WO2010110686A1

WO2010110686A1 - Pyrimidinyl and 1,3,5 triazinyl benzimidazoles and their use in cancer therapy

Info

Publication number: WO2010110686A1
Application number: PCT/NZ2010/000061
Authority: WO
Inventors: Gordon William Rewcastle; Swarnalatha Akuratiya Gamage
Original assignee: Pathway Therapeutics Limited
Priority date: 2009-03-27
Filing date: 2010-03-26
Publication date: 2010-09-30

Abstract

Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles, 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.

Description

PYRIMIDINYL AND 1,3,5 TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN

CANCER THERAPY

CROSS REFERENCE TO RELATED APPLICATION

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

61/164,358, filed March 27, 2009, the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[0002] Provided herein are pyrimidinyl and 1 ,3,5-triazinyl benzimidazoles, 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 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 Ia and Ib based on their mechanism of activation; Class Ia PI3Ks are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi lOβ, or pi 105) in complex with a regulatory p85 subunit, while the class-Ib PI3K (pi lOγ) is structurally similar but lacks lacks the p85 regulatory subunit, and instead is activated by βγ subunits of heterotrimeric G-proteins (Walker et al., MoI .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 lOβ in thrombus formation mediated by integrin αnβ₃ (Jackson et al., Nat. Med. 2005, 11, 507), and pl lOγ 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. ScL 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 p85α 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., MoI .Cell 2000, 6, 909), PI103 (slightly α-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 ScL 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), IC871 14 (J-selective) (Sadhu et al. WO 2001/81346; Billottet et al., Oncogene 2006, 25, 6648), AS605240 (γ-selective) (Camps et al., Nat. Med. 2005, 11, 936), the imidazo[l,2-α]pyridines (α-selective) (Hayakawa et al., Bioorg. Med. Chem. 2007, 15, 403; Hayakawa et al., Bioorg. Med. Chem. 2007, 75, 5837), and the imidazo[4,5-c]quinoline NVP-BEZ235 (Garcia-Echeverria, et al., WO 2006/122806).

LY294002 PI103 ZSTK474

AS605240 Imidazo[l,2-α]pyridine NVP-BEZ235

[0008] Despite the advances in developing PI3K inhibitors, there is a need for PI3K inhibitors for treatment of cancer.

SUMMARY OF THE DISCLOSURE

[0009] Provided herein is a compound of Formula I:

I 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; wherein:

R² is (a) hydrogen, cyano, halo, or nitro; (b) Q.6 alkyl, C₂-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Cβ-u aryl, C7.15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^la, -C(O)OR^lb, -C(O)NR^lbR^lc, -C(NR^a)NR^lbR^lc, -OR^Ia, -OC(O)R^la, -OC(O)OR^la, -OC(O)NR ^lbR^lc, -OC(=NR^la)NR^lbR^lc, -OS(O)R^la, -OS(O)₂R¹³, -OS(O)NR^lbR^lc, -OS (O)₂NR ^lbR^lc, -NR^lbR^lc, -NR^laC(O)R^ld, -NR¹³C(O)OR ^ld, -NR¹ "C(O)NR ^lbR^lc, -NR^laC(=NR^ld)NR^lbR^Ic, -NR^laS(O)R^ld, -NR^laS(O)₂R^Id, -NR^laS(O)NR^lbR^lc, -NR^laS(O)₂NR^lbR^lc, -SR^la, -S(O)R¹", -S(O)₂R^la, -S(O)NR^IbR^lc, or -S(O)₂NR^lbR^lc;

R³ and R⁴ are each independently hydrogen or Ci_-6 alky];

R⁵ is (a) C|.6 alkyl, C₂-6 alkenyl, C₂.₆ alkynyl, C_3-7 cycloalkyl, C₆., ₄ aryl, C₇._!5 aralkyl, heteroaryl, or heterocyclyl; or (b) -OR^la or -NR^lbR^lc;

R⁶ is hydrogen or C|_₆ alkyl;

E is a bond, -C(O)-, -C(O)O-, -C(O)NR¹³- -O-, -OC(O)O-,

-0C(0)NR^la- -NR^la- -NR^laC(O)NR^ld- -NR¹³S(O)- -NR¹³S(O)₂-, -NR¹³S(O)NR¹"-, -NR^laS(0)₂NR^ld- -S-, -S(O)- Or -S(O)₂-;

Q is C|-6 alkyl, C₂.6 alkenyl, C₂.₆ alkynyl, C_3-7 cycloalkyl, C₆.,₄ aryl, C₇-₁₅ aralkyl, heteroaryl, or heterocyclyl, with the proviso that Q is substituted with one or more O- or N-containing substituent;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ is hydrogen or C_\.(, alkyl; and each R^la, R^lb, R^Ic, and R^ld is independently (i) hydrogen; (ii) C|.₆ alkyl, C_2-6 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) R^lb and R^lc 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 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more 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(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R³, -OC(O)OR³, -0C(0)NR^bR^c, -0C(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R³, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(0)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d, -NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R³, -S(O)₂R³, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) Ci_-6 alkyl, C₂_₆ alkenyl, C₂.₆ alkynyl, C₃_₇ cycloalkyl, C_f1-_M 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) R^b and R^c 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, CO-H aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR¹R⁸, -C(NR^e)NR^rR⁶, -OR^e, -OC(O)R⁶, -OC(O)OR^e, -OC(O)NR^fR^g, -0C(=NR^e)NR^fR⁸, -OS(O)R^e, -OS(O)₂R⁶, -OS(O)NR^fR^ε, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(0)0R^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^ε, -SR^e, -S(O)R^e, -S(O)₂R^C, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R¹' is independently (i) hydrogen; (ii) Ci_-6 alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, C₃_7 cycloalkyl, C_δ-i4 aryl, C₇.]₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

[0010] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.

[001 1] Additionally provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a PBK-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, an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Further 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, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

DETAILED DESCRIPTION

[0013] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0014] 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.

[0015] 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.

[0016] 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. [0017] 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.

[0018] 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.

[0019] 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 P reformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0020] 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. [0021] 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.

[0022] 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.

[0023] 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. is), 1 to 10 (C_MO), or 1 to 6 (Cue) carbon atoms, or branched saturated 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. As used herein, linear

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, Cj.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.

[0024] 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 (C2-20X 2 to 15 (C2.15), 2 to 10 (C_MO), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent 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. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0025] 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 (C₂-₂₀X 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 alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH₂C≡CH). For example, C₂.β 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.

[0026] 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. l]heptyl, decalinyl, and adamantyl.

[0027] 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 (C6-20X from 6 to 15 (Cδ-is), or from 6 to 10 (Cβ-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.

[0028] 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

- 9 -

SDl- 1231 OvI substituted as described herein.

[0029] 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.

[0030] 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, moφholinyl, 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.

[0031] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.

[0032] The term "optionally substituted" is intended to mean that a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, e.g., (a) Ci^ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C3.7 cycloalkyl, Cβ-π 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 (-NO₂), -C(O)R^a, -C(O)OR", -C(0)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R³, -OC(O)OR³, -0C(0)NR^bR^c, -OC(=NR^a)NR^bR^c, -OS(O)R³, -OS(O)₂R³, -OS(O)NR^bR^c, -0S(0)₂NR^bR^c, -NR^bR^c, -NR³C(O)R", -NR^aC(0)0R^d, -NR^aC(0)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d, -NR^aS(O)₂R^d, -NR^aS(0)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR³, -S(O)R³, -S(O)₂R³, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) Ci_-6 alkyl, C₂.₆ alkenyl, C₂.<; alkynyl, C3.7 cycloalkyl, Cδ-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) R^b and R^c 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.

[0033] In one embodiment, each Q¹ is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Cj.6 alkyl, C2-6 alkenyl, C₂-₆ alkynyl, €3.7 cycloalkyl, C₆.₁4 aryl, C_7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR⁸, -OR^e, -OC(O)R⁶, -OC(O)OR⁶, -OC(O)NR^fR^g, -OC(=NR⁶)NR^fR⁸, -OS(O)R⁰, -OS(O)₂R⁶, -OS(O)NR^fR^ε, -OS(O)₂NR^fR^ε, -NR^fR⁸, -NR^eC(0)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR⁸, -NR⁶S(O)R^h, -NR⁶S(O)₂R^h, -NR^eS(0)NR^rR^g, -NR⁶S(O)₂NR^fR⁸, -SR^e, -S(O)R⁶, -S(O)₂R⁶, -S(O)NR^fR⁸, and -S(O)₂NR¹R⁸; wherein each R^c, R^f, R⁸, and R^h is independently (i) hydrogen; (ii) d.₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃.₇ cycloalkyl, Cβ-π aryl, C_7-I5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^r and R^g together with the N atom to which they are attached form heteroaryl or heterocyclyl.

[0034] 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.

[0035] 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. [0036] 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.

Compounds

[0037] In one embodiment, provided herein is a compound of Formula I:

R² is (a) hydrogen, cyano, halo, or nitro; (b) Q-β alkyl, C₂^ alkenyl, C₂ β alkynyl_vC₃_₇ cycloalkyl, Cβ-π aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^la, -C(O)OR¹", -C(O)NR^lbR^lc, -C(NR^a)NR^lbR^lc, -OR^la, -OC(O)R^la, -OC(O)OR^la, -OC(O)NR^lbR^lc, -OC(=NR^la)NR^lbR^lc, -OS(O)R^la, -OS(O)₂R¹³, -OS(O)NR^lbR^lc, -OS(O)₂NR^lbR^lc, -NR^lbR^lc, -NR^laC(O)R^ld, -NR¹³C(O)OR ^ld, -NR^laC(O)NR^lbR^lc, -NR^laC(=NR^ld)NR^lbR^lc, -NR^laS(O)R^ld, -NR^laS(O)₂R^ld, -NR^laS(O)NR^IbR^Ic, -NR^laS(0)₂NR^lbR^lc, -SR^la, -S(O)R^la, -S(O)₂R^la, -S(O)NR^lbR^lc, or -S(O)₂NR^lbR^lc;

R³ and R⁴ are each independently hydrogen or Q.₆ alkyl;

R⁵ is (a) Ci-6 alkyl, C₂_₆ alkenyl, C₂.₆ alkynyl, C₃.₇ cycloalkyl, C₆.i4 aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl; or (b) -OR^la or -NR^lbR^Ic;

R⁶ is hydrogen or Ci ₆ alkyl;

E is a bond, -C(O)- -C(O)O-, -C(O)NR¹³-, -O-, -OC(O)O-,

-OC(O)NR¹³-, -NR^la- -NR^laC(O)NR^Id-, -NR^laS(O)-, -NR¹³S(O)₂-, -NR ¹³S (O)NR ^ld-, -NR¹³S(O)₂NR¹"-, -S-, -S(O)- or -S(O)₂-;

Q is Ci_₆ alkyl, C₂.₆ alkenyl, C₂.6 alkynyl, C₃.₇ cycloalkyl, Ce- ₁₄ aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl, with the proviso that Q is substituted with one or more O- or N-containing substituent;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ is hydrogen or

alkyl; and each R^la, R^lb, R^lc, and R^ld is independently (i) hydrogen; (ii) Ci-₆ alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C₃.₇ cycloalkyl, C(,._\4 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) R^lb and R^Ic 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 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C|.β alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C₃.₇ cycloalkyl, C₆-₁₄ aryl, C_7-Is aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q¹ ; and (c) -C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R³, -OC(O)OR³, -0C(0)NR^bR^c, -OC(=NR^a)NR^bR^c, -OS(O)R³, -OS(O)₂R³, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR³S (O)R^d, -NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR³S(O)₂NR⁵R⁰, -SR³, -S(O)R³, -S(O)₂R³, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) d.₆ alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C₃.₇ cycloalkyl, Ce- 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) R^b and R^c 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, Cβ-π aryl, C_7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R⁶, -C(O)OR⁶, -C(0)NR^fR⁸, -C(NR^e)NR^fR^ε, -OR^C, -OC(O)R^e, -OC(O)OR⁶, -OC(O)NR^fR^ε, -0C(=NR⁶)NR^fR⁸, -OS(O)R⁶, -OS(O)₂R⁶, -OS(O)NR^fR^g, -OS(O)₂NR^fR⁸, -NR^fR⁸, -NR⁶C(0)R^h, -NR⁶C(O)OR", -NR⁶C(O)NR^fR⁸, -NR^eC(=NR^h)NR^fR⁸, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^ε, -NR^eS(O)₂NR^fR⁸, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -S(O)NR^fR⁸, and -S(O)₂NR^fR^g; wherein each R⁶, R^f, R^g, and R^h is independently (i) hydrogen; (ii) Ci_-6 alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, C₃.₇ cycloalkyl, aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R⁸ together with the N atom to which they are attached form heterocyclyl. [0038] In one embodiment, Formula I,

