WO2012044641A1 - 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy - Google Patents

1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy Download PDF

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WO2012044641A1
WO2012044641A1 PCT/US2011/053570 US2011053570W WO2012044641A1 WO 2012044641 A1 WO2012044641 A1 WO 2012044641A1 US 2011053570 W US2011053570 W US 2011053570W WO 2012044641 A1 WO2012044641 A1 WO 2012044641A1
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compound
la
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lc
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Gordon William Rewcastle
Anna Claire Giddens
Swarnalatha Akuratiya Gamage
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Pathway Therapeutics Inc.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

Provided herein are 1,3,5-triazinyl benzimidazole sulfonamides, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs formula (I); (IA).

Description

1,3,5-TRIAZINYL BENZIMIDAZOLE SULFONAMIDES AND THEIR USE IN

CANCER THERAPY

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.:

61/387,836, filed September 29, 2010; the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[0002] Provided herein are 1,3,5-triazinyl benzimidazole sulfonamides, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

BACKGROUND

[0003] Phosphoinositide-3 -kinases (PI3Ks) are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into at least three classes (Classes I, II, and III) and play an important role in cellular signaling (Stephens et al, Curr. Opin. Pharmacol. 2005, 5, 357). Class I enzymes are further classified into Classes la and lb based on their mechanism of activation; Class la PI3Ks are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi 10β, or pi 10δ) in complex with a regulatory p85 subunit, while the class-lb PI3K (pi 10γ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by βγ subunits of heterotrimeric G-proteins (Walker et al., Mol .Cell. 2000, 6, 909). The human protein sequence of the pi 10a isoform is described in Volina et al, Genomics 1994, 24, 472; and Stirdivant et al, Bioorg. Med. Chem. 1997, 5, 65.

[0004] PI3Ks play a variety of roles in normal tissue physiology (Foukas & Shepherd,

Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with pi 10a having a specific role in cancer growth, pi 10β in thrombus formation mediated by integrin απβ3 (Jackson et al, Nat. Med. 2005, 11, 507), and pi 10γ in inflammation, rheumatoid arthritis (Camps et al, Nat. Med. 2005, 11, 936) and other chronic inflammation states (Barber et al, Nat. Med. 2005, 11, 933). The PI3K enzymes produce phosphoinositide 3,4,5-triphosphate (PIP3) from the corresponding diphosphate (PIP2), thus recruiting AKT (protein kinase B) through its Pleckstrin homology (PH) domain to the plasma membrane. Once bound, AKT is phosphorylated and activated by other membrane bound kinases and is central to a cascade of events that lead to inhibition of apoptosis (Berrie, Exp. Opin. Invest. Drugs 2001, 10, 1085).

[0005] The pi 10a isoform is selectively amplified and activated in a number of cancer types (Stephens et al, Curr. Opin. Pharmacol 2005, 5, 357; Stauffer et al, Curr. Med. Chem. - Anti-Cancer Agents 2005, 5, 449). In addition, there is a high frequency of non- random mutations in specific sites, primarily in the C2 domain and or the activation loop, of the kinase in several human cancer cell lines, including colon, brain, breast, and stomach (Samuels et al, Science 2004, 304, 554). This results in a constitutively active enzyme (Ikenoue et al, Cancer Res. 2005, 65, 4562; Kang et al, Proc. Natl Acad. Sci. USA 2005, 102, 802), making pi 10a one of the most highly mutated oncogenes found in human tumors. Structural studies have shown that many of the mutations occur at residues lying at the interfaces between pi 10a and p85a or between the kinase domain of pi 10a and other domains within the catalytic subunit (Miled et al, Science 2007, 317, 239; Huang et al, Science 2007, 318, 1744).

[0006] While PI3K isoenzymes play important roles in many cellular processes, published experimental studies in mice with human tumor xenografts show that the pan-PI3K inhibitor LY294002 is well-tolerated, reduces signaling through the PI3K pathway, causes reduction of tumor volume, and is more active in cell lines over-expressing mutant forms of pi 10a than parental control cells (Semba et al, Clin. Cancer Res. 2002, 8, 1957; Hu et al, Cancer Res. 2002, 62, 1087).

[0007] Thus, PI3K, especially the pi 10a isoform, is an interesting target for drug intervention. Several classes of compounds have been identified as reversible inhibitors; for example, LY 294002 (non-selective) (Walker et al., Mol .Cell. 2000, 6, 909), PI 103 (slightly a-selective) (Knight et al, Cell 2006, 125, 733; Hayakawa et al, Bioorg. Med. Chem. Lett. 2007, 17, 2438; Raynaud et al, Cancer Res. 2007, 67, 5840), ZSTK474 (non-selective) (Yaguchi et al, J. Natl. Cancer Inst. 2006, 98, 545; Kong et al, Cancer Sci. 2007, 98, 1639), TGX221 (β-selective) (Jackson et al, Nat. Med. 2005, 11, 507), oxazines (γ-selective) (Lanni et al, Bioorg. Med. Chem. Lett. 2007, 17, 756), IC87114 (^-selective) (Sadhu et al. WO 2001/81346; BiUottet et al, Oncogene 2006, 25, 6648), AS605240 (γ-selective) (Camps et al, Nat. Med. 2005, 11, 936), the imidazo[l,2-a]pyridines (a-selective) (Hayakawa et al, Bioorg. Med. Chem. 2007, 15, 403; Hayakawa et al., Bioorg. Med. Chem. 2007, 15, 5837), and the imidazo[4,5-c]quinoline NVP-BE -Echeverria, et al, WO 2006/122806 .

Figure imgf000004_0001

LY294002 PI 103 ZSTK474

Figure imgf000004_0002

Figure imgf000004_0003

AS605240

Imidazo[l,2-a]pyridine NVP-BEZ235

[0008] mTOR (also known as FRAP) plays a critical role in cellular responses to a variety of growth stimuli, and integrates signals from mitogenic tyrosine kinase receptors, tissue oxygenation, and cellular energy and nutrient status (Fingar and Blenis, Oncogene

2004, 23, 3151). Two distinct mTOR protein complexes have been identified: mTORCl (comprising mTOR, Raptor, LST8 and PRAS40) and mTORC2 (comprising mTOR, Rictor, LST8, mSINl and PROTOR) (Guertin and Sabatini, Cancer Cell 2007, 12, 9). A further regulator of mTORCl and mTORC2, DEPTOR, has also been described (Peterson et al, Cell 2009, 137, 873). mTOR signaling is important for both cellular growth and survival, and is frequently found to be dysregulated in cancer (Guertin and Sabatini, Cancer Cell 2007, 12, 9). [0009] The mTORC 1 complex plays an important role in protein translation, through phosphorylation of the mTOR substrates 4E-BP1 (eIF4E binding protein) and p70S6 kinase (Holz et al., Cell 2005, 123, 569). mTORCl is regulated by the tuberous sclerosis complex TSC1/TSC2 and the small GTPase Rheb. In turn, TSC1/TSC2 integrates signals from multiple cellular sensors including mitogenic growth factor receptors (via PBKs and their downstream substrate kinase AKT), ATP (via AMP-activated protein kinase and its upstream regulatory kinase LKB1 (Shaw et al., Cancer Cell 2004, 6, 91)), and hypoxia (via the stress- induced proteins REDD1/REDD2 (Brugarolas et al, Genes Dev. 2004, 18, 2893)). mTORCl also responds to cellular amino acid levels (in particular leucine), in concert with the Class III PI3K, VPS34. mTORCl also promotes cell cycle progression through regulation of SGK1 kinase (Hong et al., Mol Cell 2008, 30, 701).

[0010] mTORC2 functions primarily as a regulator of PI3K pathway signaling upstream of mTORCl . Most notably, mTORC2 phosphorylates and promotes activation of AKT (Sarbassov et al., Science 2005, 307, 1098), and therefore mediates the many downstream effects of AKT signaling, including cell survival, growth, and proliferation (Mitsiades et al., Curr Cancer Drug Targets 2004, 4, 235).

[0011] The macro lide antibiotic rapamycin is a selective inhibitor of the mTORCl complex, and several rapamycin derivatives (temsirolimus, everolimus and ridaforolimus) have been tested as cancer drugs in the clinic. These inhibitors have shown promise in several tumor types including renal cell carcinoma, mantle cell lymphoma and sarcoma, and both temsirolimus and everolimus are approved for treatment of metastatic renal cell cancer. Rapamycin analogs have also shown promise in combination with other anticancer agents. However, in many tumor cells inhibition of mTORCl leads to upregulation of PI3K signaling via a negative feedback mechanism (Harrington et al., J Cell Biol 2004, 166, 213); this phenomenon has also been observed in clinical tumor biopsies (O'Reilly et al., Cancer Research 2006, 66, 1500) and may limit the efficacy of selective mTORCl inhibitors.

Therefore, inhibitors that inactivate both PI3K and mTOR may have particular utility as anticancer agents. Further preclinical data also support a role for combining PI3K and mTOR inhibitors to increase antitumor activity (for example, Fan et al., Cancer Research

2007 67, 7960).

[0012] Despite the advances in developing PI3K inhibitors, there is a need for PI3K inhibitors for treatment of cancer.

