises: (a) administering the PI3K inhibitor, (b) measuring the expression level of a biomarker in a biological cancer sample of said subject 8 days following administering of said PI3K inhibitor; (c) determining the level of said biomarker in said cancer sample relative to a predetermined level of said biomarker, (d) classifying said subject as having an increased likelihood of responding therapeutically to said method of treating cancer if said patient has a decreased level of said biomarker ing administration of said PI3K inhibitor, and (e) administering a PI3K inhibitor to said patient classified as having an increased likelihood of responding. For example, detection of decrease in one of more of CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, MMP-9, CCL17, CCL22, and CCL1 following treatment can be classified as having an increased likelihood of response to treatment in a subject with CLL.

For example, detection of decrease in one of more of CXCL13, MMP-9, TNF , CCL22, CCL1, CCL17, and MMP-12 following ent can be classified as having an increased hood of response to treatment in a subject with iNHL. In one embodiment, the PI3K inhibitor is administered at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of a cancer or e, e.g., a hematologic malignancy, with a treatment compound (e.g., a compound provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, , or PI3K-β, or a combination thereof)); (b) determining the level of the biomarker in a control sample; and (c) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the l sample; wherein the subject is likely to be sive to the treatment if the level of the biomarker in the ical sample from the subject is d (e.g., high or low) as ed to the level of the biomarker in the control sample. In one embodiment, the method further comprises a step of administering the treatment nd to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of a cancer or disease, e.g., a hematologic malignancy, with a treatment compound (e.g., a compound ed herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the biological sample, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)); and (c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered (e.g., high or low) as compared to the reference level of the biomarker. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, ed herein is a method of identifying a t who is likely to be responsive to a treatment of a cancer or disease, e.g., a hematologic malignancy, with a treatment compound (e.g., a compound ed herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the biological sample, wherein the ker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, , PI3K-α, or PI3K-β, or a combination thereof)); (c) determining the level of the biomarker in a control sample; and (d) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the control ; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is d (e.g., high or low) as compared to the level of the biomarker in the control sample. In one embodiment, the method further comprises a step of stering the ent compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of predicting the responsiveness of a subject to a treatment of a cancer or e, e.g., a hematologic ancy, with a treatment compound (e.g., a compound provided ), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)); and (b) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the difference between the level of the ker in the biological sample from the subject and the reference level of the biomarker (e.g., higher or lower) correlates with the responsiveness of the subject to the treatment. In one embodiment, the method r comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of predicting the responsiveness of a subject to a treatment of a cancer or disease, e.g., a hematologic malignancy, with a ent compound (e.g., a compound provided ), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is described herein (e.g., a ker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)); (b) ining the level of the biomarker in a control sample; and (c) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the control sample; wherein the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample (e.g., higher or lower) correlates with the responsiveness of the subject to the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a ermined period of time.

In specific embodiments, provided herein is a method of predicting the responsiveness of a subject to a treatment of a cancer or disease, e.g., a hematologic ancy, with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the biological sample, wherein the biomarker is described herein (e.g., a ker for an isoform of PI3K (e.g., PI3K-δ, , , or PI3K-β, or a combination thereof)); and (c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; n the difference n the level of the biomarker in the biological sample from the t and the reference level of the biomarker (e.g., higher or lower) correlates with the responsiveness of the subject to the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of predicting the siveness of a subject to a treatment of a cancer or disease, e.g., a hematologic malignancy, with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the biological sample, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)); (c) determining the level of the biomarker in a control sample; and (d) comparing the level of the biomarker in the biological sample from the subject to the level of the ker in the control sample; wherein the difference n the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample (e.g., higher or lower) correlates with the responsiveness of the t to the treatment. In one embodiment, the method r comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the efficacy of a treatment of a cancer or disease, e.g., a hematologic malignancy, in a subject treated with a ent nd (e.g., a nd provided herein), sing: (a) obtaining a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first biological sample, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination f)); (c) administering the treatment nd to the subject; (d) thereafter obtaining a second biological sample from the subject; (e) determining the level of the biomarker(s) in the second ical sample; and (f) comparing the levels of the biomarker(s) in the first and second biological samples; wherein the subject is responsive to the treatment if the level of the ker in the second biological sample of the subject is d (e.g., high or low) as compared to the level of the biomarker in the first biological sample of the subject. In one embodiment, the treatment compound is administered at a predetermined dosage for a predetermined period of time. In one ment, the method further comprises a step of administering the treatment compound to the t having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the compliance of a subject with a treatment of a cancer or disease, e.g., a hematologic malignancy, with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) ining the level of at least one, at least two, or at least three ker in the biological sample, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)); and (c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject; wherein the change in the level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample (e.g., high or low) indicates the compliance of the t with the treatment. In one embodiment, the method further ses a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

In one embodiment, for the methods provided herein, a change in the level of a biomarker provided herein over a period of time is indicative of a ed effect, such as, but not limited to, the likelihood of a subject to be responsive to a treatment, the responsiveness of a subject to a treatment, the efficacy of a treatment, and the compliance of a subject with a ent, of a cancer or disease, e.g., a hematologic malignancy. In one embodiment, the change in the level of a biomarker is a decrease in the level of the biomarker. In one embodiment, the change in the level of a biomarker is a decrease in the serum concentration of the ker. In one embodiment, the change in the level of a biomarker is a decrease in the serum concentration of a cytokine/chemokine biomarker. In one embodiment, the cytokine/chemokine biomarker is CXCL13, CCL4, CCL17, CCL22, or TNF-α, or a combination thereof.

In one ment, the change in the level of a biomarker is a se in the serum concentration of a matrix metaloproteinases. In one embodiment, the matrix metaloproteinase is MMP-9.

In one embodiment, the period of time is 180 days, 90 days, 50 days, 40 days, 35 days, 30 days, 28 days, 24 days, 20 days, 16 days, 14 days, 12 days, 8 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 6 hours, 3 hours, or 1 hour, after a starting time point (e.g., administration of a nd provided herein to a subject). In one embodiment, the period of time is 28 days after administration of a compound provided herein (e.g., Compound 292) to a subject. In another embodiment, the period of time is 14 days after administration of a compound ed herein (e.g., Compound 292) to a subject. In yet another embodiment, the period of time is 8 days after administration of a nd provided herein (e.g., Compound 292) to a subject.

In one ment, for the methods provided herein, a decrease in the serum concentration of CXCL13, CCL4, CCL17, CCL22, TNF-α, or MMP-9, or a combination thereof, over 28 days after the administration of a compound provided herein (e.g., Compound 292) to a subject is indicative of a targeted effect, such as, but not limited to, the hood of a subject to be responsive to a ent, the responsiveness of a subject to a ent, the efficacy of a treatment, and the compliance of a subject with a treatment, of a cancer or disease, e.g., a hematologic malignancy. In another embodiment, for the methods provided herein, a decrease in the serum concentration of CXCL13, CCL4, CCL17, CCL22, TNF- α, or MMP-9, or a ation thereof, over 8 days after the administration of a compound provided herein (e.g., Compound 292) to a subject is indicative of a targeted effect, such as, but not limited to, the likelihood of a subject to be responsive to a treatment, the responsiveness of a subject to a treatment, the efficacy of a treatment, and the compliance of a subject with a treatment, of a cancer or disease, e.g., a hematologic malignancy.

In one embodiments, the cancer or disease is a leukemia or lymphoma. In another ment, the cancer or disease is a B-cell lymphoma or T-cell lymphoma. In r embodiment, the cancer or disease is a B-cell malignancy including, but not limited to, precursor B cell neoplasm (e.g., sor B- lymphoblastic leukemia/lymphoma, and precursor B-cell acute lymphoblastic leukemia), and mature (peripheral) B-cell neoplasms (e.g., B-cell chronic cytic leukemia/small lymphocytic lymphoma (SLL/CLL), B-cell prolymphocytic leukemia, Lymphoplasmacytic lymphoma (LPL), splenic al zone B-cell ma (with/without villous lymphocytes), hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALT type (MALT), nodal marginal zone B-cell lymphoma (with/without monocytoid B-cells) (MZL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or Burkitt lymphoma/Burkitt cell leukemia (BL)). In another embodiment, the cancer or disease is a /NK-cell neoplasms ing, but not limited to, precursor T-cell neoplasm (e.g., precursor T-lymphoblastic lymphoma/leukemia, and precursor T-cell acute lymphoblastic leukemia), and mature (peripheral) T-cell neoplasms (e.g., T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell lymphoma/leukemia (NKL), adult T-cell lymphoma/leukemia 1 positive), extranodal NK/T-cell lymphoma nasal type, enteropathy-type T-cell ma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, s fungoides/Sezary syndrome, anaplastic large-cell lymphoma T/null cell primary cutaneous type, peripheral T-cell lymphoma not otherwise characterized (PTL), angioimmunoblastic T-cell lymphoma, or anaplastic cell lymphoma T/null cell y systemic type)). In another ment, the cancer or disease is non-Hodgkin lymphoma (NHL) including, but not limited to, B-cell NHL (e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small cytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, blastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma) and T-cell NHL (e.g., mycosis fungoides, anaplastic large cell lymphoma, or precursor hoblastic lymphoma). An NHL can also be d into aggressive (fast-growing) and indolent (slow-growing) (iNHL) types.

In one embodiment, the cancer or disease is iNHL, MCL, or FL. In another embodiment, the cancer or disease is a T-cell lymphoma. In yet another embodiment, the cancer or disease is CLL or SLL.

In one embodiment, the cancer or disease is CLL or SLL, and the biomarker is CCL1, IL-10, CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP-9, or a combination thereof.

In one embodiment, the cancer or disease is CLL or SLL, and the biomarker is CCL1, IL-10, CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP-9, or a combination thereof, further in combination with other known biomarkers for CLL such as pAKT and Ki-67.

In specific ments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of CLL or SLL, with a treatment compound (e.g., a compound provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, n the biomarker is CCL1, IL-10, , CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP-9, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is decreased as compared to the reference or control level of the biomarker. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, ed herein is a method of predicting the responsiveness of a subject to a treatment of CLL or SLL with a treatment compound comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL1, IL-10, CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP- 9, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a nce or control level of the ker; wherein the difference between the level of the ker in the biological sample from the subject and the reference or l level of the biomarker correlates with the responsiveness of the subject to the treatment. In one ment, the method further comprises a step of administering the ent compound to the patient having a higher likelihood to be responsive at a ermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the efficacy of a treatment of CLL or SLL in a subject treated with a ent compound (e.g., a compound provided herein), comprising: (a) obtaining a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first biological sample, wherein the biomarker is CCL1, IL- , CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP-9, or a combination thereof; (c) administering the treatment compound to the subject; (d) thereafter obtaining a second biological sample from the subject; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; n the t is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is decreased as compared to the level of the biomarker in the first biological sample of the subject.

In one embodiment, the treatment nd is administered at a predetermined dosage for a ermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a ermined period of time.

In specific embodiments, ed herein is a method of monitoring the compliance of a subject with a treatment of CLL or SLL with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a ical sample from the subject; (b) determining the level of at least one, at least two, or at least three ker in the biological sample, wherein the biomarker is CCL1, IL-10, CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, MMP-9, or a combination thereof; and (c) comparing the level of the biomarker with the level of the biomarker in a l sample from the subject; wherein the decrease in the level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

In r embodiment, the cancer or disease is lymphoma, and the biomarker is CXCL13, CCL17, MMP-9, or a combination thereof.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of lymphoma, with a treatment compound (e.g., a nd provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the t, wherein the biomarker is CXCL13, CCL17, MMP-9, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; n the subject is likely to be responsive to the ent if the level of the ker in the biological sample from the subject is decreased as compared to the reference or control level of the biomarker. In one embodiment, the method further comprises a step of administering the ent compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a ermined period of time.

