Novel compounds for treating cancer

Abstract

The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X, R1, R2, R3, R4, L, R5, m, n, o, and p is defined herein. Also provided arc methods of treating cancer.

Description

Attorney Docket No.: 272050-553087 PCT APPLICATION NOVEL COMPOUNDS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the benefit of Indian patent application no. 202311060879, filed Sept.11, 2023, and US provisional application no.63 / 592,668, filed Oct.24, 2023. Each of these documents is incorporated herein by reference. FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods of treating cancer in a subject in need thereof. BACKGROUND

[0003] Cancer remains one of the most deadly threats to human health. Certain cancers can metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult. In the United States, cancer affects nearly 1.9 million new patients each year and is the second leading cause of death after heart disease. While numerous anticancer agents are approved for use therapeutically, very few have activity against a broad spectrum of cancers. This is because there can be very significant differences among individual cancers. Additionally, most anticancer agents are believed to treat cancer via multiple mechanisms of action, further diminishing the number of agents that are broadly efficacious against a broad spectrum of cancers. Most current efforts focus on cancer treatment, with less emphasis placed on patient quality of life during cancer treatment and management of end of life care, or palliative treatment for glioblastoma multiforme patients whose condition is terminal.

[0004] Gliomas are a class of primary tumors that originate in the brain and / or spine. The most common type of gliomas are astrocytomas. Astrocytomas are graded on a scale from I to IV based on how normal or abnormal the cells appear: Grade I - pilocytic astrocytoma; Grade II – diffuse astrocytoma; Grade III – anaplastic astrocytoma; and Grade IV – glioblastoma, also known as glioblastoma multiforme (GBM). Low-grade astrocytomas are usually localized and grow slowly. High-grade astrocytomas grow at a rapid pace and require a different course of treatment.

[0005] GBM accounts for about 48% of all primary malignant brain tumors, and usually results in death within 12-15 months of diagnosis. GBM has a five-year survival rate of 3- 7%.

[0006] Currently, there is no known method of preventing GBM. Furthermore, treatment of GBM can be extremely difficult due to a variety of factors, including the brain’s limited57260921.11Attorney Docket No.: 272050-553087 PCT APPLICATION capacity for self-repair, difficulty in drugs passing the blood-brain barrier, potential of damage to the brain by use of conventional therapies (such as aggressive chemotherapy, radiation, and / or surgery), and difficulty in surgically removing all cancerous cells due to infiltration of the tumor throughout the brain. Due to these aforementioned challenges in treating GBM, most care for GBM patients involves palliative care, care to help slow the spread, and other measures aimed at temporarily improving survival and / or lifestyle of GBM patients.

[0007] Accordingly, there remains a need for compounds and methods for treating cancer generally, and GBM specifically. The compounds, pharmaceutical compositions, and methods described herein are directed toward this end. SUMMARY OF THE INVENTION

[0008] The present invention provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-6 alkyl; each R1, R2, and R4is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R1, R2, and R4is independently optionally substituted with halo, –OH, or oxo, the C2-6 alkenyl, the C2-6 alkynyl, and the monocyclic ring of each R1, R2, and R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo, and wherein each R is independently –H or C1-6alkyl; R3is –H or optionally substituted C1-6alkyl; L is a bond or a C1-6aliphatic chain optionally substituted with halo, unsubstituted C1-3alkyl, –OH, –CN, or oxo; R5is –H or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring is optionally substituted with 1-3 groups independently selected from halo,57260921.12Attorney Docket No.: 272050-553087 PCT APPLICATION –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo; and each of m and n is independently 0, 1, 2, 3, 4, or 5; o is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; provided that the compound is not a compound selected from the compounds identified in Table 1, or any pharmaceutically acceptable salt thereof.

[0009] In some embodiments, X is –O–, –S–, –NH–, or –N(CH3)–. In other embodiments, X is –O– or –S–. And, in some embodiments, X is –O–.

[0010] In some embodiments, m is 1, 2, 3, 4, or 5; and each R1is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In other embodiments, each R1is independently halo, C1-6alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, each R1is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, m is 1. For example, m is 1, and R1is –F, –Cl, –Br, –CH3, or phenyl. And, in some embodiments, m is 0.

[0011] In some embodiments, n is 1, 2, 3, 4, or 5; and each R2is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3- 6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and heterocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, each R2is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, each R2is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, R2is –F, –Cl, –Br, or –CH3. In some embodiments, n is 1. For example, n is 1, and R2is –F, –Cl, –Br, –CH3, or phenyl. In other examples, n is 1, and R2is –F, –Cl, –Br, or –CH3. And, in some embodiments, n is 0.57260921.13Attorney Docket No.: 272050-553087 PCT APPLICATION

[0012] In some embodiments, p is 1, 2, 3, or 4; and each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, or –CH . In some embodiments, p is 1. For example, p is 1, and R4is halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, or –CH3. And, in some embodiments, p is 0.

[0013] In some embodiments, R3is –H or C1-3 alkyl. In other embodiments, R3is C1-3 alkyl (e.g., methyl, ethyl, n-propyl, or iso-propyl). And, in some embodiments, R3is –H.

[0014] In some embodiments, L is a bond or a C1-3 aliphatic chain (i.e., a bivalent aliphatic chain) optionally substituted with halo, –OH, –CN, or oxo. In other embodiments, L is a aor fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, or oxo. In other embodiments, R5is –H, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the phenyl, monocyclic cycloalkyl, and heterocyclic ring of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. And, in some embodiments, R5is –H, unsubstituted phenyl, or unsubstituted cyclohexyl.

[0016] In some embodiments, o is 1, 2, or 3. In other embodiments, o is 1 or 2. And, in some embodiments, o is 1.

[0017] Another aspect of the present invention provides a compound of Formula (IA): 57260921.14Attorney Docket No.: 272050-553087 PCT APPLICATION , or a pharmaceutically R2, R4, L, R5, m, n, and p is as defined in thethereof.

[0018] In one aspect, the present invention provides a compound of Formula (IA-1): , or a pharmaceutically R2, L, and R5is as definedin the compounds of Formula ( ), or any embodiment of either of these compounds.

[0019] In some embodiments, R1is halo, C R2is –H, halo, or C L is a bond or C aliphatic chain optionally substituted with halo, –OH, –CN, or oxo; and R5is –H or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo.

[0020] Another aspect of the present invention provides a compound of Formula (IA-1a): 1a), or a pharmaceuticallyL, and R5is as defined in the compounds of Formulae (I), (IA), or (IA-1), or any embodiment of any of these compounds.57260921.15Attorney Docket No.: 272050-553087 PCT APPLICATION

[0021] In another aspect, the present invention provides a compound selected from the compounds identified in Table 2, Table 3, or a pharmaceutically acceptable salt of any of these compounds.

[0022] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of any of Formulae (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0023] Another aspect of the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0024] In some implementations, the cancer is a cancer of epithelial origin. In other implementations, the cancer is a central nervous system (CNS) cancer.

[0025] In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in cancer cells. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in cancer cells.

[0026] Another aspect of the present invention provides method of modulating activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in a cancer cell, comprising administering to the cancer cell an effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein. In one aspect, the present invention provides method of modulating activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in a cancer cell, comprising administering to the cell an effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0027] Another aspect of the present invention provides a method of treating brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.57260921.16Attorney Docket No.: 272050-553087 PCT APPLICATION

[0028] In some implementations, the brain cancer is a glioma. In other implementations, the glioma is selected from the group consisting of an astrocytoma, an ependymoma, an oligodendroglioma, a brainstem glioma, an optic nerve glioma, and a mixed glioma. In some implementations, the glioma is an astrocytoma. And, in some implementations, the astrocytoma is glioblastoma multiforme (GBM).

