Extended and delayed release compositions of substituted benzimidazoles

Abstract

Provided herein are substituted benzimidazole compounds that may be useful for inhibition of bromodomains, pharmaceutical compositions comprising said compounds, extended and delayed release compositions, and methods of treating diseases and conditions with said compositions.

Description

EXTENDED AND DELAYED RELEASE COMPOSITIONS OF SUBSTITUTED BENZIMIDAZOLESCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 505,813, filed June 2, 2023, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Bromodomains are found in a variety of mammalian DNA-binding proteins. The bromodomain, which is the conserved structural module in chromatin-associated proteins and histone acetyltransferases, is known to recognize acetyl-lysine residues on proteins. Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions, including cancer. There is therefore a need for compounds and compositions comprising said compounds that could inhibit bromodomains.SUMMARY OF THE INVENTION

[0003] Provided herein are compounds comprising substituted benzimidazoles. In some instances, the substituted benzimidazole compounds provided herein are bromodomain inhibitors, useful for the treatment of various diseases or conditions. In some instances, provided herein are methods of treating disease and conditions, including cancer comprising administering to an individual a pharmaceutical composition provided herein.

[0004] The pharmaceutical compositions provided herein may comprise delayed and / or extended- release components that allow for extended therapeutic effectiveness of the pharmaceutical compositions provided herein. In certain conditions, longer duration (e.g., continuous) exposure (e.g., above a therapeutic threshold) to a bromodomain inhibitor, such as those described herein, may be beneficial. In some embodiments, provided herein are methods of treating any disease or disorder, such as provided herein, by administering a composition (e.g., delayed release, extended release, or the like formulation described herein). In specific embodiments, the disease or disorder is cancer, such as prostate cancer or NUT carcinoma. In some instances, extended exposure (e.g., above a particular threshold) of the bromodomain inhibitors (e.g., a compound of Formula (I)) to individuals with such conditions provide improved outcomes, such as by limiting breaks in therapeutic exposure. In some instances, this is beneficial in conditions such as NUT carcinoma, which exhibit rapid growth.

[0005] In some embodiments, provided herein is a pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after at least 1 hour.

[0006] In some embodiments, provided herein is a pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 10 ng / mL after at least 4 hours.

[0007] In some embodiments, provided herein is a pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 3 hours.

[0008] In some embodiments, the pharmaceutical composition comprises the extended-release component.

[0009] In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 1 hour. In someembodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 2 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 6 hours.

[0010] In some embodiments, when the pharmaceutical composition is administered to an individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 10 ng / mL after (e.g., for) at least 4 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 5 ng / mL after (e.g., for) at least 6 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 1 ng / mL after (e.g., for) at least 8 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 50 ng / mL after (e.g., for) at least 8 hours.

[0011] In some embodiments, the extended release component is an extended release matrix.

[0012] In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 3 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 6 hours. In some embodiments, when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 8 hours.

[0013] In some embodiments, a physiological (e.g., serum or plasma) half life of the compound of Formula (I) is at least 3 hours. In some embodiments, a physiological (e.g., serum or plasma) half life of the compound of Formula (I) is at least 6 hours.

[0014] In some embodiments, the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 10 ng / mL. In some embodiments, the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 30 ng / mL. In some embodiments, the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 100 ng / mL. In some embodiments, the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 200 ng / mL.

[0015] In some embodiments, the pharmaceutical compositions provided herein further comprise an immediate release component.

[0016] In some embodiments, the immediate release component is an immediate release coating.

[0017] In some embodiments, when the pharmaceutical composition is administered to the individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) to the individual within at most 1 hour. In some embodiments, when the pharmaceutical composition is administered to the individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) to the individual within at most 30 minutes.

[0018] Provided herein in some embodiments is pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, no more than about 70% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after 1 hour.

[0019] In some embodiments, no more than about 30% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 1 hour.

[0020] In some embodiments, no more than about 90% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 5 hours.

[0021] In some embodiments, about 20% to about 80% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 1 hour.

[0022] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein no more than about 70% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 1 hour.

[0023] In some embodiments, no more than about 30% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 1 hour. In some embodiments, from about 20% by weight to about 70% by weight of the compound is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 1 hour. In some embodiments, no more than about 90% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 2 hours followed by 1000 mL of 50 mM phosphate buffer (pH 6.8) for 3 hours.

[0024] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I) in an amount of about 10% to about 30% by weight.

[0025] In some embodiments, the pharmaceutical composition further comprises one or more of a controlled-release agent, a filler, a binder, a lubricant, and a disintegrant.

[0026] In some embodiments, the pharmaceutical composition comprises the controlled release agent in an amount of about 10% to about 30% by weight.

[0027] In some embodiments, the filler in an amount of about 30% to 70% by weight (e.g., about 30% to about 50% by weight).

[0028] In some embodiments, the pharmaceutical composition comprises the binder in an amount of about 10% to about 30% by weight.

[0029] In some embodiments, the pharmaceutical composition comprises the lubricant in an amount of about 0.5% to about 1.5% by weight.

[0030] In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the controlled-release agent in an amount of about 10% to about 30% by weight;(c) the filler in an amount of about 30% to about 50% by weight;(d) the binder in an amount of about 10% to about 30% by weight; and(e) the lubricant in an amount of about 0.5% to about 1.5% by weight.

[0031] In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the lubricant in an amount of about 0.5% to about 1.5% by weight;(c) the disintegrant in an amount of about 10% to about 30% by weight; and(d) the filler in an amount of about 50% to about 70% by weight.

[0032] In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the filler (e.g., diluent) in an amount of about 30% to about 50% by weight;(c) the binder in an amount of about 10% to about 30% by weight;(d) the lubricant in an amount of about 0.5% to about 1.5% by weight; and(e) the controlled-release agent in an amount of about 10% to about 30% by weight.

[0033] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients comprise glyceryl behenate, mannitol, silicified microcrystalline cellulose, magnesium stearate, hydroxypropyl methylcellulose, lactose, and ethylcellulose.

[0034] In some embodiments, the one or more excipients comprise glyceryl behenate, mannitol, silicified microcrystalline cellulose, and magnesium stearate. In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) glyceryl behenate in an amount of about 20% by weight;(c) mannitol in an amount of about 40% by weight;(d) silicified microcrystalline cellulose in an amount of about 19% by weight; and(e) magnesium stearate in an amount of about 1% by weight.

[0035] In some embodiments, the one or more excipients comprise magnesium stearate, hydroxypropyl methylcellulose, and lactose. In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) magnesium stearate in an amount of about 1% by weight;(c) hydroxypropyl methylcellulose in an amount of about 20% by weight; and(d) lactose (e.g., monohydrate) in an amount of about 59% by weight.

[0036] In some embodiments, the one or more excipients comprise mannitol, silicified microcrystalline cellulose, magnesium stearate, and ethylcellulose. In some embodiments, the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) mannitol in an amount of about 40% by weight;(c) silicified microcrystalline cellulose in an amount of about 19% by weight;(d) magnesium stearate in an amount of about 1% by weight; and(e) ethylcellulose in an amount of about 20% by weight.

[0037] In some embodiments, the pharmaceutical composition is administered to the individual in an amount of at least 5 mg. In some embodiments, the pharmaceutical composition is administered to the individual in an amount of at least 10 mg. In some embodiments, the pharmaceutical composition is administered to the individual in an amount of at least 50 mg. In some embodiments, the pharmaceutical composition is administered to the individual in an amount of at most 250 mg. In some embodiments, the pharmaceutical composition is administered to the individual in an amount of about 50 mg to about 250 mg.

[0038] In some embodiments, the pharmaceutical composition comprises at least 20 mg of the compound of Formula (I) or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 40 mg of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the pharmaceutical composition is administered to the individual once daily. In some embodiments, the pharmaceutical composition is administered to the individual, at least once daily.

[0040] In some embodiments, the pharmaceutical composition is in a solid dosage form. In some embodiments, the pharmaceutical composition is administered orally, rectally, or via an implant. In some embodiments, the pharmaceutical composition is administered orally.

[0041] In some embodiments, the compound of Formula (I) is released in the individual for a period of at least 2 hours. In some embodiments, the compound of Formula (I) is released in theindividual for a period of at least one day. In some embodiments, the compound of Formula (I) is released in the individual for a period of about 2 hours to about one day.

[0042] Provided herein is a method of treating a disease or condition associated with bromodomain inhibition comprising administering to an individual in need thereof any one of the pharmaceutical compositions provided herein.

[0043] In some embodiments, the disease or condition is an auto-immune disorder, an inflammatory disorder, a dermal disorder, or cancer. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is brain cancer, pancreatic cancer, breast cancer, lung cancer, or prostate cancer. In some embodiments, the cancer is a lymphoma, leukemia, or sarcoma. In some embodiments, the cancer is glioblastoma multiforme or acute myeloid leukemia. In some embodiments, the disease or condition is an auto-immune disorder. In some embodiments, the disease or condition is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, irritable bowel syndrome, or psoriasis.

[0044] In some embodiments, provided herein is a method of treating a MYC-dependent cancer in an individual in need thereof, the method comprising administering to the individual a pharmaceutical composition provided herein.

[0045] In some embodiments, provided herein is a method of treating a CCR2-associated cancer in an individual in need thereof, the method comprising administering to the individual a pharmaceutical composition provided herein.

[0046] In some embodiments, provided herein is a method of treating a HEXIM1 -associated cancer in an individual in need thereof, the method comprising administering to the individual a pharmaceutical composition provided herein.

[0047] In some embodiments, provided herein is a method of treating a CD274-associated cancer in an individual in need thereof, the method comprising administering to the individual a pharmaceutical composition provided herein.

[0048] In some embodiments, provided herein is a method of treating a MYB-associated cancer in an individual in need thereof, the method comprising administering to the individual a pharmaceutical composition provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0050] FIG. 1 shows plasma concentrations after daily administration of 5 mg or 10 mg of a compound provided herein on day 1 (ng / mL) with linear axes (FIG. 1A) and semi -logarithmic axes (FIG. IB)

[0051] FIG. 2 shows plasma concentrations after daily administration of 5 mg or 10 mg of a compound provided herein on day 1 (nM) with linear axes (FIG. 2A) and semi-logarithmic axes (FIG. 2B)

[0052] FIG. 3 shows plasma concentrations after daily administration of 10 mg of a compound provided herein on day 7 (ng / mL) with linear axes (FIG. 3A) and semi-logarithmic axes (FIG.3B)

[0053] FIG. 4 shows plasma concentrations after daily administration of 10 mg of a compound provided herein on day 7 (nM) with linear axes (FIG. 4A) and semi -logarithmic axes (FIG. 4B).

[0054] FIG. 5 shows mean plasma concentrations over 24 hours on day 1 of administration with a compound provided herein.

[0055] FIG. 6 shows mean plasma concentrations over 24 hours on day 7 of administration with a compound provided herein.

[0056] FIG. 7 shows dissolution profiles for pharmaceutical compositions described herein.

[0057] FIG. 8A shows AUC / dose ((hr*ng / mL) / mg) of a compound provided herein as a function of individual’s body weight.

[0058] FIG. 8B shows AUC / dose ((hr*ng / mL) / mg) of a compound provided herein as a function of individual’s body surface area (BSA).

[0059] FIG. 9 shows plasma concentration of a compound provided herein in an individual diagnosed with prostate cancer, after administration of 5 mg of the compound.

[0060] FIG. 10 shows plasma concentration of a compound provided herein in an individual diagnosed with prostate cancer, after administration of 10 mg of the compound.

[0061] FIG. 11A-C show plasma concentrations of a compound provided herein in individuals diagnosed with prostate cancer, after administration of 20 mg of the compound.

[0062] FIG. 12A-D show plasma concentrations of a compound provided herein in individuals diagnosed with prostate cancer, after administration of 30 mg of the compound.

[0063] FIG. 13A-B show plasma concentrations of a compound provided herein in individuals diagnosed with NUT carcinoma, after administration of 30 mg of the compound.

[0064] FIG. 14A shows CCR2 response as by dose level of a compound provided herein.

[0065] FIG. 14B shows CCR2 relative quantity to pre-dose as a function of the concentration of a compound provided herein.

[0066] FIG. 15A shows HEXIM1 response as by dose level of a compound provided herein.

[0067] FIG. 15B shows HEXIM1 relative quantity to pre-dose as a function of the concentration of a compound provided herein.

[0068] FIG. 16 shows CD274 relative quantity to pre-dose as a function of the concentration of a compound provided herein.

[0069] FIG. 17 shows MYB relative quantity to pre-dose as a function of the concentration of a compound provided herein.DETAILED DESCRIPTION OF THE INVENTIONCertain Definitions

[0070] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of' the described features.

[0071] The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating, abating, ameliorating, managing, relieving, or lessening the symptoms associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute therapeutic scenario. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, disorder, or indication.

[0072] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits the target bromodomain-containing protein (such as a BET protein, e.g., BRD2, BRD3, BRD4, and / or BRD-t) with measurable affinity.

[0073] As used herein, the term “individual”, “patient”, or “subject” refers to a mammal. Preferably the subject is a human.

[0074] As used herein, the term “therapeutically effective amount” refers to any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0075] “Amino” refers to the -NH2 radical.

[0076] “Cyano” refers to the -CN radical.