In specific embodiments, ed herein is a method of predicting the responsiveness of a subject to a treatment of ma with a treatment compound comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CXCL13, CCL17, MMP-9, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; wherein the difference between the level of the biomarker in the biological sample from the subject and the reference or control level of the biomarker correlates with the siveness of the subject to the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of ring the efficacy of a treatment of lymphoma in a subject treated with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first ical sample, wherein the ker is CXCL13, CCL17, MMP- 9, or a combination thereof; (c) administering the treatment compound to the t; (d) thereafter obtaining a second biological sample from the subject; (e) ining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; n the subject is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is decreased as compared to the level of the ker in the first biological sample of the subject. In one embodiment, the treatment compound is administered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be sive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the compliance of a subject with a treatment of lymphoma with a ent compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three ker in the biological , wherein the biomarker is CXCL13, CCL17, MMP-9, or a combination thereof; and (c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject; n the decrease in the level of the biomarker in the biological sample in comparison with the level of the ker in the control sample indicates the compliance of the t with the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

In another embodiment, the cancer or disease is iNHL, and the biomarker is CCL1, CCL17, CCL22, CXCL13, IL-12 (p40), MMP-12, MMP-9, TNFα, IL-16, or a combination thereof.

] In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of iNHL, with a treatment compound (e.g., a compound provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL1, CCL17, CCL22, , IL-12 (p40), MMP- 12, MMP-9, TNFα, IL-16, or a combination thereof; and (b) comparing the level of the biomarker in the ical sample to a reference or control level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is decreased as compared to the nce or control level of the biomarker. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher hood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of predicting the siveness of a subject to a treatment of iNHL with a ent compound comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL1, CCL17, CCL22, CXCL13, IL-12 (p40), MMP-12, MMP-9, TNFα, IL-16, or a combination thereof; and (b) comparing the level of the ker in the biological sample to a nce or control level of the biomarker; wherein the difference between the level of the ker in the biological sample from the subject and the reference or control level of the biomarker correlates with the responsiveness of the subject to the treatment. In one embodiment, the method further comprises a step of administering the treatment nd to the patient having a higher likelihood to be responsive at a predetermined dosage for a ermined period of time.

In specific embodiments, provided herein is a method of monitoring the efficacy of a treatment of iNHL in a subject treated with a treatment compound (e.g., a compound provided herein), comprising: (a) ing a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first biological , wherein the biomarker is CCL1, CCL17, CCL22, CXCL13, IL-12 (p40), MMP-12, MMP-9, TNFα, IL-16, or a combination thereof; (c) administering the ent nd to the t; (d) thereafter obtaining a second biological sample from the subject; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second ical samples; wherein the subject is responsive to the ent if the level of the biomarker in the second biological sample of the subject is decreased as compared to the level of the biomarker in the first biological sample of the subject. In one embodiment, the treatment compound is administered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be sive at a predetermined dosage for a predetermined period of time.

In specific ments, ed herein is a method of monitoring the compliance of a subject with a treatment of iNHL with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the ical sample, wherein the biomarker is CCL1, CCL17, CCL22, CXCL13, IL-12 (p40), MMP-12, MMP-9, TNFα, IL-16, or a combination thereof; and (c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject; wherein the decrease in the level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

In one embodiment, the cancer or disease is MCL, and the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, or a combination thereof.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment of MCL, with a treatment compound (e.g., a compound ed herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, or a ation thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the ical sample from the subject is decreased as compared to the reference or control level of the biomarker. In one embodiment, the method further comprises a step of administering the treatment compound to the t having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, ed herein is a method of predicting the siveness of a subject to a treatment of MCL with a treatment compound comprising: (a) determining the level of at least one, at least two, or at least three ker in a biological sample from the subject, wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; wherein the difference between the level of the biomarker in the biological sample from the subject and the reference or control level of the biomarker correlates with the responsiveness of the subject to the treatment. In one embodiment, the method further comprises a step of stering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the efficacy of a treatment of MCL in a subject treated with a treatment compound (e.g., a compound provided herein), sing: (a) obtaining a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first biological , wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, or a combination thereof; (c) administering the treatment nd to the subject; (d) fter obtaining a second biological sample from the subject; (e) determining the level of the biomarker(s) in the second biological sample; and (f) comparing the levels of the biomarker(s) in the first and second biological samples; wherein the subject is sive to the treatment if the level of the biomarker in the second biological sample of the t is decreased as compared to the level of the biomarker in the first biological sample of the subject. In one embodiment, the treatment nd is administered at a predetermined dosage for a predetermined period of time. In one embodiment, the method r comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, ed herein is a method of monitoring the compliance of a subject with a treatment of MCL with a treatment compound (e.g., a compound provided herein), comprising: (a) ing a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the biological sample, wherein the ker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, or a combination thereof; and (c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject; wherein the decrease in the level of the biomarker in the biological sample in comparison with the level of the ker in the control sample indicates the compliance of the subject with the treatment. In one embodiment, the method r comprises a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

In another embodiment, the cancer or disease is T-cell lymphoma (e.g., CTCL), and the ker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, GM-CSF, IL-12 (p40), TNFα, TGFα, an ERK (extracellular signal regulated kinase), PRAS40, pS6, or a combination thereof.

In ic ments, provided herein is a method of identifying a subject who is likely to be responsive to a ent of T-cell lymphoma, with a treatment compound (e.g., a compound provided herein), comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, , IL-12 (p40), TNFα, TGFα, an ERK, PRAS40, pS6, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the ker; wherein the t is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is decreased as compared to the reference or control level of the biomarker. In one embodiment, the method further comprises a step of stering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In ic embodiments, provided herein is a method of ting the responsiveness of a subject to a treatment of T-cell lymphoma with a treatment compound comprising: (a) determining the level of at least one, at least two, or at least three biomarker in a biological sample from the subject, wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, GM-CSF, IL-12 (p40), TNFα, TGFα, an ERK, PRAS40, pS6, or a combination thereof; and (b) comparing the level of the biomarker in the biological sample to a reference or control level of the biomarker; wherein the difference between the level of the biomarker in the biological sample from the subject and the reference or control level of the ker correlates with the siveness of the subject to the treatment. In one embodiment, the method further ses a step of stering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific embodiments, provided herein is a method of monitoring the efficacy of a treatment of T-cell lymphoma in a subject treated with a treatment nd (e.g., a compound provided herein), comprising: (a) obtaining a first biological sample from the subject; (b) determining the level of at least one, at least two, or at least three biomarker in the first biological sample, wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, , IL-12 (p40), TNFα, TGFα, an ERK, PRAS40, pS6, or a combination thereof; (c) administering the treatment compound to the subject; (d) thereafter obtaining a second biological sample from the subject; (e) determining the level of the biomarker in the second biological ; and (f) comparing the levels of the biomarker in the first and second biological samples; wherein the t is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is decreased as compared to the level of the ker in the first biological sample of the subject. In one embodiment, the treatment compound is stered at a predetermined dosage for a predetermined period of time. In one embodiment, the method further comprises a step of administering the treatment compound to the patient having a higher likelihood to be responsive at a predetermined dosage for a predetermined period of time.

In specific ments, provided herein is a method of monitoring the compliance of a subject with a treatment of T-cell lymphoma with a treatment compound (e.g., a compound provided herein), comprising: (a) obtaining a biological sample from the subject; (b) determining the level of at least one, at least two, or at least three ker in the biological , wherein the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, GM-CSF, IL-12 (p40), TNFα, TGFα, an ERK, PRAS40, pS6, or a combination thereof; and (c) comparing the level of the ker with the level of the biomarker in a control sample from the t; wherein the decrease in the level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment. In one embodiment, the method further comprises a step of administering the treatment compound to the patient at a predetermined dosage for a predetermined period of time based on the patient’s compliance.

The predetermined dosage and predetermined period of time used in the methods provided herein can each independently be any treatment dosage and treatment period of time provided herein or elsewhere.

In one embodiment, each predetermined dosage is, independently, from about 0.005 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 2 to about 25 mg per day, or from about 5 to about 10 mg per day. In one embodiment, each predetermined dosage is, independently, about 0.1, about 0.2, about 0.5, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. In one ment, each predetermined dosage is, independently, within the range of from about 0.5 mg to about 100 mg per day, or from about 0.5 mg to about 50 mg per day, preferably given as a single once-a-day dose, or in d doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In one embodiment, each predetermined dosage is, independently, from about 0.5 to about mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 75, 100, or 150 mg per day. In one embodiment, each predetermined dosage is, independently, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or 100 mg per day. In one ment, each predetermined dosage is, independently, 0.5, 1, 2, 3, 4, or 5 mg per day. The dose can be escalated to 15, , 25, 30, 35, 40, 45, 50, 75, or 100 mg/day. In one embodiment, each predetermined dosage is, independently, from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 day, or from about 0.01 to about 1 mg/kg/day.

In some embodiments, each predetermined period of time is, independently, more than about 6 days, about 10 days, about 14 days, about 28 days, about two months, about six months, or about one year.

In some cases, the predetermined period of time is as long as necessary. In one embodiment, each predetermined period of time is, independently, more than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, about 21, or about 28 days. In one embodiment, each predetermined period of time is, independently, less than about 28, about 21, about 14, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 day. In one embodiment, each predetermined period of time is, independently, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, about 21, or about 28 days.

In one embodiment, the change in the level of a ker over a period of time is determined by comparing the levels of the ker at the ing of the period of time and the end of the period of time. In one embodiment, the change in the level of a biomarker over a period of time is determined by comparing the levels of the biomarker at multiple time points within the period of time (inclusive). In another ment, the change in the level of a biomarker over a period of time includes one or more change of level of biomarker within the period of time. In yet another embodiment, the change in the level of a biomarker over a period of time is determined by comparing the level of the biomarker to reference rd level(s).

In one embodiment, the methods provided herein further comprising a step of adjusting the dose of the treatment (e.g., Compound 292 treatment) based on the change in the level of a biomarker over a period of time.

In one embodiment, provided herein is a probe for ining the level of a biomarker in a sample by hybridizing with a polynucleotide of the biomarker, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)). In certain embodiments, the level of the ker is used to select a subject for a treatment with a treatment compound (e.g., a nd provided herein); to predict or r the responsiveness of a t to the treatment; or monitoring the compliance of a subject with the treatment. In n embodiments, the probe is one that hybridizes with a splice junction of a polynucleotide of the biomarker.

In ic embodiments, the probe is specific for detecting or quantitating an m of PI3K (e.g., PI3K- δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof).

In one embodiment, provided herein is a probe for determining the level of a biomarker in a sample by hybridizing with an mRNA of the biomarker, wherein the ker is described herein (e.g., a biomarker for an m of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)). In certain embodiments, the level of the biomarker is used to select a subject for a treatment with a treatment compound (e.g., a compound provided herein); to predict or monitor the responsiveness of a subject to the ent; or monitoring the compliance of a subject with the treatment. In n embodiments, the probe is one that hybridizes with a splice junction of an mRNA of the biomarker. In specific embodiments, the probe is specific for detecting or quantitating an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof).

In one embodiment, provided herein is an antibody for determining the level of a biomarker in a sample, wherein the biomarker is described herein (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or , or a combination thereof)). In certain embodiments, the level of the biomarker is used to select a subject for a ent with a treatment compound (e.g., a compound provided herein); to predict or monitor the responsiveness of a subject to the treatment; or monitoring the compliance of a subject with the treatment. In certain embodiments, the antibody is one that binds to a splice junction of the ker (e.g., a biomarker for an isoform of PI3K (e.g., PI3K-δ, PI3K-γ, PI3K-α, or PI3K-β, or a combination thereof)). In specific embodiments, the antibody is specific for detecting or quantitating an isoform of PI3K (e.g., PI3K-δ, , PI3K-α, or PI3K-β, or a combination thereof).