[0029] In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in brain cancer cells. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in brain cancer cells.

[0030] Another aspect of the present invention provides method of inducing vacuolization of mitochondria in a glioblastoma multiforme (GBM) cell, comprising administering to the cell an effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0031] In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in the cell. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell.

[0032] Another aspect of the present invention provides a method of depolarizing a mitochondrion in a glioblastoma multiforme (GBM) cell, comprising administering to the cell a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0033] In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in the cell. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell.57260921.17Attorney Docket No.: 272050-553087 PCT APPLICATION

[0034] In some implementations of any method described herein, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered at least once per day.

[0035] In some implementations of any method described herein, the method further comprises administering an additional therapeutic agent. In some implementations, the additional therapeutic agent is an anti-cancer agent. In some implementations, the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti-cancer agents, or any combination thereof. In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, and the additional therapeutic agent are administered concurrently. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, and the additional therapeutic agent are administered sequentially.

[0036] In some implementations of any method described herein, the method further comprises administering a radiation therapy.

[0037] In some implementations of any method described herein, the compound or pharmaceutically acceptable salt described herein is administered in a dosage amount of from about 1 mg to about 1,000 mg.

[0038] In some implementations of any method described herein, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered chronically.

[0039] In some implementations of any method described herein, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered orally. In some implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered as a tablet, capsule, or oral suspension. In other implementations, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, is administered intranasally.

[0040] In some implementations of any method described herein, the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition57260921.18Attorney Docket No.: 272050-553087 PCT APPLICATION described herein, is administered at least once a day from onset of treatment for a duration of at least about one year.

[0041] In some implementations of any method described herein, the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein.

[0042] In some implementations of any method described herein, the subject experiences vacuolization of mitochondria in cancer cells following treatment onset.

[0043] In some implementations of any method described herein, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The figures below are provided by way of example and are not intended to limit the scope of the claimed invention.

[0045] Figure 1 shows the cell viability of patient-derived glioblastoma multiforme (GBM) cells and fibroblasts after treatment with compounds of Formula (I) according to Example 4. DETAILED DESCRIPTION

[0046] The present invention provides compounds and methods of treating cancer in a subject in need thereof.

[0047] As used herein, the following definitions shall apply unless otherwise indicated.

[0048] I. DEFINITIONS

[0049] As used herein, the term "modulates" refers to the inhibition or potentiation of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A function. A "modulator" (e.g., a compound or pharmaceutically acceptable salt thereof that modulates BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A function) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A.

[0050] As used herein, the term "about", when referring to a numerical value or range of values, allows for a degree of variability in the value or range or values, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.

[0051] As used herein, the term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or57260921.19Attorney Docket No.: 272050-553087 PCT APPLICATION other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0053] As used herein, the term "prodrug" is intended to encompass therapeutically inactive compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. One method for making a prodrug is to design selected moieties that are hydrolyzed or cleaved at a targeted in vivo site of action under physiological conditions to reveal the desired molecule which then produces its therapeutic effect. In certain embodiments, the prodrug is converted by an enzymatic activity of the subject.57260921.110Attorney Docket No.: 272050-553087 PCT APPLICATION

[0054] In an alternate embodiment, the present invention provides prodrugs of compounds described herein (e.g., the compound of Formula (I)).

[0055] As used herein, the term "subject" to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a mammal. In other embodiments, the subject is a human.

[0056] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition (or any symptom thereof), or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates a prophylactic action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

[0057] In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat cancer (e.g., glioblastoma multiforme (GBM)). As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0058] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0059] In an alternate embodiment, the present invention contemplates administration of the compounds of the present invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise57260921.111Attorney Docket No.: 272050-553087 PCT APPLICATION specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0060] As used herein, the term "treatment onset" and "onset of treatment" are used interchangeably to refer to the day in which a treatment (e.g., administration of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds) begins. For example, the day of treatment onset is the day in which a chemotherapy is first administered. For dosage regimes comprising the administration of 2 or more therapies, treatment onset is the day in which the compound of Formula (I), (IA), (IA- 1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is first administered.

[0061] As used herein, “a cancer of epithelial origin” refers to a cancer that arises from epithelial cells. Examples of cancers of epithelial origin include, but are not limited to, brain cancer, breast cancer, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, such as squamous cell and basal cell cancers (e.g., basal cell carcinoma), prostate cancer, renal cell carcinoma, cystadenomas, endometrial cancer, and other known cancers that effect epithelial cells throughout the body.

[0062] As used herein, “a central nervous system (CNS) cancer” refers to a cancer that arises in the central nervous system (e.g., brain and / or spinal cord). Examples of CNS cancers include, but are not limited to, acoustic neuroma, adenoma, astrocytoma, glioblastoma, brain stem glioma, breast cancer and metastatic brain tumors, chondroma, chondrosarcoma, chordoma, colon cancer and metastatic brain tumors, convexity meningioma, encephaloceles, ependymoma, esthesioneuroblastoma, fibrillary astrocytoma, fibrous dysplasia, giant cell tumor, germ cell tumor, gliomas, gliomatosis cerebri, oligodendroglioma, optic nerve glioma, hemangiopericytoma, kidney cancer and metastatic brain tumors, lung cancer and metastatic brain tumors, medulloblastoma, melanoma (skin cancer) and metastatic brain tumors, meningioma, metastatic brain tumors, mixed glioma,57260921.112Attorney Docket No.: 272050-553087 PCT APPLICATION nasopharyngeal angiofibroma, neurofibroma, neurofibromatosis, olfactory neuroblastoma (esthesioneuroblastoma), oligoastrocytoma, oligodendroglioma, optic glioma, osteoma, paranasal sinus cancer, pituitary adenoma, Rathke's cleft cyst, rhabdomyosarcoma, and schwannoma.

[0063] As used herein, the term "hydroxyl" or "hydroxy" refers to an –OH moiety.

[0064] As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl, each of which being optionally substituted as set forth below.

[0065] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, 1-4, or 1-3) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.

[0066] In some embodiments, an alkyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.

[0067] In some embodiments, an alkyl group can be substituted with one or more substituents independently selected from halo, oxo, hydroxy, cyano, halo, alkoxy (e.g., C1-6 alkoxy), –C(O)-C1-6alkoxy and –C(O)-C1-6alkyl. In other embodiments, an alkyl group can be substituted with one or more substituents selected from halo, –OH, and oxo.

[0068] As used herein, an "alkenyl" group refers to an aliphatic hydrocarbon group that contains 2-12 (e.g., 2-8, 2-6, 2-4, or 2-3) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl.57260921.113Attorney Docket No.: 272050-553087 PCT APPLICATION

[0069] In some embodiments, an alkenyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.

[0070] In other embodiments, an alkenyl group can be substituted with one or more substituents independently selected from cyano, alkoxy, acyl, hydroxy, aryl, aralkyl, alkoxyaryl, sulfonylamino (such as alkyl-SO2-amino), amino, amido, cycloaliphatic, or halo. In other embodiments, an alkenyl group can be substituted with one or more substituents selected from halo, –OH, and oxo.

[0071] In some embodiments, an alkenyl group can be substituted with one or more substituents as set forth herein for alkyl groups.

[0072] As used herein, an "alkynyl" group refers to an aliphatic hydrocarbon group that contains 2-12 (e.g., 2-8, 2-6, 2-4, or 2-3) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, ethynyl, propargyl, and butynyl.