SUMMARY OF THE DISCLOSURE

[0013] Provided herein is a compound of Formula I:

Figure imgf000006_0001

(I)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

wherein:

R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,

-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,

-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;

R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;

R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_ 6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;

R5c is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;

R6 is hydrogen or Ci_6 alkyl;

Q is C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, or C2_6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -S02- group is nitrogen; and

n is an integer of 1, 2, 3, 4 or 5;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;

wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,

-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,

-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh,

-NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and

-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

[0014] Also provided herein is a hydrated compound of a compound of Formula IA:

Figure imgf000008_0001

(IA)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

wherein:

R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,

-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,

-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;

R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;

R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_

6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl

R5c and R5d are each independently hydrogen, Ci_6 alkyl, C2_6 i alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; R6 is hydrogen or Ci_6 alkyl;

Q is C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -SO2- group is nitrogen; and

n is an integer of 1 , 2, 3, 4 or 5;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R5d, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa,

-C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc,

-OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;

wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,

-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,

-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and

-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

[0015] Further provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.

[0016] Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0017] Provided herein is a method for modulating PI3K activity, comprising contacting a PI3K with a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

DETAILED DESCRIPTION

[0018] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0019] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0020] The term "subject" refers to an animal, including, but not limited to, a primate

{e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.

[0021] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0022] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0023] The term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g. , a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0024] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower

Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009. [0025] 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 "about" 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.

[0026] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0027] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0028] The term "naturally occurring" or "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by man. Similarly, "non-naturally occurring" or "non-native" refers to a material that is not found in nature or that has been structurally modified or synthesized by man.

[0029] The term "PI3K" refers to a phosphoinositide 3-kinase or mutant thereof, which is capable of phosphorylating the inositol ring of PI in the D-3 position. The term

"PI3K mutant" is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions {e.g., PI3K derivatives, homologs, and fragments), as compared to the amino acid sequence of a native PI3K. The amino acid sequence of a PI3K mutant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K. Examples of PI3K include, but are not limited to, pi 10a, pi 10β, pi 105, pi 10γ,

PI3K-C2a, PI3K-C2P, PI3K-C2y, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry,

Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell.

Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PBKs are classified into at least four classes. Class I includes i 10a, i 10β, i 105, and pi 10γ. Class II includes PI3K-C2a, PI3K-C2p, and PI3K-C2y. Class III includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is pi 10a, pi 10β, pi 105, or pi 10γ. In certain embodiments, the PI3K is a mutant of a Class I kinase. In certain embodiments, the PI3K is a pi 10a mutant.

Examples of pi 10a mutants include, but are not limited to, R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, and H1047Y (Ikenoue et al , Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al, Proc. Natl. Acad. ScL , 2007, 104, 5569-5574). In certain embodiments, the PI3K is a Class II kinase. In certain embodiments, the PI3K is PI3K-C2a, PI3K-C2p, or PI3K-C2y. In certain embodiments, the PI3K is a Class III kinase. In certain embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK.

[0030] The terms "PI3K-mediated condition, disorder or disease" and "a condition, disorder, or disease mediated by PI3K" refer to a condition, disorder, or disease characterized by abnormal or dysregulated, e.g. , less than or greater than normal, PI3K activity. Abnormal PI3K functional activity might arise as the result of PI3K overexpression in cells, expression of PI3K in cells which normally do not express PI3K, or dysregulation due to constitutive activation, caused, for example, by a mutation in PI3K. A PI3K-mediated condition, disorder, or disease may be completely or partially mediated by abnormal PI3K activity. In particular, PI3K-mediated condition, disorder, or disease is one in which modulation of a PI3K activity results in some effect on the underlying condition, disorder, or disease, e.g. , a PI3K inhibitor results in some improvement in at least some of patients being treated.

[0031] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkyl" also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci_2o), 1 to 15 (Ci_i5), 1 to 10 (Ci_io), or 1 to 6 (Ci_6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3_i5), 3 to 10 (C3_io), or 3 to 6 (C3_6) carbon atoms. As used herein, linear Ci_6 and branched C3_6 alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, Ci_6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

[0032] The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkylene" encompasses both linear and branched alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3- io), or 3 to 6 (C3-6) carbon atoms. As used herein, linear Ci_6 and branched C3-6 alkylene groups are also referred as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, Ci_6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.

[0033] The term "heteroalkylene" refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. For example, Ci_6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (Ci_io), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3_2o), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3_6) carbon atoms. As used herein, linear Ci_6 and branched C3_6 heteroalkylene groups are also referred as "lower

heteroalkylene." Examples of heteroalkylene groups include, but are not limited to, -CH20-, -CH2OCH2-, -CH2CH2O-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. In certain embodiments, heteroalkylene may also be optionally substituted as described herein.

[0034] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted as described herein. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2_6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_2o), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0035] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenylene may be optionally substituted as described herein. Similarly, the term "alkenylene" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. As used herein, the term "alkenylene" encompasses both linear and branched alkenylene, unless otherwise specified. For example, C2_6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_2o), 2 to 15 (C2-15), 2 to 10 (C2_io), or 2 to 6 (C2_6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4- methy lbuteny lene .

[0036] The term "heteroalkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more

heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. The heteroalkenylene may be optionally substituted as described herein. The term

"heteroalkenylene" embraces radicals having a "cis" or "trans" configuration or a mixture thereof, or alternatively, a "Z" or "E" configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2_6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the

heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_2o), 2 to 15 (C2-15), 2 to 10 (C2_io), or 2 to 6 (C2_6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCH20- -CH=CHS- -CH=CHSCH2- -CH=CHCH2S-, or -CH=CHCH2NH-.

[0037] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynyl may be optionally substituted as described herein. The term "alkynyl" also encompasses both linear and branched alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_2o), 2 to 15 (C2-15), 2 to 10 (C2_io), or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C2_6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

[0038] The term "cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,

bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

[0039] The term "cycloalkylene" refers to a cyclic saturated bridged and/or non- bridged divalent hydrocarbon radical, which may be optionally substituted as described herein. In certain embodiments, the cycloalkylene has from 3 to 20 (C3_2o), from 3 to 15 (C3_ 15), from 3 to 10 (C3-10), or from 3 to 7 (C3_7) carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene (e.g., 1 ,1-cyclopropylene and 1 ,2- cyclopropylene), cyclobutylene (e.g., 1 ,1-cyclobutylene, 1 ,2-cyclobutylene, or 1 ,3- cyclobutylene), cyclopentylene (e.g., 1 , 1-cyclopentylene, 1 ,2-cyclopentylene, or 1 ,3- cyclopentylene), cyclohexylene (e.g., 1 , 1-cyclohexylene, 1 ,2-cyclohexylene, 1 ,3- cyclohexylene, or 1 ,4-cyclohexylene), cycloheptylene (e.g., 1 , 1-cycloheptylene, 1 ,2- cycloheptylene, 1 ,3 -cycloheptylene, or 1 ,4-cycloheptylene), decalinylene, and adamantylene.

[0040] The term "aryl" refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-2o), from 6 to 15 (C6-15), or from 6 to 10 (C6-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted as described herein.

[0041] The term "arylene" refers to a monocyclic and/or multicyclic divalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6_2o), from 6 to 15 (C6_i5), or from 6 to 10 (C6_io) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene. Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydro-naphthylene (tetralinyl). In certain embodiments, arylene may also be optionally substituted as described herein.

[0042] The term "aralkyl" or "aryl-alkyl" refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted as described herein.

[0043] The term "heteroaryl" refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl,

benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,

imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein.

[0044] The term "heteroarylene" refers to a divalent aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, imidazolylene, isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene, triazinylene, and triazolylene. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofuranylene, benzimidazolylene, benzoisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene,

benzothienylene, benzothiophenylene, benzotriazolylene, benzoxazolylene, furopyridylene, imidazopyridinylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene, isothiazolylene, naphthyridinylene, oxazolopyridinylene, phthalazinylene, pteridinylene, purinylene, pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene,

dibenzofuranylene, perimidinylene, phenanthrolinylene, phenanthridinylene,

phenarsazinylene, phenazinylene, phenothiazinylene, phenoxazinylene, and xanthenylene. In certain embodiments, heteroaryl may also be optionally substituted as described herein.

[0045] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4- dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,

tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted as described herein.

[0046] The term "heterocyclylene" refers to a divalent non-aromatic ring system and/or multicyclic ring system that contain at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclene groups include, but are not limited to, azepinylene, benzodioxanylene, benzodioxolylene, benzofuranonylene, benzopyranonylene, benzopyranylene, benzotetrahydrofuranylene, benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene, β-carbolinylene, chromanylene, chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofurylene,

dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene, dioxolanylene, 1,4- dithianylene, furanonylene, imidazolidinylene, imidazolinylene, indolinylene,

isobenzotetrahydrofuranylene, isobenzotetrahydrothienylene, isochromanylene,

isocoumarinylene, isoindolinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene, octahydroindolylene, octahydroisoindolylene, oxazolidinonylene, oxazolidinylene, oxiranylene, piperazinylene, piperidinylene, 4-piperidonylene, pyrazolidinylene,

pyrazolinylene, pyrrolidinylene, pyrrolinylene, quinuclidinylene, tetrahydrofurylene, tetrahydroisoquinolinylene, tetrahydropyranylene, tetrahydrothienylene, thiamorpholinylene, thiazolidinylene, tetrahydroquinolinylene, and 1,3,5-trithianylene. In certain embodiments, heterocyclic may also be optionally substituted as described herein.

[0047] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.

[0048] The term "optionally substituted" is intended to mean that a group, such as an alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, may be substituted with one or more substituents independently selected from, e.g., (a) Ci_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (b) halo, cyano (-CN), nitro (-N02), -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc,

-NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.

[0049] In one embodiment, each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg,

-OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg,

-NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh,

-NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.

[0050] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%), no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%), no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.

[0051] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.