[0077] “Nitro” refers to the -NO2 radical.

[0078] “ Oxo” refers to the =0 radical.

[0079] “Hydroxyl” refers to the -OH radical.

[0080] “Alkyl” generally refers to an acyclic (e.g., straight or branched) or cyclic hydrocarbon (e.g., chain) radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated. Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl ( / .w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl ( / / -pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0081] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0082] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.

[0083] “Alkylene” or “alkylene chain” generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, / -propylene, ^-butylene, and the like. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.

[0084] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl,alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0085] “Aralkyl” or “aryl-alkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0086] “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (ie., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (z.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, - Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0087] “Carbocyclylalkyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0088] “Carbocyclylalkenyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0089] “Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula - O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0090] “Halo" or “halogen” refers to fluoro, bromo, chloro, or iodo substituents.

[0091] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trihalomethyl, dihalomethyl, halomethyl, and the like. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0092] The term “heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies - for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. - S-, -S(=O)-, or -S(=O)2-). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a Ci-Cis heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12 heteroalkyl. In some embodiments, a heteroalkyl is a Ci-Ce heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, heteroalkyl does not include alkoxy as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.

[0093] “Heteroalkylene” refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.

[0094] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl radical is saturated (z.e., containing single C-C bonds only) or unsaturated (e.g., containing one or more double bonds or triple bonds in the ring system).In some instances, the heterocyclyl radical is saturated. In some instances, the heterocyclyl radical is saturated and substituted. In some instances, the heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, - Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0095] “TV-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such TV-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0096] “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0097] “Heterocyclylalkyl” refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0098] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula - O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0099] “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl,cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 / 7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0100] ‘W-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0101] “ C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0102] “Heteroarylalkyl” refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0103] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0104] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0105] In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of a optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise stated, a substituted group provided herein (e.g., substituted alkyl) is substituted by one or more substituent, each substituent being independently selected from the group consisting of halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0106] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0107] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0108] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, 7V,7V-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0109] Provided herein are compounds that may act as bromodomain inhibitors. Bromodomain inhibitors may inhibit the binding of a bromodomain with its cognate acetylated proteins. In some embodiments, the bromodomain inhibitor is a compound which inhibits the binding of a bromodomain to acetylated lysine residues. In some embodiments, the bromodomain inhibitor is a compound which inhibits the binding o fa bromodomain to acetylated lysine residues on histones, particularly histones H3 and H4.

[0110] In some embodiments, the bromodomain inhibitor is a compound that inhibits the binding of BET family bromodomains to acetylated lysine residues (hereafter referred to as a “BET family bromodomain inhibitor”). The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4, and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.

[0111] Provided herein are substituted benzimidazole compounds. In some embodiments, provided herein are benzimidazoles substituted with (e.g., substituted) imidazoles. In some embodiments, provided herein are fused benzimidazole-imidazole compounds.

[0112] Provided herein are compounds represented by a structure of Formula (I):

[0113] Provided herein are compounds represented by a structure of Formula (II) and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0114] In some embodiments, R1is an unsubstituted Ci-Ce alkyl. In some embodiments, R1is a Ci-Ce alkyl substituted with one or more group(s) selected from halogen (such as fluorine), CN, NO2, C(O)NHRn, C(O)N(RU)2, CO2H, SO2RU, SO2NHU, and SO2N(Rn)2. In some embodiments, R1is a C2-Ce alkyl group substituted with a group selected from OR11, halogenated OCi-C6alkyl, SH, SR11, NH2, NHR11, N(Rn)2, NHC(O)Rn, and N(R11)C(O)R11. In some embodiments, R1is a group selected from C(O)Rn, C(O)NHRn, C(O)N(Rn)2, SO2Rn, SO2NHRn, and SO2N(Rn)2.

[0115] In some embodiments, R2is selected from hydrogen and a substituted or unsubstituted group selected from Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Ciocycloalkyl, C3- Cioheterocycloalkyl, C(O)R12, NH2, NHR12, N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, NHC(O)R12, SO2R12, SO2NHR12, SO2N(R12)2, NHSO2R12, N(R12)SO2R12, NHSO2NHR12, N(R12)SO2NHR12, NHSO2N(R12)2, and N(R12)SO2N(R12)2.

[0116] In some embodiments, R3and R6are each independently H or a substituted or unsubstituted group selected from Ci-C6alkyl, C(O)Rn, NH2, NHR11, N(Rn)2, C(O)NH2, C(O)NHRn, C(O)N(Rn)2, NHC(O)Rn.

[0117] In some embodiments, one of R4and R5is H or a substituted or unsubstituted group selected from Ci-C6alkyl, C(O)Rn, NH2, NHR11, N(Rn)2, C(O)NH2, C(O)NHRn, C(O)N(Rn)2, and NHC(O)Rn, and the other of R4and R5is a group of Formula (III).

[0118] In some embodiments, the compound of Formula (III) is represented by the structure:

[0119] In some embodiments, R7, R8, and R10are each independently H, halogen (e.g., F, CI), CN, or a substituted or unsubstituted Ci-Ce alkyl or C3-C6 cycloalkyl group, OR11, SR11, NHR11, N(Rn)2, NHC(O)Rn, and N(R11)C(O)R11, provided that at least one of R7, R8, and R10is other than H.

[0120] In some embodiments, R9is a substituted or unsubstituted C1-C3 alkyl or C3-C5 cycloalkyl group.

[0121] In some embodiments, R11is, independently in each occurrence, a substituted or unsubstituted Ci-Ce alkyl group.

[0122] In some embodiments, R12is, independently in each occurrence, a substituted or unsubstituted Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cs-Ciocycloalkyl, and C3- C loheterocy cloalkyl .

[0123] In some embodiments, X1, X2, and X3are each selected from N or C, wherein when X1, X2, or X3is N, then the R7, R8, or R10attached thereto is absent, provided that at least two of X1, X2, and X3is C.

[0124] In some embodiments, when any of the foregoing groups contains an alkyl group, then said alkyl is a linear or branched acyclic alkyl group.

[0125] In certain embodiments, R8is halogen (e.g., F, CI), CN, or a substituted or unsubstituted Ci-C6alkyl or C3-C6cycloalkyl, OR11, SR11, NHR11, N(Rn)2, NHC(0)Rn, or N(R11)C(O)R11.

[0126] In some embodiments, R4may be a group of Formula II and R5is hydrogen or a substituted or unsubstituted C1-C3 alkyl. In another embodiment, wherein R5is a group of Formula (III), for instance, when R4is hydrogen or a substituted or unsubstituted C1-C3 alkyl. In one embodiment, R4is hydrogen.

[0127] In some embodiments, in Formula II, groups X1, X2and X3are all carbon atoms. In another embodiment, X1is a nitrogen atom and R10is absent, and X2and X3are carbon atoms. For instance, the compound of Formula (III) may be represented by Formula (Illa):

[0128] In some embodiments, R7, R8, R9, and R10are defined elsewhere herein.

[0129] In some embodiments, R9is an unsubstituted C1-C3 alkyl or C3-C5 cycloalkyl group, such as a methyl, ethyl, n-propyl, isopropyl or cyclopropyl group. In some embodiments, R9is a methyl group, or R9is a fluorine-substituted C1-C3 alkyl or C3-C5 cycloalkyl group, such as trifluorom ethyl or difluorocyclopropyl.

[0130] In some embodiments, R7and R10are each hydrogen atoms and R8is selected from CI, CN, NHR11and a substituted or unsubstituted Ci-Ce alkyl or C3-C6 cycloalkyl group.

[0131] In some embodiments, provided herein is a substituted benzimidazole compound represented by the structure of Formula (Ila) and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0132] In some embodiments, R1, R2, R3, R5, R6, R7, R8, R9, and R10are defined elsewhere herein.

[0133] In some embodiments, provided herein is a substituted benzimidazole compound represented by the structure of Formula (lib), and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0134] In some embodiments, R1, R2, R4, R3, R6, R7, R8, R9, and R10are defined elsewhere herein.

[0135] In one embodiment, R3is H or a substituted or unsubstituted Ci-Ce alkyl, preferably R3is H. In another embodiment, R6is H or a substituted or unsubstituted Ci-Ce alkyl, preferably R6is H.

[0136] Provided herein, in some embodiments, is a substituted benzimidazole compound represented by the structure of Formula (IV) and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0137] In some embodiments, R1, R2, R4and R5are described elsewhere herein.

[0138] In some embodiments, provided herein is a substituted benzimidazole compound represented by Formula (IVa), and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0139] In some embodiments, R1, R2, R7, R8, R9, and R10are described elsewhere herein.

[0140] In some embodiments, provided herein is a substituted benzimidazole compound represented by Formula (IVb), and pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof:

[0141] In some embodiments, R1, R2, R7, R8, R9, and R10are described elsewhere herein.

[0142] In some embodiments, in Formula (IVa) or (IVb), R9is an unsubstituted d-Csalkyl or C3- Cscycloalkyl group, or R9is a fluorine-substituted C1-C3 alkyl or C3-C5 cycloalkyl group. For instance, R9is selected from methyl, trifluoromethyl, ethyl, n-propyl, isopropyl and cyclopropyl, for instance, or R9is a methyl group.

[0143] In some embodiments, in Formula (IVa) or (IVb), R7and R10are each hydrogen atoms and R8is selected from CI, CN, NHR11and a substituted or unsubstituted Ci-Ce alkyl or C3-C6 cycloalkyl group.

[0144] In some embodiments, in Formula (IVa) or (IVb), R8and R9are each independently a methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, or difluorocyclopropyl group.

[0145] In some embodiments, in any of the compounds provided herein (e.g., a compound of Formula (II), (Ila), (lib), (IV), (IVa), or (IVb)), R2is hydrogen or a substituted or unsubstituted group selected from Ci-Ce alkyl, C3-C10 cycloalkyl, or C3-C10 heterocycloalkyl group. In some embodiments, R2is a substituted or unsubstituted C1-C3 alkyl, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl group, or is a substituted or unsubstituted group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, and pyrrolidinyl.

[0146] In some embodiments, in any of the compounds provided herein (e.g., a compound of Formula (II), (Ila), (lib), (IV), (IVa), or (IVb)), R1is a branched or linear C2-C6 alkyl substituted with a group selected from fluorine, OCi-Ce alkyl, and halogenated OCi-Ce alkyl. For instance, R1is a branched or linear C2-C3alkyl substituted with a group selected from fluorine, OCi-Ce alkyl, and halogenated OCi-Ce alkyl. In an alternate embodiment, R1is selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, 2-ethoxyethyl, 2- (fluoromethoxy)ethyl, 2- (difluoromethoxy)ethyl, 2-(trifluoromethoxy)ethyl, 3,3,3-trifluoro-l- propyl, 3 -methoxy- 1 -propyl, 3- ethoxy- 1 -propyl, 3 -(fluoromethoxy)- 1 -propyl, 3- (difluoromethoxy)-l -propyl, 3 -(trifluoromethoxy)- 1 -propyl, l-methoxy-2-propyl, l-ethoxy-2- propyl, l-(fluoromethoxy)-2-propyl, 1- (difluoromethoxy)-2-propyl, l-(trifluoromethoxy)-2- propyl, 2-methoxy-l -propyl, 2-ethoxy-l- propyl, 2-(fluorom ethoxy)- 1 -propyl, 2- (difluoromethoxy)-l -propyl, or 2-(trifluoromethoxy)-l- propyl, for instance, R1is 2- methoxy ethyl, 2-(trifluoromethoxy)ethyl, l-methoxy-2-propyl, 1- (trifluoromethoxy)-2-propyl, 2- methoxy-1 -propyl, or 2-(trifluorom ethoxy)- 1 -propyl. In another embodiment, R1is methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, n-propyl, 3,3,3-trifluoro-l- propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

[0147] In some embodiments, non-limiting examples of the compounds provided herein include those included in Table 1.Table 1

[0148] Provided herein are pharmaceutical compositions comprising any one of the compounds provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a pharmaceutical composition comprising a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1, and optionally a pharmaceutically acceptable excipient.

[0149] In some embodiments, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a compound of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1.

[0150] Provided herein are pharmaceutical compositions comprising a compound, or a pharmaceutically acceptable salt thereof, represented by Formula (I):and optionally a pharmaceutically acceptable excipient.

[0151] Provided herein are pharmaceutical compositions comprising any combination of an immediate release component, a delayed release component, or an extended-release component. The pharmaceutical compositions provided herein comprising a delayed or extended-release component may be effective at increasing the time at which a dose of a compound provided herein maintains therapeutic effectiveness. The use of delayed or extended-release components in the pharmaceutical compositions provided herein may reduce the number and / or frequency of doses required to be administered to an individual provided herein.