[0073] In some embodiments, an alkynyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO2-, aliphaticamino-SO2-, or cycloaliphatic-SO2-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,57260921.114Attorney Docket No.: 272050-553087 PCT APPLICATION (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

[0074] In other embodiments, an alkynyl group can be substituted with one or more substituents independently selected from cyano, alkoxy, acyl, hydroxy, aryl, aralkyl, alkoxyaryl, sulfonylamino (such as alkyl-SO2-amino), amino, amido, cycloaliphatic, or halo. In other embodiments, an alkenyl group can be substituted with one or more substituents selected from halo, –OH, and oxo.

[0075] In some embodiments, an alkynyl group can be substituted with one or more substituents as set forth herein for alkyl groups and / or alkenyl groups.

[0076] As used herein, an "amido" encompasses both "aminocarbonyl" and "carbonylamino." These terms when used alone or in connection with another group refer to an amido group such as –N(RX)-C(O)-RYor –C(O)-N(RX)2, when used terminally, and –C(O)-N(RX)– or –N(RX)-C(O)– when used internally, wherein RXand RYcan be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0077] As used herein, an "amino" group refers to –NRXRY, wherein each of RXand RYis independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by –NRX–, where RXhas the same meaning as defined above.

[0078] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g.,57260921.115Attorney Docket No.: 272050-553087 PCT APPLICATION indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C4-8 carbocyclic moieties.

[0079] In some embodiments, an aryl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO2- or amino-SO2-]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted.

[0080] In other embodiments, an aryl group can be substituted with one or more substituents independently selected from halo [e.g., mono-, di-, and tri-halo]; carboxy [e.g., alkoxycarbonyl, (aralkyl)carbonyloxy, and alkoxycarbonyl]; amido [e.g., aminocarbonyl, ((alkylamino)alkyl)aminocarbonyl, (alkylcarbonyl)amino, arylaminocarbonyl, and ((heteroaryl)amino)carbonyl]; amino [e.g., (alkylsulfonyl)amino or (dialkyl)amino]; cyanoalkyl; alkoxy; sulfamoyl [e.g., aminosulfonyl]; alkylsulfonyl; cyano; hydroxyalkyl; (alkoxy)alkyl; hydroxy, (carboxy)alkyl; ((dialkyl)amino)alkyl; nitroalkyl; ((alkylsulfonyl)amino)alkyl; (heterocycloaliphatic)carbonyl; (alkylsulfonyl)alkyl; alkylcarbonyl; alkyl; or trihaloalkyl.

[0081] In some embodiments, an aryl group can be substituted with one or more substituents independently selected from halo, oxo, –OH, –CN, –NO2, haloalkyl, –C(O)OH, –C(O)-alkyl, –C(O)O-alkyl, –C(O)S-alkyl, –S(O)2-alkyl, –S(O)-alkyl, –S-alkyl, –O-alkyl, –O-haloalkyl, amino, amido, hydroxyalkyl, alkyl, and alkoxy. In other embodiments, an aryl group can be optionally substituted with one or more substituents independently selected57260921.116Attorney Docket No.: 272050-553087 PCT APPLICATION from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo.

[0082] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C1-4 alkyl group) that is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is benzyl.

[0083] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C1-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" are defined herein. An example of an aralkyl group is benzyl.

[0084] In some embodiments, an aralkyl group can be substituted with one or more substituents independently selected from aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0085] In some embodiments, an aralkyl group can be substituted with one or more substituents as set forth herein for aryl groups.

[0086] As used herein, a "bicyclic ring system" includes 5-12 (e.g., 8-12 or 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.

[0087] In some embodiments, a bicyclic ring system can be substituted with one or more substituents as set forth herein for aryl groups and / or aralkyl groups.

[0088] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.

[0089] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl,57260921.117Attorney Docket No.: 272050-553087 PCT APPLICATION norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0090] A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0091] In some embodiments, a cycloalkyl or cycloalkenyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0092] In some embodiments, a cycloalkyl or cycloalkenyl group can be substituted with one or more substituents as set forth herein for aryl groups and / or aralkyl groups.

[0093] As used herein, the term "heterocycloaliphatic" encompasses heterocycloalkyl groups and heterocycloalkenyl groups, each of which being optionally substituted as set forth below.

[0094] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicyclic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl,57260921.118Attorney Docket No.: 272050-553087 PCT APPLICATION octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, that would be categorized as heteroaryls.

[0095] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicyclic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.

[0096] In some embodiments, a heterocycloalkyl or heterocycloalkenyl group has 1-3 heteroatoms independently selected from N, O, or S.

[0097] In some embodiments, a heterocycloalkyl or heterocycloalkenyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0098] In some embodiments, a heterocycloalkyl or heterocycloalkenyl group can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, and / or cycloalkenyl groups.

[0099] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic57260921.119Attorney Docket No.: 272050-553087 PCT APPLICATION or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophene- yl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0100] Without limitation, monocyclic heteroaryls include furyl, thiophene-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0100] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0101] In some embodiments, a heteroaryl group has 1-3 heteroatoms independently selected from N, O, or S.

[0102] In some embodiments, a heteroaryl group can be substituted (i.e., optionally substituted) with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.57260921.120Attorney Docket No.: 272050-553087 PCT APPLICATION

[0103] In other embodiments, a heteroaryl group can be substituted with one or more substituents independently selected from halo [e.g., mono- and di-halo]; carboxy [e.g., alkoxycarbonyl]; cyano; amino [e.g., (alkylsulfonyl)amino and (dialkyl)amino]; amido [e.g., aminocarbonyl, (alkylcarbonyl)amino, (((alkyl)amino)alkyl)aminocarbonyl, ((heteroaryl)amino)carbonyl, (heterocycloaliphatic)carbonyl, and (alkylcarbonyl)amino]; cyanoalkyl; alkoxy; sulfamoyl [e.g., aminosulfonyl]; sulfonyl [e.g., alkylsulfonyl]; hydroxyalkyl; alkoxyalkyl; hydroxy; (carboxy)alkyl; ((dialkyl)amino)alkyl; heterocycloaliphatic; cycloaliphatic; nitroalkyl; ((alkylsulfonyl)amino)alkyl; (alkylsulfonyl)alkyl; cyanoalkyl; acyl [e.g., alkylcarbonyl]; alkyl; or haloalkyl [e.g., trihaloalkyl].

[0104] In some embodiments, a heteroaryl group can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, cycloalkenyl groups, heterocycloalkyl groups, and / or heterocycloalkenyl groups.

[0105] As used herein, a "heteroaraliphatic" (such as a heteroaralkyl group) refers to an aliphatic group (e.g., a C1-4alkyl group) that is substituted with a heteroaryl group. "Aliphatic," "alkyl," and "heteroaryl" have been defined above.

[0106] As used herein, a "heteroaralkyl" group refers to an alkyl group (e.g., a C1-4alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above.

[0107] In some embodiments, a heteroaralkyl is substituted (i.e., optionally substituted) with one or more substituents independently selected from alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0108] In some embodiments, a heteroaralkyl group can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, cycloalkenyl groups, heterocycloalkyl groups, heterocycloalkenyl groups, and / or heteroaryl groups.57260921.121Attorney Docket No.: 272050-553087 PCT APPLICATION

[0109] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.

[0110] As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.

[0111] In some embodiments, a bridged bicyclic ring system can be substituted (i.e., optionally substituted) with one or more substituents independently selected from alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0112] In some embodiments, a bridged bicyclic ring system can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, cycloalkenyl groups, heterocycloalkyl groups, heterocycloalkenyl groups, heteroaryl groups, and / or heteroaralkyl groups.

[0113] As used herein, an "acyl" group refers to a formyl group or RX-C(O)- (such as alkyl-C(O)-, also referred to as "alkylcarbonyl") where RXand "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[0114] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl can be substituted (i.e., optionally substituted) as provided herein.