In one embodiment, the levels of mRNAs of the kers can be detected or quantitated by a method known in the art. Exemplary detecting or quantitating methods e, but are not limited to, northern blots, ribonuclease protection assays, and PCR-based methods. When the biomarker is an mRNA molecule, the mRNA ce or a fragment thereof can be used to prepare a probe that is at least partially complementary. The probe can then be used to detect the mRNA sequence in a sample, using a method known in the art, including, not limited to PCR-based s, Northern blotting, or a dipstick assay.

In certain embodiments, the detecting or quantitating method is a northern blot, ribonuclease protection assay, or a PCR-based . In certain ments, the detecting or quantitating method is a northern blot. In certain embodiments, the detecting or quantitating method is a ribonuclease protection assay. In certain embodiments, the detecting or quantitating method is a sed method. In certain embodiments, the detecting or quantitating method is qRT-PCR.

In one embodiment, any suitable assay rm can be used to determine the presence of the mRNA in a sample. For example, an assay can be in the form of a dipstick, a membrane, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an optical fiber. An assay system can have a solid support on which a c acid ponding to the mRNA is attached. The solid support can comprise, for example, a plastic, silicon, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a , a polysaccharide, a capillary, a film a plate, or a slide. The assay components can be prepared and packaged together as a kit for detecting an mRNA.

] The mRNAs can be d, if desired, to make a tion of labeled mRNAs. In l, a sample can be labeled using methods that are known in the art (e.g., using an RNA ligase or terminal transferase, or by labeling the RNA backbone). See e.g., Ausubel et al., Short Protocols in Molecular Biology, 3rd ed., Wiley & Sons 1995 and Sambrook et al., Molecular Cloning: A Laboratory Manual, Third n, 2001 Cold Spring Harbor, N.Y. In certain embodiments, the sample is labeled with a fluorescent label. Exemplary fluorescent dyes include, but are not limited to, xanthene dyes, fluorescein dyes, rhodamine dyes, fluorescein isothiocyanate (FITC), 6-carboxyfluorescein (FAM), 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), 6- carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE or J), N,N,N',N'- ethylcarboxyrhodamine (TAMRA or T), 6-carboxy-X-rhodamine (ROX or R), 5- carboxyrhodamine 6G (R6G5 or G5), 6-carboxyrhodamine 6G (R6G6 or G6), rhodamine 110, cyanine dyes (e.g., Cy3, Cy5, and Cy7 dyes), Alexa dyes (e.g., Alexa-fluor-555), coumarin, diethylaminocoumarin, umbelliferone; benzimide dyes (e.g., Hoechst 33258), phenanthridine dyes (e.g., Texas red), ethidium dyes, acridine dyes, carbazole dyes, phenoxazine dyes, porphyrin dyes, polymethine dyes, BODIPY dyes, quinoline dyes, , fluorescein chlorotriazinyl, R110, Eosin, JOE, R6G, tetramethylrhodamine, lissamine, ROX, and napthofluorescein.

In n ments, nucleic acid probes can be present in specific, addressable locations on a solid t; each corresponding to at least a portion of mRNA sequences of a biomarker.

In certain embodiments, an mRNA assay comprises the steps of 1) obtaining surface-bound probes for one or more biomarkers; 2) hybridizing a population of mRNAs to the surface-bound probes under conditions sufficient to provide for specific binding; 3) removing unbound nucleic acids in the hybridization step; and 4) detecting the hybridized mRNAs.

Hybridization can be carried out under suitable hybridization conditions, which may vary in stringency as desired. Typical conditions are sufficient to produce probe/target complexes on a solid surface between complementary binding members, i.e., between surface-bound probes and complementary mRNAs in a .

In certain embodiments, ent hybridization conditions are used. Standard hybridization techniques (e.g., under conditions sufficient to provide for specific binding of target mRNAs in the sample to the probes) are bed in Kallioniemi et al., e 258:818-821 (1992) and WO 93/18186, the disclosure of each which is incorporated herein by reference in its ty. Several guides to general techniques are available, e.g., Tijssen, ization with Nucleic Acid , Parts I and II (Elsevier, Amsterdam 1993). For descriptions of techniques le for in situ izations, see Gall et al. Meth.

Enzymol., 21:470-480 (1981); and Angerer et al. in Genetic ering: Principles and Methods (Setlow and Hollaender, Eds.) Vol. 7, pages 43-65 (Plenum Press, New York 1985). ion of appropriate conditions, including temperature, salt concentration, polynucleotide concentration, hybridization time, and stringency of washing conditions, depends on experimental design, including the source of a sample, the identity of capture agents, the degree of complementarity expected, etc.

After the mRNA hybridization ure, the surface bound polynucleotides are washed to remove unbound nucleic acids. Washing may be performed using any convenient washing protocol. In certain embodiments, the g conditions are stringent. The hybridization of the target mRNAs to the probes is then detected using standard techniques.

In certain embodiments, the mRNA level of a biomarker is determined using a PCR-based method. es of PCR assays can be found in U.S. Pat. No. 6,927,024, the disclosure of which is incorporated by reference herein in its entirety. Examples of RT-PCR s can be found in U.S. Pat.

No. 7,122,799, the disclosure of which is orated by reference herein in its entirety. Examples of fluorescent in situ PCR methods can be found in U.S. Pat. No. 7,186,507, the disclosure of which is orated by reference herein in its entirety.

In certain embodiments, real-time reverse transcription-PCR (qRT-PCR) is used for both the detection and quantification of mRNAs (Bustin et al., Clin. Sci., 2005, 109, 365-379). Quantitative results obtained by qRT-PCR are generally more informative than qualitative data. Examples of qRT-PCR-based methods can be found in U.S. Pat. No. 7,101,663, the disclosure of which is incorporated by reference herein in its entirety.

In contrast to regular reverse riptase-PCR and analysis by agarose gels, real-time PCR gives quantitative results. An additional advantage of real-time PCR is the relative ease and convenience of use.

Instruments for real-time PCR, such as Applied Biosystems 7500, are available commercially. The reagents for real-time PCR, such as TaqMan Sequence Detection try, are also commercially available.

To determine the cycle number at which the fluorescence signal associated with a particular amplicon accumulation crosses the threshold (referred to as CT), the data can be analyzed, for e, using a 7500 Real-Time PCR System Sequence Detection software v1.3, using the comparative CT relative quantification calculation method. Using this method, the output is expressed as a fold-change in expression levels. In some ments, the threshold level can be selected to be automatically determined by the software. In some embodiments, the threshold level is set to be above the baseline, but sufficiently low to be within the exponential growth region of an amplification curve.

] The levels of the protein kers provided herein can be detected or quantitated by any methods known in the art. In certain embodiments, antibody-based methods are used. In certain embodiments, the detecting or quantitating method is immunoblotting (western blot), an enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, a tric bead array, or mass spectroscopy.

In certain embodiments, the detecting or quantitating method is immunoblotting (western blot).

In certain embodiments, the detecting or quantitating method is an enzyme-linked immunosorbent assay (ELISA). In certain embodiments, the detecting or quantitating method is a direct ELISA. In certain ments, the ing or tating method is an indirect ELISA. In certain ments, the detecting or quantitating method is an sandwich ELISA. In certain embodiments, the detecting or quantitating method is immunohistochemistry. In certain embodiments, the detecting or quantitating method is flow cytometry. In certain embodiments, the detecting or quantitating method is a cytometric bead array. In n embodiments, the detecting or quantitating method is mass spectroscopy.

Without being limited by a particular , it was found that patients having a baseline Absolute Lymphocyte Count (ALC) of greater than about 10x103/μl showed a trend in post-baseline ALC over time than thos patients having less than 10x103/μl ALC. For example, the trend showed that the patients with a higher baseline ALC exhibited rapid onset of clinical activity in CLL following the administration of Compound 292 25 mg BID, and thus are more likely to be responsive to the treatment.

Accordingly, in another embodiment, provided herein is a method of predicting the siveness of a subject to a treatment of cancer with a treatment compound comprising: (1) obtaining a blood sample from the patient; and (2) ining Absolute Lymphocyte Count (ALC) in the sample prior to the administration of the treatment compound, n the patient is likely to be responsive if the ALC is r than about 10x103/μl. In one embodiment, the cancer is CLL or SLL. In another embodiment, the compound is Compound 292. In other embodiments, also provided herein is a method of treating cancer comprising administering a compound provided herein to a patient who has been identified as a likely responder, determined based on the method described above.

] Without being limited by a particular theory, it was found that a cytokine cocktail consisting of CD40L, IL-2 and IL-10 can mimic microenvironmental proliferative signals and induce PI3K signaling and proliferation in CLL cells. Accordingly, such a cocktail can provide a valuable in vitro tool in studying cancer behavior and screening for anti-cancer compounds.

In some embodiments, ed herein is a method of inducing PI3K signaling in a cancer cell in vitro comprising contacting the cancer cell with a cytokine il consisting of CD40L, IL-2 and IL-10.

In other embodiments, provided herein is a method of inducing proliferation of a cancer cell in vitro comprising contacting the cancer cell with a cytokine cocktail consisting of CD40L, IL-2 and IL-10.

In some embodiments, ed herein is a method for determining anti-cancer activity of a test nd comprising: (a) contacting a cancer cell with a cytokine cocktail consisting of CD40L, IL-2, and IL-10; (b) determining the extent of PI3K signaling and/or cell proliferation; (c) contacting the cytokine cocktail treated cancer cell with the test compound; and (d) determining the PI3K signaling and/or cell proliferation, wherein the reduction in PI3K signaling and/or cell proliferation determined in step (d) as compared to the same determined in step (b) is indicative of the anti-cancer activity of the test compound.

Kits Also provided herein are kits useful for predicting the hood of an effective cancer or logic malignancy ent or for monitoring the effectiveness of a treatment with a compound provided herein (e.g., a nd of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, e, co-crystal, clathrate, or rph thereof).

In one embodiment, the kit comprises a solid support, and a means for ing the protein expression of at least one biomarker in a biological sample. Such a kit can , for example, a dipstick, a ne, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an l fiber.

The solid support of the kit can be, for example, a plastic, n, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a film, a plate, or a slide. The biological sample can be, for example, a cell culture, a cell line, a tissue, an oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, or a skin sample. The biological sample can be, for example, a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells.

In one embodiment, the kit comprises a solid support, at least one nucleic acid contacting the support, where the nucleic acids are complementary to at least 20, 50, 100, 200, 350, or more bases of mRNA of the biomarker, and a means for detecting the expression of the mRNA in a biological sample.

In certain embodiments, the kits provided herein employ means for detecting the expression of a biomarker by quantitative real-time PCR (QRT-PCR), microarray, flow cytometry or immunofluorescence.

In other embodiments, the expression of the biomarker is measured by ELISA-based ologies or other similar methods known in the art.

In certain embodiments, provided herein is a kit for detecting the mRNA levels of one or more biomarkers. In certain embodiments, the kit comprises one or more probes that bind ically to the mRNAs of the one or more biomarkers. In certain embodiments, the kit further comprises a washing solution. In certain embodiments, the kit further comprises reagents for performing a hybridization assay, mRNA isolation or purification means, ion means, as well as positive and ve controls. In certain embodiments, the kit further comprises an instruction for using the kit. The kit can be tailored for in-home use, clinical use, or research use.

In n embodiments, provided herein is a kit for detecting the protein level of one or more biomarkers. In certain embodiments, the kits comprises a dipstick coated with an antibody that recognizes the n biomarker, washing solutions, reagents for performing the assay, protein isolation or cation means, detection means, as well as positive and negative controls. In certain embodiments, the kit further comprises an instruction for using the kit. The kit can be tailored for in-home use, clinical use, or research use.