[0152] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate release component, the immediate release component comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate release component, the immediate release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0154] In some embodiments, provided herein is a pharmaceutical composition comprising a delayed release component, the delayed release component comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, provided herein is a pharmaceutical composition comprising a delayed release component, the delayed release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0156] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0158] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate and an extended-release component, the immediate and extended-release components comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate and an extended-release component, the immediate and extended-release components comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0160] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate and a delayed release component, the immediate and delayed release componentscomprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, provided herein is a pharmaceutical composition comprising an immediate and a delayed release component, the immediate and delayed release components comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0162] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release and a delayed release component, the extended-release and delayed release components comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release and a delayed release component, the extended-release and delayed release components comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0164] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release, immediate release, and a delayed release component, the extended-release, immediate release, and delayed release components comprising a compound provided elsewhere herein (e.g., a compound represented by a structure of any one of Formula (I), (II), (Ila), (lib), (IV), (IVa), or (IVb), or a compound provided in Table 1), or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, provided herein is a pharmaceutical composition comprising an extended-release, immediate release, and a delayed release component, the extended-release, immediate release, and delayed release components comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I).

[0166] In some embodiments, in any one of the pharmaceutical compositions provided herein, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.

[0167] In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of fillers, binders, disintegrants, and combinations thereof.

[0168] In some embodiments, the pharmaceutically acceptable excipient comprises any combination of a binder, filler (e.g., diluent), lubricant, controlled-release agent, and a disintegrant.

[0169] In some embodiments, the pharmaceutical compositions provided herein comprises a filler. In some embodiments, non-limiting examples of fillers include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose,cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and any combination thereof. In some embodiments, the pharmaceutical composition comprises a filler in an amount of at least 5% by weight (e.g., at least 10%, at least 20%, at least 40%). In some embodiments, the pharmaceutical composition comprises a filler in an amount of at most 70% by weight (e.g., at most 60%, at most 50%, at most 40%). In some embodiments, the pharmaceutical composition comprises a filler in an amount of about 5% to about 70% by weight. In some embodiments, the pharmaceutical composition comprises a filler in an amount of about 35% to about 65% by weight (e.g., about 35% to about 45% by weight, or about 50% to about 65% by weight).

[0170] In some embodiments, the filler comprises mannitol (e.g., mannitol 200SD). In some embodiments, the mannitol is present in an amount of at least 25% by weight (e.g., at least 30%, 35%, 40%, or 45% by weight). In some embodiments, the mannitol is present in an amount of at most 60% by weight (e.g., at most 55%, 50%, 45%, or 40% by weight). In some embodiments, the mannitol is present in an amount of about 25% to about 60% by weight. In some embodiments, the mannitol is present in an amount of about 30% to about 50% by weight. In some embodiments, such as described in Example 2, the mannitol is present in an amount of about 40% by weight.

[0171] In some embodiments, the filler is lactose (e.g., lactose monohydrate). In some embodiments, the lactose (e.g., lactose monohydrate) is present in an amount of at least 40% by weight (e.g., at least 45%, 50%, 55%, 58%, or 60% by weight). In some embodiments, the lactose (e.g., lactose monohydrate) is present in an amount of at most 75% by weight (e.g., at most 70%, 65%, 60%, or 55% by weight). In some embodiments, the lactose (e.g., lactose monohydrate) is present in an amount of about 40% to about 75% by weight. In some embodiments, the lactose (e.g., lactose monohydrate) is present in an amount of about 55% to about 65% by weight. In some embodiments, such as described in Example 2, the lactose (e.g., lactose monohydrate) is present in an amount of about 59% by weight.

[0172] In some embodiments, the pharmaceutical compositions provided herein comprise a binder. In some embodiments, non-limiting examples of binders include carboxymethylcellulose, methylcellulose (e.g. Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g. Klucel®), ethylcellulose (e.g. Ethocel®), microcrystalline cellulose (e.g. Avicel®), silicified microcrystalline cellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin,PVP / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g. Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, PVP (e.g. Povidone® CL, Kollidon® CL, Polyplasdone® XL- 10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and any combination thereof. In some embodiments, the pharmaceutical composition comprises a binder in an amount of at least 2.5% by weight (e.g., at least 5%, at least 10%, at least 15%). In some embodiments, the pharmaceutical composition comprises a binder in an amount of at most 25% by weight (at most 20%, at most 15%, at most 10%). In some embodiments, the pharmaceutical composition comprises a binder in an amount of about 2.5% to about 25% by weight. In some embodiments, the pharmaceutical composition comprises a binder in an amount of about 15% to about 25% by weight. In some embodiments, the pharmaceutical composition comprises a binder in an amount of about 19% by weight.

[0173] In some embodiments, the binder is silicified microcrystalline cellulose (e.g., such as described in Example 2). In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose in an amount of at least 2.5% by weight (e.g., at least 5%, at least 10%, at least 15%). In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose in an amount of at most 25% by weight (at most 20%, at most 15%, at most 10%). In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose in an amount of about 2.5% to about 25% by weight. In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose in an amount of about 15% to about 25% by weight. In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose in an amount of about 19% by weight.

[0174] In some embodiments, the pharmaceutical compositions provided herein comprise a disintegrant. In some embodiments, non-limiting examples of a disintegrant include a starch, e.g. a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g. Avicel®, Avicel® PHI 01, Avicel® PHI 02, Avicel® PHI 05, Elcema® Pl 00, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked PVP, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and any combination thereof. In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of at least 0.5% by weight (e.g., at least 1%, at least 1.5%, at least 2%, at least 3%). In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of at least 5% by weight (e.g., at least 10%, 12%, 15%, 18%, or 20% by weight). In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of at most 5% by weight (e.g., at most 4%, at most 3%, at most 2%, at most 1%). In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of at most 30% by weight (e.g., at most 28%, 25%, 22%, or 20% by weight). In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of about 0.5% to about 5% by weight. In some embodiments, the pharmaceutical compositions comprise the disintegrant in an amount of about 15% to about 25% by weight.

[0175] In some embodiments, the disintegrant comprises a hydroxypropyl methylcellulose (e.g., Benecel K4M). In some embodiments, the hydroxypropyl methylcellulose may also act as a binder or controlled-release agent, such as described elsewhere herein. In some embodiments, the hydroxypropyl methylcellulose (e.g., Benecel K4M) is present in an amount of at least 5% by weight (e.g., at least 10%, 12%, 15%, 18%, or 20% by weight). In some embodiments, the hydroxypropyl methylcellulose (e.g., Benecel K4M) is present in an amount of at most 30% by weight (e.g., at most 28%, 25%, 22%, or 20% by weight). In some embodiments, the hydroxypropyl methylcellulose (e.g., Benecel K4M) is present in an amount of about 15% to about 25% by weight. In some embodiments, the hydroxypropyl methylcellulose (e.g., Benecel K4M) is present in an amount of about 20% by weight, such as described in Example 2.

[0176] In some embodiments, the pharmaceutical compositions provided herein further comprises one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, and sweetening agents.

[0177] In some embodiments, the pharmaceutical composition is an oral formulation, a buccal formulation, a nasal formulation, or an inhalation formulation. In some embodiments, the pharmaceutical composition is in a form selected from a solid, oral, rectal, or implant.

[0178] The pharmaceutical compositions provided herein may be provided (e.g., prepared or formulated) as a solid dosage form. The pharmaceutical compositions provided herein may be a solid dosage form.

[0179] In some embodiments, the pharmaceutical compositions provided herein may be oral dosage forms. In some embodiments, the pharmaceutical compositions provided herein may provided (e.g., formulated) as an oral dosage form.

[0180] Pharmaceutical compositions that are optionally used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the pharmaceutical compositions are tablets. In some embodiments, the tablets are direct compression manufactured tablets. In other embodiments, the tablets are wet granulation manufactured tablets. In some embodiments, the tablets are biconvex tablets.

[0181] In some embodiments, the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0182] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

[0183] In addition, stabilizers might be added. All formulations for oral administration should be in dosages suitable for administration.

[0184] In some embodiments, the oral dosage form comprises an extended release component. In some embodiments, the oral dosage form comprises a delayed release component.

[0185] In some embodiments, any of the pharmaceutical compositions provided herein comprises a multi-layer (e.g., bi-layer) composition (e.g. oral dosage form). In some instances, the bi-layer compositions comprising a compound provided here (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1), or pharmaceutically acceptable salt thereof, has an enhanced bioavailability and efficacy, has a lower administration dose, decreased side effects, or prolonged therapeutic effectiveness per dose.

[0186] In some embodiments, the pharmaceutical compositions provided herein (e.g., comprising a bi-layer composition) are oral dosage form comprising an (e.g. immediate release, delayed release, or extended-release) top layer or coating and an extended release or delayed release core, such as wherein at least one of (i) the top layer or coating, or (ii) the extended release or delayed release core comprise a compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1). In some embodiments, the (e.g. immediate release, delayed release, or extended release) top layer or coating and the delayed release or extended release core both comprise a compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1), the core and coating composition provided here being the same or different.

[0187] In some embodiments, the pharmaceutical compositions provided herein comprise an extended release core, such as comprising a compound provide herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) and a coating composition, and an immediate release component surrounding the core and coating composition.

[0188] In some embodiments, the pharmaceutical compositions provided herein comprise a delayed release core, such as comprising a compound provide herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) and a coating composition, and an immediate release component surrounding the core and coating composition.

[0189] In some embodiments, the pharmaceutical compositions provided herein comprise an extended release core, comprising an extended release matrix, such as comprising a compound provide herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) and optionally a coating composition, and an immediate release component surrounding the core and coating composition.

[0190] In some embodiments, the pharmaceutical compositions provided herein comprise an extended release core, comprising an extended release matrix, such as comprising a compound provide herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1).

[0191] In some embodiments, the pharmaceutical compositions provided herein comprise a coating composition (e.g. utilized to form a coating). In some embodiments, the coating composition comprises an aqueous dispersion of a neutral ester copolymer without any functional groups. In some embodiments, the aqueous dispersion of a neutral ester copolymer without any functional groups is an ethyl acrylate and methyl methacrylate copolymer dispersion. Non-limiting examples of ethyl acrylate and methyl methacrylate copolymer dispersions include a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g. Eudragit® NE30D), a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g. Eudragit® NE40D), Eudragit® NM30D, Kollicoat® EMM30D, and combinations thereof. In some embodiments, the neutral ester copolymer without any functional groups used in the extended or delayed release coating composition is Eudragit® NE30D, Eudragit® NE40D, or a mixture thereof. In some embodiments, the neutral ester copolymer without any functional groups might is present in in an amount of from about 1% to about 35% by weight of the coating composition, depending on the therapeutically active agent used and the extended release profile desired. In some embodiments, the neutral ester copolymer without any functional groups is present in the coating composition in an amount of at least 0.1% by dry weight of the pharmaceutical composition (e.g., at least 0.2%, at least 0.4%, at least 0.8%, at least 1%, atleast 5%). In some embodiments, the neutral ester copolymer without any functional groups is present in the coating composition in an amount of at most 50% by dry weight of the pharmaceutical composition (e.g., at most 45%, at most 40%, at most 35%, at most 30%). In some embodiments, the neutral ester copolymer without any functional groups is present in the coating composition in an amount of from about 0.4% to about 39.8% by dry weight of the pharmaceutical composition. In some embodiments in an amount of from about 0.8% to about 24% by dry weight of the pharmaceutical composition. In some other embodiments, the neutral ester copolymer without any functional groups is present in the coating composition in an amount of from about 2% to about 5.5% by dry weight of the pharmaceutical composition.

[0192] In some embodiments, the extended release dosage forms provided herein do not swell in a dimensionally unrestricted manner upon imbibition of water. In certain embodiments there is some swelling of the extended release dosage form in a dimensionally restricted manner upon imbibition of water. In certain embodiments the extended release coating restricts the swelling of the dosage form upon imbibition of water.

[0193] In some embodiments, the pharmaceutical compositions provided herein comprise a coating composition. In some embodiments, a coating composition comprises a polyglycol. In some embodiments, the polyglycol (e.g., with a melting point of at least about 55° C) is a polyethylene glycol with an average molecular weight ranging from about 4,000 Daltons to about 35,000 Daltons. Non-limiting examples of a polyglycol include polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or mixtures thereof. In certain embodiments, the polyglycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, and mixtures thereof. In at least one embodiment the poly-glycol used in the coating composition is polyethylene glycol 8000. In certain embodiments the poly-glycol is present in the coating composition in an amount of from about 0.1% to about 11.2% by dry weight of the pharmaceutical composition. In other embodiments the polyglycol is present in the coating composition in an amount of from about 0.1% to about 8% by dry weight of the tablet. In still other embodiments the polyglycol is present in the coating composition in an amount of from about 0.2% to about 2.8% by dry weight of the pharmaceutical composition. In some embodiments, the polyglycol is present in an amount of at least 0.1% (e.g., at least 1%, at least 2%, at least 5%, at least 7.5%, at least 10%) by dry weight of the pharmaceutical composition. In some embodiments, the polyglycol is present in an amount of at most 15% (e.g., at most 12.5%, at most 10%, at most 7.5%, at most 5%) by dry weight of the pharmaceutical composition. In someembodiments, polyglycol derivatives (e.g., having a melting point of at least about 55° C) are Poloxamer 188, Poloxamer 338, Poloxamer 407, polyethylene oxides, polyoxyethylene alkyl ethers, polyoxyethylene stearates, or mixtures thereof.