[0115] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously. The alkyl portion of the alkoxy group can be substituted (i.e., optionally substituted) as provided herein.57260921.122Attorney Docket No.: 272050-553087 PCT APPLICATION

[0116] In some embodiments, an alkoxy group can be substituted with one or more substituents independently selected from halo, oxo, –OH, –CN, haloalkyl, alkoxy, –C(O)-C1-6alkoxy and –C(O)-C1-6 alkyl. In other embodiments, an alkoxy group can be substituted with one or more substituents independently selected from halo, –OH, –CN, and oxo.

[0117] In some embodiments, an alkoxy group can be substituted with 1-3 groups independently selected from halo and C1-6 alkoxy. In some embodiments, an alkoxy group can be substituted with 1-3 halo.

[0118] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NRXRYor -NRX-CO-O-RZ, wherein RXand RYhave been defined above and RZcan be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

[0119] As used herein, a "carboxy" group refers to –COOH, –COORX, –OC(O)H, –OC(O)RX, when used as a terminal group; or –OC(O)– or –C(O)O– when used as an internal group.

[0120] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group –CF3.

[0121] As used herein, a "mercapto" group refers to –SH.

[0122] As used herein, a "sulfo" group refers to –SO3H or –SO3RXwhen used terminally or –S(O)3– when used internally.

[0123] As used herein, a "sulfamide" group refers to the structure –NRX-S(O)2-NRYRZwhen used terminally and –NRX-S(O)2-NRY– when used internally, wherein RX, RY, and RZhave been defined above.

[0124] As used herein, a "sulfamoyl" group refers to the structure –O-S(O)2-NRYRZwherein RYand RZhave been defined above.

[0125] As used herein, a "sulfonamide" group refers to the structure –S(O)2-NRXRYor –NRX-S(O)2-RZwhen used terminally; or –S(O)2-NRX– or –NRX-S(O)2– when used internally, wherein RX, RY, and RZare defined above.

[0126] As used herein a "sulfanyl" group refers to –S-RXwhen used terminally and –S– when used internally, wherein RXhas been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.

[0127] As used herein a "sulfinyl" group refers to –S(O)-RXwhen used terminally and –S(O)– when used internally, wherein RXhas been defined above. Examples of sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl- S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.57260921.123Attorney Docket No.: 272050-553087 PCT APPLICATION

[0128] As used herein, a "sulfonyl" group refers to –S(O)2-RXwhen used terminally and –S(O)2– when used internally, wherein RXhas been defined above. Examples of sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-, cycloaliphatic-S(O)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S(O)2-, (cycloaliphatic(amido(aliphatic)))-S(O)2-or the like.

[0129] As used herein, a "sulfoxy" group refers to –O-S(O)-RXor –S(O)-O-RX, when used terminally and –O-S(O)– or –S(O)-O– when used internally, where RXhas been defined above.

[0130] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0131] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.

[0132] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0133] As used herein, a "carbonyl" refers to –C(O)–.

[0134] As used herein, an "oxo" refers to =O.

[0135] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include –P(O)(RP)2, wherein RPis aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.

[0136] As used herein, an "aminoalkyl" refers to the structure (RX)2N-alkyl–.

[0137] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl–.

[0138] As used herein, a "urea" group refers to the structure –NRX-CO-NRYRZand a "thiourea" group refers to the structure –NRX-CS-NRYRZwhen used terminally and –NRX- CO-NRY– or –NRX-CS-NRY– when used internally, wherein RX, RY, and RZhave been defined above.

[0139] As used herein, a "guanidine" group refers to the structure –N=C(N(RXRY))N(RXRY) or –NRX-C(=NRX)NRXRYwherein RXand RYhave been defined above.

[0140] As used herein, the term "amidino" group refers to the structure –C=(NRX)N(RXRY) wherein RXand RYhave been defined above.

[0141] As used herein, the term "vicinal" generally refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.57260921.124Attorney Docket No.: 272050-553087 PCT APPLICATION

[0142] As used herein, the term "geminal" generally refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

[0143] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RXO(O)C-alkyl, is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0144] As used herein, an "aliphatic chain" refers to a bivalent branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure –[CH2]v–, where v is 1-12 (e.g., 1-6). A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure –[CQQ]v– where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

[0145] The phrase "optionally substituted" is used herein interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables X, R1, R2, R3, R4, L, and R5and other variables contained in any of Formulae (I), (IA), (IA-1), or (IA-1a) described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables X, R1, R2, R3, R4, L, and R5and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same57260921.125Attorney Docket No.: 272050-553087 PCT APPLICATION atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.

[0146] As used herein, the term "substituted," whether preceded by the term "optionally" or not, refers generally to the replacement of hydrogen atoms in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0147] Unless otherwise stated, structures depicted herein also are meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein also are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0148] Compounds disclosed herein may be "isomerically pure" compounds. As used herein, the term "isomerically pure" refers to an isomeric form of a compound that is substantially free from other isomeric forms of the compound (e.g., substantially free from other stereoisomers (e.g., enantiomers, diastereomers, geometric (or conformational) isomers, etc.), constitutional isomers, isotopomers, etc.). For example, an "isomerically pure" compound having at least one asymmetric center of a particular configuration (i.e., R or S57260921.126Attorney Docket No.: 272050-553087 PCT APPLICATION configuration) is substantially free of other isomeric forms of the compound having a different configuration at the at least one asymmetric center. An "isomerically pure" compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of a single isomer of the compound based on the total weight of all isomers of the compound that are present.

[0149] Chemical structures and nomenclature are derived from ChemDraw, version 11.0.1, Cambridge, MA.

[0150] II. COMPOUNDS OF THE PRESENT INVENTION

[0151] The present invention provides compounds useful for treating cancer.

[0152] A. Compounds of Formula (I)

[0153] One aspect of the present invention provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-6alkyl; each R1, R2, and R4is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R1, R2, and R4is independently optionally substituted with halo, –OH, or oxo, the C2-6alkenyl, the C2-6alkynyl, and the monocyclic ring of each R1, R2, and R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or oxo, and wherein each R is independently –H or C1-6 alkyl; R3is –H or optionally substituted C1-6alkyl;57260921.127Attorney Docket No.: 272050-553087 PCT APPLICATION L is a bond or a C1-6 aliphatic chain optionally substituted with halo, unsubstituted C1-3alkyl, –OH, –CN, or oxo; R5is –H or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo; and each of m and n is independently 0, 1, 2, 3, 4, or 5; o is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; provided that the compound is not a compound selected from the compounds identified in Table 1, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, L is a bond or a C1-6aliphatic chain optionally substituted with halo, –OH, –CN, or oxo.

[0155] Table 1: Compounds excluded from Formula (I). Structure or a pharmaceutically a

[0156] 1. XAttorney Docket No.: 272050-553087 PCT APPLICATION

[0157] X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-6 alkyl. For example, R6is C1-6alkyl optionally substituted with 1-3 groups independently selected from halo, –OH, –CN, or oxo.

[0158] In some embodiments, X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-3 alkyl (e.g., C1-3 alkyl optionally substituted with 1-3 groups independently selected from halo, –OH, –CN, or oxo). In some embodiments, X is –O–, –S–, –NH–, –N(CH2CH3)–, or –N(CH3)–. In other embodiments, X is –O–, –S–, –NH–, or –N(CH3)–. In some embodiments, X is –O–, –S–, or –NH–. In some embodiments, X is –O– or –S–. In some embodiments, X is –NH–. In some embodiments, X is –S–. And, in some embodiments, X is –O–.

[0159] 2. m and R1

[0160] m is 0, 1, 2, 3, 4, or 5; and each R1is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R1is independently optionally substituted with halo, –OH, or oxo, the C2-6 alkenyl, the C2-6 alkynyl, and the monocyclic ring of each R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo, and wherein each R is independently –H or C1-6 alkyl.