Such a kit can , for example, a ck, a membrane, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an optical fiber. The solid support of the kit can be, for example, a plastic, silicon, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a film, a plate, or a slide. The biological sample can be, for example, a cell culture, a cell line, a tissue, an oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, or a skin sample.

] Dosing kits are also provided herein. The kits include a compound ed herein (e.g., a compound of Formula I (e.g., Compound 292), or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof), or a composition thereof, in suitable packaging, and written material. The written material can include any of the following information: instructions for use, discussion of clinical studies, listing of side effects, scientific literature nces, package insert als, clinical trial results, and/or summaries of these and the like. The written material can indicate or establish the activities and/or ages of the composition, and/or describe dosing, stration, side effects, drug interactions, or other information useful to the health care provider. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and/or s based on human clinical trials. The kit can further contain another therapy (e.g., another agent) and/or written material such as that described above that serves to provide information regarding the other therapy (e.g., the other agent). In some embodiments, the compound provided herein (e.g., a compound of Formula I (e.g., Compound 292), or an omer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, tal , clathrate, or polymorph thereof) and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound provided herein and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid ations, foil wrapping to ze exposure to air, and the like) are known in the art and can be included in the kit. Kits described herein can be provided, marketed and/or promoted to health ers, including physicians, nurses, pharmacists, formulary officials, and the like.

Kits can also, in some embodiments, be marketed directly to the consumer.

EXAMPLES Example 1: IC50 Values for ed PI3K Modulators The IC50 values for selected compounds were determined and are provided in Table 3. These data demonstrate that these compounds can serve as PI3K-δand/or PI3K-γ inhibitors.

Table 3. In Vitro IC50 data for selected compounds.

IC50(nM) + (greater than 10 ++ (less than 10 +++ (less than 1 ++++ (less than 100 microMolar) microMolar) olar nM) PI3K  Compound No. Compound No. Compound No. Compound No. 197, 199, 241, 259, 1, 5, 22, 27, 38, 39, 4, 14, 15, 17, 18, 21, 2, 3, 6, 7, 8, 9, 10, 261, 263, 280, 282, 40, 41, 46, 92, 117, 26, 29, 31, 32, 34, 11, 12, 13, 16, 19, 283, 314, 315, 318, 118, 120, 129, 132, 35, 36, 42, 43, 44, 20, 23, 24, 25, 28, 321, 322 164, 165, 172, 188, 45, 47, 49, 57, 69, 30, 33, 37, 48, 50, 186, 193, 194, 195, 71, 85, 87, 94, 106, 51, 52, 53, 54, 55, 217, 242, 246, 281, 107, 143, 175, 179, 56, 58, 59, 60, 61, 284, 305, 317, 325 181, 182, 183, 187, 62, 63, 64, 65, 66, 189, 192, 225, 226, 67, 68, 70, 72, 73, 228, 235, 236, 239, 74, 75, 76, 77, 78, 248, 250, 258, 269, 79, 80, 81, 82, 83, 274, 275, 285, 286, 84, 86, 88, 89, 90, 297,298, 299, 300, 91, 93, 95, 96, 97, 307, 309, 313, 319, 98, 99, 100, 101, 102, 103, 104, 105, 108, 109, 110, 111, 112, 113, 114, 115, 119, 123, 124, 125, 126, 128, 134, 135, 136, 137, 138, 139, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151. 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 166, 167, 168, 169, 170, 171, 173, 174, 176, 177, 178, 180, 185, 188, 190, 191, 196, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 218, 219, 220, 221, 222, 223, 224, 227, 229, 230, 231, 232, 233, 234, 237, 238, 240, 243, 244, 245, 247, 249, 251, 252, 253, 254, 255, 256, 257, 260, 262, 264, 265, 266, 267, 268, 270, 271, 272, 273, 276, 277, 278, 279, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 301, 302, 303, 306, 308, 310, 311, 312, 316, 320, 323, 324 PI3K  nd No. Compound No. Compound No. Compound No. 1, 4, 5, 18, 38, 43, 17, 34, 35, 37, 38, 2, 8, 9, 10, 11, 14, 3, 6, 7, 12, 13, 16, 60, 69, 169, 172, 40, 42, 57, 61, 65, 15, 20, 22, 27, 28, 19, 21, 23, 24, 25, 192, 193, 194, 199, 91, 92, 94, 105, 107, 39, 41, 46, 47, 49, 26, 29, 30, 31, 33, 227, 228, 233, 259, 164, 170, 175, 179, 51, 55, 58, 66, 70, 36, 44, 45, 48, 50, 263, 280, 281, 282, 181, 183, 184, 186, 71, 73, 76, 78, 80, 52, 53, 54, 56, 59, 283, 314, 315, 317, 187, 189, 195, 197, 93, 98, 99, 100, 103, 62, 63, 64, 67, 68, 318, 321, 322, 325 219, 221, 224, 232, 104, 106, 108, 109, 72, 74, 75, 77, 79, 239, 241, 242, 246, 161, 162, 163, 165, 81, 82, 83, 84, 86, 248, 258, 261, 274, 166, 180, 188 , 202, 87, 88, 89, 90, 95, 284, 285, 294, 299, 206, 209, 212, 214, 96, 97, 101, 102, 303, 305, 307, 309, 216, 218, 220, 222, 142, 145, 146, 147, 312, 313, 319 229, 234, 236, 238, 148, 149, 150, 151, 250, 267, 268, 269, 152, 160, 167, 168, 271, 275, 279, 286, 171, 173, 174, 176, 293, 298, 300, 301, 177, 178. 182, 185, 308, 316 190, 191, 196, 198, 200, 201, 203, 204, 205, 207, 208, 210, 211, 213, 215, 223, 230, 231, 235, 237, 240, 243, 244, 245, 247, 249, 251, 252, 253, 254, 255, 256, 257, 260, 262, 264, 265, 266, 270, 272, 273, 276, 277, 278, 287, 288, 289, 290, 291, 292, 295, 296, 302, 304, 306, 310, 311, 320, 323, 324 PI3K  Compound No. nd No. Compound No. Compound No. 6, 8, 9, 10,11, 12, 3, 7, 63, 66, 84, 86, 53, 95, 101, 102, 142, 148, 150, 153, 13, 14, 15, 16, 17, 89, 90, 97, 108, 113, 145, 147, 149, 151, 154, 155, 156, 157, 18, 19, 20, 21, 22, 115, 152, 168, 171, 177 , 208, 257, 260, 158, 159, 176, 201, 23, 24, 25, 26, 27, 173, 185, 190, 198, 262, 264, 270, 272, 252 28, 29, 30, 31, 32, 203, 204, 205, 206, 276, 277, 278, 287, 33, 34, 35, 36, 37, 207, 209, 210, 213, 288, 289, 320, 323 39, 40, 41, 42, 43, 223, 235, 237, 240, 44, 45, 46, 47, 48, 243, 244, 245, 251, 49, 50, 51, 52, 54, 253, 254, 255, 256, 55, 56, 57, 58, 59, 60, 61, 62, 64, 65, 269, 273, 279, 291, 67, 68, 69, 70, 71, 292, 295, 296 72, 73, 74, 79, 80, 81, 82, 83, 85, 87, 88, 91, 93, 96, 98, 99, 100, 103, 104, 105, 106, 107, 109, 110, 111, 112, 114, 146, 160, 161, 162, 163, 164, 165, 166, 167, 169, 170, 172, 174, 175, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189 , 191, 192, 193, 194, 197, 202, 211, 212, 214, 215, 216, 218, 219, 220, 221, 222, 224, 227, 228, 238, 239, 241, 242, 246, 247, 248, 249, 250, 258, 259, 261, 263, 265, 266, 267, 268, 271, 274, 275, 280, 281, 282, 283, 284, 285, 286, 290, 293, 294, 298, 299, 300, 304, 308, 309, 313, 314, 315, 316, 317, 318, 319, 321, 322,324, 325 PI3K  nd No. Compound No. Compound No. Compound No. 8, 9, 10, 11, 14, 21, 3, 12, 13, 23, 25, 53, 7, 62, 66, 82, 89, 101, 142, 155, 156, 22, 24, 26, 27, 28, 55, 58, 61, 63, 65, 90, 95, 97, 100, 102, 157 , 200, 253, 254, 29, 34, 35, 36, 37, 67, 71, 72, 74, 75, 150, 153, 159, 176, 255, 256, 257, 260, 38, 39, 40, 41, 42, 77, 81, 82, 83, 84, 185, 201, 204, 208, 262, 264, 268, 270, 43, 44, 46, 52, 54, 85, 86, 96, 99, 106, 213, 227, 237, 251, 272, 273, 278, 279, 56, 57, 59, 60, 64, 108, 110, 111, 113, 252, 267,276, 277, 287, 288, 289, 291, 68, 69, 70, 73, 76, 114, 115, 145, 147, 290, 292, 293 320, 323, 78, 79, 80, 87, 88, 149, 151, 154, 158, 91, 93, 98, 103, 104, 160, 161, 167, 168, 105, 107, 109, 112, 171, 173, 174, 177, 146, 152, 162, 163, 178, 190, 191, 198, 164, 165, 166, 169, 202, 203, 205, 206, 170, 172, 175, 179, 207, 209, 210, 211, 180, 181, 182, 183, 212, 214, 215, 219, 184, 186, 187, 188, 220, 223, 228, 235, 189, 192, 193, 194, 240, 243, 244, 247, 197, 216, 217, 218, 249, 265, 269, 274, 221, 222, 224, 238, 281, 295, 296, 298, 248, 259, 261, 263, 300, 308, 316, 324 266, 271, 275, 280, 282, 283, 284, 285, 286, 294, 299, 304, 310, 311, 312, 315, 317, 321, 322, 325 B cell proliferation Compound No. nd No. Compound No. Compound No.

EC50 (nM) 38, 162 , 199 1, 2, 5, 22, 26, 27, 4, 8, 9, 10, 11, 14, 3, 6, 7, 12, 13, 16, 39, 40, 43, 49, 57, 15, 18, 19, 20, 21, 17, 23, 33, 37, 44, 71, 87, 112, 197, 24, 25, 28, 29, 30, 48, 53, 54, 55, 62, 207, 235 31, 32, 34, 35, 36, 63, 66, 67, 68, 72, 41, 42, 45, 46, 47, 73, 74, 75, 81, 82, 50, 51, 61, 69, 70, 83, 84, 88, 89, 90, 76, 77, 78, 79, 80, 93, 95, 96, 97, 99, 85, 86, 91, 98, 100, 101, 102, 108, 109, 103, 104, 105, 106, 113, 115, 123, 107, 110, 111, 114, 125, 126, 128, 134, 119, 124, 133, 135, 136, 137, 138, 139, 145, 152, 161, 162, 141, 142, 144, 146, 163, 169, 195, 212, 147, 148, 149, 150, 243, 294, 312 151, 153, 154, 155, 156, 157, 158, 159, 160, 166, 167, 168, 170, 171, 173, 174, 176, 177, 178, 180, 187, 185, 188, 190, 191. 196, 198, 200, 201, 202, 203, 204, 205, 206, 208, 209, 210, 211, 213, 214, 215, 216, 219, 220, 221, 222, 223, 224, 227, 228, 229, 230, 231, 232, 233, 234, 237, 244, 245, 247, 248, 249, 251, 252, 253, 254, 255, 256, 257, 270, 276, 277, 278, 289, 290, 292, 295, 296, 298, 300, 301, 302, 303, 306, 308, 310, 311 Table 4. Structures of the Compounds for the IC50 results described in Table 3.