[0194] In some embodiments, the pharmaceutical compositions comprise a coating composition, such as a coating composition described elsewhere herein. In some embodiments, in addition to the copolymers and / or polyglycol, the coating composition optionally comprises one or more other pharmaceutically acceptable excipients. In some embodiments, the excipients include, but are not limited to anti-tacking agents, emulsifying agents, anti-foaming agent, hydrophilic agents, flavorings, colorants, sweeteners, or any combination thereof. In some embodiments, excipients might affect the properties of the coating composition in a series of ways, and many substances used in coating compositions might thus be described as multifunctional. A skilled artisan will know, based on their technical knowledge, which pharmaceutically acceptable excipients are suitable for the desired extended release or delayed release coating composition.

[0195] In some embodiments, any of the pharmaceutical compositions provided herein comprise a hydrophilic agent. In some embodiments, the pharmaceutical compositions comprise any suitable hydrophilic agent. In some embodiments, any of the coating compositions provided herein comprise hydrophilic agents. Hydrophilic agents may promote wetting of the coating, such as when in contact with gastrointestinal fluids. In some embodiments, the hydrophilic agents (e.g., hydrophilic polymers) comprise hydroxypropyl methylcellulose (HPMC) (e.g. Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyvinylpyrrolidone (Povidone® or Kollidon®), polyvinyl alcohol, polyethylene oxide, vinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA64), polyethylene glycol-polyvinyl alcohol copolymer (Kollicoat® IR), copolymers thereof, or combinations thereof. In some embodiments, the hydrophilic agent comprises a pH-dependent polymer. In some embodiments, the (e.g., pH dependent) hydrophilic agent is cellulose acetate phthalate (e.g. Aquacoat® CPD); cellulose acetate trimellitate, poly(methacrylic acid, ethyl acrylate) 1 : 1 (e.g. Eudragit® L30D-55); Kollicoat® MAE 30 D; poly(methacrylic acid, ethyl acrylate) 1 : 1 (e.g. Eudragit® L100-55); Kollicoat® MAE 30 DP; Eudragit® FS 30D; Hypromellose Acetate Succinate LF, MF, HF grades (e.g. AQOAT®), polyvinyl acetate phthalate, or mixtures thereof. Hydrophilic agents may be included in the pharmaceutical compositions, cores, or coating or pharmaceutical compositions in any suitable amount. In some embodiments, the hydrophilic agent is present in an amount of at least 0.1% (e.g., at least 2%, at least 5%, at least 8%, at least 12%, at least 14) by dry weight of the pharmaceutical composition. In some embodiments, the hydrophilic agent is present in an amount of at most 15% (e.g., at most 14%, atmost 12%, at most 8%, at most 4) by dry weight of the pharmaceutical composition. In certain embodiments the hydrophilic agent is present in an amount of from about 0% to about 14% by dry weight of the pharmaceutical composition. In some embodiments the hydrophilic agent is present in an amount of from about 0.2% to about 6% by dry weight of the pharmaceutical composition.

[0196] In some embodiments, any of the pharmaceutical compositions provided herein comprise an anti-tacking agent. In some embodiments, any of the coating compositions provided herein comprise an anti-tacking agent. In some instances, the tackiness of polymeric films is important for the coating of dosage forms. In some instances, during coating with either cellulosic or acrylic polymers, an unwanted, and sometimes irreversible agglomeration of several granules or beads or, in the worst case, of the complete batch, might occur, especially at higher product processing temperatures. In some embodiments, the addition of anti-tacking agents to coating compositions is desirable. In some embodiments, the anti-tacking agent comprises adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, glyceryl monostearate, talc (e.g. Talc 400), sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, or mixtures thereof. In some embodiments, mixtures of the anti-tacking agents are utilized. In some embodiments, any suitable amount of anti-tacking agent is utilized in the coating composition or pharmaceutical compositions provided herein. In some embodiments, the antitacking agent is present in an amount of at least 0.1% (e.g., at least 5%, at least 10%, at least 15%, at least 20%) by dry weight of the pharmaceutical composition. In some embodiments, the antitacking agent is present in an amount of at most 20% (e.g., at most 15%, at most 10%, at most 5%) by dry weight of the pharmaceutical composition. In certain embodiments the anti-tacking agent is present in an amount of from about 0% to about 20% by dry weight of the pharmaceutical composition. In some embodiments, the anti-tacking agent is present in an amount of from about 0% to about 12% by dry weight of the pharmaceutical composition.

[0197] In some embodiments, the pharmaceutical compositions provided herein comprise a controlled-release agent. In some embodiments, the controlled-release agent is present in an amount of at least 5% by weight (e.g., at least 10%, 12.5%, 15%, 17.5%, or 20% by weight). In some embodiments, controlled-release agent is present in an amount of at most 40% by weight (e.g., at most 35%, 30%, 27.5%, 25%, 22.5%, or 20% by weight). In some embodiments, the controlled-release agent is present in an amount of about 10% to about 30% by weight. In some embodiments, the controlled-release agent is present in an amount of about 15% to about 25% by weight. In some embodiments, the controlled-release agent is present in an amount of about 20% by weight.

[0198] In some embodiments, the controlled-release agent comprises any combination of Compritol 888 ATO and Surelease (e.g., Surelease E-7-19040).

[0199] In some embodiments, the controlled-release agent comprises a lipid excipient (e.g., Compritol 888 ATO). In some embodiments, the lipid excipient (e.g., Compritol 888 ATO) is present in an amount of at least 5% by weight (e.g., at least 10%, 12.5%, 15%, 17.5%, or 20% by weight). In some embodiments, lipid excipient (e.g., Compritol 888 ATO) is present in an amount of at most 40% by weight (e.g., at most 35%, 30%, 27.5%, 25%, 22.5%, or 20% by weight). In some embodiments, the lipid excipient (e.g., Compritol 888 ATO) is present in an amount of about 10% to about 30% by weight. In some embodiments, the lipid excipient (e.g., Compritol 888 ATO) is present in an amount of about 15% to about 25% by weight. In some embodiments, the lipid excipient (e.g., Compritol 888 ATO) is present in an amount of about 20% by weight, such as described in Example 2.

[0200] In some embodiments, the controlled-release agent comprises ethylcellulose (e.g., Surelease E-7-19040). In some embodiments, the ethylcellulose (e.g., Surelease E-7-19040) is present in an amount of at least 5% by weight (e.g., at least 10%, 12.5%, 15%, 17.5%, or 20% by weight). In some embodiments, ethylcellulose (e.g., Surelease E-7-19040) is present in an amount of at most 40% by weight (e.g., at most 35%, 30%, 27.5%, 25%, 22.5%, or 20% by weight). In some embodiments, the ethylcellulose (e.g., Surelease E-7-19040) is present in an amount of about 10% to about 30% by weight. In some embodiments, the ethylcellulose (e.g., Surelease E-7-19040) is present in an amount of about 15% to about 25% by weight. In some embodiments, the ethylcellulose (e.g., Surelease E-7-19040) is present in an amount of about 20% by weight, such as described in Example 2.

[0201] In some embodiments, the pharmaceutical compositions provided herein comprise a lubricant. In some embodiments, the lubricant is present in an amount of at least 0.01% by weight (e.g., at least 0.2%, 0.5%, 0.6%, 0.7%, 0.8%, or at least 0.9% by weight). In some embodiments, the lubricant is present in an amount of at most about 5% by weight (e.g., at most 4%, 3%, 2.5%, 2%, 1.5%, or at most 1% by weight). In some embodiments, the lubricant is present in an amount of from about 0.1% to about 1.5%. In some embodiments, the lubricant is present in an amount of from about 0.5% to about 1.5%. In some embodiments, the lubricant is present in an amount of about 1% by weight.

[0202] In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the magnesium stearate is present in an amount of at least 0.01% by weight (e.g., at least 0.2%, 0.5%, 0.6%, 0.7%, 0.8%, or at least 0.9% by weight). In some embodiments, the magnesium stearate is present in an amount of at most about 5% by weight (e.g., at most 4%, 3%, 2.5%, 2%,1.5%, or at most 1% by weight). In some embodiments, the magnesium stearate is present in an amount of from about 0.1% to about 1.5%. In some embodiments, the magnesium stearate is present in an amount of from about 0.5% to about 1.5%. In some embodiments, such as described in example 2, the lubricant is present in an amount of about 1% by weight.

[0203] In some embodiments, any of the pharmaceutical compositions provided herein comprise an anti-foaming agent. In some embodiments, any of the coating compositions provided herein comprise an anti-foaming agent. In some embodiments, the anti-foaming agent comprises silicon oil, simethicone (e.g. simethicone emulsion), or mixtures thereof. In some embodiments, the antifoaming agent is present in an amount of at least 0.1% (e.g., at least 0.2%, at least 0.4%, at least 0.8%, at least 1%, at least 1.5%) by dry weight of the pharmaceutical composition. In some embodiments, the anti-foaming agent is present in an amount of at most 2% (e.g., at most 1.7%, at most 1.5%, at most 1.3%, at most 1.1%, at most 0.8%) by dry weight of the pharmaceutical composition. In certain embodiments the anti-foaming agent is present in an amount of from about 0% to about 1.5% by dry weight of the pharmaceutical composition.

[0204] In some embodiments, any of the pharmaceutical compositions provided herein comprise an emulsifying agent. In some embodiments, any of the coating compositions provided herein comprise an emulsifying agent. In some embodiments, the emulsifying agent facilitates actual emulsification during manufacture of the coating, and / or to provide emulsion stability during the shelf-life of the product. In some embodiments, the emulsifying agent comprises naturally occurring materials and their semi synthetic derivatives, such as the polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters and polysorbates. In some embodiments, emulsifying agents comprise mixtures of emulsifying agents. In some embodiments, the emulsifying agent is present in an amount of at least 0.1% (e.g., at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%) by dry weight of the pharmaceutical composition. In some embodiments, the emulsifying agent is present in an amount of at most 1% (e.g., at most 0.8%, at most 0.6%, at most 0.4%) by dry weight of the pharmaceutical composition. In some embodiments, the emulsifying agent is present in an amount of about 0% to about 1% by dry weight of the pharmaceutical composition.

[0205] In some embodiments, any of the pharmaceutical compositions provided herein comprise a colorant. In some embodiments, any of the coating compositions provided herein comprise an colorant. In some instances, the colorant is a water-insoluble color (pigment). In some instances, pigments have certain advantages over water-soluble colors in that they tend to be more chemically stable towards light, provide better opacity and covering power, and optimize the impermeability of a given film to water vapor. In some embodiments, colorants comprise iron oxide pigments,titanium dioxide, and Aluminum Lakes. Mixtures may be operable. In at least one embodiment the pigment or colorant used is titanium dioxide. In some embodiments, the coloring agent is present in an amount of at least 0.1% (e.g., at least 1%, at least 2%, at least 3%, at least 5%, at least 8%) by dry weight of the pharmaceutical composition. In some embodiments, the coloring agent is present in an amount of at most 10% (e.g., at most 8%, at most 6%, at most 4%, at most 2%, at most 1%) by dry weight of the pharmaceutical composition. In some embodiments, the coloring agent is present in an amount of about 0% to about 10% by dry weight of the pharmaceutical composition.

[0206] In some embodiments, the pharmaceutical compositions provided herein comprise:(a) a compound provided herein in an amount of about 10% to about 30% by weight;(b) a controlled-release agent in an amount of about 10% to about 30% by weight;(c) a filler (e.g., diluent) in an amount of about 30% to about 50% by weight;(d) a binder in an amount of about 10% to about 30% by weight; and(e) a lubricant in an amount of about 0.5% to about 1.5% by weight.

[0207] In some embodiments, the pharmaceutical compositions provided herein comprise:(a) a compound provided herein in an amount of about 10% to about 30% by weight;(b) a lubricant in an amount of about 0.5% to about 1.5% by weight;(c) a disintegrant in an amount of about 10% to about 30% by weight; and(d) a filler (e.g., diluent) in an amount of about 50% to about 70% by weight.

[0208] In some embodiments, the pharmaceutical compositions provided herein comprise:(a) a compound provided herein in an amount of about 10% to about 30% by weight;(b) a filler (e.g., diluent) in an amount of about 30% to about 50% by weight;(c) a binder in an amount of about 10% to about 30% by weight;(d) a lubricant in an amount of about 0.5% to about 1.5% by weight; and(e) a controlled-release agent in an amount of about 10% to about 30% by weight.

[0209] In some embodiments, any one of the pharmaceutical compositions provided herein comprise a first and second pharmaceutically acceptable excipient. In some embodiments, the second pharmaceutically acceptable excipients (e.g. in the extended release coating) comprises at least one of a neutral ester copolymer without any functional groups (e.g. Eudragit® NE30D, Eudragit® NE40D, Eudragit® NM30D, Kollicoat® EMM30D, or a mixture thereof), HPMC (e.g. Pharmacoat®606), talc (e.g. Talc 400), polyethylene glycol (e.g. polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or a mixture thereof), simethicone, Polysorbate 80, titanium dioxide, or mixtures thereof.

[0210] In some embodiments, any one of the pharmaceutical compositions, coating compositions, or cores hydrates when placed into water. In some embodiments, a dosage form that is coated with the delayed or extended release coating) floats in water. In some embodiments, the (e.g. delayed or extended release) dosage form, upon oral administration to a patient, provides extended or delayed release of an effective amount of the active drug to at least one region of the patient's upper gastrointestinal tract (e.g. the stomach).