[0161] In some embodiments, m is 0, 1, 2, 3, 4, or 5 (e.g., m is 0, 1, 2, or 3); and each R1is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, m is 0, 1, 2, 3, 4, or 5 (e.g., m is 0, 1, 2, or 3); and each R1is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, m is 0, 1, 2, 3, 4, or 5 (e.g., m is 0, 1, 2, or 3); and each R1is independently57260921.129Attorney Docket No.: 272050-553087 PCT APPLICATION halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, m is 0, 1, 2, or 3 (e.g., m is 0 or 1); and each R1is independently –F, –Cl, –Br, –CH3, or phenyl. And, in some embodiments, m is 0 or 1; and R1is –Cl, –CH3, or phenyl. In some embodiments, m is 1 and R1is –F. In some embodiments, m is 1; and R1is –Cl. In some embodiments, m is 1 and R1is –Br. In some embodiments, m is 1; and R1is –CH3. In some embodiments, m is 1; and R1is phenyl. And, in some embodiments, m is 1 or 0; and R1is –H.

[0162] 3. n and R2

[0163] n is 0, 1, 2, 3, 4, or 5; and each R2is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R2is independently optionally substituted with halo, –OH, or oxo, the C2-6 alkenyl, the C2-6 alkynyl, and the monocyclic ring of each R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo, and wherein each R is independently –H or C1-6alkyl.

[0164] In some embodiments, n is 0, 1, 2, 3, 4, or 5 (e.g., n is 0, 1, 2, or 3); and each R2is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, n is 0, 1, 2, 3, 4, or 5 (e.g., m is 0, 1, 2, or 3); and each R2is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, n is 0, 1, 2, or 3 (e.g., n is 0, 1, or 2); and each R2is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S.57260921.130Attorney Docket No.: 272050-553087 PCT APPLICATION In some embodiments, n is 0, 1, 2, or 3 (e.g., n is 0, 1, or 2); and each R2is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, n is 0, 1, or 2 (e.g., n is 0 or 1); and each R2is independently –F, –Cl, –Br, or –CH3. In some embodiments, n is 0, 1, or 2 (e.g., n is 0 or 1); and each R2is independently –H, –Cl, or –CH3. In some embodiments, n is 1; and R2is –F. In some embodiments, n is 1; and R2is –Cl. In some embodiments, n is 1; and R2is –Br. In some embodiments, n is 1; and R2is –CH3. In some embodiments, n is 1; and R2is unsubstituted phenyl. And, in some embodiments, n is 0 or 1; and R2is –H.

[0165] 4. R3

[0166] R3is –H or optionally substituted C1-6alkyl.

[0167] In some embodiments, R3is –H or C1-6 alkyl optionally substituted with 1-3 groups independently selected from halo, –OH, –CN, or oxo. In some embodiments, R3is –H or C1-3alkyl optionally substituted with 1-3 groups independently selected from halo, –OH, –CN, or oxo. In other embodiments, R3is –H or C1-3alkyl. In some embodiments, R3is –H. In some embodiments, R3is methyl, ethyl, n-propyl, or iso-propyl. In some embodiments, R3is methyl or –H. And, in some embodiments, R3is methyl.

[0168] 5. p and R4

[0169] p is 0, 1, 2, 3, or 4; and each R4is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R4is independently optionally substituted with halo, –OH, or oxo, the C2-6 alkenyl, the C2-6 alkynyl, and the monocyclic ring of each R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo, and wherein each R is independently –H or C1-6alkyl.

[0170] In some embodiments, p is 0, 1, 2, 3, or 4 (e.g., p is 0, 1, 2, or 3), and each R4is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated57260921.131Attorney Docket No.: 272050-553087 PCT APPLICATION heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In other embodiments, p is 0, 1, 2, or 3 (e.g., p is 0, 1, or 2), and each R4is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, p is 0, 1 or 2, and each R4is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, p is 0, 1 or 2, and each R4is independently –F, –Cl, –Br, or –CH3. In some embodiments, p is 0 or 1, and R4is –F. In some embodiments, p is 0 or 1, and R4is –Cl. In some embodiments, p is 0 or 1, and R4is –Br. In some embodiments, p is 0 or 1, and R4is –CH3. In some embodiments, p is 0 or 1, and R4is phenyl. And, in some embodiments, p is 0 or 1, and R4is –H.

[0171] 6. L

[0172] L is a bond or a C1-6 aliphatic chain optionally substituted with halo, unsubstituted C1-3alkyl (e.g., methyl), –OH, –CN, or oxo. For example, L is a C1-6aliphatic chain optionally substituted with up to 3 groups independently selected from halo, unsubstituted C1-3alkyl (e.g., methyl), –OH, –CN, and oxo. In some embodiments, L is a bond or a C1-6aliphatic chain optionally substituted with halo, –OH, –CN, or oxo. For example, L is a C1-6 aliphatic chain optionally substituted with up to 2 groups independently selected from halo, –OH, –CN, and oxo.

[0173] In some embodiments, L is a bond or C1-3 aliphatic chain optionally substituted with halo, –OH, –CN, or oxo. For example, L is a C1-3aliphatic chain optionally substituted with up to 2 groups independently selected from halo, –OH, –CN, and oxo. In some embodiments, L is a bond or a C1-3alkyl chain optionally substituted with halo, –OH, –CN, or oxo. In some embodiments, L is a bond or a C1-3 alkyl chain optionally substituted with oxo. In other embodiments, L is a . Insome embodiments, L is a . In some embodiments, L is abond or . In some a In some embodiments, L is57260921.132Attorney Docket No.: 272050-553087 PCT APPLICATION . In some embodiments, L is . In some embodiments, L is .And, in some .

[0174] 7. 5

[0175] R is –H or a 3-7 partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or oxo.

[0176] In some embodiments, R5is –H or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo. In other embodiments, R5is –H, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the phenyl, monocyclic cycloalkyl, and heterocyclic ring of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is phenyl or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl –H, phenyl, or cyclohexyl. In some embodiments, R5is a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the heterocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is –H, phenyl, or cyclohexyl. In some embodiments, R5is –H or phenyl. In some embodiments, R5is –H. In other embodiments, R5is phenyl. And, in some embodiments, R5is cyclohexyl.57260921.133Attorney Docket No.: 272050-553087 PCT APPLICATION

[0177] 8. m and n

[0178] Each of m and n is independently 0, 1, 2, 3, 4, or 5.

[0179] In some embodiments, one of m and n is 1, 2, 3, 4, or 5 and the other of m and n is 0. In other embodiments, one of m and n is 1, 2, 3, or 4 and the other of m and n is 0. In some embodiments, one of m and n is 1, 2, or 3 and the other of m and n is 0. In some embodiments, one of m and n is 1 or 2 and the other of m and n is 0. In some embodiments, one of m and n is 1 and the other of m and n is 0. For example, m is 1 and n is 0. And, in some embodiments, n is 1 and m is 0.

[0180] In some embodiments, one of m and n is 1, 2, 3, 4, or 5 and the other of m and n is 1. In other embodiments, one of m and n is 1, 2, 3, or 4 and the other of m and n is 1. In some embodiments, one of m and n is 1, 2, or 3 and the other of m and n is 1. In some embodiments, one of m and n is 1 or 2 and the other of m and n is 1. And, in some embodiments, each of m and n is 1.

[0181] In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In other embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In other embodiments, m is 5. And, in some embodiments, m is 0.

[0182] In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In other embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In other embodiments, n is 5. And, in some embodiments, n is 0.

[0183] 9. o

[0184] o is 0, 1, 2, 3, or 4.