R² is hydrogen, halo, -OR^la, or -NR^lbR^lc;

R³ and R⁴ are each independently hydrogen or C_\._$ alkyl, optionally substituted with one or more -OR^a or -NR^bR^c;

R⁵ is (a) Ci_-6 alkyl, C₂-β alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹; or (b) -OR^Ia or -NR^lbR^lc;

R⁶ is hydrogen or Q_₆ alkyl, optionally substituted with one or more substituents, each independently selected from halo, -OR\ and -NR^bR^c;

E is a bond, -C(O)NR¹³-, -O-, -OC(O)NR¹³-, -NR^la-, -NR^laC(O)NR^ld-, or -NR¹³S(O)₂-;

Q is (a) C |.₆ alkyl, optionally substituted with one, two, or three substituents, each independently selected from (i) cyano; (ii) heterocyclyl, optionally substituted with one or more substituents Q¹; and (iii) -C(O)OR³, -C(0)NR^bR^c, -0R\ -OC(O)R^a, -OC(O)NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aS(O)₂R^d, -S(O)R^a, -S(O)₂R³, and -S(O)₂NR^bR^c; or (b) C_ό-₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹; each R^la, R^lb, R^lc, and R^ld is independently C_1-6 alkyl, optionally substituted with one or more -OR³ or -NR^bR^c; each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) Ci_-6 alkyl, optionally substituted with substituents Q¹, each Q¹ independently selected from halo, -OR^e, and -NR^rR^s, where R^e, R^f, and R⁸ are each independently hydrogen or C|.₆ alkyl; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, each optionally substituted with one or more substituents Q¹; and

X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.

[0039] In another embodiment, Formula I,

R² is hydrogen or halo;

R³ and R⁴ are each independently hydrogen or Cι_6 alkyl; R⁵ is C₃-7 cycloalkyl, Ce- ₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹; RR⁶⁶ iiss hhyyddrrooggeenn oorr CC ₁i--₆₆ aallkkyyll,, oopr tionally substituted with one to three halo; E is a bond, -C(O)NR¹³-, -O- -OC(O)NR¹³-, -NR^la-, -NR¹³C(O)NR¹"-, or -NR¹³S(O)₂-;

Q is (a) C i-6 alkyl, optionally substituted with one, two, or three substituents, each independently selected from (i) cyano; (ii) heterocyclyl, optionally substituted with one or more substituents Q¹ ; and (iii) -C(O)OR³, -C(O-)NR^bR^c, -OR^a, -OC(O)R³, -0C(0)NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aS(O)₂R^d, -S(O)R^α, -S(O)₂R³, and -S(O)₂NR^bR^c; or (b) Cβ-i4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹; each R^la, R^lb, R^lc, and R^ld is independently C|.₆ alkyl, optionally substituted with one or more -0R^a or -NR^bR^c; each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) Ci_₆ alkyl, optionally substituted with substituents Q¹, each Q¹ independently selected from halo, -OR^e, and -NR^fR^s, where R^e, R^f, and R⁸ are each independently hydrogen or Ci_₆ alkyl; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, each optionally substituted with one or more substituents Q¹; and

[0040] In yet another embodiment, Formula I,

R² is hydrogen;

R³ and R⁴ are each independently hydrogen, methyl, or ethyl;

R⁵ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidii pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, imidazolyl, or pyridyl;

R⁶ is hydrogen, methyl, fluoromethyl, difluoromethyl, or trifluorometh

E is a bond, -C(O)NH-, -O-, -OC(O)NH-, -NH-, -NHC(O)NH-, or

-NHS(O)₂-;

Q is aminomethyl, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, aminopropyl, dimethylaminopropyl, hydroxyethyl, hydroxypropyl, (morphlinyl)ethyl, (morphlinyl)propyl, carboxymethyl, dihydroxypropyl, dimethylamino-hydroxy-propyl, or hydroxy-(morphlinyl)-propyl;

[0041] In still another embodiment, Formula I,

R², R³, and R⁴ are hydrogen; R⁵ is moφholin-l-yl;

R⁶ is difluoromethyl;

E is -O- -NH-, Or-C(O)NH-;

Q is aminomethyl, dimethylaminomethyl, 2-aminoethyl, dimethylaminoethyl, 3-aminopropyl, 3-dimethylaminopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-(moφholin-l- yl)-ethyl, 3-(morpholin-l-yl)-propyl, carboxy methyl, 2,3-dihydroxypropyl, 3-dimethylamino- 2-hydroxy-propyl, or 2-hydroxy-3-(moφhoIin-l-yl)-propyl;

[0042] The groups, R², R³, R⁴, R⁵, R⁶, E, Q, X, Y, and Z in Formula I, 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.

[0043] In certain embodiments, R² is hydrogen, cyano, halo, or nitro. In certain embodiments, R² is Cj-β alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, C3.7 cycloalkyl, Cβ-π aryl, C7-₁5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹. In certain embodiments, R² is-C(O)R^la, -C(O)OR^lb, -C(O)NR^lbR^lc, or -C(NR^a)NR^lbR^lc, wherein R^la, R^lb, and R^lc are each as defined herein. In certain embodiments, R² is -OR^la, -OC(O)R^la, -OC(O)OR^la, -OC(O)NR ^lbR^lc, -0C(=NR^la)NR^lbR^lc, -OS(O)R^Ia, -OS(O)₂R^ia, -OS(O)NR^lbR^lc, or -OS(O)₂NR^lbR^lc, wherein R^la, R^lb, and R^lc are each as defined herein. In certain embodiments, R² is -NR^lbR^lc, -NR^laC(O)R^ld, -NR^laC(O)OR^ld, -NR^laC(O)NR^lbR^lc, -NR^laC(=NR^ld)NR^lbR^lc, -NR^laS(O)R^Id, -NR^laS(O)₂R^ld, -NR^laS(O)NR^lbR^lc, or -NR^laS(O)₂NR^lbR^le, wherein R^la, R^lb, R^lc, and R^ld are each as defined herein. In certain embodiments, R² is -SR^la, -S(O)R^la, -S(O)₂R^la, -S(O)NR^lbR^lc, or -S(O)₂NR^lbR^lc; wherein R^la, R^lb, and R^lc are each as defined herein. In certain embodiments, R² is hydrogen, methoxy, ethoxy, propoxy, isopropoxy, or dimethylaminopropoxy. In certain embodiments, R² is hydrogen.

[0044] In certain embodiments, R³ is hydrogen or Ci_-6 alkyl, optionally substituted with one or more substituents Q¹. In certain embodiments, R³ is hydrogen, methyl, ethyl, or propyl (e.g., /i-propyl, isopropyl, or 2-isopropyl). In certain embodiments, R³ is hydrogen.

[0045] In certain embodiments, R⁴ is hydrogen or C₁.₆ alkyl, optionally substituted with one or more substituents Q¹. In certain embodiments, R⁴ is hydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl). In certain embodiments, R⁴ is hydrogen.

[0046] In certain embodiments, R⁵ is Ci-β alkyl, C₂-6 alkenyl, or C₂.<j alkynyl, each optionally substituted with one or more substituents Q¹. In certain embodiments, R⁵ is C₃.₇ cycloalkyl, Cβ-π aryl, C7.₁5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹. In certain embodiments, R⁵ is -OR^la or -NR^lbR^ic, where R^la, R^lb, and R^lc are each as defined herein. In certain embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, imidazolyl, or pyridyl. In certain embodiments, R⁵ is morpholin-1-yl.

[0047] In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is Q.6 alkyl, optionally substituted with one or more substituents Q . In certain embodiments, R is C|_6 alkyl, optionally substituted with one or more halo. In certain embodiments, R⁶ is Ci_₆ alkyl, optionally substituted with one to three halo. In certain embodiments, R⁶ is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0048] In certain embodiments, E is a bond, -C(O)-, -C(O)O-, -O-, -OC(O)O-, -S-,

-S(O)- or -S(O)₂-. In certain embodiments, E is -C(O)NR¹S -OC(O)NR^la- -NR^la- -NR¹³C(O)NR ^ld- -NR^IaS(O)-, -NR¹³S(O)₂-, -NR^laS(O)NR^ld-, or -NR^l3S(O)₂NR^ld- where R^la and R^lb are each as defined herein. In certain embodiments, R^la is hydrogen or methyl. In certain embodiments, R^ld is hydrogen or methyl. In certain embodiments, E is a bond, -C(O)NH-, -O-, -OC(O)NH- -NH-, -NHC(O)NH-, or -NHS(O)₂-.

[0049] In certain embodiments, Q is C |.₆ alkyl, C₂.₆ alkenyl, or C₂_6 alkynyl, each optionally substituted with one, two, or three substituents, each independently selected from (i) cyano; (ii) heterocyclyl, optionally substituted with one or more substituents Q¹; and (iii) -C(O)OR^a, -C(O)NR^bR^c, -OR^a, -OC(O)R³, -0C(0)NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR³S(O)₂R^d, -S(O)R^a, -S(O)₂R³, and -S(O)₂NR^bR^c; where R³, R^b, R^c, and R^d are each as defined herein. In certain embodiments, Q is C₃.₇ cycloalkyl, C_O-_H aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, Q is aminomethyl, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, aminopropyl, dimethylaminopropyl, hydroxyethyl, hydroxypropyl, (morphlinyl)ethyl, (morphlinyl)propyl, carboxymethyl, dihydroxypropyl, dimethylamino-hydroxy-propyl, or hydroxy-(morphlinyl)-propyl. In certain embodiments, Q is aminomethyl, dimethylaminomethyl, 2-aminoethyl, dimethylaminoethyl, 3-aminopropyl, 3-dimethylaminopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-(morpholin-l-yl)-ethyl, 3- (morpholin-l -yl)-propyl, carboxymethyl, 2,3-dihydroxyρropyl, 3-dimethylamino-2-hydroxy- propyl, or 2-hydroxy-3-(moφholin-l-yl)-propyl.

[0050J In certain embodiments, X is nitrogen or CR⁹, wherein R⁹ is as defined herein.

In certain embodiments, X is nitrogen or CH. In certain embodiments, Y is nitrogen or CR⁹, wherein R⁹ is as defined herein. In certain embodiments, Y is nitrogen or CH. In certain embodiments, Z is nitrogen or CR⁹, wherein R⁹ is as defined herein. In certain embodiments, Z is nitrogen or CH.

[0051] In certain embodiments, X, Y, and Z are nitrogen. In certain embodiments, X and Y are nitrogen, and Z is CH. In certain embodiments, X and Z are nitrogen, and Y is CH. In certain embodiments, Y and Z are nitrogen, and X is CH.

[0052] In one embodiment, provided herein is a compound selected from:

2-({2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl } oxy )ethanol ;

3-({2-(difluoromethyl)-l-[4,6-di(4-moipholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)-l-propanol;

3-({2-(difluoromethyl)-l-[4,6-di(4-moφho]inyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)- 1 ,2-propanediol;

2-({2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)- l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)ethanamine;

2-({2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-ylJ-l//- benzimidazol-4-yl}oxy)-N,N-dimethylethanarnine;

2-(difluoromethyl)-l-[4,6-di(4-moφhdlinyl)-l,3,5-triazin-2-yl]-4-[2-(4- moφholinyl)ethoxy]-l//-benzimidazole;

3-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)- l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)- 1 -propanamine;

3-({2-(difluoromethyI)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-lH- benzimidazol-4-yl } oxy)-/V,N-dimethyl- 1 -propanamine;

2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-4-[2-(4- moφholinyl)propoxy]-l//-benzimidazole; l-({2-(difluoiOmethyl)-l-[4,6-di(4-moφholinyl)-l ,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)-3-(dimethylamino)-2-propanol; l-({2-difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l#- benzimidazol-4-yl}oxy)-3-(4-morpholinyI)-2-propanol;

({2-(difluoromethyI)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy )acetic acid;

Λ/¹-{2-(difluoromethyl)-l'[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazoM-yll-A^A^-dimethyl-l^-ethanediamine;

2-amino-N-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]- 1 //-benzi midazol-4-y 1 } acetamide ;

N- { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yl}-2-(dimethylamino)acetamide;

3-amino-yV- { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 //-benzimidazol-4-yl } propanamide; iV-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } -3-(dimethy lamino)propanamide;

2-(difluoromethyl)-Λ^-[2-(dimethylamino)ethyl]-l-[4,6-di(4-morpholinyl)- l,3,5-triazin-2-yl]-l//-benzimidazole-4-carboxamide;

3-({2-(difluoromethyl)-l-l4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)- 1 -propanol; and

3-( { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)-2-pyrimidiriyI]- 1 H- benzimidazol-4-yl } oxy)-N,N-dimethyl- 1 -propanamine; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

[0053] 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.