[0211] In some embodiments, any one of the coating compositions provided herein (e.g., provided in the pharmaceutical compositions provided herein) is used to coat compounds provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), and provided in Table 1), and might be adjusted to obtain a desired drug release profile. The length and time for the delay may be extended by rate of hydration and the thickness of the coat. The drug release rate subsequent to the delay may be determined by the thickness and permeability of the hydrated coat. In some instances, it is possible to regulate the rate of hydration and permeability of the coat so that the desired extended release drug profile might be achieved. In some instances, other parameters in combination with the thickness of the coat include varying the concentrations of some of the ingredients of the stable coat composition and / or varying the curing temperature and length of curing the coated tablet cores. The skilled artisan will understand which parameters or combination of parameters to change for a desired extended or delayed release profile.

[0212] In some embodiments, the pharmaceutical compositions provided herein comprise an immediate release component.

[0213] In some embodiments, when the pharmaceutical compositions provided herein are administered to an individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) to the individual within at most 15 minutes (e.g., at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 90 minutes). In some embodiments, when the pharmaceutical compositions provided herein are administered to an individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) to the individual within at most 60 minutes (e.g., at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 90 minutes). In some embodiments, when the pharmaceutical composition is administered to an individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or providedin Table 1) to the individual within at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes). In some embodiments, when the pharmaceutical composition is administered to an individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) to the individual within about 5 minutes to about 60 minutes.

[0214] In some embodiments, any composition or pharmaceutical composition provided herein (e.g. oral dosage form) provided herein comprises an immediate-release coating (e.g. providing immediate release of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1). In some embodiments, the immediate-release coating comprises a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1). In some embodiments, the immediate-release coating comprises more than one compound, such as a compound provided herein. In further embodiments, the immediate release coating comprises a pharmaceutically acceptable excipient. In some embodiments, the immediate release coating comprises a compound, such as a compound provided herein, and an additional (e.g. pharmaceutically active) agent. In other embodiments, the immediate release coating comprises an additional (e.g. pharmaceutically active) agent, but not a compound provided herein.

[0215] In some embodiments, an (e.g. therapeutically) effective amount of a compound provided herein in immediate release form is coated onto the delayed or extended release components (e.g., pharmaceutical compositions comprising a compound described herein and a coating composition) described herein. For example, in some instances where the extended release of a compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), and provided in Table 1)) is due to an extended release coating, the immediate release layer of the additional agent would be overcoated on top of the extended release coating. In some embodiments, the immediate release layer of the additional agent is coated onto the surface of substrates wherein the compound, such as compound provided elsewhere herein, is incorporated in an extended release matrix.

[0216] In some embodiments, a composition or pharmaceutical composition provided herein (e.g. a pharmaceutical composition comprising an immediate release component and an extended or delayed release component) is in the form of a bi-layered tablet, such as comprising a first layer and a second layer. In some embodiments, the first layer is an immediate release layer and / or the second layer is an extended release layer or a delayed release layer. In some embodiments, the second layer is an extended release layer. In some embodiments, the second layer is an extendedrelease layer. The bi-layered tablet provides a therapeutically effective physiological concentration of any one of the compounds provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IVa), (IVb)).

[0217] In some embodiments, any of the pharmaceutical compositions provided herein comprise an extended release component. In some embodiments, the extended release components provided herein are extended release matrices. In some instances, active agents (e.g., drugs or therapeutic agents) are released from an extended release matrix in any suitable manner. In some instances, exemplary mechanisms of release of the compound provided herein (e.g., a compound of Formula(I), (II), (Ila), (lib), (IV), (IVa), (IVb)) from an extended release matrix include diffusion and / or degradation. Diffusion may occur when the bioactive agent is released either through pores in the polymer matrix or by passing between polymer chains of the matrix. In some instances, in a diffusion system, the compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb)) may be dispersed throughout the matrix, or localized within a reservoir adjacent to or within the matrix. In some embodiments, the extended release component utilizes a reservoir system, which typically comprises a reservoir of a compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb)) within a polymer matrix and is surrounded by an extended release material through which the compound is able to diffuse. In some instances, in a degradable system, the compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb)) is released as the matrix is degraded in vivo. In some instances, compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb)) is released by a combination of such mechanisms. In some embodiment of the extended release matrix described herein, the release of the compound provided herein (e.g., a compound of Formula (I),(II), (Ila), (lib), (IV), (IVa), (IVb)) is driven by a combination of both diffusion and degradation. In certain instances, the release rate is extended by varying the drug to polymer ratio (e.g. a higher drug concentration tends to result in a faster rate of release) and / or by varying the chemistry of polymeric matrix (e.g. inclusion of polymers having a glass transition temperature (Tg) of less than about 40° C or less than about 0°C would tend to result in a faster elution rate than polymers with Tgs greater than 40°C, polymers that absorb water tend to elute drug more quickly than more hydrophobic polymers that do not absorb water). In some instances, these variables are extended by the selection of materials used in the manufacturing process.

[0218] In some embodiments, any of the pharmaceutical compositions provided herein comprise an extended release matrix. In some embodiments, the extended release matrix is configured to release at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%) of the compound provided herein, such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb),within 24 hours of administration. In some embodiments, the extended release matrix is configured to release at most 100% (e.g., at most 99%, at most 95%, at most 90%, at most 80%, at most 70%, at most 60%) of the compound provided herein, such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), within 24 hours of administration. In some embodiments, the extended release matrix is configured to release about 20% to about 99% of the compound provided herein, such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), within 24 hours of administration. In some embodiments, such as described in Example 2, the extended release matrix is configured to release about 80% to about 99% of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, within 24 hours of administration.

[0219] In some instances, the extended release matrix is configured to release from about 40% to about 70% of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, within 5 hours of administration. In some embodiments, the extended release matrix is configured to release about 50%, 52%, 54%, 56%, 58%, or about 60% of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, within 5 hours of administration. In other embodiments, the extended-release matrix is configured to release from about 75% to about 90% of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, within 5 hours of administration. In some embodiments, the extended-release matrix is configured to release about 75%, 77%, 79%, 80%, 82%, 84%, or 85% of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, within 5 hours of administration.

[0220] In some embodiments, any of the pharmaceutical compositions provided herein comprise an extended release matrix. In some embodiments, the extended release matrix is biodegradable. In some embodiments, the extended release matrix comprises a biodegradable polyester. In some embodiments, the extended release matrix comprises polycaprolactone (PCL), polylactic acid (PLA), polyglycolide (PGA), or copolymers thereof, such as poly(lactic-co-glycolic acid) polymers (PLGA) and poly(glycolide-co-caprolactone) (PGC). In some embodiments, the extended release matrix comprises poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), and poly(butylene succinate) (PBS), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), and poly(butylene succinate) (PBS). In some embodiments, extended release matrix is biostable. In some embodiments, the extended release matrix comprises polyurethanes, silicone rubbers, styrene- isobutylene-styrene block copolymers, ether-ester block copolymers (e.g. RTP 1500-40D from RTP Co.) and vinyl materials, including but not limited to poly(ethylene-co-vinyl acetate) (PEVA). In some embodiments, the extended release matrix includes an elastomeric polymeric material that includes a copolymer with an elastomeric (or “soft”) component and a non-elastomeric (or “hard”) component. In some embodiments, the elastomeric polymeric material includes a polymeric blend having an elastomeric component and a non-elastomeric component. In some embodiments, the extended-release matrix comprises a thermoplastic. As used herein, the term “thermoplastic” refers to a polymer or polymeric material that can be softened by heat, hardened by cooling and then softened by heat over and over again.

[0221] In some embodiments, the compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1)) is incorporated into the extended release matrix provided herein, using any suitable technique, such as any of various techniques known to the skilled artisan. In some embodiments, the compound provided herein (e.g., compounds of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1)) is dispersed throughout the extended release matrix. Techniques for preparing the extended release matrix include, but are not limited to, melt extrusion processes, injection molding, or spray casting. In some instances, techniques for preparing the extended release matrix include direct compression or wet granulation.

[0222] In some embodiments, any one of the pharmaceutical compositions provided herein comprises an extended release component or an extended release matrix. The extended release component may comprise an extended release matrix. In some embodiments, the extended release matrix comprises any one of the compounds provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1), one or more hydrophilic extended- release polymers, such as a hydrophilic agent provided elsewhere herein, and one or more pharmaceutically acceptable excipients. The hydrophilic extended-release polymer may be any hydrophilic extended-release polymer required to extend drug release of a compound provided herein in an aqueous solution. In some embodiments, the hydrophilic extended-release polymer comprises cellulose derivatives selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose; and gums selected from xanthan gum, karaya gum, locust bean gum, alginic acid or sodium alginate. In some embodiments, the extended-release matrix may be used in combination with a coating layer provided elsewhere herein, such as to further extend release of the compound provided herein. In some embodiments, the extended-release matrix may be used as a core material in a pharmaceutical composition (e.g., tablet) provided herein.

[0223] In some embodiments, such as when the pharmaceutical composition is administered to an individual, no more than about 70% (e.g., no more than about 80%, 75%, 65%, or 60%) by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 1 hour. In some embodiments, no morethan about 50% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 1 hour. In some embodiments, about 15% to about 80% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 1 hour. In some embodiments, about 15% to about 60% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 1 hour. In some embodiments, about 20%, about 50%, or about 75% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition, such as described in Example 2.

[0224] In some embodiments, such as when the pharmaceutical composition is administered to an individual, no more than about 85% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 5 hours. In some embodiments, no more than about 60% (e.g., no more than about 75%, 70%, 65%, 55%, or 50%) by weight the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 5 hours. In some embodiments, about 40% to about 90% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 5 hours. In some embodiments, about 40% to about 60% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1 is released from the pharmaceutical composition after about 5 hours.

[0225] In some embodiments, the pharmaceutical compositions provided herein exhibit extended release profiles, such as when exposed to 750 mL 0.1 M HC1 for 2 hours followed by 1000 mL of 50 mM (pH 6.8) phosphate buffer for 22 hours, such as described in Example 2.

[0226] In some embodiments, the pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) release at most 80% by weight of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours. In some embodiments, the pharmaceutical compositions comprising a compound provided herein release at most 60% by weight (e.g., at most 50%, 45%, 40%, 35%, 30%, or 25% by weight) of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours. In some embodiments, the pharmaceutical compositions comprising a compound provided herein release from about 20% by weigh to about 80% by weight (e.g., about 20% by weight to about 60% by weight, about 40% by weight to about 60% by weight, or about 20% by weight to about 30% by weight) of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours.

[0227] In some embodiments, the pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) release at most 90% by weight of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours followed by 50 mM (pH 6.8) phosphate buffer for 3 hours. In some embodiments, the pharmaceutical compositions comprising a compound provided herein release at most 70% by weight (e.g., at most 65%, 60%, or 55% by weight) of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours followed by 50 mM (pH 6.8) phosphate buffer for 3 hours. In some embodiments, the pharmaceutical compositions comprising a compound provided herein release from about 50% to about 90% by weight (e.g., about 50% to about 85% by weight, about 50% to about 75% by weight, or about 50% to about 60% by weight) of the compound after exposure to 750 mL of 0.1 M HC1 for about 2 hours followed by 50 mM (pH 6.8) phosphate buffer for 3 hours.

[0228] In some embodiments, the extended release matrix comprises at least 10% by weight (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% by weight) of the compound of compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises at least 50% by weight of the compound of compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises at least 80% by weight of the compound of compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises at most 100% by weight (e.g., at most 99%, at most 98%, at most 97%, at most 92%, at most 90%, at most 85% by weight) of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises about 10% to about 99% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises about 10% to about 30% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1. In some embodiments, the extended release matrix comprises about 20% by weight of the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1.

[0229] In some embodiments, the pharmaceutical compositions provided herein (e.g., such as described in Example 2) comprise Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, and any combination of glyceryl behenate (Compritol® 888 ATO), mannitol, silicified microcrystalline cellulose, magnesium stearate, hydroxypropylmethylcellulose (Benecel K4M), lactose, and ethylcellulose (Surelease E-7-19040).

[0230] In some embodiments, the pharmaceutical compositions comprise the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, glyceryl behenate(Compritol® 888 ATO), mannitol, silicified microcrystalline cellulose, and magnesium stearate. In some embodiments, the pharmaceutical composition comprises Tablet 1 of Table 3.

[0231] In some embodiments, the pharmaceutical compositions comprise the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, magnesium stearate, hydroxypropylmethylcellulose (Benecel K4M), and lactose. In some embodiments, the pharmaceutical composition comprises Tablet 2 of Table 3.

[0232] In some embodiments, the pharmaceutical compositions comprise Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1, mannitol, silicified microcrystalline cellulose, magnesium stearate, and ethylcellulose (Surelease E-7-19040). In some embodiments, the pharmaceutical composition comprises Tablet 3 of Table 3.

[0233] In some embodiments, immediate release component provided herein provides a therapeutically effective amount of the compounds provided herein and the extended release components (e.g., or extended release matrix) or delayed release component maintains the therapeutically effective amount of the compound for any suitable period of time.