[0185] In some embodiments, o is 1, 2, 3, or 4. In some embodiments, o is 1, 2, or 3. In other embodiments, o is 1 or 2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In other embodiments, o is 4. And, in some embodiments, o is 0.

[0186] 10. p

[0187] p is 0, 1, 2, 3, or 4.

[0188] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In other embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is 4. And, in some embodiments, p is 0.

[0189] Another aspect of the present invention provides a compound of Formula (IA):57260921.134Attorney Docket No.: 272050-553087 PCT APPLICATION , or a pharmaceutically R2, R4, L, R5, m, n, and p is as defined in thethereof, with the proviso that the compound is not a compound selected from the compounds identified in Table 1, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-3 alkyl (e.g., C1-3 alkyl optionally substituted with 1-3 groups independently selected from halo, –OH, –CN, or oxo). In some embodiments, X is –O–, –S–, –NH–, –N(CH2CH3)–, or –N(CH3)–. In other embodiments, X is –O–, –S–, –NH–, or –N(CH3)–. In some embodiments, X is –O–, –S–, or –NH–. In some embodiments, X is –O– or –S–. In some embodiments, X is –NH–. In some embodiments, X is –S–. And, in some embodiments, X is –O–.

[0191] In some embodiments, each R1is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, each R1is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, each R1is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, each R1is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, each R1is independently –Cl, –CH3, or phenyl. In some embodiments, R1is –F. In some embodiments,57260921.135Attorney Docket No.: 272050-553087 PCT APPLICATION R1is –Cl. In some embodiments, R1is –Br. In some embodiments, R1is –CH3. In some embodiments, R1is phenyl. And, in some embodiments, R1is –H.

[0192] In some embodiments, each R2is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, each R2is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, each R2is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, each R2is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, each R2is independently –F, –Cl, –Br, or –CH3. In some embodiments, each R2is independently –H, –Cl, or –CH3. In some embodiments, R2is –F. In some embodiments, R2is –Cl. In some embodiments, R2is –Br. In some embodiments, R2is –CH3. In some embodiments, R2is phenyl. And, in some embodiments, R2is –H.

[0193] In some embodiments, each R4is independently –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R4is57260921.136Attorney Docket No.: 272050-553087 PCT APPLICATION optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In other embodiments, each R4is independently halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, each R4is independently –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, each R4is independently –F, –Cl, –Br, or –CH3. In some embodiments, R4is –F. In some embodiments, R4is –Cl. In some embodiments, R4is –Br. In some embodiments, R4is –CH3. In some embodiments, R4is phenyl. And, in some embodiments, R4is –H.

[0194] L is a bond or a C1-6 aliphatic chain optionally substituted with halo, –OH, –CN, or oxo.

[0195] In some embodiments, L is a bond or C1-3 aliphatic chain optionally substituted with halo, methyl, –OH, –CN, or oxo. In some embodiments, L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo. In some embodiments, L is a bond or a C1-3alkyl chain optionally substituted with oxo. In some embodiments, L is a bond or a C1-3alkyl chain optionally substituted with methyl. In other embodiments, L is a bond, someisor fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo. In other embodiments, R5is –H, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the phenyl, monocyclic cycloalkyl, and heterocyclic ring of57260921.137Attorney Docket No.: 272050-553087 PCT APPLICATION R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is phenyl or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl –H, phenyl, or cyclohexyl. In some embodiments, R5is a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the heterocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is –H, phenyl, or cyclohexyl. In some embodiments, R5is –H or phenyl. In some embodiments, R5is –H. In other embodiments, R5is phenyl. And, in some embodiments, R5is cyclohexyl.

[0197] In some embodiments, one of m and n is 1, 2, 3, 4, or 5 and the other of m and n is 0. In other embodiments, one of m and n is 1, 2, 3, or 4 and the other of m and n is 0. In some embodiments, one of m and n is 1, 2, or 3 and the other of m and n is 0. In some embodiments, one of m and n is 1 or 2 and the other of m and n is 0. In some embodiments, one of m and n is 1 and the other of m and n is 0. For example, m is 1 and n is 0. And, in some embodiments, n is 1 and m is 0.

[0198] In some embodiments, one of m and n is 1, 2, 3, 4, or 5 and the other of m and n is 1. In other embodiments, one of m and n is 1, 2, 3, or 4 and the other of m and n is 1. In some embodiments, one of m and n is 1, 2, or 3 and the other of m and n is 1. In some embodiments, one of m and n is 1 or 2 and the other of m and n is 1. And, in some embodiments, each of m and n is 1.

[0199] In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In other embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In other embodiments, m is 5. And, in some embodiments, m is 0.

[0200] In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In other embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some57260921.138Attorney Docket No.: 272050-553087 PCT APPLICATION embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In other embodiments, n is 5. And, in some embodiments, n is 0.

[0201] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In other embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is 4. And, in some embodiments, p is 0.

[0202] Another aspect of the present invention provides a compound of Formula (IA-1): ,or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, L, and R5is as defined in the compounds of Formula (I) or (IA), or any embodiment of either of these compounds, with the proviso that the compound is not a compound selected from the compounds identified in Table 1, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, R1is –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R1is halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In other embodiments, R1is halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, R1is –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, R1is –Cl, –CH3, or phenyl. In57260921.139Attorney Docket No.: 272050-553087 PCT APPLICATION some embodiments, R1is –F. In some embodiments, R1is –Cl. In some embodiments, R1is –Br. In some embodiments, R1is –CH3. In some embodiments, R1is phenyl. And, in some embodiments, R1is –H.

[0204] In some embodiments, R2is –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, – NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R2is halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In other embodiments, R2is halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, R2is–F, –Cl, –Br, –CH3, or phenyl. In some embodiments, R2is –F, –Cl, –Br, or –CH3. In some embodiments, R2is –H, –Cl, or –CH . In some embodiments, R2is –F. In some embodiments, R2is –Cl. In some embodiments, R2is –Br. In some embodiments, R2is –CH3. In some embodiments, R2is phenyl. And, in some embodiments, R2is –H.

[0205] In some embodiments, L is a bond or C1-3 aliphatic chain optionally substituted with halo, methyl, –OH, –CN, or oxo. For example, L is a C1-3aliphatic chain optionally substituted with up to 2 groups independently selected from halo, methyl, –OH, –CN, and oxo. In some embodiments, L is a bond or a C1-3alkyl chain optionally substituted with halo, –OH, –CN, or oxo. For example, L is a C1-3 alkyl chain optionally substituted with up to 2 groups independently selected from halo, –OH, –CN, and oxo. In some embodiments, L is a bond or a C1-3 alkyl chain optionally substituted with oxo. In other embodiments, L is a57260921.140Attorney Docket No.: 272050-553087 PCT APPLICATION embodiments, L is a bond. In some embodiments, L is . In some embodiments, L is . In some embodiments, L is .embodiments, L is unsaturated,or from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo. In other embodiments, R5is –H, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the phenyl, monocyclic cycloalkyl, and heterocyclic ring of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is phenyl or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl –H, phenyl, or cyclohexyl. In some embodiments, R5is a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the heterocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is –H, phenyl, or cyclohexyl. In some embodiments, R5is –H or phenyl. In some embodiments, R5is –H. In other embodiments, R5is phenyl. And, in some embodiments, R5is cyclohexyl.

[0207] In some embodiments, R1is halo, C1-6 alkyl, or phenyl; R2is –H, halo, or C1-6alkyl; L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo; and57260921.141Attorney Docket No.: 272050-553087 PCT APPLICATION R5is –H or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo.

[0208] In some embodiments, R1is halo, C1-6 alkyl, or phenyl; R2is –H, halo, or C1-6 alkyl; L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo; and R5is –H, phenyl, or cyclohexyl.