[0054] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomer^ 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.

[0055] 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. ScL 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).

[0056] 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, α- 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.

[0057] 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-(diethyIamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, ,/V-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.

[0058] In certain embodiments, the compounds provided herein are pharmacologically acceptable salts of the compounds with one or more of hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and isoethonic acids; or with one or more of potassium carbonate , sodium or potassium hydroxide, ammonia, triethylamine, and triethanolamine.

[0059] 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., Marcel! 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, 1 15-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381 ; Farquhar et al., J. Pharm. ScL 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. ScL 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.

Methods of Synthesis

[0060] 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.

[0061 ] For example, the compounds of Formula I can be prepared via the formation of a bond between E and Q (Method A), as illustrated in Scheme 1, where X¹ is a leaving group, such as halo or sulfonate.

Scheme 1

[0062] The compounds of Formula I can also be prepared by the combination of a benzimidazole unit containing a preformed E-Q bond, with a pyrimidinyl or 1,3,5-triazinyl unit (Method B), as illustrated in Scheme 2. Scheme 2

[0063] Furthermore, the compounds of Formula I can be prepared by the modification of existing compounds of Formula I (Method C), as illustrated in Scheme 3, wherein Q^Λ is defined the same as Q, but Q^A is different from Q.

Scheme 3

Pharmaceutical Compositions

[0064] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula I as defined herein, and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.

[0065] 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.

[0066] 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, or 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.

[0067] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, 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.

[0068] 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.

[0069] The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, 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 al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).

[0070] 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.

[0071] 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.

[0072] In another embodiment, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.

[0073] In yet another embodiment, provided herein is the use of a compound of

Formula I in the manufacture of a medicament for the treatment of cancer. 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

[0074] 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.

[0075] 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 com 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.

[0076] 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.

[0077] 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; microcrystailine 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.

[0078] 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.

[0079] 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.

[0080] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0081] 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.

[0082] 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, control led-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [0083] 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)₁ 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.

[0084] 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 diøower 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] Coloring and flavoring agents can be used in all of the above dosage forms.

[0089] 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

[0090] 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.

[0091] 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).

[0092] 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.

[0093] 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, jV,/V-dimethylacetamide, and dimethyl sulfoxide.

[0094] 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 metabisulfϊte. 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 α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL^®, CyDex, Lenexa, KS).

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[00100] 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

[00101] 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.

[00102] 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.

[00103] 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. [00104] 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).

[00105] 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 (OAV) 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.

[00106] 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.

[00107] 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. [00108] 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.

[00109] 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.

[00110] 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.

[00111] 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- tetrafluoroethane 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. [001 12] 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.

[001 13] 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.

[00114] 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.

[001 15] 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

[001 16] 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).

[00117] 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

[001 18] 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).

[00119] 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.

[00120] 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.

[00121] 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.

[00122] 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.

[00123] 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

[00124] 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).

[00125] 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.

[00126] 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.

[00127] 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 MANNOGEM 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.

[00128] 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.

[00129] 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.

[00130] 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.

[00131] 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.

(00132J 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.

[00133] 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.

[00134] 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).

[00135] 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. [00136] 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

[00137] 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 μm to about 3 mm, about 50 μm to about 2.5 mm, or from about 100 μm 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 Pelletizaύon Technology; Marcel Dekker: 1989.

[00138] 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

[00139] 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

[00140] In one embodiment, provided 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, including 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.

[00141 ] In another embodiments, provided 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, including 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.

[00142] In yet another embodiment, provided is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PDK 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, including 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.

[00143] In yet another embodiment, provided 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, including 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.

[00144] In yet another embodiment, provided herein are uses of a compound provided herein, e.g., a compound of Formula I, including 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, in the manufacture of a medicament for the treatment of cancer.

[00145] In certain embodiments, the compound selectively targets the pi 10a subunit of

PI3K. In certain embodiments, the compound selectively inhibits the PI3K via its interaction with its pi 10a subunit. In certain embodiments, the compound selectively alkylates the pi lOα subunit of PI3K. [00146] 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.

[00147] 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, HFV or RLV infection, bacterial, flugal, 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 HFV. [00148] 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 myeloblasts, promyelocyte, 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; (1 1) 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), spermatocyte, 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 ai, 1985, Medicine, 2ά Ed., J. B. Lippincott Co., Philadelphia and Murphy et ai, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

[00149] 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.

[00150] 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.

[00151] 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. [00152] 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.

[00153] 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, including 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. In one embodiment, the PIK3 enzyme is inside a cell.

[00154] The compounds provided herein, e.g., a compound of Formula I, including 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, 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.

[00155J Suitable other therapeutic agents can also include, but are not limited to,.(l) 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 amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, 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; (11) 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.

[00156] 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).

[00157] 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.

[00158] In another embodiment, the method provided herein comprises administration of a compound of Formula I, 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 of Formula 1 as defined herein.

[00159] Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, e.g., a compound of Formula I, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, 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.

[00160] 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 NSADD, the weight ratio of the compound to the NSAED 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. [00161] 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.

[00162] 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, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00163] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.

[00164] 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.

[00165] 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. [00166] The disclosure will be further understood by the following non-limiting examples.

EXAMPLES

[00167] 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); μL (microliters); M (molar); mM (millimolar); μM (micromolar); eq. (equivalent); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); mp (melting point); HRMS (high resolution mass spectrometry); FAB, (fast atom bambardment); DMF (dimethyformamide); DMSO (dimethylsulfoxide); DMSO-J₁₅ (deuterated dimethylsulfoxide); EtOH (ethanol); EtOAc (ethyl acetate); MeOH (methanol); THF (tetrahydrofuran); DIPEA (N,N- diisopropylethylamine); DMAP (dimethylaminopyridine); HOAc (acetic acid); TFA (trifluoroacetic acid); EDCI (l-ethyl-3-(3'-dimethylamino-propyl)carbodiirnide); COl,(N,N'- carbonyldiimidazole); TBDMSCl (rerf-butylchlorodimethylsilane); TBAF (tetra-n- butylammonium fluoride); Me (methyl); Et (ethyl); and EDTA (ethylenediaminetetraacetic acid).

[00168] 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 ⁰C (degrees Centigrade). AH 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.

[00169] 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-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l/f- benzimidazol-4-yl }oxy)ethanol

[00170] The compound was synthesized according to Method A.

[00171J A mixture of 85 mg (0.0196 mmol) of 2-(difluoromethyl)-l-[4,6-di(4- moφholinyl)-l,3,5-triazin-2-yl]-ltf-benzimidazol-4-ol (WO 2004/037812), 37 mg (0.22 mmol) of 2-iodoethanol, and 83 mg (0.6 mmol) of powdered K₂CO₃ in 10 mL of DMF was stirred at room temperature overnight, and then diluted with water. The product was collected by filtration, dried, and purified by chromatography on silica eluting with EtOAc to give 47 mg (50% yield) of 2-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l ,3,5-triazin-2- yl]-l//-benzimidazol-4-yl}oxy)ethanol: mp (EtOAc) 243-246 ⁰C; ¹H NMR (DMSO-d₆) δ 7.89 (d, J = 8.1 Hz, IH), 7.70 (t, 7_HF = 52.8 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 6.95 (d, 7 = 7.9 Hz, IH), 4.93 (t, J = 5.5 Hz, exchangeable with D₂O, IH), 4.24 (t, J = 5.0 Hz, 2 ), 3.84- 3.79 (m, 10H), 3.69 (m, 8H); Anal. Calcd. for C₂IH₂₅F₂N₇O₄: C, 52.83; H, 5.28; N, 20.53; Found: C, 52.86; H, 5.22; N, 20.5%. Example 2

Synthesis of 3-({ 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl }oxy)-l-ρropanol

[00172] The compound was synthesized according to Method B.

[00173] A mixture of 7.2 g (46.7 mmol) of 2-amino-3-nitrophenol, 6.6 g (1.5 equiv) 3- chloropropanol, and 19.3 g (3 eq.) dry powdered K₂CO3 in 50 mL acetone was heated and stirred under reflux for 20 hrs. The mixture was concentrated to dryness and the residue was diluted with water and extracted with ethyl acetate and dried (Na₂SO₄). Evaporation of the solvent and chromatography of the residue on silica eluting with CH₂Cl₂ZEtOAc (4:1) gave 10.0 g (100% yield) of 2-(2-amino-3-nitrophenoxy)ethanol as a yellow solid: mp (CH₂Cl₂/hexanes) 72-74 ⁰C; ¹H NMR (CDCl₃) δ 7.71 (dd, J = 8.9, 1.2 Hz, IH), 6.92 (d, J = 7.7 Hz, IH), 6.60 (dd, J = 8.9, 7.8 Hz, I H), 6.42 (s, exchangeable with D₂O, 2H), 4.20 (t, J = 6.1 Hz, 2H), 3.89 (q, J = 5.7 Hz, 2H), 2.12 (pentet, J = 6.1 Hz, 2H), 1.48 (t, J = 5.0 Hz, exchangeable with D₂O, IH); Anal. Calcd. for C₉Hi₂N₂O₄: C, 50.9; H, 5.7; N, 13.3; Found: C, 51.0; H, 5.7; N, 13.3%.

[00174] A solution of 4.3 g (20.26 mmol) of 2-(2-amino-3-nitrophenoxy)ethanol in 50 mLMeOH was hydrogenated over lOOmg 10% Pd on C and then filtered into a solution of 5 mL cone. HCl in MeOH (50 mL). After removal of the solvents, the resulting residue was dissolved in a mixture of 60 mL 4 N HCl and 5 mL of difluoroacetic acid, and the resulting mixture was heated under reflux for 6 hrs. After cooling to 20 ⁰C, the mixture was diluted with water (100 mL), neutralized with aq. NH₃, extracted with EtOAc, and dried (Na₂SO₄). Evaporation of the solvent gave intermediate 2-{ [2-(difluoromethyl)-l//-benzimidazol-4- yl]oxy Jethanol which was combined with 6.1 g (2 equiv) TBDMSCl in 15 mL pyridine. The mixture was stirred at 20 °C for 3 hrs before being poured into water and extracted with EtOAc. The organics were washed with water and dried (Na₂SO₄). Evaporation of the solvents and the chromatography of the residue on silica eluting with CH₂ChZEtOAc (9:1) gave 5.79 g (84% yield) of 4-(2-{ [rerr-butyl(dimethyl)silyl]oxy}ethoxy)-2-(difluoromethyl)- l//-benzimidazole: mp (CH₂Cl₂/hexanes) 133-135 ⁰C; ¹H NMR (DMSO-J₆) (tautomeric mixture) δ 13.40 and 13.23 (s, exchangeable with D₂O, 1H),.7.36-7.05 (m, 3H), 6.86 and 6.75 (2d, J = 7.8 Hz and 7.4 Hz, IH), 4.27 and 4.22 (2t, J = 6.3 Hz, 2H), 3.87 and 3.81 (2t, J = 6.1 Hz, IH), 2.05-1.95 (m, 2H), 0.85 and 0.84 (2s, 9H), 0.02 and 0.01 (2s, 6H).