[0234] In some embodiments, the pharmaceutical compositions provided herein are administered to an individual at any frequency required to provide therapeutic benefit. In some embodiments, the pharmaceutical compositions are administered to an individual at most once per day, twice per day, or three times per day. In some embodiments, the pharmaceutical compositions are administered to an individual once per day. In some embodiments, the pharmaceutical compositions provided herein are administered to an individual daily, every day, every alternate day, five days a week, once a week, every other week, two weeks per month, three weeks per month, or once a month. In some embodiments, the pharmaceutical compositions provided herein are administered to an individual for any period of time required to achieve the desired therapeutic benefit. In some embodiments, the pharmaceutical compositions provided herein are administered to an individual for at least 1 week, at least 2 weeks, at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more.

[0235] In some embodiments, the pharmaceutical compositions and compositions provided herein (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) are administered to an individual in any amount suitable as determined by one skilled in the art. In some embodiments, the compounds provided herein are administered to an individual in an amount of at least 0.01 mg / kg (e.g., at least 0.1 mg / kg, at least 1 mg / kg). In some embodiments, the compounds provided herein are administered to an individual in an amount of at most 10 mg / kg(e.g., at most 1 mg / kg, at most 0.1 mg / kg). In some embodiments, the compounds provided herein are administered to an individual in an amount of about 0.01 mg / kg to about 10 mg / kg.

[0236] In some embodiments, the compounds provided herein (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) are administered to an individual in an amount of at least 1 mg (e.g., at least 5 mg, at least 10 mg, at least 25 mg, at least 50 mg, at least 100 mg, at least 250 mg). In some embodiments, the compounds provided herein are administered to an individual in an amount of at most 1000 mg (e.g., at most 500 mg, at most 250 mg, at most 100 mg, at most 50 mg). In some embodiments, the compounds provided herein are administered to an individual in an amount of about 1 mg to about 1000 mg. In some embodiments, the compounds provided herein are administered to an individual in an amount of about 50 mg to about 250 mg. In some embodiments, the compounds provided herein are administered to an individual in an amount of about 20 mg to about 80 mg (e.g., of the Compound). In some embodiments, the compounds provided herein are administered to the individual in an amount of about 40 mg, such as via a tablet described in Example 2. In some embodiments, the compounds provided herein are administered to the individual in an amount of 5 mg or 10 mg, such as described in Example 1. In some embodiments, the compound provided herein are administered to an individual in an amount of about 20 mg. In some embodiments, the compounds provided herein are administered to an individual in an amount of about 30 mg.

[0237] In some embodiments, the extended-release and / or delayed release components (e.g., of the pharmaceutical compositions) provided herein have modified pharmacokinetics in comparison to an immediate release component provided herein. In some embodiments, the extended-release components (e.g., of the pharmaceutical compositions) provided herein have modified pharmacokinetics in comparison to the delayed or immediate release components provided herein. In some embodiments, the delayed release components (e.g., of the pharmaceutical compositions) provided herein have modified pharmacokinetics in comparison to an immediate release component provided herein.

[0238] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) after at least 1 hour (e.g., at least 2 hours, at least 4 hours, at least 6 hours, at least 10 hours, at least 16 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided inTable 1) after at least 4 hours. In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) after at least 8 hours.

[0239] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) after at most 24 hours (e.g., at most 20 hours, at most 16 hours, at most 12 hours, at most 8 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) after about 1 hour to about 24 hours. In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) after about 1 hour to about 8 hours.

[0240] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) for at least 1 hour (e.g., at least 2 hours, at least 4 hours, at least 6 hours, at least 10 hours, at least 16 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) for at most 24 hours (e.g., at most 20 hours, at most 16 hours, at most 12 hours, at most 8 hours).

[0241] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) for about 1 hour to about 24 hours. In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a therapeutically effective physiological (e.g., serum or plasma)concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) for about 1 hour to about 8 hours.

[0242] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 1 ng / mL (e.g., at least 2.5 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) for at least 2 hours (e.g., at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 20 ng / mL for at least 2 hours (e.g., at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 1 ng / mL (e.g., at least 2.5 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) for at least 6 hours.

[0243] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at most 40 ng / mL (e.g., at most 30 ng / mL, at most 20 ng / mL, at most 15 ng / mL, at most 10 ng / mL, at most 5 ng / mL, at most 2.5 ng / mL, at most 1 ng / mL) for at least 2 hours (e.g., at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours).

[0244] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 1 ng / mL (e.g., at least 2.5 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) for at most 24 hours (e.g., at most 18 hours, at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 2 hours).

[0245] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma)concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at most 40 ng / mL (e.g., at most 30 ng / mL, at most 20 ng / mL, at most 15 ng / mL, at most 10 ng / mL, at most 5 ng / mL, at most 2.5 ng / mL, at most 1 ng / mL) for at most 24 hours (e.g., at most 18 hours, at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 2 hours).

[0246] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of about 1 ng / mL to about 40 ng / mL for about 2 hours to about 24 hours.

[0247] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 1 ng / mL (e.g., at least 2.5 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) after at least 2 hours (e.g., at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours).

[0248] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at most 40 ng / mL (e.g., at most 30 ng / mL, at most 20 ng / mL, at most 15 ng / mL, at most 10 ng / mL, at most 5 ng / mL, at most 2.5 ng / mL, at most 1 ng / mL) after at least 2 hours (e.g., at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours).

[0249] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at least 1 ng / mL (e.g., at least 2.5 ng / mL, at least 5 ng / mL, at least 10 ng / mL, at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) after at most 24 hours (e.g., at most 18 hours, at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 2 hours).

[0250] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of at most 40 ng / mL (e.g., at most 30 ng / mL, at most 20 ng / mL, atmost 15 ng / mL, at most 10 ng / mL, at most 5 ng / mL, at most 2.5 ng / mL, at most 1 ng / mL) after at most 24 hours (e.g., at most 18 hours, at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 2 hours).

[0251] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) of about 1 ng / mL to about 40 ng / mL after about 2 hours to about 24 hours.

[0252] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 2 hours (e.g., at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours). In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 8 hours.

[0253] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 4 hours. In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 6 hours. In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 8 hours.

[0254] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma)concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at most 18 hours (e.g., at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 3 hours, at most 2 hours).

[0255] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after about 2 hours to about 18 hours.

[0256] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration for at least 2 hours (e.g., at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours).

[0257] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration for at most 18 hours (e.g., at most 12 hours, at most 8 hours, at most 6 hours, at most 4 hours, at most 3 hours, at most 2 hours).

[0258] In some embodiments, when any one of the pharmaceutical compositions provided herein is administered to an individual, the individual maintains a physiological (e.g., serum or plasma) concentration of the compound (e.g., the compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration for about 2 hours to about 18 hours.

[0259] In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is at least about 15 ng / mL (e.g., at least 20 ng / mL, at least 30 ng / mL, at least 40 ng / mL) (FIG. 1A-B, FIG 3A-B). In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is at most 60 ng / mL (e.g., at most 50 ng / mL, at most 40 ng / mL, at most 30 ng / mL, at most 20 ng / mL). In some embodiments, the maximum physiological (e.g. plasma) concentration, such as describedin Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is about 15 ng / mL to about 60 ng / mL.

[0260] In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is at least about 30 nM (e.g., at least 50 nM, at least 70 nM, at least 90 nM, at least 110 nM) (FIG. 2A- B, FIG 4A-B) In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is at most 120 nM (e.g., at most 100 nM, at most 80 nM, at most 60 nM, at most 40 nM). In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is at most 120 nM (e.g., at most 100 nM, at most 80 nM, at most 60 nM, at most 40 nM). In some embodiments, the maximum physiological (e.g., plasma) concentration of a compound described herein (e.g., a Compound of Formula (I)) is at most 350 ng / mL (e.g., at most 325 ng / mL, 300 ng / mL, 290 ng / mL, 280 ng / mL, 250 ng / mL, 200 ng / mL, or 150 ng / mL). In some embodiments, the maximum physiological (e.g. plasma) concentration, such as described in Example 1, of a compound described herein (e.g., a Compound of Formula (I)) is about 40 nM to about 110 nM. In some embodiments, the maximum physiological (e.g., plasma) concentration of a compound described herein (e.g., a Compound of Formula (I)) is from about 10 ng / mL to about 300 ng / mL, about 10 ng / mL to about 30 ng / mL, about 20 ng / mL to about 50 ng / mL, about 50 ng / mL to about 110 ng / mL, or about 100 ng / mL to about 300 ng / mL.

[0261] In some embodiments, the maximum physiological (e.g., plasma) concentration (e.g., Cmax) of a compound described herein is at least 10 ng / mL (e.g., at least 20 ng / mL, 30 ng / mL, 40 ng / mL, 50 ng / mL, 75 ng / mL, 100 ng / mL, 150 ng / mL, 200 ng / mL, or 250 ng / mL), such as described in Table 5 and Table 6. In some embodiments, the maximum physiological (e.g., plasma) concentration (e.g., Cmax) of a compound described herein is at most 300 ng / mL (e.g., at most 280 ng / mL, 250 ng / mL, 225 ng / mL, 200 ng / mL, 150 ng / mL, 125 ng / mL, or 100 ng / mL), such as described in Table 5 and Table 6. In some embodiments, the maximum physiological (e.g., plasma) concentration (e.g., Cmax) of a compound described herein is about 10 ng / mL to about 300 ng / mL (e.g., about 20 ng / mL to about 50 ng / mL, about 50 ng / mL to about 110 ng / mL, or about 100 ng / mL to about 290 ng / mL).

[0262] Example 1 describes the physiological half life of a compound provided herein provided as an instant release formulation. In some embodiments, the physiological (e.g., serum or plasma) half life of a pharmaceutical composition comprising a delayed or extended release component provided herein (e.g., comprising a Compound of Formula (I)) is at least 3 hours (e.g., at least 4hours, at least 6 hours, at least 8 hours, at least 12 hours). In some embodiments, the physiological (e.g., serum or plasma) half life of a pharmaceutical composition comprising a delayed or extended release component provided herein (e.g., comprising a Compound of Formula (I)) is at most 18 hours (e.g., at most 16 hours, at most 12 hours, at most 8 hours). In some embodiments, the physiological (e.g., serum or plasma) half life of a pharmaceutical composition comprising a delayed or extended release component provided herein (e.g., comprising a Compound of Formula (I)) is at about 3 hours to about 18 hours.

[0263] In some instances, the physiological half life (T1 / 2) of an instant release composition provided herein is at least 1.5 hr (e.g., at least 1.6 hr, 1.7 hr, 1.8 hr, 1.9 hr, 2 hr, 2.2 hr, 2.4 hr, 2.6 hr, 2.8 hr, or at least 3 hr). In some embodiments, the physiological half life (T1 / 2) of an instant release composition provided herein is at most 6 hr (e.g., at most 6.5 hr, 6.3 hr, 6 hr, 5.5 hr, 5 hr, 4.5 hr, 4 hr, 3.5 hr, or at most 3 hr). In some embodiments, the physiological half life (T1 / 2) of an instant release composition provided herein is about 1.5 hr to about 6 hr (e.g., about 1.5 hr to about 4 hr, or about 1.5 hr to about 3 hr).

[0264] In some embodiments, administration of a compound provided herein provides an AUCo-t of at least 50 hr*ng / mL (e.g., at least 60 hr*ng / mL, 70 hr*ng / mL, or 80 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-tau of at most 100 hr*ng / mL (e.g., at most 95 hr*ng / mL, 90 hr*ng / mL, 85 hr*ng / mL, or 80 hr*ng / mL). In some embodiments, administration o fa compound provided herein provides an AUCo-tau of from about 50 hr*ng / mL to about 100 hr*ng / mL (e.g., about 50 hr*ng / mL to about 90 hr*ng / mL, about 60 hr*ng / mL to about 90 hr*ng / mL or about 70 hr*ng / mL to about 90 hr*ng / mL).

[0265] In other embodiments, administration of a compound provided herein provides an AUCo-t of at least 80 hr*ng / mL (e.g., at least 85 hr*ng / mL, 90 hr*ng / mL, 95 hr*ng / mL, 100 hr*ng / mL, 110 hr*ng / mL, 125 hr*ng / mL, or 140 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of at most 170 hr*ng / mL (e.g., at most 160 hr*ng / mL, 150 hr*ng / mL, 140 hr*ng / mL, 130 hr*ng / mL, 120 hr*ng / mL, 110 hr*ng / mL, or 100 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of from about 80 hr*ng / mL to about 170 hr*ng / mL (e.g., about 80 hr*ng / mL to about 160 hr*ng / mL, about 90 hr*ng / mL to about 160 hr*ng / mL, about 80 hr*ng / mL to about 110 hr*ng / mL, or about 140 hr*ng / mL to about 170 hr*ng / mL).

[0266] In other embodiments, administration of a compound provided herein provides an AUCo-t of at least 175 hr*ng / mL (e.g., at least 180 hr*ng / mL, 190 hr*ng / mL, 200 hr*ng / mL, 210 hr*ng / mL, 220 hr*ng / mL, or 250 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of at most 500 hr*ng / mL (e.g., at most 400hr*ng / mL, 300 hr*ng / mL, 275 hr*ng / mL, 250 hr*ng / mL, 225 hr*ng / mL, or 200 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of from about 175 hr*ng / mL to about 500 hr*ng / mL (e.g., about 190 hr*ng / mL to about 300 hr*ng / mL, about 190 hr*ng / mL to about 250 hr*ng / mL, or from about 200 hr*ng / mL to about 250 hr*ng / mL).