[0209] In some embodiments, R1is halo, C1-6alkyl, or phenyl; R2is –H, halo, or C1-6 alkyl; L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo; and R5is –H or phenyl.

[0210] In some embodiments, R1is halo, C1-6 alkyl, or phenyl; R2is –H, halo, or C1-6alkyl; L is a bond or a C1-3 alkyl chain optionally substituted with oxo; and R5is –H or phenyl.

[0211] In some embodiments, R1is –Cl, –CH3, or phenyl; R2is –H, –Cl, or –CH3; L is a bond or a C1-3alkyl chain optionally substituted with oxo; and R5is –H or phenyl.

[0212] In some embodiments, R1is –Cl, –CH3, or phenyl; R2is –H, –Cl, or –CH3; L is a bond or and R5is –H

[0213] In another aspect, the present invention provides a compound of Formula (IA-1a):57260921.142Attorney Docket No.: 272050-553087 PCT APPLICATION 1a), or a pharmaceuticallyR1, L, and R5is as defined in the compounds of Formulae (I), (IA), or (IA-1), or any embodiment of any of these compounds, with the proviso that the compound is not a compound selected from the compounds identified in Table 1, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, R1is –H, halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R1is halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. In other embodiments, R1is halo, C1-6 alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, R1is –F, –Cl, –Br, –CH3, or phenyl. In some embodiments, R1is –Cl, –CH3, or phenyl. In some embodiments, R1is –F. In some embodiments, R1is –Cl. In some embodiments, R1is –Br. In some embodiments, R1is –CH3. In some embodiments, R1is phenyl. And, in some embodiments, R1is –H.

[0215] In some embodiments, L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo. In some embodiments, L is a bond or a C1-3 alkyl chain optionally substituted with halo, –OH, –CN, or oxo. In some embodiments, L is a bond or a C1-3alkyl chain optionally substituted with oxo. In other embodiments, L is a ,57260921.143Attorney Docket No.: 272050-553087 PCT APPLICATION or. some L is asome embodiments, L isInsome embodiments, L is . And, in some embodiments, L .

[0216] In some R5is –H or a 3-6 memberedunsaturated,or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo. In other embodiments, R5is –H, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the phenyl, monocyclic cycloalkyl, and heterocyclic ring of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl. In some embodiments, R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is phenyl or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R5are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl –H, phenyl, or cyclohexyl. In some embodiments, R5is a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O, or S, wherein the heterocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl. In some embodiments, R5is –H, phenyl, or cyclohexyl. In some embodiments, R5is –H or phenyl. In some embodiments, R5is –H. In other embodiments, R5is phenyl. And, in some embodiments, R5is cyclohexyl.57260921.144Attorney Docket No.: 272050-553087 PCT APPLICATION

[0217] Another aspect of the present invention provides a compound selected from the compounds identified in Table 2, or a pharmaceutically acceptable salt thereof.57260921.145Attorney Docket No.: 272050-553087 PCT APPLICATION

[0218] Table 2: Representative compounds of Formula (I). Cmp # Structure Characterization 1H MR 4 MH D l# P ), J z, 7 $ ), 5, r , ,57260921.146Attorney Docket No.: 272050-553087 PCT APPLICATION Cmp # Structure Characterization 5791 5363 5335 5256 5143, r , 1 +$ , C 4, ), , , -$ 8,57260921.147Attorney Docket No.: 272050-553087 PCT APPLICATION Cmp # Structure Characterization 5321 3333 2858 M 9 ), s d . , d, ,57260921.148Attorney Docket No.: 272050-553087 PCT APPLICATION Cmp # Structure Characterization C H F N O MW 44240 = C 3. .9 , 9.

[0219] Another aspect of the present invention provides a compound selected from the compounds identified in Table 3, or a pharmaceutically acceptable salt thereof.

[0220] Table 3: Selected representative compounds of Formula (I). Compound57260921.149Attorney Docket No.: 272050-553087 PCT APPLICATION Compound Structure No. or a phar

[0221] In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of Formula ( ). For example, the pharmaceutically acceptable salt is a hydrochloride, dihydrochloride, or maleate salt of a compound of Formula (I), (IA ). In other examples, the pharmaceutically acceptable salt is a maleate salt of a compound of Formula ( IA-1), or (IA-1a). In some examples, the present invention provides a pharmaceutically acceptable salt (e.g., a hydrochloride, a dihydrochloride, or a maleate salt) of a compound in Table 2. And, in other examples, the present invention provides a pharmaceutically acceptable salt (e.g., a hydrochloride, a dihydrochloride, or a maleate salt) of a compound in Table 3.

[0222] B. Compounds of Formula (

[0223] In another aspect, the present invention provides a compound of Formula (II): or a pharmaceutically acceptableeach of R7and R8is independently –H or halogen;57260921.150Attorney Docket No.: 272050-553087 PCT APPLICATIONor a pharmaceutically

[0224]

[0225] Each of R is independently –H or halogen. In some embodiments, R7and R8are each independently –H, –F, or –Cl.

[0226] In some embodiments, one of R and R8is halogen. In some embodiments, one of R is –F or –Cl. In some embodiments, one of R is –F. And, in some embodiments, one of R

[0227] In some embodiments, R

[0228] In some embodiments, R are each halogen. In some embodiments, one of R7and R8is halogen. In some embodiments, one of R7and R8is –F and the other of R is –F or –Cl. . In some embodiments, one of R7and R8is –F and the other of R is –Cl and the other of R7is –Cl and the other of R7and R is –Cl. And, in some embodiments, each of R

[0229] .Attorney Docket No.: 272050-553087 PCT APPLICATION inIn some embodiments, q is 0 or 1. In some embodiments, q is 0 or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. And, Another aspect of the present invention provides a compound of Formula (IIA), R9and n are as defined ) or any embodiment thereof, with the proviso that the , or a pharmaceutically

[0236] In another aspect of the present invention, a compound is selected from the compounds identified in Table 4, or a pharmaceutically acceptable salt thereof. 57260921.152Attorney Docket No.: 272050-553087 PCT APPLICATION

[0237] Table 4: Representative compounds of Formula (II). Compound No. Structureor a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of Formula (II) or (IIA). For example, the pharmaceutically acceptable salt is a hydrochloride, dihydrochloride, or maleate salt of a compound of Formula (II) or (IIA). In other examples, the pharmaceutically acceptable salt is a maleate salt of a compound of Formula (II) or (IIA). And, in some embodiments, the pharmaceutically acceptable salt is a hydrochloride or dihydrochloride of a compound of Formula (II) or (IIA).

[0239] C. PHARMACEUTICAL COMPOSITIONS / FORMULATIONS

[0240] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable57260921.153Attorney Docket No.: 272050-553087 PCT APPLICATION carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the invention described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

[0241] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent. Pharmaceutical compositions of this invention comprise a therapeutically effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt thereof. In other embodiments, pharmaceutical compositions of this invention comprise a therapeutically effective amount of a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt thereof.

[0242] It also will be appreciated that certain of the compounds of the present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative (e.g., a salt) thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0243] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.

[0244] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids57260921.154Attorney Docket No.: 272050-553087 PCT APPLICATION such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil- soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0245] A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.

[0246] The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, the use57260921.155Attorney Docket No.: 272050-553087 PCT APPLICATION of such conventional carrier medium is contemplated to be within the scope of this invention. As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.

[0247] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.57260921.156Attorney Docket No.: 272050-553087 PCT APPLICATION

[0248] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0249] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions also may contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0250] The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents also may be added.

[0251] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room57260921.157Attorney Docket No.: 272050-553087 PCT APPLICATION temperature but liquid at rectal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0252] The pharmaceutically acceptable compositions of this invention also may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0253] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches also may be used.