[0052] The term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (UC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (140), oxygen-15 (150), oxygen-16 (160), oxygen-17 (170), oxygen-18 (180), fiuorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an "isotopic variant" of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen- 14 (14N), nitrogen-15 (15N), oxygen-16 (160), oxygen-17 (170), oxygen-18 (180), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an "isotopic variant" of a compound is in an unstable form, that is, radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (UC), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (140), oxygen-15 (150), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, for example, or any carbon can be 13C, for example, or any nitrogen can be 15N, for example, or any oxygen can be 180, for example, where feasible according to the judgment of one of skill. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).

[0053] The term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0054] The term "hydrated compound" refers to a compound that contains one or more hydroxyl groups, in one embodiment, one hydroxyl group, which are formed via the addition of one or more water molecules to a precursor of the compound or via the oxidation of a precursor of the compound.

[0055] The phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof has the same meaning as the phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isototpic variant of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isototpic variant of the compound referenced therein."

Compounds

[0056] In one embodiment, provided herein is a compound of Formula I:

Figure imgf000024_0001

(I)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

wherein:

R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6_i4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,

-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,

-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-i4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;

R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;

R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_ 6 alkynyl, C3_7 cycloalkyl, C6-i4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;

R5c is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-i4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; R6 is hydrogen or Ci_6 alkyl;

Q is C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -SO2- group is nitrogen; and

n is an integer of 1 , 2, 3, 4 or 5;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;

wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,

-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,

-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh,

-NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and

-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl. [0057] In one embodiment, in Formula I,

R1 is hydrogen or -ORla; wherein Rla is Ci_6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c is hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci_6 alkyl, optionally substititued as described herein;

Q is C6-i4 arylene or heterocyclylene, each optionally substititued as described herein;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, where the alkyl is optionally substititued as described herein; and

n is an integer of 1, 2, 3, or 4.

[0058] In another embodiment, in Formula I,

R1 is hydrogen or -ORla; wherein Rla is Ci_6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c is hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci_6 alkyl, optionally substititued as described herein;

Q is piperazinylene or phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, where the alkyl is optionally substititued as described herein; and

n is an integer of 1, 2, 3, or 4. [0059] In yet another embodiment, in Formula I,

R1 is hydrogen or -ORla; wherein Rla is Ci_6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or C1-6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or C1-6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c is hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci-6 alkyl, substititued with one, two, or three halo;

Q is piperazinylene or phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, where the alkyl is optionally substititued as described herein; and

n is an integer of 2.

[0060] In still another embodiment, in Formula I,

R1 is methoxy;

R2 is hydrogen or amino;

R3 and R4 are hydrogen;

R5a and R5b are hydrogen;

R5c is hydrogen or methyl;

R6 is difluoromethyl;

Q is 1 ,4-piperazinylene or 1 ,4-phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen; and

n is an integer of 2. [0061] In one embodiment, the compound of Formula I has the structure of Formula

II:

Figure imgf000028_0001

(Π)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5c, and R6 are each as defined herein.

[0062] In another embodiment, the compound of Formula I has the structure of

Figure imgf000028_0002

(III)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5c, and R6 are each as defined herein. [0063] In another embodiment, provided herein is a hydrated compound of a compound of Formula IA:

Figure imgf000029_0001

(IA)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

wherein:

R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,

-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,

-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;

R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;

R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_

6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl

R5c and R5d are each independently hydrogen, Ci_6 alkyl, C2_6 i alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; R6 is hydrogen or Ci_6 alkyl;

Q is C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -SO2- group is nitrogen; and

n is an integer of 1 , 2, 3, 4 or 5;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R5d, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa,

-C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc,

-OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;

wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,

-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,

-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and

-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

[0064] In one embodiment, in Formula IA,

R1 is hydrogen or -ORla; wherein Rla is Ci_6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c and R5d are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci_6 alkyl, optionally substititued as described herein;

Q is C6-i4 arylene or heterocyclylene, each optionally substititued as described herein;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein; and

n is an integer of 1 , 2, 3, or 4.

[0065] In another embodiment, in Formula I A,

R1 is hydrogen or -ORla; wherein Rla is Ci_6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c and R5d are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci_6 alkyl, optionally substititued as described herein;

Q is piperazinylene or phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein; and

n is an integer of 1 , 2, 3, or 4. [0066] In yet another embodiment, in Formula IA,

R1 is hydrogen or -ORla; wherein Rla is C1-6 alkyl, optionally substititued as described herein;

R2 is hydrogen or amino;

R3 and R4 are each independently hydrogen or C1-6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5a and R5b are each indpendently hydrogen, halo, or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R5c and R5d are each independently hydrogen or Ci_6 alkyl, wherein the alkyl is optionally substititued as described herein;

R6 is Ci_6 alkyl, substititued with one, two, or three halo;

Q is piperazinylene or phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen or Ci_6 alkyl, where the alkyl is optionally substititued as described herein; and

n is an integer of 2.

[0067] In still another embodiment, in Formula IA,

R1 is methoxy;

R2 is hydrogen or amino;

R" and R4 are hydrogen;

R5a and R5b are hydrogen;

R5c and R5d are each independently hydrogen or methyl;

R6 is difiuoromethyl;

Q is 1 ,4-piperazinylene or 1,4-phenylene;

T1 is a bond or -NR7-; wherein R7 is hydrogen; and

n is an integer of 2.

[0068] In one embodiment, the hydrated compound of a compound of Formula IA has the structure of Formula IIA:

Figure imgf000033_0001

(IIA)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5a, R5b, R5c, R5d, R6, Q, T1, and n are each as defined herein.

[0069] In one embodiment, the hydrated compound of Formula IIA has the structure of Formula IIIA:

Figure imgf000033_0002

(IIIA)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5c, R5d, and R6 are each as defined herein. In another embodiment, the compound of Formula IIA has the structure of

Figure imgf000034_0001

(IVA)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5c, R5d, and R6 are each as defined herein.

[0071] The groups, R1, R2, R3, R4, R5a, R5b, R5c, R5d, R6, Q, T1, and n in Formulae provided herein, e.g., Formulae I to III, and IA to IVA, are further defined in the

embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of this disclosure.

[0072] In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is cyano.

In certain embodiments, R1 is halo. In certain embodiments, R1 is fluoro, chloro, bromo, or iodo. In certain embodiments, R1 is nitro. In certain embodiments, R1 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is C2_6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is C3-7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is C6-i4 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is C7-15 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is heterocyclyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R1 is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -OCH3. In certain embodiments, R1 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R1 is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R1 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R1 is -NRlaS(0)R1 , wherein Rla and Rld are each as defined herein. In certain embodiments, R1 is

-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -SRla, wherein Rla is as defined herein. In certain

embodiments, R1 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is

-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein. In certain embodiments, R is hydrogen, methoxy, ethoxy, propoxy, isopropoxy, or dimethylaminopropoxy. In certain embodiments, R1 is hydrogen, methoxy, or 3 -dimethylaminopropoxy.

[0073] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is cyano.

In certain embodiments, R2 is halo. In certain embodiments, R2 is fluoro, chloro, bromo, or iodo. In certain embodiments, R2 is nitro. In certain embodiments, R2 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is C2-6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is C2-6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is C3_7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is C6-14 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is C7_i5 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is heterocyclyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R2 is -C(0)Rla, wherein Rla is as defined herein. In certain

embodiments, R2 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R2 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -ORla, wherein Rla is as defined herein. In certain embodiments, R2 is -OCH3. In certain embodiments, R2 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R2 is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is amino (-NH2). In certain embodiments, R2 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is

-NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R2 is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -SRla, wherein Rla is as defined herein. In certain embodiments, R2 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is hydrogen, methoxy, ethoxy, propoxy, isopropoxy,

dimethylaminopropoxy, or amino. In certain embodiments, R2 is hydrogen, methoxy, or amino.

[0074] In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R3 is hydrogen, methyl, ethyl, or propyl (e.g. , n-propyl, isopropyl, or 2- isopropyl).

[0075] In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R4 is hydrogen, methyl, ethyl, or propyl (e.g. , n-propyl, isopropyl, or 2- isopropyl).

[0076] In certain embodiments, R3 and R4 are linked together to form a bond. In certain embodiments, R3 and R4 are linked together to form Ci_6 alkylene, optionally substituted with one or more substituents as described herein. In certain embodiments, R3 and R4 are linked together to form methylene, ethylene, or propylene, each optionally substituted with one or more substituents as described herein. In certain embodiments, R3 and R4 are linked together to form Ci_6 heteroalkylene, optionally substituted with one or more substituents as described herein. In certain embodiments, R3 and R4 are linked together to form C2_6 alkenylene, optionally substituted with one or more substituents as described herein. In certain embodiments, R3 and R4 are linked together to form C2_6 heteroalkenylene, optionally substituted with one or more substituents as described herein.

[0077] In certain embodiments, R5a is hydrogen. In certain embodiments, R5a is halo.

In certain embodiments, R5a is fluoro, chloro, bromo, or iodo. In certain embodiments, R5a is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is C2_6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R a is C3-7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is C6-14 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is C7_i5 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5a is heterocyclyl, optionally substituted with one or more substituents as described herein.

[0078] In certain embodiments, R5b is hydrogen. In certain embodiments, R5b is halo.

In certain embodiments, R5b is fluoro, chloro, bromo, or iodo. In certain embodiments, R5b is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is C2_6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is C3_7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is C6-14 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is C7_i5 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5b is heterocyclyl, optionally substituted with one or more substituents as described herein.

[0079] In certain embodiments, R5a and R5b are both hydrogen.