[00175] A mixture of 4-(2-{[rerf-butyl(dimethyl)silyl]oxy}ethoxy)-2-(difluoromethyl)-

1/f-benzimidazole (684 mg, 1.92 mmol), dry powdered K₂CO₃ (530 mg, 3.84 mmol), and 2- chloro-4,6-di(4-morpholinyl)-l,3,5-triazine (285 mg, 3.84 mmol) in DMSO (5 mL) was heated at 130 ⁰C for 3 hrs. The cooled reaction mixture was diluted with water, and the resulting precipitate was filtered, washed with water, and recrystallized from CH₂Cl₂ZEtOH to give 971 mg (83% yield) of 4-(3-{ [fe/-f-butyl(dimethyl)silyl]oxy}propoxy)-2- (difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-ylJ-l//-benzimidazole: ¹H NMR (DMSO-J₆) δ 7.88 (d, J = 8.2 Hz, IH), 7.48 (t, 7_HF - 53.5 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.87 (d, J = 8.0 Hz, IH), 4.38 (t, J = 6.6 Hz, 2H), 3.88-3.84 (m, 6H), 3.81-3.78 (m, 4H) 2.16 (pentet, J = 6.3 Hz, 2H), 0.91 (s, 9H), 0.62 (s, 3H), 0.02 (s, 3H).

[00176] To a solution of 4-(3-{ [fe>t-butyI(dimethyl)silyljoxy}propoxy)-2-

(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-tπazin-2-yl]-l//-benzimidazole (809 mg, 1.35 mmol) in THF (10 ml) was added 1 M TBAF in THF (2.5 mL) and the reaction mixture was stirred for 30 min. The mixture was then diluted with H₂O and stirred for 1 hr. The resulting precipitate was filtered, washed with water, and dried. Chromatography on silica - eluting with CH₂Cl₂ZMeOH (96:4) gave 504 mg (81% yield) of 3-({2-(difluoromethyl)-l- [4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-yl }oxy)-l -propanol: mp (CH₂Cl₂ZEtOH) 200-203 ⁰C; ¹H NMR (CDCl₃) δ 7.93 (d, J = 8.0 Hz, IH), 7.48 (t, 7_HF = 53.5 Hz, IH), 7.33 (t, J = 8.2 Hz, IH), 6.91 (d, J = 7.8 Hz, IH), 4.48 (t, J = 5.9 Hz, 2H), 3.97 (q, J = 5.6 Hz, 2H), 3.88-3.86 (m, 8H), 3.79-3.77 (m, 8H), 3.12 (t, J = 6.0 Hz, exchangeable with D₂O, IH), 2.16-2.10 (m, 2H); Anal. Calcd. for C₂₂H₂₇F₂N₇O₄; C, 57.8; H, 5.5; N, 20.0; Found: C, 54.0; H, 5.6; N, 20.2%. Example 3

Synthesis of 3-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)-l,2-propanediol

[00177] The compound was synthesized according to Method A.

[00178] To a solution of 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2- yl]-l//-benzimidazol-4-ol (208 mg. 0.48 mmol) in DMF (5 mL) was added powdered K₂CO₃ (331 mg, 2.4 mmol) and 3-chloro-l,2-ρropanediol (1 mL). The stirred mixture was heated at 50 ⁰C for 48 hrs and then diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CH₂CbZMeOH gave 150 mg (62% yield) of 3-({2-(difluoromethyl)-l -l4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl }oxy)- l,2-propanediol: mp 229-231⁰C; ¹H NMR (CDCl₃) δ 7.96 (dd, J = 8.4, 0.6 Hz, IH), 7.51 (t, J_HF = 53.5 Hz, I H), 7.34 (t, J = 8.2 Hz, IH), 6.92 (dd, J = 8.0, 0.4 Hz, IH), 4.41-4.31 (m, 2H), 4.22-4.16 (m, IH), 3.89-3.84 (m, 11H), 3.81-3.77 (m, 8H), 3.09 (t, J = 6.5 Hz, exchangeable with D₂O, IH); Anal. Calcd. for C₂₂H₂₇F₂N7O₅.O.25 H₂O: C, 51.6; H, 5.4; N, 19.2; Found: C, 51.6; H, 5.4: 19.0%.

Example 4

Synthesis of 2-({ 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl }oxy)ethanamine

[00179] The compound was synthesized according to Method A.

[00180] A mixture of 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]- l//-benzimidazol-4-ol (281 mg, 0.65 mmol) and powdered K₂CO₃ (449 mg, 3.25 mmol) in dry DMF (5 mL) was stirred at 20 ⁰C for 30 min, and then Λ/-(2-bromoethyl)phthalimide (330 mg) was added. The resulting mixture was heated and stirred at 50 ⁰C for 24 hrs, and a second batch of 330 mg of N-(2-bromoethyl)phthalimide was added. After an additional 24 hrs, the reaction mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CH₂CIaZEtOH gave 366 mg (93% yield) of 2-[2-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-lH- benzimidazol-4-yl }oxy)ethyl]-l//-isoindole-I,3(2//)-dione: mp 250-252 ⁰C; ¹H NMR (CDCb) δ 7.90 (d, J = 4 Hz, lH),7.87-7.84 (m, 2H), 7.73-7.70 (m, 2H), 7.44 (t, J_HP = 53.5 Hz, IH), 7.31 (t, J = 8.2 Hz, IH), 6.90 (d, J = 7.8 Hz, IH), 4.61 (t, J = 6.6 Hz, 2H), 4.22 (t, J = 6.6 Hz, 2H), 3.87-3.86 (m, 8H), 3.79-3.76 (m, 8H).

[00181] To a solution of the isoindole (292 mg, 0.25 mmol) in CH₂Cl₂ (15 mL) and

THF ( 10 mL) was added hydrazine monohydrate (2 mL), and the resulting mixture was stirred at room temperature for 24 hrs. After removal of the solvent under vacuum, the residue was diluted with water, and the resulting precipitate was collected by filtration, and dried. Chromatography on neutral alumina eluting with CHaCb/MeOH (95:5) gave 133 mg (58% yield) of 2-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-lH- benzimidazol-4-yl}oxy)ethanamine: mp (CΗ₂Cl₂/hexanes) 201-203 ⁰C; ¹H NMR (CDCIa) S 7.90 (d, J = 8.4 Hz, I H), 7.49 (t, 7_Hp = 53.5 Hz, IH), 7.33 (t, J = 8.2 Hz, IH), 6.84 (d, J = 7.8 Hz, IH), 4.31 (t, J = 5.2 Hz, 2H), 3.88-3.87 (m, 8H), 3.79-3.77 (m, 8H) 3.25 (t, J = 5.2 Hz, 2H); Anal. Calcd. for C_2IH₂₆F₂N₈O₃ CS H₂O: C, 52.0; H, 5.6; N, 23.1 ; Found: C, 52.2; H, 5.4: N, 22.1%.

Example 5

Synthesis of 2-({ 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)-N,N-dimethylethanamine

100182] The compound was synthesized according to Method A.

[00183] A mixture of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- l//-benzimidazol-4-ol (301 mg, 0.69 mmol), NaI (1 g), and K₂CO₃ (956 mg, 6.9 mmol) in DMF (5 mL) was stirred at 20 ⁰C for 5 min when a yellow suspension was obtained. An excess of 2-Λ',N-dimethylaminoethyl chloride hydrochloride (1 g) was added, and the mixture was stirred at 50 ⁰C for 3 days. The reaction mixture was diluted with water, extracted with CH₂Cl₂, and dried (Na₂SO,)). After solvent removal, the residue was chromatographed on silica eluting with CH₂Cl₂/Me0H (9: 1 ) containing 1 % aq. NH₃. Further chromatography on alumina eluting with CH₂Cl₂/Me0H (94:6) gave 19 mg (5% yield) of 2-({2-(difluoromethyl)- l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-yl}oxy)-N,/V- dimethylethanamine: mp (CH₂Cl₂/hexanes) 190-192 °C; ¹H NMR (CDCl₃) «57.89 (d, J = 8.1 Hz, IH), 7.46 (t, J_HF = 53.5 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.84 (d, J = 7.9 Hz, IH), 4.39 (t, J = 6.3 Hz, 2H), 3.88-3.87 (m, 8H), 3.79-3.77 (m, 8H), 2.91 (t, J = 6.3 Hz, 2H); HRMS (FAB⁺) Calcd. for C₂₃H₃₀F₂N₈O₃ [MH⁺]: m/z 505.2487, Found: 505.2479; Anal. Calcd. for C₂₃H₃₀F₂N₈O₃0.5 H₂O: C, 53.8; H, 6.1 ; N, 21.8; Found: C, 53.7; H, 5.8; N, 21.5%. Example 6

Synthesis of 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l ,3,5-triazin-2-yl]-4-[2-(4- morpholinyl)ethoxy] - 1 //-benzimidazole

[00184] The compound was synthesized according to Method A.

[00185] A mixture of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l ,3,5-triazin-2-yl]- l//-benzimidazol-4-ol (215 mg, 0.49 mmol), K₂CO₃ (683 mg, 4.9 mmol), and 4-(2- chloroethyl)moφholine hydrochloride (455 mg, 2.5 mmol) in DMF (5 mL) was stirred at 50 ⁰C for 2 hrs. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CHaCl₂ZEtOH gave 193 mg (73% yield) of 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)- l ,3,5-triazin-2-yl]-4-[2-(4- moφholinyl)ethoxy]-l//-benzimidazole: mp 228-230 ⁰C; ¹H NMR (CDCl₃) δ 7.90 (dd, J = 8.3, 0.5 Hz, IH), 7.47 (t, 7_HF = 53.5 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.83 (d, J = 1.1 Hz, IH), 4.41 (t, J = 6.1 Hz, 2H), 3.88-3.86 (m, 8H), 3.96-3.74 (m, 12H), 2.95 (t, J = 6.1 Hz, 2H), 2.62 (br t, J = 4.6 Hz, 4H); Anal. CaIc. for C₂₅H₃₂F₂N₈O₄: C, 54.9; H, 5.9; N, 20.5; Found: C, 55.0; H, 6.0; N, 20.4%.

Example 7

Synthesis of 3-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)- 1 -propanamine

[00186] The compound was synthesized according to Method A.

[00187] Similarly to Example 4, reaction of 2-(difluoromethyl)-l-[4,6-di(4- rnorpholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-ol with N-(3-bromopropyl)phthalimide gave 2-[3-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-lf/- benzimidazol-4-yI}oxy)propyI]-l//-isoindole-l,3(2//)-dione in 96% yield: mp (CH₂Cl₂/EtOH) 212-215 ⁰C; ¹H ΝMR (CDCl₃) δ 7.87 (d, J = 8.1 Hz, IH), 7.85-7.80 (m, 2H), 7.71-7.67 (m, 2H), 7.40 (t, Λ,_F = 53.6 Hz, IH), 7.30 (t, J = 8.2 Hz, IH), 6.80 (d, J = 7.8 Hz, IH), 4.37 (t, 7 = 6.5 Hz, 2H), 3.96 (t, J = 6.7 Hz, 2H), 3.88-3.86 (m, 8H), 3.79-3.76 (m, 8H), 2.35 (pentet, J = 6.6 Hz, 2H).

[00188] Similar deprotection of the isoindole with hydrazine monohydrate gave 3-({2-

(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l/f-benzimidazol-4-yl }oxy)-l - propanamine in 28% yield: mp (CH₂Cl₂/hexanes) 218-221 ⁰C; ¹H ΝMR (CDCl_a) «57.91 (d, J = 8.1 Hz, IH), 7.50 (t, J_HF = 53.6 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.87 (d, / = 7.9 Hz, IH), 4.40 (t, J = 6.1 Hz, 2H), 3.88-3.86 (m, 4H), 3.79-3.76 (m, 4H), 3.15 (t, J = 6.5 Hz, 2H), 2.19 (pentet, / = 6.2 Hz, 2H). Example 8

Synthesis of 3-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l ,3,5-triazin-2-yI]-l//- benzimidazol-4-yl}oxy)-N,N-dimethyl-l-propanamine

[00189] The compound was synthesized according to Method C.