Structure F F F O O O O O N N N N N N N N N N N N N N N N N N N N I N N N HO H2N H2N H2N H2N H2N Compound 1 Compound 5 Compound 2 F nd 3 Compound 4 Structure O O F F O O N N N N N N N N N N N N N N N N N N N N I N N N N H2N H2N HO H2N H2N HO H2N Compound 6 HO F F Compound 8 Compound 10 Compound 7 Compound 9 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N I H2N HO H2N HO H2N H2N Compound 11 F Compound 15 Compound 13 Compound 12 Compound 14 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N N N N Br Cl Br Cl HO H2N H2N H2N H2N H2N Compound 17 nd 18 Compound 19 Compound 20 nd 16 O F O O F O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N H2N HO HO H2N Cl H2N Cl O Cl Cl O Cl HO Compound 21 Compound 23 Compound 24 Compound 25 Compound 22 Structure F O F F O O O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N Cl H2N H2N H2N HO F F HO F Compound 28 HO HO Compound 26 Compound 27 Compound 29 Compound 30 O O O F F O O N N N N N N N N N N N N N N N N N N N N N N N N N I Cl Br H2N HO H2N HO H2N H2N H2N Compound 31 Compound 32 F Compound 34 Compound 35 Compound 33 O F F O O O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N Cl H2N Cl H2N HO F H2N Compound 38 Compound 39 Compound 36 Compound 37 nd 40 O F O F O O O N N N N N N N N N N N N N N N N N N N N N N N N N F H2N H2N HO H2N O H2N H2N nd 41 Compound 42 Compound 43 O O Compound 44 Compound 45 F F O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N H2N H2N O H2N HO O N Cl NH Compound 46 Compound 47 Compound 49 Compound 48 Compound 50 Structure O O O O F O N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N HO H2N HO H2N H2N HO HO Compound 51 F Cl N S F Compound 55 Compound 52 AcHN Compound 54 Compound 53 F O O O F O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N I H2N HO H2N H2N Compound 57 Compound 60 F Compound 58 Compound 59 Compound 56 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N HO H2N HO H2N H2N HO H2N HO H2N Compound 61 Compound 62 F F Compound 65 Compound 63 Compound 64 O O O O N N O N N N N N N N N N N N N N N N N N N N N N N HO H2N H2N HO H2N N HO HO H2N I F Compound 69 Compound 66 F F Compound 70 Compound 67 Compound 68 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N H2N N N HO H2N HO HO H2N H2N I HO H2N Cl Cl Compound 73 Compound 71 nd 74 Compound 75 Compound 72 Structure Cl O HO O O O O N O N N N N N N N N N N N N N N N N N N N N N N N I N I I H2N I N H2N H2N Compound 76 H2N nd 78 Compound 79 Compound 77 HO Compound 80 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N H2N HO H2N HO H2N H2N HO H2N HO Compound 81 HO Compound 85 Compound 82 Compound 83 Compound 84 O O HO N O O N N N N N N N N N N N N N N N N N N N N N I N H2N I N N Compound 86 HO H2N HO H2N HO H2N nd 87 Compound 88 F Compound 90 Compound 89 O O O O N N N N N N N N N N N N N N N N N N N N N N N N N I N H2N H2N HO H2N HO H2N HO HO H2N Compound 91 Compound 92 F Compound 94 Compound 93 Compound 95 Structure Cl Cl Cl O O O O N N N N N N N N N N N N N N N N N N N N N N N H2N H2N H2N H2N HO HO HO HO Compound 96 F Compound 98 Compound 100 Compound 99 Compound 97 O O O O O N N N O O N N N N N N N N N N N N N N N I N N N H2N N N N H2N Compound 103 I I H2N HO H2N H2N Compound 104 nd 105 F nd 102 Compound 101 O O O O O N N O N O N O N O N N N N N N N N N N N N N N N N N N H2N H2N N HO HO N N N I F O H2N H2N Compound 109 H2N Compound 108 HO Compound 107 Compound 106 F Compound 110 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N H2N H2N HO H2N HO H2N HO H2N HO HO Compound 111 Compound 112 F Compound 114 F Compound 113 Compound 115 O O F O O O O N N N N N N N N N N N N N N N N N N N N N N N I I H2N H2N H2N H2N HO H2N Compound 116 O Compound 117 H2N Compound 120 Compound 119 Compound 118 Structure O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N H2N I H2N H2N H2N H2N HO H2N HO HO O Compound 122 Compound 121 Cl F Compound 124 Compound 123 Compound 125 O O O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N I HOOC H2N HO H2N H2N H2N HO H2N Compound 126 Compound 129 Compound 130 nd 127 F Compound 128 Cl O F F O F O O F O N N N N N N N N N N N N N N N N N N N N N N N N I I H2N H2N HO H2N H2N HO H2N HO nd 131 Compound 132 Compound 133 F Compound 135 Compound 134 O Cl O Cl O Cl O N N N N N N N N N N N N N N N N N N N N HO H2N HO H2N HO H2N H2N F Compound 139 Compound 137 F Compound 136 Compound 138 Cl O Cl O F O F O O N N N N N N N N N N N N N N N N N N N N N N N N H2N HO H2N HO HO H2N HO H2N N S Compound 141 F F Compound 143 Compound 142 Compound 144 Compound 145 Structure O O O O O N N N N N N N N N N N N N N N N N N N N N O S N N N N H2N N HO H2N HO H2N H H Compound 146 Compound 148 N F N Compound 147 Compound 149 H2N Compound 150 O O O O O N N N N N N N N N N N N N N N N N N N N N N O S O S O H2N H2N H2N H2N S H2N N NH2 N N N N N N H O H H NH2 Compound 153 Compound 154 Compound 155 Compound 151 Compound 152 Cl O Cl O F O O N N N N N N N N N N N N N N N N N N N N N N N O S H2N O S H2N O S H2N O S H2N N N N N N N N N N H H H Compound 156 HN H2N Compound 157 nd 158 Compound 159 N Compound 160 F F O F O O O O N N N N N N N N N N N N N N N N N N N N N N N N N HN H2N N H2N N H2N N H2N N H2N N N N N N nd 161 OH OH Compound 164 Compound 165 Compound 162 Compound 163 O F O O O O N F N N N N N N N N N NH N N N N N N O N N S H2N N N N NC NC HN H2N N N H H2N H2N N N Compound 166 Compound 168 Compound 169 Compound 170 Compound 167 Structure O O O O O N N N N N N N N O N N N N N N N N O N N HN N N HN N N N S H2N HN N O S H2N H2N O H2N O H2N Compound 171 O NH2 NH2 Compound 172 Compound 173 Compound 174 nd 175 O O O O N N F N N N N N N N N N N N N N N N N N N N N O N S H2N S N N O N N S N H2N N H H2N H H2N Compound 176 N N Compound 178 Compound 180 H Compound 179 Compound 177 O O F O O N N N N N N N N N N N N N N N N N N N H H N N N N O H2N N N N N N H2N H2N H HN H2N F nd 183 Compound 184 N Compound 181 Compound 182 Compound 185 O O Cl F O F O N N N N N N N N N N N N N N N N N N N N N N N N H HN H2N N HN H2N HN H2N Compound 186 N N N HN H2N Compound 187 N Compound 188 Compound 189 Compound 190 Structure O O O O CH3 O N N N N N N N N NH N N N N N N NH N N N N N N N N O H2N H2N O H2N N N O H N N N N Compound 191 Compound 194 H O O nd 195 nd 192 Compound 193 CH3 O CH3 O CH3 O CH3 O CH3 O N N N N N CH3 CH3 CH3 CH3 CH3 NH NH NH NH NH N N N N N N N N N N N N N N H H N N N N H H Compound 196 Compound 197 Compound 198 Compound 199 Compound 200 N N N N Compound 201 Compound 202 Compound 204 Compound 205 Compound 203 Compound 206 Compound 208 Compound 207 Compound 209 Compound 210 Compound 211 Compound 212 Compound 213 Compound 214 Compound 215 Structure N N N N Compound 216 Compound 217 Compound 218 Compound 219 Compound 220 Compound 223 nd 225 Compound 221 Compound 222 Compound 224 Compound 227 Compound 226 Compound 228 Compound 229 Compound 230 Compound 231 Compound 232 Compound 233 Compound 234 Compound 235 nd 238 Compound 236 Compound 237 Compound 239 Compound 240 Structure Compound 241 Compound 245 Compound 242 Compound 244 Compound 243 N N Compound 246 H Compound 248 Compound 249 Compound 247 Compound 250 Compound 251 Compound 254 Compound 255 Compound 252 Compound 253 NH NH2 N N Compound 256 Compound 257 Compound 258 Compound 259 Compound 260 nd 261 Compound 263 Compound 262 nd 264 Compound 265 Structure Compound 266 Compound 267 Compound 268 Compound 270 Compound 269 Compound 271 Compound 272 Compound 273 Compound 274 Compound 275 nd 280 Compound 276 Compound 277 Compound 278 Compound 279 Compound 281 Compound 282 Compound 284 Compound 283 Compound 285 Compound 287 Compound 288 nd 286 Compound 289 Compound 290 Structure Compound 294 Compound 291 Compound 293 Compound 295 Compound 292 nd 296 Compound 297 Compound 298 Compound 299 Compound 300 Compound 301 Compound 303 Compound 305 Compound 302 Compound 304 Compound 306 Compound 307 nd 308 Compound 309 Compound 310 Compound 311 Compound 312 Compound 313 Compound 314 Compound 315 Structure Compound 316 Compound 317 Compound 318 Compound 319 nd 320 Compound 321 Compound 322 nd 323 Compound 324 Compound 325 Example 2: Expression and Inhibition Assays of p110/p85, p110/p85, p85, and p110 Class I PI3Ks can be either purchased (p110/p85, p110/p85, p110/p85 from Upstate, and p110 from Sigma) or expressed as previously described (Knight et al., 2004). IC50 values are measured using either a standard TLC assay for lipid kinase ty (described below) or a high-throughput membrane capture assay. Kinase reactions are med by ing a reaction mixture containing , a compound provided herein (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 g/ml). Reactions are initiated by the addition of ATP ning 10 Ci of -32P-ATP to a final concentration 10 or 100 M and allowed to proceed for 5 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 L 1N HCl followed by 160 l CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly fuged, and the organic phase is transferred to a new tube using a gel loading e tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3 – 4 hours in a 65:35 solution of n-propanol:1M acetic acid.

The TLC plates are then dried, exposed to a phosphorimager screen (Storm, Amersham), and quantitated.

For each compound, kinase activity is measured at 10 – 12 compound concentrations representing ld ons from the highest concentration tested (typically, 200 M). For compounds showing significant activity, IC50 determinations are repeated two to four times, and the reported value is the average of these independent measurements.

Other commercial kits or systems for assaying PI3K activities are available. The commercially available kits or systems can be used to screen for modulators, e.g., inhibitors and/or agonists, of PI3Ks including but not limited to PI 3-Kinase , and . An exemplary system is PI 3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried out according to the procedures suggested by the manufacturer. Briefly, the assay is a time resolved FRET assay that indirectly measures PIP3 product formed by the ty of a PI3K. The kinase reaction is performed in a microtitre plate (e.g., a 384 well microtitre . The total reaction volume is approximately 20uL per well. In the first step, each well receives 2uL of test compound in 20% dimethylsulphoxide resulting in a 2% DMSO final concentration.

Next, approximately 14.5uL of a kinase/PIP2 mixture (diluted in 1X reaction buffer) is added per well for a final tration of 0.25-0.3ug/mL kinase and 10uM PIP2. The plate is sealed and incubated for 15 minutes at room temperature. To start the reaction, 3.5uL of ATP (diluted in 1X reaction ) is added per well for a final concentration of 10uM ATP. The plate is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 5uL of Stop Solution per well and then 5uL of Detection Mix is added per well. The plate is sealed, incubated for 1 hour at room temperature, and then read on an appropriate plate reader. Data is analyzed and IC50s are generated using GraphPad Prism® 5.

Example 3: Compound 292 Inhibits PI3K-δ, PI3K-γ, PI3K-β, and PI3K-α.

The PI3K inhibitory activity of Compound 292 was tested in several assays described .