[0080] In certain embodiments, R5c is hydrogen. In certain embodiments, R5c is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is methyl. In certain embodiments, R5c is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is C2_6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is C3_7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is C6-14 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is C7_i5 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5c is heterocyclyl, optionally substituted with one or more substituents as described herein.

[0081] In certain embodiments, R5d is hydrogen. In certain embodiments, R5d is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is methyl. In certain embodiments, R5d is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is C2_6 alkynyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is C3-7 cycloalkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is C6-14 aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is C7_i5 aralkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R5d is heterocyclyl, optionally substituted with one or more substituents as described herein.

[0082] In certain embodiments, R5c and R5d are both hydrogen. In certain

embodiments, R5c and R5d are both methyl. In certain embodiments, R5c is hydrogen and R5d is methyl.

[0083] In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R6 is Ci_6 alkyl, optionally substituted with one or more, in one embodiment, one, two, or three, halo. In certain embodiments, R6 is Ci_6 alkyl, optionally substituted with one or more, in one embodiment, one, two, or three, fluoro. In certain embodiments, R6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R6 is difluoromethyl.

[0084] In certain embodiments, Q is C3-7 cycloalkylene, optionally substituted with one or more substituents as described herein. In certain embodiments, Q is cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, each optionally substituted with one or more substituents as described herein. In certain embodiments, Q is C6-14 arylene, optionally substituted with one or more substituents as described herein. In certain embodiments, Q is phenylene, optionally substituted with one or more substituents as described herein. In certain embodiments, Q is 1 ,2-phenylene, 1,3-phenylene, or 1 ,4-phenylene, each optionally substituted with one or more substituents as described herein. In certain embodiments, Q is heteroarylene, optionally substituted with one or more substituents as described herein. In certain embodiments, Q is pyrrolylene, thiazolylylene, pyrazolylene, or pyridylene, each optionally substituted with one or more substituents as described herein. In certain

embodiments, Q is heterocyclylene, optionally substituted with one or more substituents as described herein. In certain embodiments, Q is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene, each optionally substituted with one or more substituents as described herein. In certain embodiments, Q is phenylene or piperazinylene, each optionally

substituted with one or more substituents as described herein. In certain embodiments, Q is 1 ,4-phenylene or 1 ,4-piperazinylene, each optionally substituted with one or more

substituents as described herein.

[0085] In certain embodiments, T1 is a bond, with the proviso that the atom of Q directly attached to the -S02- group is nitrogen. In certain embodiments, T1 is -NR7-, wherein R7 is as defined herein. In certain embodiments, T1 is -NH-.

[0086] In certain embodiments, R7 is hydrogen. In certain embodiments, R7 is Ci_6 alkyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R7 is C2_6 alkenyl, optionally substituted with one or more substituents as described herein. In certain embodiments, R7 is C2_6 alkynyl, optionally substituted with one or more substituents as described herein.

[0087] In certain embodiments, Rla is hydrogen. In certain embodiments, Rla is Ci_6 alkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is C2_6 alkenyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is C2_6 alkynyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is C3_7 cycloalkyl, optionally substituted with one or more substituents as defined herein. In certain

embodiments, Rla is C6-14 aryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is C7_i5 aralkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is heteroaryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rla is heterocyclyl, optionally substituted with one or more substituents as defined herein. [0088] In certain embodiments, R is hydrogen. In certain embodiments, R is Ci_6 alkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is C2_6 alkenyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is C2_6 alkynyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is C3-7 cycloalkyl, optionally substituted with one or more substituents as defined herein. In certain

embodiments, Rlb is C6-14 aryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is C7_i5 aralkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is heteroaryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlb is heterocyclyl, optionally substituted with one or more substituents as defined herein.

[0089] In certain embodiments, Rlc is hydrogen. In certain embodiments, Rlc is Ci_6 alkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is C2_6 alkenyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is C2_6 alkynyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is C3_7 cycloalkyl, optionally substituted with one or more substituents as defined herein. In certain

embodiments, Rlc is C6-14 aryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is C7_i5 aralkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is heteroaryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rlc is heterocyclyl, optionally substituted with one or more substituents as defined herein.

[0090] In certain embodiments, Rlb and Rlc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents as defined herein.

[0091] In certain embodiments, Rld is hydrogen. In certain embodiments, Rld is Ci_6 alkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is C2_6 alkenyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is C2_6 alkynyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is C3_7 cycloalkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, R is C6-14 aryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is C7_i5 aralkyl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is heteroaryl, optionally substituted with one or more substituents as defined herein. In certain embodiments, Rld is heterocyclyl, optionally substituted with one or more substituents as defined herein.

[0092] In certain embodiments, n is an integer of 1. In certain embodiments, n is an integer of 2. In certain embodiments, n is an integer of 3. In certain embodiments, n is an integer of 4. In certain embodiments, n is an integer of 5.

[0093] In one embodiment, provided herein is a compound selected from:

2-amino-N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}ethanesulfonamide;

N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide;

2-amino-N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}ethanesulfonamide; and

N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide;

and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

[0094] In another embodiment, provided herein is a hydrated compound selected from:

2-(difluoromethyl)- 1 -(4-(4-(2-(dimethylamino)ethylsulfonyl)piperazin- 1 -yl)- 6-morpholino-l,3,5-triazin-2-yl)-4-methoxy-2,3-dihydro-lH-benzimidazol-2-ol; and

N-(4-(4-(2-(difluoromethyl)-2-hydroxy-4-methoxy-2,3-dihydro-lH- benzimidazol-l-yl)-6-morpholino-l,3,5-triazin-2-yl)phenyl)-2-(dimethylamino)ethane- sulfonamide;

and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

[0095] The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers. Where structural isomers are

interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0096] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the

preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0097] When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al. , J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).

[0098] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)- camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,

naphthalene-2-sulfonic acid, naphthalene- 1, 5 -disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino- salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0099] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,

lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l,3-propanediol, and tromethamine.

[00100] The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula I, and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be

bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221- 294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al, Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al, Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al, Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al, Ed., Marcell Dekker, 185- 218, 2000; Balant et al, Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol.

1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al, Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49- 59; Gangwar et al, Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al, Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63- 80; and Waller et al, Br. J. Clin. Pharmac. 1989, 28, 497-507.

[00101] In certain embodiments, the compounds provided herein are inhibitors of PI3K.

In certain embodiments, the compounds provided herein are selective inhibitors of PI3K iso forms. In certain embodiments, the compounds provided herein are reversible inhibitors of PI3K. In certain embodiments, the compounds provided herein are selective reversible inhibitors of PI3K isoforms.

[00102] In certain embodiments, the compounds provided herein are inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective inhibitors of pi 10a. In certain embodiments, the compounds provided herein are reversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective reversible inhibitors of pi 10a.

[00103] In certain embodiments, the compounds provided herein are inhibitors of mTOR. In certain embodiments, the compounds provided herein are inhibitors of pi 10a and mTOR. In certain embodiments, the compounds provided herein are inhibitors of pi 105 and mTOR. In certain embodiments, the compounds provided herein are inhibitors of pi 10γ and mTOR. [00104] In certain embodiments, the sulfonamide compounds provided herein exhibit greater pharmacological stability than the corresponding carboxamides. In certain embodiments, the sulfonamide compounds provided herein exhibit an increase of no less than 2-fold, 3 -fold, 4-fold, or 5 -fold in pharmacological stability than the corresponding carboxamides. In certain embodiments, the sulfonamide compounds provided herein exhibit greater stability in human plasma than the corresponding carboxamides. In certain embodiments, the sulfonamide compounds provided herein exhibit an increase of no less than 2-fold, 3 -fold, 4-fold, or 5 -fold in stability in human plasma than the corresponding carboxamides.

Methods of Synthesis

[00105] The compound provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art, and the following examples are only representative and do not exclude other related procedures. For example, the compounds of Formula I can be prepared as shown in Scheme 1 or 2.

Scheme 1

Figure imgf000046_0001
Scheme 2

Figure imgf000047_0001

Pharmaceutical Compositions

[00106] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.

[00107] In one embodiment, the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection.

[00108] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin.

[00109] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. Where pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen- free and has a suitable pH, isotonicity, and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles, such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection. Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.

[00110] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.

[00111] The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et ah, Eds., Marcel Dekker, Inc.: New York, NY, 2008). [00112] The pharmaceutical compositions provided herein can be provided in a unit- dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.

[00113] The pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

[00114] In another embodiment, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.

[00115] In yet another embodiment, provided herein is the use of a compound of

Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in the manufacture of a medicament for the treatment of a PI3K-mediated condition, disorder, or disease. In certain embodiments, the medicament is in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein. A. Oral Administration

[001 16] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration.

Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

[001 17] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC),

hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101 , AVICEL-PH-103, AVICEL RC-581 , AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the

pharmaceutical compositions provided herein. [00118] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[00119] Suitable disintegrants include, but are not limited to, agar; bentonite;

celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The

pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[00120] Suitable lubricants include, but are not limited to, calcium stearate;

magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[00121] Suitable glidants include, but are not limited to, colloidal silicon dioxide,

CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium

carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol

monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[00122] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[00123] The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[00124] The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[00125] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be

encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

[00126] The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions,

suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and

hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a

pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[00127] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,

polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[00128] The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.

[00129] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

[00130] Coloring and flavoring agents can be used in all of the above dosage forms. [00131] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

B. Parenteral Administration

[00132] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.

Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular,

intrasynovial, intravesical, and subcutaneous administration.

[00133] The pharmaceutical compositions provided herein for parenteral

administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes,

microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).