[00190] To a solution of 150 mg (0.31 mmol) of 3-({2-(difluoromethyl)-l-[4,6-di(4- morpholinyl)-] ,3,5-triazin-2-yl]-lH-benzimidazol-4-yl}oxy)-l-propanol (Example 2) and 0.5 mL Et₃N in TΗF (15 mL) at 0 ⁰C was added methanesulphonyl chloride (0.37 mmol). The reaction mixture was stirred at 0 ⁰C for 45 min, and then 3 mL of a 40% aqueous solution of dimethylamine was added. The resulting mixture was stirred at 20 ⁰C for 24 hrs. The solvent was removed under vacuum, the residue was diluted with water, and the resulting precipitate was collected, washed with water, and dried. Chromatography on silica eluting with CH₂Cl₂MeOH (95:5) containing 1% aq. NH₃ gave 130 mg (81% yield) of 3-({2- (difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 tf-benzimidazol-4-yl } oxy)- N,/V-dimethyl-l-propanamine: mp (CH₂Cl₂/hexanes) 191-193 ⁰C; HRMS (FAB⁺) Calcd. for C₂₄H₃₂F₂N₈O₃ [MH⁺]: m/z 519.2644, Found: 519.2644; Hydrochloride: ¹H NMR (DMSO-ds) δ 9.97 (br s, exchangeable with D₂O, IH), 7.92 (d, J = 8.1 Hz, IH), 7.70 (t, Λ,_F = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.98 (d, J = 7.9 Hz, IH), 4.33 (t, J = 6.1 Hz, 2H), 3.82-3.80 (m, 8H); 3.69 (m, 8H), 3.25 (m, 2H), 2.81 (s, 6H), 2.27-2.20 (m, 2H); Anal. Calcd. for C₂₄H₃₂F₂N₈O₃ 1.2 HCl H₂O: C, 49.7; H, 6.1; Cl, 7.3; N, 19.3; Found: C, 49.6; H, 6.0; Cl, 7.4; N, 19.1%. Example 9

Synthesis of 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyI)- 1 ,3,5-triazin-2-yl]-4-[3-(4- morpholinyl)propoxy]-l//-benzimidazole

[00191] The compound was synthesized according to Method A.

[00192] Similarly to Example 6, reaction of 2-(difluoromethyl)-l-[4,6-di(4- morpholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-ol with 4-(3-bromopropyl)morpholine hydrobromide gave 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l ,3,5-triazin-2-yl]-4-[3-(4- morpholinyl)propoxy]-l//-benzimidazole in 29% yield; mp (CH₂CI₂/Et0H) 188-190 ⁰C; ¹H NMR (CDCl₃) δ 7.88 (d, J = 8.3 Hz, 1 H), 7.47 (t, J_HF = 53.5 Hz, 1 H), 7.32 (t, J = 1.9 Hz, IH), 6.85 (d, J = 8.0 Hz, IH), 4.34 (t, J = 8.0 Hz, 2H), 3.90-3.87 (m, 8H), 3,79-3.76 (m, 8H), 3.73-3.71 (m, 4H), 2.60-2.58 (m, 4H), 2.49 (m, 4H), 2.15-2.10 (m, 2H); Anal. Calcd. for C₂₆H₃₄F₂N₈O₄: C, 55.7; H, 6.1 : N, 20.0; Found: C, 55.7; H, 6.1 ; N, 20.1%.

Example 10

Synthesis of l-({ 2-(difluoromethyl)- l-[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yl } oxy)-3-(dimethylamino)-2-propanol

[00193] The compound was synthesized according to Method C. [00194] A mixture of 2-(difluoromethyl)-l -[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- lH-benzimidazol-4-ol (288 mg. 0.66 mmol) and powdered K₂CO3 (454 mg, 2.4 mmol) in DMF (5 mL) was stirred at 20 ⁰C for 30 min and epibromohydrin (0.5 mL) was added. The resulting mixture was heated at 50 ⁰C for 30 min, cooled, and diluted with water. The resulting precipitate was filtered, washed with water, and dried to give 341 mg (97% yield) of 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-4-(2-oxiranylmethoxy)-l//- benzimidazole: ¹H NMR (CDCl₃) δ 7.92 (d, J = 7.9 Hz, IH), 7.48 (t, 7_HF = 53.4 Hz, IH), 7.33 (t, 7 = 8.1 Hz, IH), 6.89 (d, J = 7.9 Hz, IH), 4.51 (dd, J = 1 1.5, 3.8 Hz, IH), 4.35 (dd, J = 11.5, 5.4 Hz, IH), 3.88-3.87 (m, 8H), 3.79-3.77 (m, 8H), 3.52-3.48 (m, IH), 2.93 (U J = 4.6 Hz, IH), 2.80 (dd, J = 4.9, 2.6 Hz, IH).

[00195] Reaction of the above epoxide with aq. dimethylamine in THF (10 mL) and

MeOH (10 mL) gave l-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l ,3,5-triazin-2-yl]-lH- benzimidazol-4-yl}oxy)-3-(dimethylamino)-2-propanol in 96% yield: mp (CH₂Cl₂/hexanes) 197-200 ⁰C; ¹H NMR (CDCl₃) J 7.91 (d, J = 7.9 Hz, IH), 7.48 (t, J_HF = 53.5 Hz, IH), 7.33 (t, J = 8.3 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 4.33-4.20 (m, 1 H), 4.30 (t, J = 4.9 Hz, 2H), 3.89- 3.86 (m, 8H), 3.79-3.77 (m, 8H), 2.61-2.49 (m, 2H), 2.33 (s, 6H); Anal. Calcd. for C₂₄H₃₂F₂N₈O₄.0.25H₂O: C, 53.4; H, 5.9; N, 20.7; Found: C, 53.5; H, 6.1; N, 20.8%.

Example 11

Synthesis of l-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)-3 -(4-moφholi nyl)-2-propanol

[00196] The compound was synthesized according to Method C.

[00197J Moφholine (0.26 g, 3 mmol) was added to a solution of 300 mg (0.61 mmol) of (2-(difluoromethyl)- 1 -[4,6-di(4-moφholinyl)- 1 ,3,5-triazin-2-yl]-4-(2-oxiranylmethoxy)- l//-benzimidazole (Example 10) in THF (10 mL) and MeOH (10 mL). The resulting mixture was stirred at 20 ⁰C for 16 hrs. The reaction mixture was evaporated to dryness and the residue was triturated with water. The resulting precipitate was collected, dried, and recrystallized from CH₂Cl₂/hexanes to give 353 mg (100% yield) of l-({2-(difluoromethyl)- l-[4,6-di(4-morpholinyl)-l ,3,5-triazin-2-yI]-lH-benzimidazol-4-yl}oxy)-3-(4-mθφholinyl)- 2-propanol: mp 173-175 ⁰C; ¹H NMR (CDCl₁) δ 7.91 (dd, J = 8.4, 0.6 Hz, IH), 7.48 (t, J_HF = 53.4 Hz, IH), 7.33 (t, 7 = 8.1 Hz, IH), 6.90 (d, J = 7.6 Hz, IH), 4.35-4.26 (m, 3H), 3.89-3.86 (m, 8H), 3.79-3.77 (m, 8H), 3.74-3.71 (m, 4H), 2.69-2.60 (m, 4H), 2.55-2.49 (m, 2H); Anal. Calcd. for C₂₅H₃₄F₂N₈O₅: C, 54.2; H, 5.9; N, 19.4; Found: C, 54.4; H, 5.9; N, 19.5%.

Example 12

Synthesis of {2-(difluoromethyI)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-lH- benzimidazol-4-yl }oxy)acetic acid

[00198] The compound was synthesized according to Method A.

[00199J A mixture of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- l//-benzimidazol-4-ol (275 mg, 0.63 mmol) and dry K₂CO₃ (800 mg) in DMF (3 mL) was stirred at 20 ⁰C for 30 min. A premixed suspension of K₂CO₃ (1.0 g) and bromoacetic acid (1 mL) in DMF (3 mL) was then added. The reaction mixture was stirred at 50 ⁰C for 24 hrs and then diluted with water. After filtration through a pad of celite, the filtrate was acidified with cone. HCl. The precipitate was collected by filtration, washed with water, and dried. Two recrystallizations from CH₂Cl₂/Et0H gave 190 mg (60% yield) of { 2-(difluoromethyl)- l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-lH-benzimidazol-4-yl}oxy)acetic acid: mp 305- 308 ⁰C; ^!H NMR (DMSO-dβ) δ 13.0 (br s, exchangeable with D₂O, IH), 7.91 (d, J = 8.4 Hz, IH), 7.70 (t, 7_HF = 52.8 Hz, IH), 7.37 (t, J = 8.2 Hz, IH), 6.86 (d, 7 = 8.1 Hz, IH), 4.96 (s, 2H), 3.82-3.80 (m, 8H), 3.69 (m, 8H); Anal. Calcd. for C₂,H₂₃F₂N₈O₅.0.25H₂O: C, 50.9; H, 4.8; N, 19.8; Found C, 50.8; H, 4.5; N, 19.9%.

Example 13

Synthesis of yv'-{2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l₎3,5-triazin-2-yl]-l//- benzimidazol-4-yl } -N²,N²-dimethyl- 1 ,2-ethanediamine

[00200] The compound was synthesized according to Method C.

[00201] A mixture of 0.455 g (1.05 mmol) of 2-(difluoromethyl)-l-[4,6-di(4- moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-ylamine (WO 2002/0881 12) and 0.70 g (3.2 mmol) of di-tert-butyl dicarbonate in dioxane (50 mL) was heated under reflux for 2 days. Dilution with water gave a white solid which was collected and dried. Chromatography on alumina eluting with CH₂CI₂ gave 0.47 g (84% yield) of tert-buty\ 2- (difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4- ylcarbamate: mp (CH₂Cl₂/MeOH) 248-251 ^QC; ¹H ΝMR (CDCIa) δ 8.05 (d, J = 8.0 Hz, 1 H), 7.90 (dd, J = 8.3, 0.6 Hz, IH), 7.80 (br s, exchangeable with D₂O, IH)₁ 7.56 (t, 7_HF = 53.6 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 3.88 (m, 8H), 3.78 (m, 8H), 1.55 (s, 9H); Anal. Calcd. for C₂₄H₃₀F₂N₈O₉: C, 54.2; H, 5.7; N, 21.0; Found: C, 54.0; H, 5.7; N, 21.3%.

[00202] The above carbamate (149 mg, 0.3 mmol) was suspended in dry DMF (2 mL) at 0 ⁰C, NaH (64 mg 2.7 mmol) was then added. The reaction mixture was stirred for 30 min. A solution of /V,/V-dimethylaminoethyl chloride (generated from 5 g amine hydrochloride and aq. K₂CO₃) in dry benzene was added, and the mixture was stirred at 20 ⁰C for 24 hrs. The reaction mixture was then quenched with H₂O and extracted with EtOAc. The organic fraction was dried (Na₂Sθ₄) and evaporated to dryness. Chromatography of the residue on silica eluting with CH₂Cl₂/MeOH (95:5) gave 111 mg (61 % yield) of crude terf-butyl 2- (difluoromethyl)-l -[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-yl[2- (dimethylamino)ethyl]carbamate, which was treated with TFA (5 mL) in CH₂Cl₂ (5 mL) for 48 hrs. The reaction mixture was evaporated to dryness at 20°. After neutralizing with NH₃, the product was purified by chromatography on silica eluting with CH₂Cl₂/MeOH (9:1) to give a white solid, which was recrystallized from CH₂Cl₂/hexanes to give 25 mg (18% yield) of yV^l-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4- yl }-yV²,iV²-dimethyl-l,2-ethanediamine: mp 237-239 ⁰C; ¹H NMR (CDCl₃) δ 7.55 (d, J = 8.2 Hz, IH), 7.52 (t, J_HF = 53.7 Hz, IH), 7.20-7.23 (m, IH), 6.48 (d, J = 7.8 Hz, IH), 5.33( I, J = 5.1 Hz, exchangeable with D₂O, IH), 3.87 (m, 8H), 3.79-3.76 (m, 8H), 3.3^'8 (q, J = 5.6 Hz, 2H), 2.62 (t, J = 6.2 Hz, 2H), 2.30 (s, 6H); HRMS (EI⁺) calcd. for C₃₃H₃₃N₃O₂: 503.2573; Found: 503.2575.

Example 14

Synthesis of 2-amino-N-{ 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } acetamide

[00203] The compound was synthesized according to Method A.