The results are shown in Table 5 below, indicating that Compound 292 is a potent inhibitor of PI3K-δ and PI3K-γ. In these assays, Compound 292 inhibits PI3K-δ activity at lower doses as compared to other PI3Ks (e.g., at least 10-fold lower dose compared to , PI3K-β or PI3K-α).

Table 5: Biochemical and Cellular Activity Data for Compound 292 nd 292 PI3K-α PI3K-β PI3K-δ PI3K-γ Ki > 10,000 pM 1,000 - 10,000 pM < 100 pM 100 – 1,000 pM TLC IC50 1,000 – 10,000 10 - 1000 nM < 10 nM 10 – 1,000 nM Cellular IC50 1,000 – 10,000 10 - 1000 nM < 10 nM 10 – 1,000 nM Example 4: Functional Cellular Activity of Compound 292 ] The functional ar activities of Compound 292 were assessed. The s are shown in Table 6 below. Compound 292 suppressed murine B-cell proliferation and human B-cell proliferation at omolar concentrations, with an EC50 of 0.5 nM. Compound 292 suppressed human T-cell proliferation at nanomolar concentrations, with an EC50 of 9.5 nM.

To determine PI3K- isoform activity in vitro, Compound 292 was assessed in PI3K-and PI3K- selective ased assays. To assess the ability to inhibit the PI3K-isoform, AKT orylation (T308) was measured by enzyme-linked immunosorbent assay (ELISA) in anti-IgM antibody-stimulated RAJI cells, a human Burkitt lymphoma cell line, in the presence or absence of Compound 292. nd 292 potently inhibited AKT phosphorylation with an IC50 value of 2.0 nM. To assess the ability to t the PI3K- isoform, the murine hage-like cell line, RAW 264.7, was stimulated with C5a, and the level of AKT phosphorylation (T308) was measured by ELISA. Compound 292 inhibited PI3K- in C5a activated RAW 264.7 cells with an IC50 value of 44.0 nM. Compound 292 is a potent inhibitor of both PI3K- and PI3K- in isoform-selective ased assays.

Table 6: Compound 292 Functional Cellular Activity Functional Cellular Activity EC50 Murine B-cell proliferation < 5 nM Human B-cell eration < 5 nM Human T-cell proliferation 5 - 10 nM PI3K-δ selective assay (RAJI cells, human lymphoma cell line) < 5 nM PI3K-γ selective assay (RAW 264.7, murine macrophage-like cell 10 - 100 nM line) Anti-fCER1 BAT (delta) 10 - 100 nM In one ary assay tested, Compound 292 potently inhibited PI3K-δ specific basophil activation in human whole blood with an IC50 of 78 nM.

Example 5: Safety Pharmacology Studies of Compound 292 In vitro hERG Assay The in vitro effects of Compound 292 on the hERG channel current were examined as a surrogate for IKr, the rapidly activating, delayed rectifier cardiac potassium current. Compound 292 inhibited hERG current by 11.9% at 10 μM, 33.2% at 30 μM, 71.1% at 100 μM, and 92.8% at 300 μM compared to 0.9% in the vehicle control. The IC50 value for the inhibitory effect of Compound 292 on hERG potassium current was 49.8 μM (Hill cient = 1.3).

Compound 292 was highly bound in vitro to components of plasma of all species tested, including the rat, monkey, and human. In rat, monkey, and human plasma, nd 292 was 85.8, 76.8, and 85.9% protein bound, respectively, at 100 μM (41700 ng/mL). The hERG assay was performed in a protein-free solution. Therefore, based on the free fractions, the IC50 value of 49.8 μM (20800 ng/mL) for d Compound 292 would equate to total plasma concentrations of 351 μM (146200 ng/mL), 215 μM (89500 ng/mL), and 353 μM (147200 ng/mL) in rat, monkey, and human, respectively. These high concentrations suggest a very low potential for QT gation in humans.

Neurofunctional Study in Sprague-Dawley Rat ] This study was conducted to evaluate the potential effects of Compound 292 on the l nervous system following a single oral stration in male rats. During this study, a Functional Observation Battery (FOB) test and motor activity evaluation were performed pre-dose and at 2, 6, and 24 h following Compound 292 administration.

Compound 292, administered to male rats as a single oral dose up to 350 mg/kg, caused no changes in qualitative or quantitative FOB ters up to 24 h post-dose. Significant decreases in locomotor activity were observed in animals tested 2 h after a 350 mg/kg dose. However, given that no concurrent effects on locomotor activity or arousal were noted in the FOB arena at the same time period, a definitive effect of Compound 292 could not be confirmed at these assessment intervals. No effects on the central nervous system were observed at dose levels ≤50 mg/kg.

Respiratory Study in Sprague-Dawley Rat This study was conducted to evaluate the potential effects of Compound 292 on the respiratory system following a single oral administration in the male rat. During this study, animals were placed in “head out” plethysmographs and respiratory parameters (tidal volume, respiratory rate, and derived minute volume) were measured for a period of approximately 30 s pre-dose, continuously from 1 to 3 h post-dose, and for 30-minute intervals at 6 and 24 h post-dose.

A single oral administration of Compound 292 at dose levels up to 350 mg/kg ed in no Compound 292-related effects on respiratory parameters, including respiratory rate, tidal volume, and minute volume.

Cardiovascular Study in Instrumented Cynomolgus Monkey This study was conducted to evaluate the potential effects of Compound 292 on the hemodynamic and electrocardiographic parameters following a single oral stration to cynomolgus monkeys via telemetry. Four ive, male s implanted with radiotelemetry transmitters were utilized during the conduct of this study.

No Compound 292-related effects were observed on hemodynamic or ocardiographic ters (arterial blood pressures (systolic, diastolic, mean and pulse pressure), heart rate, and quantitative electrocardiographic intervals (PR, QRS, QT and QTc)) following a single oral dose of 5, 30, and 150 mg/kg in male cynomolgus monkeys. In addition, no rm abnormalities or arrhythmias related to the administration of nd 292 up to 150 mg/kg were noted.

Example 6: Pharmacokinetics of Compound 292 in Animals The absorption and pharmacokinetics of Compound 292 were investigated in absolute bioavailability studies in mice, rats, dogs, and monkeys. The results of these bioavailability studies are summarized in Table 7. The data demonstrate that Compound 292 was y absorbed in a majority of the nonclinical test species when administered as a suspension formulation with oral bioavailability values of 57%, 40%, 40% and 7% in rats, monkeys, dogs and mice, respectively. The half-life of Compound 292 was hrs in monkeys, 2 hrs in the dog, and less than 2 hrs in the rat and mouse. Compound 292 achieved a high volume of distribution and showed low to moderate clearance in monkey and rat. Binding of Compound 292 to plasma proteins was concentration and species dependent. Percent Compound 292 free in rat and monkey plasma was consistently higher than in human plasma at all concentrations tested. Distribution of Compound 292 into rat tissues was rapid and ive based on the blood to tissue ratio being greater than 1 for a majority of tissues. Elimination of radiolabelled Compound 292 from tissues was also rapid with a majority of tissues without fiable levels of radioactivity at 24 hr.

Table 7: Compound 292 Pharmacokinetic Parameters in BALB/c Mice, Sprague-Dawley Rats, Beagle Dogs and lgus Monkeys Following Intravenous and Oral Administration Species # Dose AUC0-last Cmax Tmax AUC0-inf T1/2 Cl Vss Foral (Report animals/ Route (mg/kg mL (ng/mL) (h) (ng*h/mL) (h) (L/h/kg) (L/kg) (%) Number) gender ) ) 27/M IVc 10 5563 0.083 1900 1903 5.25 1.14 --- Mouse 2 27/M POd 10 390 0.083 136.8 NC NC --- --- 7i 3/M IVc 2 1519 0.083 1153 1157 1.83 1.66 --- Rat 3 3/M POd 10 785 1.2 2929 3298 2.4 --- --- 57 3/M IVe 0.5 4413a NC 11738b 11921 2 0.051 0.13 --- Dog 105068 3/M POf 5 9597 3.00 107062 3.9 --- --- 97g,i 1.8 0.49 3/M IVe 1 1804a NC 5875b 6268 0.194 --- 3 3 3/M POf 5 2367 1.33 10942b 13805 --- --- 40h,i 4/(2M, IVc 1 1545 0.083 2357 2379 5.0 0.43 1.27 --- Monkey 4/(2M, POd 5 1327 1.5 4596 4685 5.4 --- --274- --- = not applicable NC = not calculated a. Reported value is C0 b. AUC0-24 c. IV formulation (mouse, rat, monkey) = 5% NMP, 10% Solutol® HS 15, 30% PEG400, 55% water with 3% dextrose d. PO formulation (mouse, rat, monkey) = 0.5% (w/v) low viscosity CMC and 0.05% (v/v) TWEEN® 80 in ultra pure water e. IV formulation (dog) = 5% 0.1N HCl, 5% PEG400 in 10% (2-hydroxypropyl)–β-cyclodextrin or 2.5% 1N HCl, 20% PEG400 in PBS f. PO formulation (dog) = 5% NMP, 60% PEG400 and 35% water solution (ADME008) or 5% NMP and 95% water suspension (ADME009) g. Foral was calculated using 0.5 mg/kg IV dose as reference h. Foral was calculated using 1 mg/kg IV dose as reference i. Foral was calculated using AUC0-last Membrane permeability and interaction of Compound 292 with human P-glycoprotein was assessed in vitro using Caco-2 cell monolayers. It was determined that Compound 292 has te cell membrane permeability, is a P-gp substrate and has the potential to t the active transport of other P-gp substrates.

Example 7: Toxicology of Compound 292 in Animals -dose ty study was conducted to determine the maximum tolerated dose (MTD) following a single oral dose and ial toxicity following 7-day repeat oral doses of Compound 292 in monkeys. It was determined that the MTD following a single oral administration of Compound 292 in monkeys was 500 mg/kg. 4- and 13-Week repeat-dose nonclinical safety studies were conducted in which rats and cynomolgus monkeys received daily Compound 292 doses by oral gavage. The no observed adverse effect level (NOAEL) in the 13-week rat study was 25 mg/kg/day (150 mg/m2/day) and the NOAEL in the 13- week monkey study was 5 mg/kg/day (60 mg/m2/day). On Day 91, the mean AUC0-24hr values for ed sexes at the NOAELs were 14150 ng*h/mL in the rat, and 4015 ng*h/mL in the monkey. Based on PK data from the clinical study in healthy ts, exposure in humans following repeated oral doses of mg BID Compound 292 (mean 4hr = 2582 ng*h/mL following 14 days of oral dosing) is less than exposure at either the rat or monkey NOAEL.

There was no genetic toxicity associated with Compound 292 in the in vitro genetic ty studies, and nd 292 had no direct adverse effect in the in vivo rat micronucleus assay.

Reproductive toxicity of Compound 292 was assessed in embryo/fetal developmental toxicity studies in rats and rabbits. The al and fetal NOAELs of Compound 292 in the rat and rabbit were 35 mg/kg/day (210 mg/m2/day) and 75 mg/kg/day (900 mg/m2/day), respectively. On the last day of dosing, the mean AUC0-24hr values at the NOAELs were 62200 ng*h/mL and 66200 L for pregnant rats and rabbits, respectively.

Example 8: Clinical Studies in Human A randomized, double-blind, placebo-controlled, clinical study in healthy adult ts was conducted with Compound 292. ndred and six (106) subjects were enrolled overall, which included 36 subjects in the single ascending dose (SAD) portion (24 active treatment; 12 placebo), 48 subjects in the multiple ascending dose (MAD) portion (36 active treatment; 12 placebo), 6 subjects in the food effect (FE) effect portion (consisting of Compound 292 dosing with sequential fed and fasting portions), and 16 subjects in the DDI portion (consisting of Compound 292 dosing s with and t ketoconazole).