[00134] The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[00135] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[00136] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin

(CAPTISOL®, CyDex, Lenexa, KS).

[00137] When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[00138] In one embodiment, the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

[00139] The pharmaceutical compositions provided herein for parenteral

administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

[00140] The pharmaceutical compositions provided herein for parenteral

administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.

[00141] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers,

polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[00142] Suitable outer polymeric membranes include but are not limited to,

polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene

terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

[00143] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

[00144] The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[00145] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[00146] The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

[00147] The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in- water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives. [00148] Suitable cream base can be oil-in- water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[00149] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.

[00150] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

[00151] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[00152] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[00153] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafiuoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

[00154] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[00155] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[00156] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.

[00157] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

D. Modified Release

[00158] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).

[00159] Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 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; 5,733,566; 5,739,108; 5,891,474; 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; 6,589,548; 6,613,358; and 6,699,500. 1. Matrix Controlled Release Devices

[00160] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art (see, Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2,

Mathiowitz Ed., Wiley, 1999).

[00161] In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[00162] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;

starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);

polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters;

polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid

(EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid- glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl

methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

[00163] In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate -methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross- linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.

[00164] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.

[00165] The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

[00166] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s). [00167] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,

polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium

croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[00168] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[00169] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MA NOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

[00170] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

[00171] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[00172] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[00173] The delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.

5,612,059 and 5,698,220.

[00174] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

[00175] The pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

[00176] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art {see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al, Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[00177] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry

granulation, wet granulation, and a dip-coating method.

[00178] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

3. Multiparticulate Controlled Release Devices

[00179] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μιη to about 3 mm, about 50 μιη to about 2.5 mm, or from about 100 μιη to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[00180] Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.

4. Targeted Delivery

[00181] The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652; 6,274,552;

6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

[00182] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition associated with PI3K activity in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[00183] In another embodiments, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition responsive to the modulation of PI3K activity in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[00184] In yet another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PI3K enzyme in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of

Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[00185] In yet another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of cancer in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[00186] In yet another embodiment, provided herein is use of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of a PI3K-mediated condition, disorder, or disease.

[00187] In certain embodiments, the compound provided herein selectively targets the pi 10a subunit of PI3K. In certain embodiments, the compound provided herein selectively inhibits the PI3K via its interaction with its pi 10a subunit.

[00188] In certain embodiments, the PI3K is a wild type PI3K. In certain

embodiments, the PI3K is a PI3K mutant.

[00189] In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is i 10a, i 10β, i 105, or pi 10γ. In certain embodiments, the PI3K is a wild type of a Class I kinase. In certain embodiments, the PI3K is a mutant of a Class I kinase.

[00190] In certain embodiments, the PI3K is pi 10a. In certain embodiments, the PI3K is a wild type of pi 10a. In certain embodiments, the PI3K is a pi 10a mutant. In certain embodiments, the pi 10a mutant is R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, Ml 043V, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K, Q546K, I800L, Ml 0431, H1047L, or H1047Y.

[00191] In certain embodiments, the PI3K is a Class IV kinase. In certain

embodiments, the PI3K is a wild type of a Class IV kinase. In certain embodiments, the PI3K is a mutant of a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PI3K is mTOR.

[00192] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In yet another embodiment, the subject is a primate other than a human, a farm animal such as cattle, a sport animal, or a pet such as a horse, dog, or cat.

[00193] The disorders, diseases, or conditions treatable with a compound provided herein, include, but are not limited to, (1) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, fiugal, and other parasital cutaneous pathologies, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, exercise induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung diseases, and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus

erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) graft rejection (including allograft rejection and graft-v-host disease), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure,

atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10)

cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g. , esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue disease, and sarcoidosis, (13) genital and reproductive conditions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurologic disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (17) pain; (18) renal disorders; (19) ocular disorders, including glaucoma,; and (20) infectious diseases, including HIV.

[00194] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic,

promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to,

insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer , including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and

choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma,

hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

[00195] Depending on the disorder, disease, or condition to be treated, and the subject's condition, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g. , transdermal or local) routes of administration and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period. [00196] In the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to 100 mg per kg subject body weight per day (mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg per day.

[00197] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.

[00198] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[00199] Also provided herein are methods of modulating PI3K activity, comprising contacting a PIK3 enzyme with a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PIK3 enzyme is inside a cell.

[00200] In certain embodiments, the PI3K is a wild type PI3K. In certain

embodiments, the PI3K is a PI3K mutant. [00201] In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is pi 10a, pi 10β, pi 105, or pi 10γ. In certain embodiments, the PI3K is a wild type of a Class I kinase. In certain embodiments, the PI3K is a mutant of a Class I kinase.

[00202] In certain embodiments, the PI3K is pi 10a. In certain embodiments, the PI3K is a wild type of pi 10a. In certain embodiments, the PI3K is a pi 10a mutant. In certain embodiments, the pi 10a mutant is R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, Ml 043V, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K, Q546K, I800L, Ml 0431, H1047L, or H1047Y.

[00203] In certain embodiments, the PI3K is a Class IV kinase. In certain

embodiments, the PI3K is a wild type of a Class IV kinase. In certain embodiments, the PI3K is a mutant of a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PI3K is mTOR.

[00204] In certain embodiments, the compound provided herein, e.g. , a compound of

Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a PI3K and a mutant thereof.

[00205] In certain embodiments, the compound provided herein, e.g., a compound of

Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a wild type of a PI3K. In certain embodiments, the PI3K is pi 10a. In certain embodiments, the PI3K is mTOR.

[00206] In certain embodiments, the compound provided herein, e.g. , a compound of

Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a PI3K mutant. In certain embodiments, the PI3K mutant is a pi 10a mutant. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K,

Q546K, I800L, M1043I, H1047L, or H1047Y.

[00207] The compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; can also be combined or used in combination with other agents or therapies useful in the treatment, prevention, or

amelioration of one or more symptoms of the disorders, diseases, or conditions for which the compounds provided herein are useful, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, infectious diseases, and those pathologies noted herein.

[00208] Suitable other therapeutic agents can also include, but are not limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycin,

dactinomycin, and plicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8) antifungal agents, such as amorolfme, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifme, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafme, terconazole, tioconazole, and voriconazole; (9) antiinflammatories, e.g., non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; (1 1) anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferatives, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) beta-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) calcium channel blockers, such as amlodipine besylate; (18)

chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprine and

cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; (24) enzymes, such as L- asparaginase; (25) Factor Vila Inhibitors and Factor Xa Inhibitors; (26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP) inhibitors; (31) hormonal agents, such as

glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists, such as

spironolactone and eplerenone; (34) microtubule-disruptor agents, such as ecteinascidins; (35) microtubule-stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, and vardenafil); (39) plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (41) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids, such as aldosterone, beclometasone, betamethasone,

deoxycorticosterone acetate, fludrocortisone, hydrocortisone (Cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents, such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; and (54) other miscellaneous agents, such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds.

[00209] In certain embodiments, the other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects (e.g., antiemetics).

[00210] In certain embodiments, the other therapeutic agents that may be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine), and methotrexate), purine antagonists and pyrimidine antagonists (6- mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies; See, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby

incorporated by reference. [0021 1] In another embodiment, the method provided herein comprises administration of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, together with administering one or more

chemotherapeutic agents and/or therapies selected from: alkylation agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumour antibiotics (e.g., adriamymycin and bleomycin); antitumour vegetable alkaloids (e.g., taxol and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumour immunological agents (e.g. , interferon α, β, and γ); radiation therapy; and surgery. In certain embodiments, the one or more chemotherapeutic agents and/or therapies are administered to the subject before, during, or after the administration of the compound provided herein.

[00212] Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. When a compound provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.

[00213] The weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient.

Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a NSAID, the weight ratio of the compound to the NSAID can range from about 1 ,000: 1 to about 1 : 1 ,000, or about 200: 1 to about 1 :200. Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[00214] The compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[00215] Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[00216] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, e.g., a compound of Formula I or a hydrated compound of a compound of Formula IA, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in a container comprising one or more other therapeutic agent(s) described herein.

[00217] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.

[00218] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[00219] The disclosure will be further understood by the following non- limiting examples.

EXAMPLES

[00220] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); (microliters); M (molar); mM (millimolar); μΜ (micromolar); eq. (equivalent); mmol (millimoles); Hz (Hertz); MHz (megahertz); hr or hrs (hours); min (minutes); MS (mass spectrometry); APCI (atmospheric pressure chemical ionization); mp (melting point); DMF (dimethyformamide); DMSO (dimethylsulfoxide); DMSO-<¾ (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); EtOH (ethanol); MeOH (methanol); THF (tetrahydrofuran); DIPEA (N,N-diisopropylethylamine); TFA (trifluoroacetic acid); Me (methyl); Et (ethyl); PdCl2(dppf), ((1 ,1*- bis(diphenylphosphino)ferrocene) dichloropalladium(II)); and EDTA

(ethy lenediaminetetraacetic acid) .

[00221] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

General Experimental Information.

[00222] Elemental analyses (combustion analysis) were carried out in the

Microchemical Laboratory, University of Otago, Dunedin, NZ. Melting points were determined on an Electrothermal 9100 Melting Point Apparatus. NMR spectra were obtained on a Bruker Avance-400 spectrometer at 400 MHz for 1H and 100 MHz for 13C spectra, referenced to TMS (Si(CH3)4). Mass spectra were determined on a VG-70SE mass spectrometer using an ionizing potential of 70 eV at a nominal resolution of 1000. High- resolution spectra were obtained at nominal resolutions of 3000, 5000, or 10000 as

appropriate. All MS spectra were obtained as electron impact (EI) using perfluorokerosene (PFK) as a reference unless otherwise stated. Column chromatography was carried out on silica gel (Merck 230-400 mesh), unless otherwise stated.