[0267] In other embodiments, administration of a compound provided herein provides an AUCo-t of at least 600 hr*ng / mL (e.g., at least 700 hr*ng / mL, 800 hr*ng / mL, 900 hr*ng / mL, 1000 hr*ng / mL, 1100 hr*ng / mL, 1200 hr*ng / mL, or 1300 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of at most 1700 hr*ng / mL (e.g., at most 1600 hr*ng / mL, 1500 hr*ng / mL, 1400 hr*ng / mL, 1300 hr*ng / mL, 1200 hr*ng / mL, 1100 hr*ng / mL, or 1000 hr*ng / mL). In some embodiments, administration of a compound provided herein provides an AUCo-t of from about 600 hr*ng / mL to about 1700 hr*ng / mL (e.g., about 600 hr*ng / mL to about 1500 hr*ng / mL, about 700 hr*ng / mL to about 1500 hr*ng / mL, or about 800 hr*ng / mL to about 1500 hr*ng / mL).

[0268] In some instances, AUC (exposure) is independent of an individual’s body weight or body surface area.

[0269] In some instances, the compounds provided herein do not accumulate after, for example, 6 days of dosing.

[0270] Provided herein are methods of treating diseases or conditions comprising administering to an individual any one of the pharmaceutical compositions provided herein.

[0271] In some embodiments, the methods provided herein comprise administering a therapeutically effective amount of a compound provided herein. In some embodiments, the methods provided herein comprise administering a therapeutically effective amount of a compound provided herein comprised in a pharmaceutical composition provided herein.

[0272] In some embodiments, provided herein are methods of treating a disease or condition associated with bromodomain inhibition comprising administering to an individual in need thereof a pharmaceutical composition provided else herein (e.g., such as a composition comprising a compound provided elsewhere herein and one or more of an immediate release, extended release, and delayed release component). In some embodiments, the pharmaceutical compositions are administered in any frequency or dosage provided elsewhere herein.

[0273] In some embodiments, the disease or condition provided herein is an auto-immune disorder, an anti-inflammatory disorder, a dermal disorder, or cancer.

[0274] In some embodiments, the disease or disorder is an auto-immune disorder.

[0275] In some embodiments, the disease or disorder is an inflammatory disorder.

[0276] In some embodiments, the inflammatory disorder is rheumatoid arthritis, irritable bowel syndrome, or psoriasis. In some embodiments, the inflammatory disorder is rheumatoid arthritis. In some embodiments, the inflammatory disorder is irritable bowel syndrome. In some embodiments, the inflammatory disorder is psoriasis.

[0277] In some embodiments, the disease or disorder is cancer.

[0278] In some embodiments, provided herein are methods of treating cancer comprising administering to an individual in need thereof a pharmaceutical composition provided else herein (e.g., such as a composition comprising a compound provided elsewhere herein and one or more of an immediate release, extended release, and delayed release component).

[0279] In some embodiments, the cancer is brain cancer, pancreatic cancer, breast cancer, lung cancer, or prostate cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is bowel cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is non-hodgkin lymphoma. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is skin cancer.

[0280] In some embodiments, the cancer is a lymphoma, leukemia, or sarcoma. In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a sarcoma.

[0281] In some embodiments, the cancer is glioblastoma multiforme or acute myeloid leukemia. In some embodiments, the cancer is glioblastoma multiforme. In some embodiments, the cancer is acute myeloid leukemia.

[0282] In specific embodiments, the cancer is nuclear protein in testis (NUT) carcinoma. NUT carcinoma is a rare, aggressive type of cancer, in some instances characterized by chromosomal rearrangements involving the NUT gene. NUT carcinoma may be NUT midline carcinoma (e.g., occurring in the midline structures of the body such as the head, neck, and lungs).

[0283] In some embodiments, the cancer is an MYC-dependent cancer. In some instances, MYC- dependent cancers include lymphoma, lung cancer, neuroblastoma, colorectal cancer, multiple myeloma, ovarian cancer, or prostate cancer.

[0284] In specific embodiments, the cancer is prostate cancer.

[0285] Provided herein is a method of treating an individual with an MYC-dependent cancer, comprising administering to the individual a BET inhibitor (e.g., a compound provided herein suchas a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1) that is identified as capable of decreasing at least one of MYC mRNA expression, MYC protein expression and tumor mass, wherein following the administration, there is a decrease in at least one of MYC mRNA expression, MYC protein expression and tumor mass, thereby treating the disease.

[0286] Provided herein is a method of decreasing CCR2 (C-C Motif Chemokine Receptor 2) expression in an individual with cancer (e.g., a CCR2 associated cancer). In some embodiments, provided herein is a method of treating a CCR2-associated cancer in an individual. In some embodiments, the method comprises administering to the individual a compound provided herein such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1.

[0287] A CCR2-dependent cancer (e.g., cancer associated with CCR-2 dysregulation) may comprise breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, or ovarian cancer. In some instances, the CCR2-associated cancer is prostate cancer. CCR2 may be involved in the recruitment of immune cells to the tumor microenvironment in prostate cancer, thereby aiding in cancer progression. The compounds provided herein may be useful in decreasing CCR2 expression, as described in Example 4.

[0288] Provided herein is a method of increasing HEXIM1 (hexamethylene bisacetamide- inducible protein 1) expression in individuals with cancer (e.g., cancer associated with (e.g., decreased) HEXIM1 expression). In some embodiments, provided herein is a method of treating cancer in individuals with decreased levels of HEXIM1. In some embodiments, the method comprises administering to the individual a compound provided herein such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1.

[0289] Cancers associated with (e.g., decreased) HEXIM1 expression (e.g., associated with dysregulation of HEXIM1) may comprise breast cancer, prostate cancer, lung cancer, and leukemia. In some instances, the cancer associated with HEXIM1 expression is pancreatic cancer. HEXIM1 may inhibit the growth of prostate cancer cells and its low expression may be associated with advanced stages of prostate cancer. The compounds provided herein may be useful in increasing HEXIM1 expression, as described in Example 4.

[0290] Provided herein is a method of decreasing CD274 (programmed death ligand 1 (PD — LI)) expression in an individual with cancer (e.g., a CD274 associated cancer). In some embodiments, provided herein is a method of treating a CD274-associated cancer in an individual. In some embodiments, the method comprises administering to the individual a compound provided herein such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1.

[0291] Cancers associated with CD274 (e.g., related to dysregulation of CD274) may include nonsmall cell lung cancer (NSCLC), breast cancer, melanoma, kidney cancer, bladder cancer, and Hodgkin’s lymphoma. The compounds provided herein may be useful in decreasing CD274 expression, as described in Example 4.

[0292] Provided herein is a method of decreasing MYB expression in an individual with cancer (e.g., a MYB associated cancer). In some embodiments, provided herein is a method of treating a MYB-associated cancer in an individual. In some embodiments, the method comprises administering to the individual a compound provided herein such as a compound of Formula (I), (II), (Ila), (lib), (IV), (IVa), (IVb), or provided in Table 1.

[0293] MYB associated cancers (e.g., related to dysregulation of MYB) may comprise acute myeloid leukemia (AML), breast cancer, colorectal cancer, and adenoid cystic carcinoma. The compounds provided herein may be useful in decreasing MYB expression, as described in Example 4.

[0294] In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent, such as a chemotherapeutic agent.

[0295] Acetylated histone recognition and bromodomain-containing proteins (such as BET proteins) have been implicated in proliferative disease. BRD4 knockout mice die shortly after implantation and are compromised in their ability to maintain an inner cell mass, and heterozygotes display pre- and postnatal growth defects associated with reduced proliferation rates. BRD4 regulates genes expressed during M / GI, including growth- associated genes, and remains bound to chromatin throughout the cell cycle. BRD4 also physically associates with Mediator and P- TEFb (CDK9 / cyclin Tl) to facilitate transcriptional elongation. CDK9 is a validated target in chronic lymphocytic leukemia (CLL), and is linked to c-MYC- dependent transcription.

[0296] BRD4 is translocated to the NUT protein in patients with lethal midline carcinoma, an aggressive form of human squamous carcinoma. In vitro analysis with RNAi supports a causal role for BRD4 in this recurrent t(l 5 ; 19) chromosomal translocation. Pharmacologic inhibition of the BRD4 bromodomains results in growth arrest / differentiation of BRD4-NUT cell lines in vitro and in vivo.

[0297] Bromodomain-containing proteins (such as BET proteins) have also been implicated in inflammatory diseases. BET proteins {e.g., BRD2, BRD3, BRD4, and BRDT) regulate assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression. Key inflammatory genes (secondary response genes) are down-regulated upon bromodomain inhibition of the BET subfamily, and non-responsive genes (primary response genes) are poisedfor transcription. BET bromodomain inhibition protects against LPS-induced endotoxic shock and bacteria-induced sepsis in vivo.

[0298] In certain embodiments, a compound provided herein inhibits one or more of BRD2, BRD3, BRD4, BRDT, and / or another member of the bromodomain-containing proteins, or a mutant thereof. In some embodiments, a provided compound inhibits two or more of BRD2, BRD3, BRD4, BRDT, and / or another member of the bromodomain-containing proteins, or a mutant thereof. Provided compounds are inhibitors of one of more of the bromodomain-containing proteins, such as BRD2, BRD3, BRD4, and / or BRDT and are therefore useful for treating one or more disorders associated with activity of one or more of the bromodomain-containing proteins, such as BRD2, BRD3, BRD4, and / or BRDT. Thus, in certain embodiments, the present description provides a method for treating an bromodomain-containing protein-mediated disorder, such as a BET- mediated, a BRD2-mediated, a BRD3 -mediated, a BRD4-mediated disorder, and / or a BRDT- mediated disorder comprising the step of inhibiting a bromodomain-containing protein, such as a BET protein, such as BRD2, BRD3, BRD4, and / or BRDT, or a mutant thereof, by administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable composition thereof.

[0299] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.EXAMPLESExample 1: Pharmacokinetics of Compound 1

[0300] The pharmacokinetics of Compound 1 were examined in 2 individuals over the course of 7 days. The individuals were orally administered instant release formulations of 5 mg, 10 mg, 20 mg, 30 mg, or 45 mg of the compound once daily for the 7 day treatment. In some instances, the individuals had targeted advanced solid tumors. The plasma concentrations over the course of 12 hours were measured on day 1 of administrations with 5 mg, 10 mg, 20 mg, 30 mg, or 45 mg of the compound in ng / mL and / or nM (FIG. 1A-1B, FIG. 2A-2B, and FIG. 5). The data on both day 1 and day 7 timepoints indicated a peak in plasma concentration within about 2-3 hours. The peak plasma concentration for the individual receiving the 10 mg dose was 47.8 ng / mL. The peakplasma concentration for the individual receiving the 5 mg dose was 19.6 ng / mL. On day 7, plasma concentrations of the compound in Subject 2, receiving 10 mg of the compound, were examined (FIG. 3A-3B, FIG. 4A-4B). On day 7, plasma concentrations of the compound in 2-6 individuals were measured after receiving 10 mg, 20 mg, 30 mg, or 45 mg of the compound (FIG. 6). In one instance, the plasma concentrations peaked within 4 hours on day 7 (e.g., for Subject 002-002). The maximum plasma concentration was 30.2 ng / mL. Half lives and other pharmacokinetic parameters were determined as found in Table 2 A and 2B. Half lives of Compound 1 were found to be from about 2 to about 5 hours. For instance, the half life of compound one was found to be 2.44 hr and 2.64 hr for Subject 2 receiving 10 mg doses on day 1 and 7 respectively.Table 2ATable 2BExample 2: Modified Release Compositions

[0301] Extended release (ER) tablets were manufactured using direct compression and wet granulation processes (Table 3). The tablets were analyzed using 2-stage dissolution in acid medium (0.1 N HC1) for 2 hours followed by 50 mM phosphate buffer pH 6.8 until 24 hours.Table 3

[0302] All ER tablets exhibited greater than 90% release of Compound 1 by 24 hours. Each of the dissolution profiles show decrease in % release after 1 hour in the pH 6.8 buffer, which may be due to slower solubilization of Compound 1 at pH 6.8. Compound 1 was fully solubilized after 2 hours in the buffer (e.g., at the 4-hour sampling time point).

[0303] Comparative dissolution profiles (FIG. 7 & Table 4) show the direct compression lipid- based tablet (Tablet 1) rapidly dissolves with full release by 2 hours, slightly slower than the comparative 10 mg immediate release (IR) tablet (Tablet 4). The wet granulation ethylcellulose- based tablet (Tablet 3) showed a slower release profile with 84% released by 5 hours. In some instances, the tablets do not disintegrate, but split into two halves. The direct compression hypromellose-based tablet (Tablet 2) showed a dissolution profile with 57% of Compound 1 released at 5 hours and full release at 24 hours. The dissolution profiles in FIG. 7 and Table 4 include dissolution in 750 mL 0.1 M HC1 for 2 hours followed by 22 hours in 1000 mL of 50 mM phosphate buffer (pH 6.8).Table 4Dissolution conditions = Paddles % 50 rpm, 750 mL 0. IN HC1 x 2 hrs, 1000 mL 50 mM phosphate buffer, pH 6.8 (n = 6)Example 3: Pharmacokinetics of Compound 1 in Individuals with Prostate Cancer or NUT Carcinoma

[0304] Pharmacokinetics of Compound 1 were evaluated in individuals diagnosed with prostate cancer or nuclear protein in testis (NUT) carcinoma. The individuals were administered a dose of 5, 10, 20, or 30 mg of Compound 1. As shown in FIG. 8 A and FIG. 8B, AUC / dose((hr*ng / mL) / mg) was measured as a function of individual body weight and body surface area (BSA). The data at both days 1 and 7 of administration with the compound generally show a decrease in AUC / dose with increasing weight and BSA.