[00204] A mixture of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- l//-benzimidazol-4-ylamine (202 mg, 0.48 mmol), [(tert-butoxycarbonyl)amino]acetic acid (164 mg, 0.96 mmol), DMAP (230 mg, 1.9 mmol), and EDCI (360 mg, 1.9 mmol) in DMF (5 mL) was stirred at 20 ⁰C for 6 hrs, when additional [(terf-butoxycarbonyl)aminojacetic acid (82 mg, 0.24 mmol) was added. After additional 2 hrs, the reaction mixture was diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CH₂Cl₂/Et0H gave 238 mg (86% yield) of /erf-butyl 2-({2- (difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-lH-benzimidazol-4-yl }amino)- 2-oxoethylcarbamate: mp 238 ⁰C; ¹H NMR (DMSO-^₆) δ 9.79 (s, IH), 8.10 (d, J = 7.7 Hz, IH), 8.01 (dd, J = 8.3, 0.7 Hz, IH), 7.74 (t, J_HF - 52.7 Hz, IH), 7.44 (t, J = 8.2 Hz, IH), 7.33(t, J = 4.8 Hz, IH), 3.87 (d, J = 6.1 Hz, 2H), 3.82-3.80 (m, 8H), 3.69 (m, 8H), 1.42 (s, 9H); Anal. Calcd. for C₂₆H₃₃F₂N₉O₅: C, 53.0; H, 5.6; N, 21.4; Found: C, 52.7; H, 5.8; N, 21.1%.

[00205] A mixture of the above carbamate (205 mg, 0.35 mmol) and TFA (6 mL) in

CH₂Cl₂ (10 mL) was stirred at room temperature for 16 hrs before being evaporated to dryness. The residue was triturated with MeOH/EtOAc and the resulting precipitate was collected, washed with EtOAc, and dried to give 195 mg (92% yield) of 2-amino-jV-{2- (difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4- yl }acetamide trifluoroacetate: mp 218-221 °C; ¹H NMR(DMSO-^₆) δ 10.65 (s, exchangeable with D₂O, IH), 8.01 (br s, exchangeable with D₂O, 2H), 8.13 (d, J = 8.07 Hz, IH), 8.07 (d, J = 8.28 Hz, IH), 8.07 (d, J = 8.3 Hz, IH), 7.76 (t, J_Hv = 52.6 Hz, IH), 7.49 (t, J = 8.2 Hz, IH), 3.99 (s, 2H),3.83-3.81 (m, 8H), 3.70 (m, 8H); Anal. Calcd. for C₂₃H₂₆F₅N₉O₅-H₂O, C, 44.6, H, 4.5, N, 20.3; Found: C, 44.8; H, 4.5, N, 20.3%.

Example 15

Synthesis of N- { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yl}-2-(dimethylamino)acetamide

[00206] The compound was synthesized according to Method C.

[00207] To a suspension of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-

2-yl]-lH-benzimidazol-4-ylamine (158 mg, 0.37 mmol) and K₂CO₃ (200 mg, 2.9 mmol) in CH₂Cl₂ (10 mL) was added chloroacetyl chloride (1 mL). The reaction mixture was stirred for 4 hrs. The mixture was diluted with water, extracted with CH₂Cl₂, and dried (Na₂SO/)). The solvent was removed and the residue was recrystallized from CH₂Cl₂/hexanes to give 188 mg (100% yield) of 2-chloro-N-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5- triazin-2-yl]-lH-benzimidazol-4-yl}acetamide: mp 287-289°C, ¹H NMR (DMSO-^₆) δ 10.39 (s, exchangeable with D₂O, I H), 8.12 (d, J = 7.9 Hz, IH), 8.06 (dd, J = 8.3, 0.7 Hz, IH), 7.75 (t; 7_HF = 52.6 Hz, IH), 7.46 (t, J = 8.2 Hz, IH) 4.53 (s, 2H), 3.83-3.80 (m, 8H), 3.70 (m, 8H); Anal. Calcd. for C₂IH₂₃CIF₂N₈O₃: C, 49.6; H, 4.6; N, 22.0; Found: C, 49.5; H, 4.6; N, 21.9%.

[00208] A mixture of the above chloroacetamide (206 mg, 0.40 mmol)) and 40% aq. dimethylamine (2 mL) in ethanol (10 mL) was refluxed for 2 hrs. The solvent was removed and the residue was recrystallized from CH₂Cl₂ZEtOH to give 171 mg (83% yield) of N- {2- (difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 //-benzimidazol-4-yl } -2- (dimethylamino)acetamide: mp 259-261 ⁰C; ¹H NMR (DMSO- ₆) δ 9.96 (s, exchangeable with D₂O, IH), 8.25 (d, J = 8.0 Hz, IH), 8.01 (dd, J = 8.4, 0.7 Hz, IH), 7.74 (t, /_HF = 52.7 Hz, IH), 7.45 (t, J = 8.2 Hz, IH), 3.82-3.80 (m, 8H), 3.70 (m, 8H), 3.19 (s, 2H), 2.37 (s, 6H); Anal. Calcd. for C₂₃H₂₉F₂N₉O₃: C, 53.3; H, 5.7; N, 24.4; Found: C, 53.5; H, 5.6; N, 24.5%.

Example 16

Synthesis of 3-amino-Λ'-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3_>5-tπazin-2-yl]-l//- benzimidazol-4-yl } propanamide

[00209] The compound was synthesized according to Method A.

[00210] Following the procedure of Example 14, reaction of 2-(difluoromethyl)-l-[4,6- di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-ylamine and N-(/m- butoxycarbonyl)-β-alanine gave tert-bniyl 3-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)- l,3,5-triazin-2-yl]-l//-benzimidaz^'ol-4-yl}amino)-3-oxopropylcarbamate in 85% yield: mp (CH₂Cl₂/Et0H) 217-219 ⁰C; ¹H ΝMR (DMSO-40 δ 9.96 (s, exchangeable with D₂O, IH), 8.10 (d, J = 7.7 Hz, IH), 8.01 (dd, J = 8.3, 0.7 Hz, IH), 7.74 (t, J_Hp = 52.65, IH), 7.41 (t, J = 8.2 Hz, I H), 6.79 (br s, exchangeable with D₂O, IH), 3.83-3.80 (m, 8H), 3,69 (m, 8H), 3,28- 3.23 (m, 2H), 2.68 (t, J = 7.0 Hz, 2H), 1.38 (s,-9H); Anal. Calcd. for C₂₇H₃₅F₂N₉O₅: C, 53.7; H, 5.8; N, 20.9; Found: C, 53.7; H, 5.9; N, 21.1 %. [0021 1] Following the procedure of Example 14, deprotection of the above carbamate with TFA in CH₂Cl₂ gave 3-amino-/V-(2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3₁5- triazin-2-yl]- l//-benzimidazol-4-yl}propanamide trifluoroacetate in 86 % yield: mp (MeOH/EtOAc) 237-240 ⁰C; ¹H NMR (DMSO-ύk) δ 10.31 (s, exchangeable with D₂O, I H), 8.09 (d, J = 7.8 Hz, IH), 8.04 (d, J = 8.2 Hz, IH), 7.75 (t, J = 52.6 Hz, 1H),7.69 (br s, exchangeable with D₂O, 2H), 7.45 (t, J = 8.2 Hz, IH), 3.83-3.80 (m, 8H), 3.69 (m, 8H), 3.13 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.2 Hz, 2H); Anal. Calcd. for C₂₄H₂₈F₅N₉O₅: C, 46.7; H₁ 4.6; N, 20.4; Found: C, 46.7; H, 4.6; N, 20.7%.

Example 17

Synthesis of N- { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl } -3-(dimethyIamino)propanamide

[00212] The compound was synthesized according to Method C.

[00213] To a mixture of 2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2- yl]-l//-benzimidazol-4-ylamine (198 mg, 0.45 mmol) and DBPEA (1 mL) in CH₂Cl₂ (10 mL) at 0 ⁰C was added acryloyl chloride (1 mL). The reaction mixture was allowed to warm to 20 ⁰C and then stirred for additional 2 hrs. The mixture was diluted with water, extracted with CH₂CI₂, and dried (Na₂SO₄). The solvents were removed and the residue was recrystallized from CH₂Cl₂ZEtOH to give(168 mg (76% yield) of N-{2-(difluoromethyl)-l-[4,6-di(4- moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazol-4-yl}acrylamide: mp 246-249 ⁰C; ¹H ΝMR (DMSO-J₆) δ 10.27 (s, exchangeable with D₂O, IH), 8.19 (d, J = 8.2 Hz, IH), 8.04 (dd, J = 8.3, 0.6 Hz, IH), 7.75 (t, 7_HF = 52.6 Hz, IH), 7.45 (t, J = 8.2 Hz, IH), 6.90 (dd, J = 17.0, 10.2 Hz, IH), 6.31 (dd, J = 17.0, 2.0 Hz, IH), 5.78 (dd, 7 = 10.2, 2.0 Hz, IH), 3.82-3.81 (m, 8H), 3.70 (m, 8H). [00214] Reaction of the above acrylamide with 40% aq. dimethylamine in EtOH (5 mL) gave N-{2-(difluoromethyl)- l -[4,6-di(4-morpholinyl)- 1,3, 5-triazin-2-yl]-l H- benzimidazol-4-yl}-3-(dimethyIamino)propanamide in 35% yield after chromatography on neutral alumina eluting with CH₂Cl₂ /EtOAc (4: 1): mp (CH₂Cl₂ /MeOH) 228-230 ⁰C; ¹H NMR (DMSO-J₆) δ 1 1.38 (s, exchangeable with D₂O, IH), 8.16 (d, J = 7.9 Hz, IH), 7.98 (dd, J = 8.3, 0.6 Hz, IH), 7.74 (t, J_H? = 52.8 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 3.82-3.80 (m, 8H), 3.69 (m, 8H), 2.65-2.52 (m, 4H), 2.30 (s, 6H); Anal. Calcd. for C₂₄H_3IF₂N₉O₃: C, 54.2; H, 5.9; N, 23.7; Found: C, 54.3; H, 5.8; N, 24.0%.

Example 18

Synthesis of 2-(difluoromethyl)-iV-[2-(dimethylamino)ethyl]-l-[4,6-di(4-moφholinyl)- 1,3,5- triazin-2-yl]-l//-benzimidazole-4-carboxamide

[00215] The compound was synthesized according to Method C.

[00216] A mixture of 3.42 g (18.13 mmol) of 2,3-diaminobenzoic acid and 6.96 g (4.6 mL, 72.5 mmol) of difluoroacetic acid in 4 M HCl (20 mL) was refluxed for 16 hrs, before being diluted with water and cooled. The reaction mixture was basified with aq. NH₃, and the resulting clear solution was filtered and neutralized with aq. HOAc. The resulting precipitate was collected by filtration, washed with water, and dried to give 3.7 g (96% yield) of 2-(difluoromethyl)-l//-benzimidazole-4-carboxylic acid: mp (aq. MeOH) 280-282 ⁰C; ¹H NMR (DMSO-J₆) δ 13.39-13.10 (br, exchangeable with D₂O, 2H), 8.01 (d, J = 8.0 Hz, IH), 7.93 (dd, J = 7.6, 0.7 Hz, IH), 7.40 (t, J = 7.7 Hz, IH), 7.25 (d, J_Hr = 53.3 Hz, IH); Anal. CaIc. for C₉H₆F₂N₂O₂: C, 51.0; H; 2.9; F, 17.9; N, 13.2; Found: C, 50.9; H, 3.0, F, 18.2; N, 13.3%. [00217] The above acid (570 mg, 2.7 mmol) was refluxed in SOCl₂ (6 mL) with a catalytic amount of DMF for 1 hr. Excess thionyl chloride was removed under vacuum and the resulting residue was dissolved in dioxane (10 mL) and cooled in an ice bath. N,N- Dimethylaniline (0.8 mL, 5.0 mmol) and benzyl alcohol (0.6 mL, 5.4 mmol) were added. After being stirred at 20⁰C for 2 hrs, the mixture was then heated under reflux for 16 hrs. After removal of the solvent, the residue was dissolved in CH₂Cl₂ and washed with aq. NH₃. The organic layer was separated, dried (Na₂SO₄), and the solvent was removed. Chromatography of the residue on silica eluting with CH₂Cl₂ gave 1.3 g of a mixture of benzyl alcohol and benzyl 2-(difluoromethyl)-lH-benzimidazole-4-carboxylate: ¹H NMR (DMSO-40 δ 10.76 (br, exchangeable with D₂O, 1 H), 8.06 (d, J = 7.7 Hz, 1 H), 8.04 (d, J = 8.1 Hz, IH), 7.50-7.25 (m, 6H), 6.89 (t, J_HV = 53.5 Hz, IH), 5.46 (s, 2H).