Example 1

Synthesis of 2-({4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)- 1 ,3 ,5-triazin-2-yl]- 1 -piperazinyl} sulfonyl)ethylamine 1

Figure imgf000081_0001

1

[00223] Compound 1 was prepared according to Scheme 1.

[00224] A solution of 0.224 g (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-l-[4-(4- morpholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole (WO 2009/120094) and 25 mg of DMAP in 10 mL of pyridine was cooled to 0 °C and 0.122 g (0.75 mmol) of 2- chloroethanesulfonyl chloride was added dropwise over 5 min. The mixture was stirred at 0 °C for 2 hrs and water was added to give a precipitate which was collected and dried.

Chromatography on silica eluting with CH2Ci2/EtOAc (4: 1) gave 183 mg (31% yield) of 2- (difluoromethyl)-4-methoxy- 1 - {4-(4-morpholinyl)-6-[4-(vinylsulfonyl)- 1 -piperazinyl]- 1 ,3,5- triazin-2-yl}-lH-benzimidazole: mp (MeOH) 242-244 °C; 1H NMR (CDC13) δ 7.85 (dd, J = 8.4, 0.7 Hz, 1H), 7.43 (t, JHF = 53.5 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.43 (dd, J = 16.6, 9.8 Hz, 1H), 6.29 (d, J = 16.6 Hz, 1H), 6.07 (d, J = 9.8 Hz, 1H), 4.05 (s, 3H), 4.01 (m, 4H), 3.87 (m, 4H), 3.78 (m, 4H), 3.26 (m, 4H); MS (APCI+) m/z 538.4; Anal. Calcd. for C22H26F2N8O4S: C, 49.25; H, 4.9; N, 20.9; Found: C, 49.1; H, 5.0; N, 20.4%.

[00225] A mixture of the above 2-(difluoromethyl)-4-methoxy-l-{4-(4-morpholinyl)-

6-[4-(vinylsulfonyl)-l-piperazinyl]-l,3,5-triazin-2-yl}-lH-benzimidazole (118 mg, 0.220 mmol) and aqueous NH3 (25%, 5 mL) was refluxed in THF (20 mL) for 1 hr. 1,4-Dioxane (20 mL) was then added and the mixture was continued refluxing. After 5 hrs, additional aqueous NH3 (25%, 10 mL) was added and the reaction mixture was refluxed for another 22 hrs. At this time aqueous NH3 (25%, 10 mL) was added and the mixture was continued refluxing for a further 20 hrs. The solvents were then removed under vacuum and the resulting residue was recrystallized from CFLCb/MeOH/hexane to give 2-({4-[4-[2- (difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3 ,5-triazin-2-yl]- 1 - piperazinyl}sulfonyl)ethylamine 1 (117 mg, 96%): mp (CH2Cl2/MeOH/hexanes) 244-246 °C; 1H NMR (pMSO-< e) <5 7.89 (d, J= 7.9 Hz, 1H), 7.69 (t, JHF = 52.8 Hz, 1H), 7.41 (t, J= 8.2 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 3.98 (s, 3H), 3.93-3.91 (m, 4H), 3.83-3.80 (m, 4H), 3.71- 3.68 (m, 4H), 3.28-3.21 (m, 4H ), 3.14 (t, J= 6.8 Hz, 2H), 2.91 (t, J= 6.8 Hz, 2H); Anal. Calcd. for C22H29F2N9O4S.O.O6CH2CI2: C, 47.4; H, 5.25; N, 22.6; Found: C, 47.3; H, 5.25; N,

22.7%.

Example 2

Synthesis of N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide 2

Figure imgf000082_0001

[00226] Compound 2 was prepared according to Scheme 1.

[00227] Reaction of 2-(difluoromethyl)-4-methoxy-l-{4-(4-morpholinyl)-6-[4-

(vinylsulfonyl)-l-piperazinyl]-l,3,5-triazin-2-yl}-lH-benzimidazole in THF with a solution of 40% aqueous methylamine at room temperature gave N-{4-[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2- (methylamino)ethanesulfonamide 2 in 90% yield.

[00228] Reaction of N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-

(4-morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide with methanesulfonic acid in MeOH gave a methanesulfonate salt: mp (MeOH/EtOAc) 236- 239 °C; 1H NMR (OMSO-d6) δ 8.45 (br s, 2H), 7.89 (d, J = 8.04 Hz, 1H), 7.70 (t, JHF = 52.9 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 3.97 (s, 3H), 3.95 (m, 4H), 3.83 (m, 4H), 3.70 (m, 4H), 3.49-3.45 (m, 2H), 3.53-3.17 (m, 5H), 2.62 (s, 3H), 2.31 (s, 3H); Anal. Calcd. for C24H35F2N907S2: C, 43.4; H, 5.32; N, 19.0; Found: C, 43.3; H, 5.3; N, 19.3%.

Example 3

Synthesis of 2-amino-N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}ethanesulfonamide 3

Figure imgf000083_0001

[00229] Compound 3 was prepared according to Scheme 2.

[00230] A mixture of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-

(difiuoromethyl)-4-methoxy-lH-benzimidazole (WO 2009/120094) (100 mg, 0.252 mmol), 4-[(tert-butoxycarbonyl)amino]phenylboronic acid (90 mg, 0.380 mmol), PdCl2(dppf) (10.3 mg, 0.0126 mmol), and aq. K2C03 (2M, 2 mL) in 1,4-dioxane (10 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H20. The aqueous phase was extracted with CH2C12 (3 x). The combined organic extracts were dried (Na2S04) and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2C12, followed by recrystallization from CH2Cl2/MeOH/hexanes gave tert-butyl 4-[4- [2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4-morpholinyl)- 1 ,3 ,5 -triazin-2- yl]phenylcarbamate (99 mg, 71%): mp (CH2Cl2/MeOH/hexanes) 188-190 °C; 1H NMR (CDCls) δ 8.41 (d, J= 8.8 Hz, 2H), 8.08 (dd, J= 8.4, 0.6 Hz, 1H), 7.62 (t, JHF = 53.4 Hz, 1H), 7.52 (d, J= 8.8 Hz, 2H), 7.41 (t, J= 8.2 Hz, 1H), 6.86 (d, J= 7.7 Hz, 1H), 6.69 (s, 1H), 4.12 (m, 2H), 4.07 (s, 3H), 3.99 (m, 2H), 3.85 (m, 4H), 1.55 (s, 9H); Anal. Calcd. for

C27H29F2N704: C, 58.6; H, 5.3; N, 17.2; Found: C, 58.5; H, 5.0; N, 17.2%.

[00231 ] Reaction of the above tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy- 1H- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]phenylcarbamate (300 mg, 0.542 mmol) with an excess of TFA (2 mL) in CH2C12 (10 mL) at room temperature for 3 hrs, followed by treatment with aq. NH3 gave 4-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]aniline (217 mg, 88%), which was used directly in the next step without further purification: 1H NMR (DMSO-<¾) δ 8.17 (d, J = 8.7 Hz, 2H), 8.05 (dd, J= 8.3, 0.4 Hz, 1H), 7.80 (t, JHF = 52.9 Hz, 1H), 7.47 (t, J= 8.2 Hz, 1H), 6.99 (d, J= 7.8 Hz, 1H), 6.68 (d, J= 8.8 Hz, 2H), 6.05 (s, 2H), 4.01 (m, 2H), 3.99 (s, 3H), 3.88 (m, 2H), 3.75 (m, 4H).

[00232] 2-Chloroethanesulfonyl chloride (0.090 mL, 0.861 mmol) was added drop- wise to a suspension of the above 4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l- yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]aniline (190 mg, 0.419 mmol) in pyridine (4 mL) at 0 °C. The mixture was stirred at 0 °C for 2.5 hrs, then diluted with H20, and warmed to room temperature. The resulting precipitate was collected by filtration and dried to give N- {4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)- 1,3,5- triazin-2-yl]phenyl}ethylenesulfonamide, which was used directly in the next step without further purification.

[00233] A mixture of the above N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]phenyl}ethylenesulfonamide (250 mg crude material) and aqueous NH3 (25%>, 15 mL) was refluxed in 1,4-dioxane (25 mL) for 17 hrs. The mixture was then cooled to room temperature and the solvent was removed under vacuum until a precipitate began to form. The residue was diluted with water and extracted with CH2C12 (3 x). The combined organic fractions were dried (Na2S04) and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 92:8) gave 2-amino-N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l- yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]phenyl}ethanesulfonamide 3 (81 mg, 56% over 2 steps): mp (CH2Cl2/MeOH) 201-205 °C; 1H NMR (DMSO-< 5) δ 8.29 (d, J= 8.8 Hz, 2H), 8.07 (d, J= 8.4 Hz, 1H), 7.81 (t, JHF = 52.8 Hz, 1H), 7.48 (t, J= 8.2 Hz, 1H), 7.19 (d, J= 8.8 Hz, 2H), 7.00 (d, J= 7.9 Hz, 1H), 4.07-4.00 (m, 2H), 4.00 (s, 3H), 3.93-3.86 (m, 2H), 3.80- 3.73 (m, 4H), 3.20-3.16 (m, 2H), 3.03 (t, J= 6.6 Hz, 2H); Anal. Calcd. for

C24H26F2N8O4S.0.5H2O: C, 50.6; H, 4.8; N, 19.7; Found: C, 50.2; H, 4.7; N, 19.5%.