The total t exposure to Compound 292 is summarized in Table 8.

Table 8: Subject Exposure of Compound 292 in Clinical Safety Studies Total Total No. of on of Exposure per Subjects PART Treatment Exposure Treatment Subject (mg) Exposed SAD Placebo SD 1 day 0 12 1 mg Compound 292 SD 1 day 1 4 2 mg Compound 292 SD 1 day 2 4 mg Compound 292 SD 1 day 5 4 mg Compound 292 SD 1 day 10 4 mg Compound 292 SD 1 day 20 4 mg Compound 292 SD 1 day 30 4 MAD Placebo Q12h or Q24h 14 days 0 12 1 mg Compound 292 Q12h* 14 days 26 9 2 mg Compound 292 Q12h* 14 days 52 9 mg nd 292 Q12h* 14 days 130 9 mg Compound 292 Q24h 14 days 140 9 FE 25 mg Compound 292 Fasted-Fed 2 days 50 3 mg Compound 292 sted 2 days 50 3 DDI 10 mg Compound 292 SD 2 days 20 16 SD = single dose; Q12h = once every 12 hrs; Q24h = once every 24 hrs; SAD = single ascending dose; MAD = multiple ascending dose; FE = food effect; DDI = drug-drug interaction. *includes QD dosing on Days 1 and 14.

] Compound 292 was well tolerated at the doses evaluated. There were no deaths and no serious adverse events (SAEs). There did not appear to be a dose-related increase in AEs across the single dose range of 1 to 30 mg or the multiple dose range of 2 to 10 mg daily of Compound 292. No clinically significant safety laboratory or electrocardiogram (ECG) abnormalities were ed during any portion of the study.

Pharmacokinetic assessments demonstrated that Compound 292 was rapidly absorbed following single and multiple dose oral administration, with the m plasma concentration observed lly 1 hr after . Across the dose ranges evaluated, Compound 292 exposure sed tionally to dose. The mean elimination half-life ranged from 6.5 to 11.7 hrs after repeat dosing and did not depend on the dose level administered. Compound 292 accumulation was less than 2-fold following 14 days of Q12 h oral administration. A summary of Compound 292 PK parameters from the single dose portion is provided in Table 9 below. A summary of Compound 292 PK parameters from the multiple dose portion is provided in Table 10 below.

Table 9: Summary of Compound 292 PK Parameters Following Single Dose Administration (Mean, %CV) Compound Cmax Tmax AUC(0-t) AUC(0-24) AUC(0-inf) CL/F Vz/F T1/2 292 Dose (ng/mL) (hr)* (ng*hr/mL) (ng*hr/mL) (ng*hr/mL) (L/h) (L) (hr) 1 mg 43.4 (31) 1.00 (1.00-1.00) 148 (68) 149 (67) 151 (68) 8.39 (42) 38.8 (28) 3.52 (29) 2 mg 78.8 (16) 1.00 (0.50-2.00) 291 (45) 289 (43) 296 (44) 7.69 (37) 57.9 (38) 5.43 (25) mg 246 (16) 1.00 (0.50-1.50) 735 (5) 733(5) 743 (5) 6.74 (5) 53.0 (15) 5.43 (10) mg 454 (40) 0.50 (0.50-1.50) 905 (15) 891 (14) 914 (14) 11.1 (15) 147 (29) 9.47 (38) mg 997 (32) 1.00 1.00) 2243 (16) 2193 (16) 2250 (16) 9.09 (18) 99.1 (46) 7.79 (51) mg 1140 (38) 1.00 (0.50-1.00) 3384 (38) 3263 (38) 3395 (38) 9.73 (33) 113 (31) 8.12 (18) *median (range); h= hours Table 10: Summary of Compound 292 PK Parameters Following Multiple Dose Administration (Mean, %CV) Compound 292 Tmax tau) T1/2 Day Cmax (ng/mL) Racc Dose Regimen (h)* (ng*h/mL) (h) 1 mg Q12h 1 49.1 (26) 0.52 (0.50-1.00) 124 (40) 3.46 (39) -- 14 66.8 (36) 1.00 (0.50-1.50) 199 (39) 6.46 (20) 1.65 (19) 2 mg Q12h 1 101 (31) 1.00 (0.50-2.00) 290 (49) 6.34 (35) -- 14 140 (36) 1.00 (0.50-2.00) 524 (47) 9.75 (37) 1.83 (22) mg Q12h 1 257 (38) 1.00 (0.50-1.50) 774 (41) 5.76 (11) -- 14 355 (37) 1.00 (0.50-2.02) 1291 (38) 8.32 (35) 1.71 (15) mg Q24h 1 553 (27) 0.52 (0.50-1.52) 1527 (37) 6.00 (13) -- 14 605 (16) 1.00 (0.50-1.55) 2232 (25) 11.7 (82) 1.54 (18) h= hours, CV = coefficient of variation, Racc = accumulation ratio, * Median (range) Data from the food effect portion indicate that food does not significantly alter systemic re to Compound 292. When administered in the presence of a high fat meal, Compound 292 concentration sed by approximately 10% and median Tmax was delayed from 1 hr (fasted) to 3 hrs (fed). Overall exposure, as assessed by AUC (0-last) and AUC (0-inf), increased by approximately 9% in the presence of a high fat meal.

Data from the DDI portion indicated that itant administration of 200 mg q12h ketoconazole sed exposure to Compound 292. On average, Cmax,AUC0-last and AUC0-inf increased by imately 66%, 285% and 295%, respectively, in the ce of ketoconazole compared to Compound 292 administered alone.

Following single and multiple Compound 292 doses, a dose-dependent reduction of basophil activation was observed at all dose levels, with a maximum reduction at 1 hr post dose; no notable change was observed ing treatment with placebo. The PK/PD summary following single dose administration is shown in 3, which demonstrates that the PD response was rapid and that maximal response was achieved at 5 mg dosing. A relationship was apparent between reduction of basophil activation and Compound 292 plasma concentrations, with saturation of the effect at higher Compound 292 plasma concentrations.

Serial ECGs were med at multiple time points after dosing in all study groups. No subject had a QTcF greater than 500 msec at any assessment, and the largest change from baseline in QTcF was 37 msec.

Overall, Compound 292 was well ted in healthy subjects at single doses up to 30 mg (highest dose ) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of Compound 292 is characterized by rapid absorption (peak plasma concentrations reached within 0.5-1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). l accumulation was observed after le dose administration (accumulation ratio 1.65-1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged Compound 292 in urine was <2% of the administered dose, indicating minimal renal elimination of parent drug. CD63 expression on the surface of activated CCR3+ basophils was reduced in a dose-dependent manner at all single and multiple dose levels, with a maximum ion at 1 hour post dose, corresponding to the time of maximum Compound 292 plasma concentrations. Inhibition of basophil activation ed the nd 292 concentration-time profile, with CD63 expression returning to baseline levels as plasma trations declined. Administration of 5 mg BID maintained PI3K-δ inhibition (EC50 = 48 ng/mL) throughout the 12 hour dosing al. itant administration of a high-fat, high-calorie meal decreased Cmax approximately 10%, shifted median Tmax from 1 to 3 hours, and increased overall exposure (AUC) approximately 8-9%. These data t Compound 292 can be administered without regard to meals.

Thus, nd 292 was rapidly absorbed after single and multiple doses. Mean systemic exposure (Cmax and AUC) increased dose proportionally, indicating linear PK. Mean apparent terminal elimination half-life (t1/2) following 14 days of Compound 292 dosing ranged from 6.5 to 11.7 hours.

Accumulation ratio (mean ratio of Day 14/Day 1 AUC) was 1.54 for QD dosing, 1.65 to 1.83 over BID dose range. Following administration with a high-fat, high e meal, AUC0-inf increased by 9%, Cmax decreased by 10%, and median Tmax shifted from 1 hr to 3 hr. Based on the magnitude of these changes, Compound 292 can be administered t regard to meals. In addition, a rapid response was observed, assessed as reduction in CD63+ expression on CCR3+ basophils in an ex vivo anti-FcεR1 activation assay (3). Maximal response was observed at the time of maximal plasma concentrations, one hour after single- and multiple-dose administration. CD63+ expression returned to baseline as plasma drug trations declined. Moreover, Compound 292 was well-tolerated at all doses studied: single doses up to 30 mg, and multiple doses up to 10 mg daily for 14 days. In subjects who received multiple doses of nd 292 (n=36) (PLB n=12) for 2 weeks, the most common adverse events (AEs) were related to blood draws and protocol-associated procedures. The most common non-procedural AEs occurring in ≥ 2 subjects were headache (8% vs. 25% PLB), a (6% vs. 8% PLB), and nasopharyngitis (6% vs. 0% PLB). No dose-related trends in AEs were ed. No clinical significant findings in safety lab studies of ECGs were observed. No increases in IgE related to Compound 292 were observed.

Example 9: Clinical Studies in Advanced Hematologic Malignancies A Phase 1 dose-escalation study was designed to evaluate the safety, pharmacokinetics (PK), and activity of orally administered Compound 292 in patients with advanced hematologic malignancies, including T-cell lymphomas/leukemias. tial cohorts of patients were enrolled at ssively higher dose levels with expansion cohorts of patients with select hematologic malignancies. Compound 292 was administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response was evaluated based on disease-specific standard criteria.

The study had ed 20 (or more) patients; 5 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 4 with indolent non-Hodgkin lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2; and Richter’s n=1], 3 with le myeloma (MM), 2 with Hodgkin lymphoma (HL), 2 with T-cell lymphoma [anaplastic cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these patients, 11 were male and 9 female, with a median [range] age of 63 years [30-81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1-8].

Compound 292 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) patients uing on treatment. Adverse events (AEs) had occurred in 13 (65%) ts, including 7 (35%) patients with AEs Grade >3. Treatment-related AEs occurred in 11 patients (55%) with Grade >3 occurring in 5 patients (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade >3 hematological laboratory abnormalities included penia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM patient with onset 6 weeks after initiation of dosing of Compound 292.

PK indicated dose-proportional increases in plasma Cmax and AUC over the dose range studied.

Further, the PK and initial pharmacodynamic (PD) data from the first three cohorts (8 25 mg BID) predicted continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater.

In the evaluable patients (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 in L (0 CR/2 PR/1 SD), 1/2 in iNHL (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). All patients with at least SD after 2 cycles (n=6) remained on treatment including the first patient dosed.

] PK and PD markers were evaluated after the first dose (e.g., 8 mg BID) and at steady state. PD activity (PI3K inhibition) in whole blood was ted using a il tion assay which measured reduction in CD63 expression on the e of basophils following ex vivo stimulation.

The data demonstrated rapid drug absorption and dose-proportional PK. As in y subjects, maximum inhibition of basophil activation was observed 1 hour post dose. Prior to dose stration at the beginning of Cycle 2 (i.e. after 28 days of BID dosing), CD63 expression was reduced 45% or more relative to the start of treatment. Mean steady-state trough concentrations were maintained above levels sufficient for PI3K-δ inhibition following doses ≥15 mg BID. Clinical response were observed.

Thus, in both s (in healthy subjects and in advanced hematologic malignancies), Compound 292 drug absorption was rapid and exposure was proportional to dose. CD63 expression on the surface of activated basophils was reduced in the presence of Compound 292 in both healthy and oncology ts, an observation consistent with PI3K-δ inhibition. An exposure-response relationship was evident, suggesting a concentration-dependent pharmacological response to Compound 292. PK/PD data from the oncology study demonstrated inhibition of PI3K-δ activity and ted higher doses increasingly suppress PI3K-γ activity.

Based on the PK/PD and activity observed in patients with CLL (e.g., CLL/SLL), iNHL and MCL, an expansion cohort to further evaluate the safety and preliminary activity of Compound 292 was enrolling ts in these select hematologic diseases dosed at 25 mg BID. Dose escalation continued with a focus on patients with T-cell malignancies and DLBCL, where sing suppression of the PI3K-γ isoform can improve the efficacy profile.