[00218] A mixture of the above crude ester (1.22 g), 2,4-dichloro-6-(4-morphoIinyl)-

1,3,5-triazine (698 mg, 2.96 mmol), and powdered dry K₂CO₃ (1.13 g, 8.18 mmol) in THF (20 mL) was stirred at 20 ⁰C for 16 hrs. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, and dried. Chromatography on silica eluting with CH₂Cl₂/Et0Ac (95:5) gave benzyl l-[4-chloro-6-(4- morpholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-l//-benzimidazole-4-carboxylate (107 mg, 7%): mp (CH₂Cl₂/Et0Ac) 207-207 ⁰C; ¹H NMR (CDCl₃) δ 8.69 (dd, J = 8.4, 1.1 Hz, IH), 8.11 (dd, J = 7.7, 1.1 Hz, IH), 7.65-7.62 (m, 2H), 7.57-7.52 (m, IH), 7.42-7.38 (m. 2H), 7.35-7.31 (m, 1), 5.52 (s, 2H), 4.00-3.95 (m, 4H), 3.85-3.80 (m, 4H); HRMS (ED Calcd. for C₂₃Hi₉ ³⁵Cl F₂N₆O₃ [MH⁺]: m/z 500.1178; Found: 500.1185. Calcd. for C₂₃Hi₉ ³⁷Cl F₂N₆O₃ [MH⁺]: m/z 502.1146; Found: 502.1153; Anal. Calcd. for C₂₃Hi₉ClF₂N₆O₃: C, 55.2; H, 3.8; Cl, 7.1; F, 7.6; N, 16.8; Found: C, 55.4; H, 3.7; Cl, 7.4; F, 7.3; N, 16.6%.

[00219] Morpholine (0.5 mL) was added to a suspension of the above compound (314 mg, 0.63 mmol) in THF (30 mL). The mixture was stirred at 20 ⁰C for 16 hrs. After dilution with water, the resulting precipitate was collected by filtration, washed with water, and dried. Chromatography on silica eluting with CH₂Cl₂/EtOAc (95:5) gave 280 mg (81% yield) of benzyl l-{ [4,6-di(4-moφholinyl)-l ,3,5-triazin-2-yl]methyl }-2-methyl-lH-benzimidazole-4- carboxylate: mp (CH₂Cl₂/ hexanes) 220-222 ⁰C; ¹H NMR (CDCl₃) δ 8.56 (dd, J = 8.4, 1.0 Hz, IH), 8.07 (dd. J = 7.6, 1.0 Hz, IH), 7.65 (d, J = 7.5 Hz, 2H), 7.52-7.30 (m, 5H), 3.89-3.87 (m, 8H), 3.80-3.70 (m, 8H); Anal. Calcd. for C₂₇H₂₇F₂N₇O₄: C, 58.8; H.4.9; F. 6.9; N, 17.8; Found: C, 59.1 ; H, 4.8; F, 7.0; N, 18.0%. [00220] The above ester (250 mg, 0.45 mmol) was hydrogenated in THF with 5% Pd on C at 60 mm Hg for 2 hrs. The reaction mixture was filtered to remove Pd/C residues and the filtrate was evaporated to dryness, and the resulting residue was recrystallized from MeOH to give 196 mg (93% yield) of 2-(difluoromethyl)-l-[4,6-di(4-morphoIinyl)-l,2- dihydro-l,3,5-triazin-2-yl]-lH-benzimidazole-4-carboxylic acid; ¹H NMR (DMSO-^₅) S 12,75 (br, exchangeable with D₂O, IH), 7.93 (dd, J = 7.6, 0.8 Hz, IH), 7.23 (dd, J = 8.1, 1.0 Hz, IH), 7.10 (br s, exchangeable with D₂O, 1 H), 6.64 (t, J = 7.9 Hz, 1 H), 6.38 (t, 7_HF = 55.8 Hz, IH), 6.26. (dd, J = 17.8, 2,7 Hz, IH), 3.71 (br, 8H), 3.65 (br, 8H); Anal. Calcd. for C₂₀H₂₁F₂N₇O₄: C, 51.8; H, 5.0; F, 8.2; N, 21.2; Found: C, 51.9; H, 5.0; F. 8.5; N, 21.0%.

[00221] The above dihydro compound (156 mg, 0.34 mmol) was dissolved in hot THF

(30 mL) and MnO₂ (58 mg 0.64 mmol) was then added. The mixture was heated under reflux for 16 hrs and further MnO₂ (58 mg, 0.68 mmol) was added. After heating for another 5 hrs, the reaction mixture was filtered through celite to remove MnO₂ residues. The filtrate was evaporated to dryness and the residue was recrystallized from THF/EtOH to give 83 mg (53% yield) of 2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-lW- benzimidazole-4-carboxylic acid: ¹H NMR (DMSO-cfø) δ 13.00 (br, exchangeable with D₂O, IH), 8.55 (br d, J = 9.3 Hz, IH), 7.91 (br d, J = 7.6 Hz, IH), 7.74 (t, J_w = 52.5 Hz, IH), 7.58 (t, J = 7.9 Hz, IH), 3.83-3.80 (m, 8H), 3.70 (m, 8H).

[00222] The above carboxylic acid (80 mg, 0.17 mmol) was dissolved in DMF (2 mL),

CDI (42 mg, 2.6 mmol) was added and the mixture was heated at 50 °C for 2 hrs. After cooling to 20 °C /V.N-dimethylethylenediamine (excess) was added and the mixture stirred at this temperature for 2 hrs before being poured into water and extracted with EtOAc. After drying (Na₂SO₄) and removal of the solvent, the resulting residue was chomatographed on silica eluting with CH₂Cl₂MeOH (94:6) to give 80 mg (87% yield) of 2-(difluoromethyl)-N- [2-(dimethylamino)ethyl]-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//-benzimidazole-4- carboxamide: ¹H NMR (CDCl₃) δ 9.74 (t, J = 4.9 Hz, exchangeable with D₂O, IH), 8.45 (dd, 7 = 8.4, 1.0 Hz, 1 H), 8.27 (dd, 7 = 7.6, 1.0 Hz, IH), 7.54 (t, J_HF = 53.3 Hz, IH), 7.53 (t, J = 8.0 Hz, IH), 3.88 (br t, J = 4.7 Hz, 8H), 3.80 (br t, J = 4.5 Hz, 8H), 3.79-3.72 (m, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.39 (s, 6H); HRMS (FAB⁺) Calcd. for C₂₄H₃₂F₂N₉O₃ [MH⁺]: m/z 532.2596; Found: 532.2602. Example 19

Synthesis of 3-( { 2-(difl uoromethyl)- 1 -[4,6-di(4-moφholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl}oxy)-l-propanol

[00223] The compound was synthesized according to Method A.

[00224] A mixture of 1.08 g (2.5 mmol) of 2-(difluoromethyl)- 1 -[4,6-di(4- tnoφholinyl)-2-pyrimidinylJ- l//-benzimidazol-4-ol (WO 2006/095906), 0.98 g (7.5 mmol) of 3-bromopropanol, and 1.73 g (12.5 mmol) of powdered K₂CO₃ in 30 mL dry DMF was stirred at room temperature overnight. The mixture was diluted with water (200 mL), and the solid precipitate was collected and dried. Chromatography on silica eluting with CH₂Cl₂/Et0Ac (1 : 1) gave 1.11 g (91 % yield) of 3-({ 2-(difluoromethyl)-l -[4,6-di(4- moφholinyl)-2-pyrimidinyl]-l//-benzirnidazol-4-yl}oxy)-l-propanol: mp (CH₂Cl₂ZMeOH) 200-210 ⁰C; ¹H NMR (CDCl₃) δ 7.82 (dd, J = 8.4, 0.8 Hz, IH), 7.44 (t, 7_HF = 53.6 Hz, IH), 7.30 (t, J = 8.2 Hz, IH), 6.89 (dd, J = 8.0, 0.8 Hz, IH), 5.51 (s, IH), 4.49 (t, J = 5.9 Hz, 2H)₁ 3.97 (m, 2H), 3.82 (m, 8H), 3.62 (m, 8H), 3.40 (m, exchangeable with D₂O, IH), 2.13 (m, 2H); Anal. Calcd. for C₂₃H₂₈F₂N₅O₄: C, 56.3; H; 5.75; N, 17.1; Found: C, 56.1; H, 5.9, N, 17.0%.

Example 20

Synthesis of 3-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-2-pyrimidinyl]-l//- benzimidazol-4-yl}oxy)-/V,N-dimethyl-l-propanamine

[00225] The compound was synthesized according to Method C.

[00226] A stirred mixture of 0.49 g (1 mmol) of 3-({2-(difluoromethyl)-l-[4,6-di(4- moφholinyl)-2-pyrimidinyl]-lH-benzimidazol-4-yl}oxy)-l-propanol (Example 19) and 0.3 g (3 mmol) Et₃N in 50 mL THF was cooled to 0 °C and 0.29 g (2.5 mmol) methanesulfonyl chloride was added. The mixture was stirred at 0 ⁰C for 1 hr and 10 mL of a 40% aqueous solution of dimethylamine was added. The resulting mixture was stirred at room temperature for 2 days before being concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with CH₂CI₂. Chromatography on alumina eluting with CHaC^/EtOAc (1 : 1), followed by acidification with 1.25 M HCl in MeOH, and recrystallization from EtOH/EtOAc gave 0.382 g (69% yield) of 3-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)- 2-pyrimidinyl]- l//-benzimidazol-4-yl }oxy)-/V,N-dimethyl-l-propanarnine hydrochloride: mp 250-252 ⁰C; ¹H ΝMR (DMSO-ώfc) δ 10.41 (m, exchangeable with D₂O, IH), 7.81 (d, J = 8.3 Hz, IH), 7.65 (t, J_HF = 53.0 Hz, IH), 7.37 (t, J = 8.2 Hz, IH), 6.94 (d, J = 8.0 Hz, IH), 5.98 (s, IH), 4.34 (t, J = 6.1 Hz, 2H), 3.71 (m, 8H); 3.62 (m, 8H), 3.28 (m, 2H), 2.80 (s, 6H), 2.25 (m, 2H); Anal. Calcd. for C₂₅H₃₄F₂N₇O₃-HCl-O-S^O: C, 53.3; H; 6.3; N, 17.4; Cl, 6.3; Found: C, 53.3; H, 6.2, N, 17.3; CI, 6.3%.

Example 21 Biological Activity

A. Inhibition of isolated enzyme

[00227] Compounds were evaluated for their ability to inhibit Class I PI 3-kinase enzymes pi 10δ/p85, pi 10α/p85, and pi iθβ/p85. Reaction mixtures comprising 0.1 μg of a recombinant enzyme, 10 μg of L-α-phosphatidylinositol, and 2X Lipid Kinase Buffer (40 mM Tris-HCl, pH 7.4, 200 mM NaCl, 1 mM EDTA), which contains either DMSO only as a control or the test compound in DMSO (the final DMSO concentration is 1 %), were activated by the addition of an ATP mix (5 mM MgCl₂, 100 μM ATP, and 0.1 μL [γ³³P]ATP). Reactions were incubated at room temperature for 1 hr, and then stopped by the addition of IM HCl. The lipids were then extracted using a two step procedure. Firstly, 200 μL of chloroform/methanol (1: 1) was added, the biphasic reactions mixed and centrifuged briefly, and the inorganic phase was removed and discarded. Following this, 80 μL of methanol:HCI (1 :1) was added and the same procedure followed. The organic phase (70 μL) was then transferred to a clean 1.6 mL tube and the reactions were dried using a Speedvac, with no heating, for 30 min. The reactions were spotted onto TLC plates (Merck Ltd) and developed for 1 hr in propanol-1 :2 M acetic acid (13:7). The TLC plates were then dried at room temperature and quantified using a phosphorimager (Stormlmager, Amersham). Nine compound concentrations were used for each test compound to determine its IC₅₀ value. Each experiment was performed twice and the average IC₅₀ value is used herein. The results are summarized in Table 1.