Example 4

Synthesis of N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide 4

Figure imgf000085_0001

4

[00234] Compound 4 was prepared according to Scheme 2.

[00235] A mixture of N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-

6-(4-morpholinyl)-l ,3,5-triazin-2-yl]phenyl}ethylenesulfonamide (200 mg crude material) and methylamine (40% solution in water, 5 mL) in THF (20 mL) was refluxed for 2 hrs. After cooling to room temperature, the solvent was removed under vacuum. The residue was partitioned between CH2C12 and water. The layers was separated and the aqueous layer was extracted with CH2C12 (2 x). The combined organics were dried (Na2S04) and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 95:5) gave N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide 4 (105 mg, 89% over 2 steps).

[00236] Treatment of N- {4-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-

6-(4-morpholinyl)-l ,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide with methanesulfonic acid in CH2Cl2/MeOH and recrystallization from MeOH/EtOAc gave a methanesulfonate salt: mp (MeOH/EtOAc) 195-198 °C; 1H NMR (DMSO-<¾) δ 8.46 (d, J = 8.8 Hz, 2H), 8.07 (d, J= 8.0 Hz, 1H), 7.82 (t, JHF = 52.8 Hz, 1H), 7.49 (t, J= 8.2 Hz, 1H), 7.43 (d, J= 8.8 Hz, 2H), 7.01 (d, J= 7.9 Hz, 1H), 4.08-4.04 (m, 2H), 4.00 (s, 3H), 3.95-3.90 (m, 2H), 3.81-3.75 (m, 4H), 3.63-3.59 (m, 2H), 3.32-3.28 (m, 2H), 2.62 (s, 3H), 2.30 (s, 3H); Anal. Calcd. for C26H32F2N8O7S2: C, 46.6; H, 4.8; N, 16.7; Found: C, 46.5; H, 4.6; N, 16.6%.

Example 5

ADAPTA® assay

[00237] Compounds were evaluated for their ability to inhibit PI 3 -kinase enzymes using the ADAPTA® time-resolved fluorescence energy transfer (TR-FRET) (Invitrogen, Carlsbad, CA), as described in U.S. Pat. No. 7,332,278, the disclosure of which is

incorporated by reference in its entirety.

[00238] Briefly, the ADAPTA® assay was divided into two phases: a kinase reaction phase and an ADP detection phase. In the kinase reaction phase, all components required for the kinase reaction, including a test compound if its biological activity was to be determined, were added to a well, and the reaction was allowed to incubate for 60 min. After the kinase reaction, a detection solution containing a europium labeled anti-ADP antibody, an Alexa Fluor 647 labeled ADP tracer, and EDTA was added to the reaction mixture to stop the kinase reaction and to generate signals for detection.

[00239] Generally, a test compound was screened in 1% DMSO (final) in a well using

10 point titrations, where 3-fold serial dilutions were employed. All substrate/kinase mixtures were diluted to a 2X working concentration in the appropriate kinase butter as described herein for each specific kinase. All ATP solutions were diluted to a 4X working concentration in water. Detection mix was prepared in TR-FRET dilution buffer. The detection mix contained EDTA (30 mM), Eu-anti-ADP antibody (30 11M), and ADP tracer. The detection mix also contained the EC6o concentration of the tracer for 5-10 μΜ ATP.

[00240] For each assay, Corning, low volume, white 384-well plates were used. Each well in the plates contained a test compound (2.5 μί, 4X in 30 mM HEPES or 10 nL 100X in 100% DMSO plus 2.4 μΕ 30 mM HEPES), the ATP solution (2.5 μΕ, 4X), and the substrate/kinase mixture (5 μί, 2X). After addition of reagents, the plates were shaken for 30 sec, centrifuged at 1 ,000 x g for 2 min, and incubated at room temperature for 60 min. Then, the detection mix (5 μί) was added to each well. The plates were shaken for 30 sec, centrifuged at 1 ,000 x g for 2 min, and read on a fluorescence plate reader. For each assay, each plate contained 0% conversion control (100% inhibition control), 100% conversion control, 0% inhibition control, and a known inhibitor control.

[00241] The maximum emission ration was established by the 0% conversion control, which contained no ATP in the kinase reaction. After addition of the detection mix containing EDTA, ATP was added to the wells. The 100% conversion control wells contained ADP instead of ATP and were designed to allow for the calculation of percent ATP conversion. The minimum emission ration in a screen was established by the 0% inhibition control, which contained active kinase. A known inhibitor control standard curve, 10 point titration, was run for each individual kinase on the same plate as the kinase to ensure the kinase was inhibited within an expected IC50 range determined previously.

[00242] Data were analyzed using XLfit from IDBS. The ATP/ADP standard curve was fit using a sigmoidal dose-response model. The dose response curve was also fit using the same sigmoidal dose-response model. If the bottom of the curve did not fit between -20%> and 20% inhibition, it was set to 0% inhibition. If the top of the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

[00243] For pi 10a (p85a), the 2X pi 10a /PIP2:PS mixture was prepared in 50 mM

HEPES, pH 7.5, 100 mM NaCl, 0.03% CHAPS, 3 mM MgCl2, and 1 mM EGTA. The final 10 kinase reaction mixture contained 0.3 to 1.5 ng pi 10a and 50 μΜ PIP2:PS in 32.5 mM HEPES, pH 7.5, 50 mM NaCl, 0.015% CHAPS, 1.5 mM MgCl2, and 0.5 mM EGTA. After 1 hr kinase reaction incubation, 5 of the detection mix was added.

[00244] For pi 10δ (ρ85α), the 2X pi 105/PIP2:PS mixture was prepared in 50 mM

HEPES, pH 7.5, 100 mM NaCl, 0.03% CHAPS, 3 mM MgCl2, and 1 mM EGTA. The final 10 μΐ^ kinase reaction mixture contained 0.47 to 2.6 ng pi 105 and 50 μΜ PIP2:PS in 32.5 mM HEPES, pH 7.5, 50 mM NaCl, 0.015% CHAPS, 1.5 mM MgCl2, and 0.5 mM EGTA. After 1 hr kinase reaction incubation, 5 μΐ^ of the detection mix was added.

[00245] For pi 10γ, the 2X pi 10y/PIP2:PS mixture was prepared in 50 mM HEPES, pH 7.5, 3 mM MgCl2, and 1 mM EGTA. The final 10 μΐ^ kinase reaction mixture contained 3.5 to 26 ng pi 10γ and 50 μΜ PIP2:PS in 32.5 mM HEPES, pH 7.5, 1.5 mM MgCl2, and 0.5 mM EGTA. After 1 hr kinase reaction incubation, 5 μΐ^ of the detection mix was added. [00246] The biological results are summarized in Table 1 , wherein A represents a value no greater than 20 nM, and B represents a value greater than 20 nM but less than 100 nM, C represents a value no less than 100 nM but no greater than 500 nM, and D represents a value greater than 500 nM.

Example 6

Z'-LYTE® assay

[00247] Compounds were evaluated for their ability to inhibit mTOR using the Z'-

LYTE® fluorescence resonance energy transfer (FRET) assay (Invitrogen, Carlsbad, CA). The assay employs a fluorescence-based, coupled-enzyme format, based the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with two fluorophores, one at each end, to make up a FRET pair.

[00248] Generally, a test compound was screened in 1% DMSO (final) in a well using

10 point titrations, where 3-fold serial dilutions were employed. All peptide substrate/kinase mixtures were diluted to a 2X working concentration in the appropriate kinase butter as described herein for the specific kinase (mTOR). All ATP solutions were diluted to a 4X working concentration in 50 mM HEPES, pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA. A development reagent solution was diluted in a development buffer, which is described herein for the specific kinase (mTOR).

[00249] For each assay, Corning, low volume, white 384-well plates were used. Some wells in the plates each contained a test compound (2.5 μί, 4X test compound; or 10 nL, 100X plus 2.4 μΕ of the kinase buffer), the peptide substrate/kinase mixture (5 μί, 2X), and the ATP solution (2.5 mL, 4X). After addition of reagents, the plates were shaken for 30 sec and incubated at room temperature for 60 min. Then, the development reagent solution (5 μί) was added to each well. The plates were shaken for 30 sec, incubated at room temperature for 60 min, and read on a fluorescence plate reader. For each assay, each plate contained 0% phosphorylation control (100% inhibition control), 100% phosphorylation control, 0% inhibition control, and a known inhibitor control. The development reaction interference was established by comparing the test compound control wells that do not contain ATP versus the 0% phosphorylation control that does not contain the test compound. The expected value for non-interfering compound should be 100%. Any value outside of 90%> to 1 10% was flagged. The test compound fluorescence interference was determined by comparing the test compound control wells that did not contain the peptide substrate/kinase mixture (zero peptide substrate control) versus the 0% inhibition control. The expected value of a non- fluorescence compound should be 0%. Any value above 20% was flagged.

[00250] Data were analyzed using XLfit from IDBS. The dose response curve was fit using a sigmoidal dose-response model. If the bottom of the curve did not fit between -20%> and 20% inhibition, it was set to 0% inhibition. If the top of the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

[00251] For mTOR, the 2X mTOR/Ser/Thr 1 1 mixture was prepared in 50 mM

HEPES, pH 7.5, 0.01% BRIJ-35, 10 mM MnCl2, 1 mM EGTA, 2 mM DTT, and 0.02% NaN3 The final 10 μΐ^ kinase reaction mixture contained 10.5 to 62.3 ng mTOR and 2 μΜ Ser/Thr 1 1 in 50 mM HEPES, pH 7.5, 0.01% BRIJ-35, 5 mM MgCl2, 5 mM MnCl2, 1 mM EGTA, 1 mM DTT, and 0.02% NaN3. After 1 hr kinase reaction incubation, 5 μΐ^ of a 1 : 16 dilution of the development reagent was added.