[0305] Plasma concentration of the compound were evaluated over about 20 hours on day 1 of treatment in a subject with prostate cancer and administered 5 mg of the compound (FIG. 9). In this instance, the plasma concentration reached a maximum at about 2 hours after administration. The half life was determined to be about 2.6 hr.

[0306] Similarly, plasma concentrations of the compound were evaluated over in a subject with prostate cancer, after administration with 10 mg of the compound. Plasma concentration was measured on days 1 and 7 of administration with the compound (FIG. 10). On day 1, the plasma concentration reached a maximum at about 1 hour after administration. On day 7, the blood plasma concentration reached a maximum at about 2 hours after administration. The half lives of the compound on days 1 and 7 were determined to be about 2.44 hr and 1.96 hr, respectively.

[0307] Plasma concentrations of the compound were evaluated in subjects with prostate cancer, after administration with 20 mg of the compound. Plasma concentrations were measured on days 1 and 7 of administration (FIG. 11A-C). On day 1, the plasma concentration reached a maximum at about 0.5 hr to 2 hr after administration. On day 7, the plasma concentration reached a maximum at between 0.5 hr and 3 hr after administration. The average half life of the compound on day 1 was about 2.5 hr (between 2 hr and 2.4 hr). The average half life of the compound on day 7 was about 3.1 hr (between 2.5 hr and 3.7 hr).

[0308] Plasma concentrations of the compound were evaluated in subjects with prostate cancer, after administration with 30 mg of the compound. Plasma concentrations were measured on days 1 and 7 of administration (FIG. 12A-D). On day 1, the plasma concentration reached a maximum at about 0.5 hr to 4 hr. On day 7, the plasma concentration reached a maximum at about 1 hr to 4 hr. The average half life of the compound on day 1 was about 4.1 hr (between 3.6 hr to 5.1 hr). The average half life of the compound on day 7 was about 3.8 hr (between 3.2 hr and 4.2 hr).

[0309] A summary of the pharmacokinetic studies on individuals with prostate cancer is shown in Table 5.Table 5

[0310] Plasma concentrations of the compound were evaluated in subjects with NUT carcinoma, after administration with 30 mg of the compound. Plasma concentrations were measured on days 1 and 7 of administration (FIG. 13A-B). On day 1, the plasma concentration reached a maximum at about 1 hr. On day 7, the plasma concentration reached a maximum (Tmax) at about 1 hr or 4 hr. The half life of the compound on day 1 was 3.52 or 4.33 hr. The half life of the compound on day 7 was 3.25 hr. A summary of the pharmacokinetic studies on individuals with NUT carcinoma are shown in Table 6.Table 6Example 4: Modulation of Gene Expression After Administration of Compound 1

[0311] Subjects administered with varying amounts of Compound 1 were evaluated for modulation of expression of CCR2, HEXIM1, MYC, CD274, and MYB.

[0312] The CCR2 response to Compound 1 was evaluated in 1 subject administered 10 mg of Compound 1, 1 subject administered 20 mg of Compound 1, 4 subjects administered 30 mg of Compound 1, and 3 subjects administered 45 mgs of Compound 1. All doses resulted in decrease in CCR2 expression 4 and 8 hours post-administration (FIG. 14A-B).

[0313] The HEXIM1 response to Compound 1 was evaluated in 1 subject administered 10 mg of Compound 1, 1 subject administered 20 mg of Compound 1, 4 subjects administered 30 mg of Compound 1, and 3 subjects administered 45 mgs of Compound 1. 20-45 mg doses of Compound resulted in increased HEXIM1 expression 4 and 8 hours post-administration (FIG. 15A-B).

[0314] MYC response to Compound 1 was evaluated in subjects administered 10 mg, 20 mg, 30 mg, and 45 mg. Higher doses (e.g., 30-40 mg) resulted in decreasing quantity of MYC postadministration. Lower doses (e.g., 10 mg, 20 mg) were only evaluated on single subjects resulting in more inconsistent preliminary results.

[0315] CD274 response to Compound I was evaluated in 3 subjects, 2 of which were administered 30 mg of the compound, and 1 of which was administered 45 mg of the compound. Higher doses of Compound I resulted in decreases in CD274 expression post-administration (FIG. 16).

[0316] MYB response to Compound I was evaluated in 3 subjects, 2 of which were administered 30 mg of the compound, and 1 of which was administered 45 mg of the compound. Higher doses of Compound I resulted in decreases in MYB expression post-administration (FIG. 17).

Claims

CLAIMSWe claim:

1. A pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after at least 1 hour.

2. A pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 10 ng / mL after at least 4 hours.

3. A pharmaceutical composition, comprising a delayed or extended-release component, the delayed or extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, the individual has a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after at least 3 hours.

4. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the extended-release component.

5. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 1 hour.

6. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 2 hours.

7. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) after (e.g., for) at least 6 hours.

8. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to an individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 10 ng / mL after (e.g., for) at least 4 hours.

9. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 5 ng / mL after (e.g., for) at least 6 hours.

10. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 1 ng / mL after (e.g., for) at least 8 hours.

11. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) of at least 50 ng / mL after (e.g., for) at least 8 hours.

12. The pharmaceutical composition of any one of the preceding claims, wherein the extended release component is an extended release matrix.

13. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has(e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 3 hours.

14. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 6 hours.

15. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the individual has (e.g., maintains) a physiological (e.g., serum or plasma) concentration of the compound of Formula (I) that is at least 50% of the maximum physiological (e.g., serum or plasma) concentration after (e.g., for) at least 8 hours.

16. The pharmaceutical composition of any one of the preceding claims, wherein a physiological (e.g., serum or plasma) half life of the compound of Formula (I) is at least 3 hours.

17. The pharmaceutical composition of any one of the preceding claims, wherein a physiological (e.g., serum or plasma) half life of the compound of Formula (I) is at least 6 hours.

18. The pharmaceutical composition of any one of the preceding claims, wherein the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 10 ng / mL.

19. The pharmaceutical composition of any one of the preceding claims, wherein the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 30 ng / mL.

20. The pharmaceutical composition of any one of the preceding claims, wherein the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 100 ng / mL.

21. The pharmaceutical composition of any one of the preceding claims, wherein the maximum physiological (e.g., serum or plasma) concentration of compound of Formula (I) in the individual is at least 200 ng / mL.

22. The pharmaceutical composition of any one of the preceding claims, further comprising an immediate release component.

23. The pharmaceutical composition of any one of the preceding claims, wherein the immediate release component is an immediate release coating.

24. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) to the individual within at most 1 hour.

25. The pharmaceutical composition of any one of the preceding claims, wherein when the pharmaceutical composition is administered to the individual, the immediate release component provides a therapeutically effective physiological (e.g., serum or plasma) concentration of the compound of Formula (I) to the individual within at most 30 minutes.

26. A pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein when the pharmaceutical composition is administered to an individual, no more than about 70% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after 1 hour.

27. The pharmaceutical composition of claim 26, wherein no more than about 30% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 1 hour.

28. The pharmaceutical composition of claim 26 or 27, wherein no more than about 90% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 5 hours.

29. The pharmaceutical composition of any one of claims 26-28, wherein about 20% to about 80% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after about 1 hour.

30. A pharmaceutical composition comprising an extended-release component, the extended-release component comprising a compound, or pharmaceutically acceptable salt thereof, represented by Formula (I):wherein no more than about 70% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 1 hour.

31. The pharmaceutical composition of claim 30, wherein no more than about 30% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for1 hour.

32. The pharmaceutical composition of claim 30 or 31, wherein from about 20% by weight to about 70% by weight of the compound is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 1 hour.

33. The pharmaceutical composition of any one of claims 30-32, wherein no more than about 90% by weight of the compound or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition after exposure to 750 mL of 0.1 M HC1 for 2 hours followed by 1000 mL of 50 mM phosphate buffer (pH 6.8) for 3 hours.

34. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.

35. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the compound of Formula (I) in an amount of about 10% to about 30% by weight.

36. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more of a controlled-release agent, a filler, a binder, a lubricant, and a disintegrant.

37. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the controlled release agent in an amount of about 10% to about 30% by weight.

38. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the filler in an amount of about 30% to 70% by weight (e.g., about 30% to about 50% by weight).

39. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the binder in an amount of about 10% to about 30% by weight.

40. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the lubricant in an amount of about 0.5% to about 1.5% by weight.

41. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the controlled-release agent in an amount of about 10% to about 30% by weight;(c) the filler in an amount of about 30% to about 50% by weight;(d) the binder in an amount of about 10% to about 30% by weight; and(e) the lubricant in an amount of about 0.5% to about 1.5% by weight.

42. The pharmaceutical composition of any one of claims 1-40, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the lubricant in an amount of about 0.5% to about 1.5% by weight;(c) the disintegrant in an amount of about 10% to about 30% by weight; and(d) the filler in an amount of about 50% to about 70% by weight.

43. The pharmaceutical composition of any one of claims 1-40, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) in an amount of about 10% to about 30% by weight;(b) the filler (e.g., diluent) in an amount of about 30% to about 50% by weight;(c) the binder in an amount of about 10% to about 30% by weight;(d) the lubricant in an amount of about 0.5% to about 1.5% by weight; and(e) the controlled-release agent in an amount of about 10% to about 30% by weight.

44. The pharmaceutical composition of any one of claims 34-43, wherein the one or more pharmaceutically acceptable excipients comprise glyceryl behenate,mannitol, silicified microcrystalline cellulose, magnesium stearate, hydroxypropylmethylcellulose, lactose, and ethylcellulose.

45. The pharmaceutical composition of claim 44, wherein the one or more excipients comprise glyceryl behenate, mannitol, silicified microcrystalline cellulose, and magnesium stearate.

46. The pharmaceutical composition of claim 45, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) glyceryl behenate in an amount of about 20% by weight;(c) mannitol in an amount of about 40% by weight;(d) silicified microcrystalline cellulose in an amount of about 19% by weight; and(e) magnesium stearate in an amount of about 1% by weight.

47. The pharmaceutical composition of claim 44, wherein the one or more excipients comprise magnesium stearate, hydroxypropylmethylcellulose, and lactose.

48. The pharmaceutical composition of claim 47, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) magnesium stearate in an amount of about 1% by weight;(c) hydroxypropylmethylcellulose in an amount of about 20% by weight; and(d) lactose (e.g., monohydrate) in an amount of about 59% by weight.

49. The pharmaceutical composition of claim 44, wherein the one or more excipients comprise mannitol, silicified microcrystalline cellulose, magnesium stearate, and ethylcellulose.

50. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition comprises:(a) the compound of Formula (I) or pharmaceutically acceptable salt thereof in an amount of about 20% by weight;(b) mannitol in an amount of about 40% by weight;(c) silicified microcrystalline cellulose in an amount of about 19% by weight;(d) magnesium stearate in an amount of about 1% by weight; and(e) ethylcellulose in an amount of about 20% by weight.

51. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual in an amount of at least 5 mg.

52. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual in an amount of at least 10 mg.

53. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual in an amount of at least 50 mg.

54. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual in an amount of at most 250 mg.

55. The pharmaceutical composition of any one of the preceding claims wherein the pharmaceutical composition is administered to the individual in an amount of about 50 mg to about 250 mg.

56. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises at least 20 mg of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

57. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises about 40 mg of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

58. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual once daily.

59. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered to the individual, at least once daily.

60. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is in a solid dosage form.

61. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered orally, rectally, or via an implant.

62. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is administered orally.

63. The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is released in the individual for a period of at least 2 hours.

64. The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is released in the individual for a period of at least one day.

65. The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is released in the individual for a period of about 2 hours to about one day.

66. A method of treating a disease or condition associated with bromodomain inhibition comprising administering to an individual in need thereof a pharmaceutical composition of any one of the preceding claims.

67. The method of claim 66, wherein the disease or condition is cancer.

68. The method of claim 67, wherein the cancer is brain cancer, pancreatic cancer, breast cancer, lung cancer, or prostate cancer.

69. The method of claim 67, wherein the cancer is a lymphoma, leukemia, or sarcoma.

70. The method of any one of claims 67-69, wherein the cancer is glioblastoma multiforme or acute myeloid leukemia.

71. A method of treating a MYC-dependent cancer in an individual in need thereof, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-65.

72. A method of treating a CCR2-associated cancer in an individual in need thereof, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-65.

73. A method of treating a HEXIM 1 -associated cancer in an individual in need thereof, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-65.

74. A method of treating a CD274-associated cancer in an individual in need thereof, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-65.

75. A method of treating a MYB-associated cancer in an individual in need thereof, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-65.

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