B. Cellular growth inhibition.

[00228] The compounds were evaluated against two early passage human cell lines

NZB5 and NZOV9 (Marshall et al., Oncol. Res. 2004, 14, 297). The cells were grown in ITS medium (α-modified minimal essential medium supplemented insulin, transferrin, selenite, and 5% fetal bovine serum) and grown on 96-well tissue culture plates under an atmosphere of 5% O₂, 5% CO₂, and 90% N₂. Individual wells contained 500- 1 ,000 cells (depending on the growth rate) in a volume of 150 μL. Compounds were added at 10-fold concentration steps to a maximum of 20 μM and plates were incubated for five days, with ³H-thymidine being added over the last 6 hrs. Cells were harvested and incorporated radioactivity measured. Duplicate samples were analyzed for each compound dose with multiple control samples. Data were fitted by a least-squares method to an exponential of the form y = yo + ae ^bx, where y is the radioactivity (corrected for background and normalized to 100% of the control), x is the radiation dose, and yo, a, and b are variables, and the IC₅₀ value defined as the compound concentration reducing ³H-thymidine levels by 50%. The results are summarized in Table 1.

*A. < 0.1 μM; B. 0.1-1.0 μM; C > 1.0 μM

* * * * *

[00229] 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 incoiporated herein by reference.

Claims

What is claimed is:

1. A compound of Formula I:

R² is (a) hydrogen, cyano, halo, or nitro; (b) Q_₆ alkyl, C₂_₆ alkenyl, C₂.6 alkynyl, C₃.₇ cycloalkyl, Cβ-u aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^la, -C(O)OR^lb, -C(O)NR^lbR^lc, -C(NR^a)NR^lbR^lc, -OR^la, -OC(O)R^Ia, -OC(O)OR^la, -OC(O)NR ^lbR^lc, -OCC=NR^{1 a})NR^lbR^lc, -OS(O)R^la, -OS(O)₂R¹⁸, -OS(O)NR^lbR^lc, -OS(O)₂NR^lbR^ic, -NR^lbR^lc, -NR^laC(O)R^Id, -NR^laC(0)0R^ld, ~NR^laC(0)NR^lbR^lc, -NR^laC(=NR^ld)NR^lbR^lc, -NR^laS(O)R^ld, -NR^laS(O)₂R^ld, -NR¹³S(O)NR¹V⁰, -NR^laS(O)₂NR^lbR^IC, -SR^la, -S(O)R^la, -S(O)₂R¹³, -S(0)NR^lbR^lc, or -S(O)₂NR^lbR^)c;

R³ and R⁴ are each independently hydrogen or Q-β alkyl;

R⁵ is (a) Cι-₆ alkyl, C₂_₆ alkenyl, C₂-₆ alkynyl, C₃.7 cycloalkyl, C₆_i4 aryl, C₇-1₅ aralkyl, heteroaryl, or heterocyclyl; or (b) -0R^la or -NR^{l b}R^Ic;

R⁶ is hydrogen or C].(, alkyl;

E is a bond, -C(OK -C(O)O-, -C(O)NR¹³-, -O-, -OC(O)O-,

-OC(O)NR¹³-, -NR^Ia-, -NR¹³C(O)NR¹"-, -NR¹³S(O)-, -NR^laS(O)₂- -NR^laS(O)NR^ld-, -NR¹³S(O)₂NR¹"-, -S-, -S(O)- or -S(O)₂-;

Q is Ci-₆ alkyl, C₂-₆ alkenyl, C₂_₆ alkynyl, C₃.₇ cycloalkyl, C₆._]4 aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl, with the proviso that Q is substituted with one or more O- or N-containing substituent;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ is hydrogen or Q.₆ alkyl; and each R^la, R^lb, R^lc, and R^ld is independently (i) hydrogen; (ii) C|.₆ alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, C₃.₇ cycloalkyl, C₆-i4 aryl, C₇.|₅ aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q¹ ; or (iii) R^lb and R^lc 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 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C^ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C_{3 7} cycloalkyl, C₆-_M 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(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R³, -OC(O)OR³, -OC(O)NR^bR^c, -0C(=NR^a)NR^bR^c, -OS(O)R³, -OS(O)₂R³, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d, -NR^aS(O)₂R^d, -NR^aS(0)NR^bR^c, -NR^aS(0)₂NR^bR^c, -SR³, -S(O)R^a, -S(O)₂R³, -S(O)NR^bR^c, and -S(O)₂NRV, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C_1-6 ' alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C₃.₇ cycloalkyl, C₆-_H aryl, C₇.₁₅ aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, subslituents Q¹ ; or (iii) R^b and R^c 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 Q ; wherein each Q¹ is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) d-₆ alkyl, C₂.₆ alkenyl, C_2-6 alkynyl, C₃-₇ cycloalkyl, C₆-_H aryl, C_7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R⁶, -C(O)OR⁶, -C(0)NR^fR^g, -C(NR^e)NR^fR^g, -0R^e, -OC(O)R⁶, -OC(O)OR⁶, -OC(O)NR^fR^ε, -OC(=NR^e)NR^fR^g, -OS(O)R⁶, -OS(O)₂R⁶, -OS(O)NR^fR^g, -OS(O)₂NR^fR^£, -NR^fR^ε, -NR^eC(O)R^h, -NR⁶C(O)OR^h, -NR⁶C(O)NR¹R⁶, -NR^eC(=NR^h)NR^fR^ε, -NR⁶S(0)R^h, -NR⁶S(O)₂R¹¹, -NR⁶S(O)NR¹R⁸, -NR⁶S(O)₂NR^fR^E, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -S(O)NR¹R⁸, and -S(O)₂NR^fR^ε; wherein each R^e, R^f, R⁶, and R^h is independently (i) hydrogen; (ii) C_1-6 alkyl, C₂_₆ alkenyl, C₂.₆ alkynyl, C₃.₇ cycloalkyl, C₆-i4 aryl, C_7-I5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^ε together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1 , wherein R² is hydrogen or d.₆ alkyl, optionally substituted with one or more substituents Q¹.

3. The compound of claim 1, wherein R² is hydrogen.

4. The compound of any of claims 1 to 3, wherein R³ is hydrogen or Cι_₆ alkyl, optionally substituted with one or more substituents Q¹.

5. The compound of claim 4, wherein R³ is hydrogen or methyl.

6. The compound of any of claims 1 to 5, wherein R⁴ is hydrogen or C^ alkyl, optionally substituted with one or more substituents Q¹.

7. The compound of claim 6, wherein R⁴ is hydrogen or methyl.

8. The compound of any of claims 1 to 7, wherein R⁵ is C3-7 cycloalkyl, Cβ-u aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹.

9. The compound of claim 8, wherein R⁵ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, imidazolyl, or pyridyl.

10. The compound of claim 8, wherein R⁵ is morpholin-1-yl.

11. The compound of any of claims 1 to 7, wherein R⁵ is -OR^la or -NR^lbR^lc.

12. The compound of claim 1 1 , wherein R^la, R^lb, and R^lc are each independently C₃-₇ cycloalkyl, C₆-₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q¹.

13. The compound of any of claims 1 to 12, wherein R is hydrogen or Ci-^ alkyl, optionally substituted with one to three halo.

14. The compound of claim 13, wherein R⁶ is hydrogen, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

15. The compound of claim 13, wherein R⁶ is hydrogen or difluoromethyl.

16. The compound of any of claims 1 to 15, wherein E is a bond, -C(O)NH-, -O- -OC(O)NH- -NH-, -NHC(O)NH-, Or -NHS(O)₂-.

17. The compound of any of claims 1 to 16, wherein Q is C|.₆ alkyl, C₂-₆ alkenyl, or C₂-₆ alkynyl, each optionally substituted with one, two, or three substituents, each independently selected from (i) cyano; (ii) heterocyclyl, optionally substituted with one or more substituents Q¹ ; and (iii) -C(O)OR^a, -C(O)NR^bR^c, -OR\ -OC(O)R³, -OC(O)NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(0)0R^d, -NR^aS(O)₂R^d, -S(O)R^a, -S(O)₂R², and -S(O)₂NR^bR^c.

18. The compound of claim 17, wherein Q is aminomethyl, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, aminopropyl, dimethylaminopropyl, hydroxyethyl, hydroxypropyl, (morphlinyl)ethyl, (morphlinyl)propyl, carboxymethyl, dihydroxypropyl, dimethylamino-hydroxy-propyl, or hydroxy-(moφhlinyl)-propyl.

19. The compound of claim 17, wherein Q is aminomethyl, dimethylaminomethyl, 2-aminoethyl, dimethylaminoethyl, 3-aminopropyl, 3-dimethylaminopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-(morphlin-l-yl)-ethyl, 3-(morphlin-l-yl)-propyl, carboxymethyl, 2,3- dihydroxypropyl, 3-dimethylamino-2-hydroxy-propyl, or 2-hydroxy-3-(morphlin-l-yl)- propyl.

20. The compound of any of claims 1 to 19, wherein X is CH.

21. The compound of any of claims 1 to 19, wherein Y is CH.

22. The compound of any of claims 1 to 19, wherein Z is CH.

23. The compound of any of claims 1 to 19, wherein X, Y, and Z are N.

24. The compound of claim 1 selected from the group consisting of:

2-({ 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 H- benzimidazol-4-yl } oxy)ethanol ;

3-({ 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yl } oxy)- 1 -propanol ;

3-({2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy )- 1 ,2-propanediol ;

2-({2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } oxy)ethanamine;

2-( { 2-(difluoromethyl)- 1 -[4,6-di(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yI}oxy)-N,N-dimethylethanamine;

2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-4-[2-(4- morpholinyl)ethoxyj- 1 //-benzimidazole;

3-({2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)-l-propanamine;

3-({2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yI }oxy)-Λ',Λ'-dimethyl-l-propanamine;

¹ 2-(difluoromethyI)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-4-[2-(4- moφholinyl)propoxy]-l/7-benzimidazole;

1 -( { 2-(difluoromethyl)- 1 -[4,6-di(4-moφholinyl)- 1 ,3,5-triazin-2-yl]- \H- benzimidazol-4-yl}oxy)-3-(dimethylamino)-2-propanol; l-({2-difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)-3-(4-morpholinyl)-2-propanol;

({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl}oxy)acetic acid; yV¹-{2-(difluoromethyl)-l -[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l«- benzimidazol-4-yl }-/V ,N -dimethyl- 1,2-ethanediamine;

2-amino-Λ/-{2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- l//-benzimidazol-4-yl }acetamide; yV-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazoI-4-yl } -2-(dimethylamino)acetamide;

3-amino-N-{2-(difluoromethyl)-l-[4,6-di(4-morpholinyl)-l,3,5-triazin-2-yl]- 1 //-benzimidazoI-4-yl } propaπamide;

N-{2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-l,3,5-triazin-2-yl]-l//- benzimidazol-4-yl } -3-(dimethylamino)propanamide;

2-(difluoromethyl)-iV-[2-(dimethylamino)ethyl]-l-[4,6-di(4-moφholinyl)- l,3,5-triazin-2-yI]-l/f-benzimidazole-4-carboxamide;

3-( { 2'(difluoromethyl)- 1 -[4,6-di(4-moφholinyl)- 1 ,3 ,5-triazin-2-yl] - 1 H- benzimidazol-4-yl } oxy)- 1 -propanol ; and

3-({2-(difluoromethyl)-l-[4,6-di(4-moφholinyl)-2-pyrimidinyl]-lH- benzimidazol-4-yl } oxy)-N,Λ'-dimethyl- 1 -propanatnine; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

25. A pharmaceutical composition comprising a compound of any of claims 1 to 24, 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.

26. The pharmaceutical composition of claim 25, further comprising a second therapeutic agent.

27. The pharmaceutical composition of claim 25 or 26, wherein the composition is formulated for single dose administration.

28. The pharmaceutical composition of any of claims 25 to 27, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

29. The pharmaceutical composition of claim 28, wherein the oral dosage form is a tablet or capsule.

30. 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 a therapeutically effective amount of the compound of any of claims 1 to 24 or a pharmaceutical composition of any of claims 25 to 29.

31. A method for cancer treatment, which comprises administering to a subject a therapeutically effective amount of the compound of any of claims 1 to 24 or a pharmaceutical composition of any of claims 25 to 29.

32. The method of claim 30 or 31, wherein the compound or the composition is administered in combination with a second therapeutic agent.

33. A method for modulating PI3K enzymatic activity, comprising contacting a PI3K enzyme with the compound of any of claims 1 to 24 or a pharmaceutical composition of any of claims 25 to 29.