[00252] The biological results are summarized in Table 1 , wherein A represents a value no greater than 20 nM, and B represents a value greater than 20 nM but less than 100 nM, C represents a value no less than 100 nM but no greater than 500 nM, and D represents a value greater than 500 nM.

TABLE 1. Biological Activity

Figure imgf000089_0001

[00253] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein.

Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000091_0001
(I)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein:
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_ 6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;
R5c is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; R6 is hydrogen or Ci_6 alkyl;
Q is C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -SO2- group is nitrogen; and
n is an integer of 1 , 2, 3, 4 or 5;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;
wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,
-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,
-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh,
-NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and
-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
2. A hydrated compound of a compound of Formula IA:
Figure imgf000093_0001
(IA)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein:
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; wherein each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
R3 and R4 are each independently hydrogen or Ci_6 alkyl; or R3 and R4 are linked together to form a bond, Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_ 6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;
R5c and R5d are each independently hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;
R6 is hydrogen or Ci_6 alkyl;
Q is C3_7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; T1 is a bond or -NR7-; wherein R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, or C2_6 alkynyl; with the proviso that when T1 is a bond, the atom of Q that is directly attached to the -S02- group is nitrogen; and
n is an integer of 1, 2, 3, 4 or 5;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R5a, R5b, R5c, R5d, R6, R7, Rla, Rlb, Rlc, Rld, Q, and T1 is optionally substituted with one or more groups, in one embodiment, one, two, three, or four groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(0)Ra, -C(0)ORa,
-C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc,
-OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1;
wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg,
-OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh,
-NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and
-S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
3. The hydrated compound of claim 2 having the structure of Formula IIA:
Figure imgf000095_0001
(IIA)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
4. The hydrated compound of claim 2 or 3, wherein R5d is hydrogen or Ci_6 alkyl, where the alkyl is optionally substituted with one or more substituents.
5. The hydrated compound of claim 4, wherein R5d is hydrogen or methyl.
6. The compound of claim 1 or the hydrated compound of claims 2 to 5, wherein Q is C6-i4 arylene or heterocyclylene, each optionally substituted with one or more
substituents.
7. The compound or the hydrated compound of claim 6, wherein Q is phenylene or piperazinylene, each optionally substituted with one or more substituents.
8. The compound of any of claims 1 , 6, and 7 or the hydrated compound of claims 2 to 7, wherein T1 is a bond.
9. The compound of any of claims 1 , 6, and 7 or the hydrated compound of claims 2 to 7, wherein T1 is -NR7-.
10. The compound or the hydrated compound of claim 9, wherein R7 is hydrogen or Ci_6 alkyl, where the alkyl is optionally substituted with one or more substituents.
1 1. The compound or the hydrated compound of claim 9, wherein T1 is -NH-.
12. The compound of any of claims 1 and 6 to 1 1 or the hydrated compound of any of claims 2 to 11, wherein R5a is hydrogen or halo.
13. The compound of any of claims 1 and 6 to 12 or the hydrated compound of any of claims 2 to 12, wherein R5b is hydrogen or halo.
14. The compound or the hydrated compound of claim 12 or 13, wherein R5a and
R are hydrogen.
15. The compound of any of claims 1 and 6 to 14 or the hydrated compound of any of claims 2 to 14, wherein n is an integer of 2.
16. The compound of claim 1 having the structure of Formula II:
Figure imgf000096_0001
(Π)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
17. The compound of claim 1 having the structure of Formula III:
Figure imgf000096_0002
(III)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
18. The hydrated compound of claim 3 having the structure of Formula IIIA:
Figure imgf000097_0001
(IIIA)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
19. The hydrated compound of claim 3 having the structure of Formula IVA:
Figure imgf000097_0002
(IVA)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
20. The compound of any of claims 1 and 5 to 17 or the hydrated compound of any of claims 2 to 15, 18, and 19, wherein R1 is hydrogen or methoxy.
21. The compound of any of claims 1, 5 to 17, and 20 or the hydrated compound of any of claims 2 to 15 and 18 to 20, wherein R2 is hydrogen or amino.
22. The compound of any of claims 1, 5 to 17, 20, and 21 or the hydrated compound of any of claims 2 to 15 and 18 to 21 , wherein R3 is hydrogen.
23. The compound of any of claims 1 , 5 to 17, and 20 to 22 or the hydrated compound of any of claims 2 to 15 and 18 to 22, wherein R4 is hydrogen.
24. The compound of any of claims 1 , 5 to 17, and 20 to 23 or the hydrated compound of any of claims 2 to 15 and 18 to 23, wherein R5c is hydrogen or Ci_6 alkyl, where the alkyl is optionally substituted with one or more substituents.
25. The compound or the hydrated compound of claim 24, wherein R5c is hydrogen or methyl.
26. The compound of any of claims 1 , 5 to 17, and 20 to 25 or the hydrated compound of any of claims 2 to 15 and 18 to 25, wherein R6 is Ci_6 alkyl, optionally substituted with one or more substituents.
27. The compound or the hydrated compound of any of claim 26, wherein R6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
28. The compound or the hydrated compound of any of claim 27, wherein R6 is difluoromethyl.
29. The compound of claim 1 selected from the group consisting of:
2-amino-N- {4-[4-[2-(difluoromethyl)-4-methoxy- IH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l ,3,5-triazin-2-yl]phenyl}ethanesulfonamide;
N- {4-[4-[2-(difluoromethyl)-4-methoxy- IH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l ,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide;
2-amino-N- {4-[4-[2-(difluoromethyl)-4-methoxy- IH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l ,3,5-triazin-2-yl]phenyl}ethanesulfonamide; and
N- {4-[4-[2-(difluoromethyl)-4-methoxy- IH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l ,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide;
and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
30. The compound of claim 1 , wherein the compound is N-{4-[4-[2- (difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3 ,5-triazin-2- yl]phenyl}-2-(methylamino)ethanesulfonamide.
31. The hydrated compound of claim 2 selected from the group consisting of:
2-(difluoromethyl)- 1 -(4-(4-(2-(dimethylamino)ethylsulfonyl)piperazin- 1 -yl)-
6-morpholino-l,3,5-triazin-2-yl)-4-methoxy-2,3-dihydro-lH-benzimidazol-2-ol; and
N-(4-(4-(2-(difluoromethyl)-2-hydroxy-4-methoxy-2,3-dihydro-lH- benzimidazol- 1 -yl)-6-morpholino- 1 ,3 ,5-triazin-2-yl)phenyl)-2- (dimethylamino)ethanesulfonamide;
and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
32. A pharmaceutical composition comprising the compound of any of claims 1, 5 to 17, and 20 to 30 or the hydrated compound of any of claims 2 to 15, 18 to 28, and 31, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
33. The pharmaceutical composition of claim 32, wherein the composition is formulated for single dose administration.
34. The pharmaceutical composition of claim 32 or 33, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
35. The pharmaceutical composition of claim 34, wherein the oral dosage form is a tablet or capsule.
36. The pharmaceutical composition of any of claims 32 to 35, further comprising a second therapeutic agent.
37. A method for the treatment, prevention, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, which comprises administering to the subject the compound of any of claims 1, 5 to 17, and 20 to 30, the hydrated compound of any of claims 2 to 15, 18 to 28, and 31, or the pharmaceutical composition of any of claims 32 to 36.
38. The method of claim 37, whererin the PI3K-mediated disorder, disease, or condition is cancer.
39. The method of claim 37 or 38, wherein the compound or the composition is administered in combination with a second therapeutic agent.
40. A method for modulating PI3K enzymatic activity, comprising contacting a PI3K enzyme with the compound of any of claims 1, 5 to 17, and 20 to 30, the hydrated compound of any of claims 2 to 15, 18 to 28, and 31, or the pharmaceutical composition of any of claims 32 to 36.
41. The method of claim 40, wherein the PI3K is a wild type.
42. The method of claim 40, wherein the PI3K is a PI3K mutant.
43. The method of any of claims 40 to 42, wherein the PI3K is a Class I PI3K.
44. The method of claim 43, wherein the PI3K is pi 10a.
45. The method of claim 43 , wherein the PI3K is a p 110a mutant.
46. The method of claim 45, wherein the pi 10a mutant is R38H, Kl 1 IN, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y.
47. The method of claim 40, wherein the PI3K is mTOR.
48. A method for the treatment, prevention, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, which comprises administering to the subject N- {4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-morpholinyl)-l ,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
49. The method of claim 48, whererin the PI3K-mediated disorder, disease, or condition is cancer.
50. The method of claim 48 or 49, wherein the compound is administered in combination with a second therapeutic agent.
51. A method for modulating PI3K enzymatic activity, comprising contacting a PI3K enzyme with N-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenyl}-2-(methylamino)ethanesulfonamide or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
52. The method of claim 51 , wherein the PI3K is a wild type.
53. The method of claim 51 , wherein the PI3K is a PI3K mutant.
54. The method of any of claims 51 to 53, wherein the PI3K is a Class I PI3K.
55. The method of claim 54, wherein the PI3K is p 1 10a.
56. The method of claim 54, wherein the PI3K is a pi 10a mutant.
57. The method of claim 56, wherein the pi 10a mutant is R38H, Kl 1 IN, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y.
58. The method of claim 51 , wherein the PI3K is mTOR.
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