] Additional ion cohorts can be opened in T-cell lymphoma, DLBCL, roliferative neoplasms, acute leukemias, T-cell/aggressive NHL, and the CLL/iNHL/MCL to further define disease specific activity.

Thus, Compound 292, an oral, potent , γ inhibitor or modulator, is well tolerated at doses ranging from 8 mg BID to 50 mg BID, and has shown clinical activity in patients with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits , providing a rationale for expansion in CLL/iNHL/MCL.

Example 10: Clinical Studies in Hematologic Malignancies: Additional Data PI3K-δ and PI3K-γ are involved in leukocyte ing and B-cell, T-cell, and myeloid cell function, including differentiation, activation, proliferation and migration. PI3K-δ and PI3K-γ support the growth and survival of certain B- and T-cell malignancies. As exemplified herein, Compound 292 is a potent oral inhibitor of PI3K-δ and PI3K-γ isoforms (e.g., Table 11).

Table 11: y of Compound 292 In Vitro Activities PI3K Isoforms* PI3K-δ PI3K-γ PI3K-α PI3K-β Primarily Primarily sion Ubiquitous tous Leukocytes Leukocytes B-cell activation and Innate immune function function Platelet activation Insulin signaling Role T-cell activation and Immune cell Insulin signaling Angiogenesis function trafficking Isoform Specific Cellular Assay 1 nM 43 nM 171 nM 1547 nM Inhibition of pAKT (IC50) Biochemical Activity (KD ) 23 pM 243 pM 1564 pM 25900 pM Whole Blood Assay (IC50) 69 nM 1200 nM 4700 nM (Healthy Donors) cεR1 fMLP Platelet * PI3K-α and PI3K-β (ubiquitous expression) not shown.

In a Phase I study in healthy subjects, single and multiple doses of Compound 292 were well tolerated with dose-proportional pharmacokinetics through 5 mg BID and a t1/2 of 6.5 to 11.7 hr and pharmacodynamic response (anti-FcεR1) mirrored plasma concentrations, with maximal effects observed at the time of maximal plasma concentrations (e.g., FIGS. 1–3).

Study Design: One clinical study of Compound 292 is a Phase I, abel study enrolling 1–6 adult patients per dose level with hematologic malignancies at progressively higher dose levels. Dosing was orally, twice daily (BID) on a 28-day cycle. The y objectives were to determine safety and MTD for Compound 292. Endpoints included safety, efficacy, cokinetics (PK), and pharmacodynamics (PD). Expansion cohorts of selected hematologic malignancies are allowed at ≤ MTD based on PK/PD/clinical activity for PI3K-δ and PI3K-γ inhibition. Key ion criteria ed: (1) progressed during, tory to, intolerant of, or ineligible for established therapy, or has disease with no established therapy; (2) adequate c and renal on (≤ Grade 1); (3) adequate hematopoietic on (escalation phase only) with ne ANC ≥ 750 cells/µL, platelets ≥ , and hemoglobin > 8.0 g/dL; (4) no prior treatment with a PI3K inhibitor (escalation phase) or within 4 weeks of first dose of Compound 292 (expansion phase). Dose escalation study included the following doses: 8 mg BID, 15 mg BID, 25 mg BID, 35 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, and 100 mg BID (enrolling). Cohort expansions at ≤ MTD are carried out in hematologic malignancies such as diffuse large B-cell lymphoma, T-cell lymphomas, acute lymphocytic leukemia, myeloproliferative neoplasms, CLL/SLL, iNHL, and MCL (for example, 25 mg BID expansion was carried out in L, iNHL, and MCL). Dose-limiting toxicities (DLTs) during Cycle 1, used to determine MTD, include (1) death; (2) Grade ≥ 4 hematologic toxicity lasting > 7 days, or Grade 3 febrile neutropenia, Grade 3 thrombocytopenia with Grade ≥ 2 hemorrhage, or Grade 4 thrombocytopenia of any duration requiring transfusion; (3) Grade 3 ea or nausea lasting ≥ 24 hours, despite medical treatment, or any other Grade 3 non-hematologic toxicity of any duration.

The patient demographics and disposition are summarized in Tables 12 and 13. After dose escalation to 75 mg BID, MTD was not yet reached and dose escalation was continuing. There were three discontinuations due to treatment related AEs: (1) Grade 3 pneumonitis (15 mg BID); (2) Grade 4 ALT elevation (25 mg BID); (3) AE grade and etiology not reported at data cut-off (25 mg BID).

Table 12: Patient Demographics Evaluable Patients (Safety), n 55 (28 Escalation, 27 Expansion at 25 mg BID) Evaluable ts (Efficacy), n 41 (24 Escalation, 17 Expansion at 25 mg BID) Median Age, years (range) 67 (30-86) s, n (%) 19 (35%) 17 iNHL 4 MCL 16 L 3 MM Diagnosis* 7 T-cell Lymphoma 3 HL Aggressive B-cell NHL (aNHL) ECOG Score 0-1 (%) 51 (93%) Poor/High Risk Lymphoma (IPI/FLIPI/MIPI), n 13 of 24 (54%) Prior Systemic Therapies, median (range) 4 (1–13) Patients with ≥ 3 Prior Systemic Therapies 39 (72%) Months Since Last Therapy to First Dose of < 6 months ≥ 6 months Compound 292, n (%) 30 (58%) 22 (42%) * iNHL (indolent non-Hodgkin lymphoma), MCL (mantle cell lymphoma), CLL/SLL(chronic lymphocytic leukemia/small lymhocytic lymphoma), MM (multiple myeloma), HL (Hodgkin lymphoma) Table 13: Patient Disposition Compound 292 Dose Patients (n) Disposition 8 mg BID 1 1 on study mg BID 6 2 on study / 4 off study (3 PD/ 1 AE) mg BID 7 5 on study / 2 off study (PD) mg BID (expansion) 27 21 on study / 6 off study (3 PD, 2 AE, 1 ineligible) mg BID 3 3 off study (2 PD, 1 withdrew consent) 50 mg BID 3 1 on study / 2 off study (1 PD/ 1 CR → ransplant) 60 mg BID 3 3 on study 75 mg BID 5 4 on study / 1 off study (PD) Total* 55 37 on study / 18 off study (12 PD) cokinetics and pharmacodynamics data are summarized in FIGS. 4 and 5. Compound 292 was rapidly absorbed with a linear PK profile h 50 mg BID (eliminating t1/2 was 6 to 10 hours). The data showed that complete inhibition of PI3K-δ can be achieved at doses of 15 mg BID or greater; and doses of 25 mg BID or r increasingly suppress PI3K-γ (. In addition, rapid and sustained inhibition of AKT phosphorylation by Compound 292 in CLL/SLL cells was observed by flow try after one dose (25 mg) (. These PK/PD results supported an expansion cohort at 25 mg BID to te the tolerability and activity of Compound 292 in selected hematologic malignancies. al efficacy data for nd 292 in B-cell and T-cell malignancies are summarized in Tables 14 and maximum change in tumor size on treatment with Compound 292 are shown in Reduction in tumor mass was observed in all indications and at all dose levels evaluated. Patients with measurable disease by CT scan and with ≥ 1 on-treatment CT assessment are shown in including patients (n=2) who have not had a response assessment. Patients off study with PD before first CT assessment (n=2) or disease not ed by CT (n=4) are not shown in the figure.

Table 14: Clinical Response in B-Cell and T-Cell Hematologic Malignancies.

Population ts (n) Best Observed Response (n) a Time to Response in Months Treated Evaluable b CR PR SD PD Median (range) iNHL 17 13 1 7 4 1 1.8 (1.7, 2.8) L 16 11 0 6 4 c 1 2.9 (1.8, 5.6) T-Cell Lymphoma 7 6 1 1 1 3 2.4 (1.8, 3.1) aNHL 5 3 0 0 1 2 N/A MCL 4 3 0 2 0 1 1.9 (1.9, 1.9) MM 3 3 0 0 1 2 N/A HL 3 2 1 0 0 1 1.7 (1.7, 1.7) a. Responses: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD). b. At least one response assessment or progressive disease (PD). c. Four nodal responses.

Rapid onset of clinical activity of Compound 292 was observed in CLL/SLL (. Clinical activity of Compound 292 in T-cell lymphoma was observed (, with first response ment after 2 cycles of Compound 292 therapy: 1 complete response (CR), 1 partial response (PR), 1 stable disease (SD), 3 progressive disease (PD) (and 1 status unknown). Four patients remained on study. In addition, a 72- year-old patient with pathy-associated T-cell lymphoma demonstrated complete resolution of pulmonary metastases (white arrows), as shown by , after 2 cycles of Compound 292 (60 mg BID) (.

Further, among ts having T cell lymphoma, it was found that Compound 292 has efficacy in treating both peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL), as shown in Table 15 below: Table 15: Clinical Responses in TCL Patients (n) Best Observed Response (n) Median Time to Response in Population T/E* CR PR SD PD Months (range) TCL Total 17/9 1 2 2 4 1.9 (1.7-2.7) PTCL 7/5 1 1 0 3 2.3 (1.9-2.7) CTCL 10/4 0 1 2 1 1.7 (--) * d/Evaluable able = at least 1 response assessment or PD prior to C3D1 response assessment) CR = te Response; PR = Partial Response; SD = Stable Disease; PD = Progressive Disease Percent changes in measurable disease as assessed by CT scans following the administration of Compound 292 at the specified doses (all BID) is illustrated in . As shown in the figure, 33% of the patients (2 PTCL and 1 CTCL) showed at least 50% tumor response.

Clinical ses ed in various B cell lymphoma patients are summarized in Table 16 below: Table 16: Clinical ses in BCL Patients (n) Best Observed Response, n(%) Median Time to Rsp Population T/E* Overall CR PR MR SD PD in Months (Range) iNHL 26/19 13 (68) 3 (16) 10 (53) 1 (5) 3 (16) 2 (11) 1.8 (1.7-4.1) MCL 9/6 4 (67) 1 (17) 3 (50) N/A 1 (17) 1 (17) 1.8 (1.6-1.9) HL 3/3 1 (33) 1 (33) 0 N/A 1 (33) 1 (33) 1.7 aNHL 13/10 0 0 0 N/A 4 (40) 6 (60) N/A * d/Evaluable CR = Complete Response; PR = Partial Response; MR = Minor Response for Waldenstrom’s; SD = Stable e; PD = Progressive Disease iNHL included 11 follicular lymphoma, 2 Waldenstrom’s, 1 marginal zone lymphoma (MZL) and 12 iNHL As can be seen above, responses were observed (including CRs) in nt, mantle and Hodgkin’s lymphomas. Responses occurred early in 16 out of 18 responders (89%) by first assessment, within about 2 months. Percent changes in measurable disease assessed by CT scans for MCL, HL and a NHL patients are provided in , and those for iNHL (including follicular lymphoma, Waldenstrom’s and MZL) are provided in .

Clinical safety data for Compound 292 are summarized in Tables 17 and 18. No dose-related trends were observed in related Grade 3 or Grade 4 AEs. DLTs included Grade 4 neutropenia (15 mg BID) and Grade 3 cellulitis (wound infection, 75 mg BID).

Table 17: Safety of Compound 292.

Subject Safety Outcomes 25 mg BID Safety tion (n = 34) (n = 55) Deaths on Study, n (%)* 0 (0%) 3 (5%) AE Leading to Discontinuation, n (%) 2 (6 %) 3 (5%) SAE, n (%) 4 (12%) 11 (20%) Related SAE, n (%) 1 (3%) 4 (7%) All infectious SAEs, n (%) 1 (3%) 3 (5%) Any AE 27 (79%) 46 (84%) Grade