[0254] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0255] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention also may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.57260921.158Attorney Docket No.: 272050-553087 PCT APPLICATION

[0256] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions also can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0257] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[0258] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0259] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to57260921.159Attorney Docket No.: 272050-553087 PCT APPLICATION polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations also are prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0260] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also may comprise buffering agents.

[0261] Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Solid dosage forms optionally may contain opacifying agents. These solid dosage forms also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0262] The active compounds also can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as57260921.160Attorney Docket No.: 272050-553087 PCT APPLICATION sucrose, lactose or starch. Such dosage forms also may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms also may comprise buffering agents. They may optionally contain opacifying agents and also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0263] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops also are contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers also can be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0264] The compounds of the invention preferably are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase "dosage unit form" refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0265] Compounds and / or compositions of the invention can be delivered in a controlled release system. In one embodiment, a pump can be used to facilitate controlled release of the compounds and / or compositions of the invention (see Langer, supra; Sefton, CRC Crit. Ref.57260921.161Attorney Docket No.: 272050-553087 PCT APPLICATION Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989)). In another embodiment, compositions of the invention can comprise polymeric materials to provide sustained, intermediate, pulsatile, or alternate release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol.25:351(1989); Howard et al., J. Neurosurg. 71:105 (1989); Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990)). Other controlled-release systems discussed in the review by Langer (Science 249:1527-1533 (1990)) can be used.

[0266] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0267] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, also may be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0268] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of any of Formulae (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0269] In some embodiments, the pharmaceutical composition is a nasal spray having a viscosity of from about 100 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of at least about 100 cP, at least about 250 cP, at least about 500 cP, at least about 750 cP, at least about 1000 cP, at least about 1250 cP, at least about 1500 cP, at least about 1750 cP, at least about 2000 cP, at least about 2250 cP, or at least about 2500 cP, and / or no more than about 100 cP, no more than about 250 cP, no more than about 500 cP, no more than about 750 cP, no more than about 1000 cP, no more than about 1250 cP, no more than57260921.162Attorney Docket No.: 272050-553087 PCT APPLICATION about 1500 cP, no more than about 1750 cP, no more than about 2000 cP, no more than about 2250 cP, or no more than about 2500 cP.

[0270] In some embodiments, the nasal spray has a viscosity of about 100 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of at least about 100 cP. In some embodiments, the nasal spray has a viscosity of at most about 2,500 cP. In some embodiments, the nasal spray has a viscosity of about 100 cP to about 250 cP, about 100 cP to about 500 cP, about 100 cP to about 750 cP, about 100 cP to about 1,000 cP, about 100 cP to about 1,250 cP, about 100 cP to about 1,500 cP, about 100 cP to about 1,750 cP, about 100 cP to about 2,000 cP, about 100 cP to about 2,250 cP, about 100 cP to about 2,500 cP, about 250 cP to about 500 cP, about 250 cP to about 750 cP, about 250 cP to about 1,000 cP, about 250 cP to about 1,250 cP, about 250 cP to about 1,500 cP, about 250 cP to about 1,750 cP, about 250 cP to about 2,000 cP, about 250 cP to about 2,250 cP, about 250 cP to about 2,500 cP, about 500 cP to about 750 cP, about 500 cP to about 1,000 cP, about 500 cP to about 1,250 cP, about 500 cP to about 1,500 cP, about 500 cP to about 1,750 cP, about 500 cP to about 2,000 cP, about 500 cP to about 2,250 cP, about 500 cP to about 2,500 cP, about 750 cP to about 1,000 cP, about 750 cP to about 1,250 cP, about 750 cP to about 1,500 cP, about 750 cP to about 1,750 cP, about 750 cP to about 2,000 cP, about 750 cP to about 2,250 cP, about 750 cP to about 2,500 cP, about 1,000 cP to about 1,250 cP, about 1,000 cP to about 1,500 cP, about 1,000 cP to about 1,750 cP, about 1,000 cP to about 2,000 cP, about 1,000 cP to about 2,250 cP, about 1,000 cP to about 2,500 cP, about 1,250 cP to about 1,500 cP, about 1,250 cP to about 1,750 cP, about 1,250 cP to about 2,000 cP, about 1,250 cP to about 2,250 cP, about 1,250 cP to about 2,500 cP, about 1,500 cP to about 1,750 cP, about 1,500 cP to about 2,000 cP, about 1,500 cP to about 2,250 cP, about 1,500 cP to about 2,500 cP, about 1,750 cP to about 2,000 cP, about 1,750 cP to about 2,250 cP, about 1,750 cP to about 2,500 cP, about 2,000 cP to about 2,250 cP, about 2,000 cP to about 2,500 cP, or about 2,250 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of about 100 cP, about 250 cP, about 500 cP, about 750 cP, about 1,000 cP, about 1,250 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, or about 2,500 cP.

[0271] In some embodiments, the pharmaceutical composition comprises a tablet, capsule, or oral suspension.

[0272] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.57260921.163Attorney Docket No.: 272050-553087 PCT APPLICATION

[0273] In some embodiments, the pharmaceutical composition is a nasal spray having a viscosity of from about 100 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of at least about 100 cP, at least about 250 cP, at least about 500 cP, at least about 750 cP, at least about 1000 cP, at least about 1250 cP, at least about 1500 cP, at least about 1750 cP, at least about 2000 cP, at least about 2250 cP, or at least about 2500 cP, and / or no more than about 100 cP, no more than about 250 cP, no more than about 500 cP, no more than about 750 cP, no more than about 1000 cP, no more than about 1250 cP, no more than about 1500 cP, no more than about 1750 cP, no more than about 2000 cP, no more than about 2250 cP, or no more than about 2500 cP.

[0274] In some embodiments, the nasal spray has a viscosity of about 100 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of at least about 100 cP. In some embodiments, the nasal spray has a viscosity of at most about 2,500 cP. In some embodiments, the nasal spray has a viscosity of about 100 cP to about 250 cP, about 100 cP to about 500 cP, about 100 cP to about 750 cP, about 100 cP to about 1,000 cP, about 100 cP to about 1,250 cP, about 100 cP to about 1,500 cP, about 100 cP to about 1,750 cP, about 100 cP to about 2,000 cP, about 100 cP to about 2,250 cP, about 100 cP to about 2,500 cP, about 250 cP to about 500 cP, about 250 cP to about 750 cP, about 250 cP to about 1,000 cP, about 250 cP to about 1,250 cP, about 250 cP to about 1,500 cP, about 250 cP to about 1,750 cP, about 250 cP to about 2,000 cP, about 250 cP to about 2,250 cP, about 250 cP to about 2,500 cP, about 500 cP to about 750 cP, about 500 cP to about 1,000 cP, about 500 cP to about 1,250 cP, about 500 cP to about 1,500 cP, about 500 cP to about 1,750 cP, about 500 cP to about 2,000 cP, about 500 cP to about 2,250 cP, about 500 cP to about 2,500 cP, about 750 cP to about 1,000 cP, about 750 cP to about 1,250 cP, about 750 cP to about 1,500 cP, about 750 cP to about 1,750 cP, about 750 cP to about 2,000 cP, about 750 cP to about 2,250 cP, about 750 cP to about 2,500 cP, about 1,000 cP to about 1,250 cP, about 1,000 cP to about 1,500 cP, about 1,000 cP to about 1,750 cP, about 1,000 cP to about 2,000 cP, about 1,000 cP to about 2,250 cP, about 1,000 cP to about 2,500 cP, about 1,250 cP to about 1,500 cP, about 1,250 cP to about 1,750 cP, about 1,250 cP to about 2,000 cP, about 1,250 cP to about 2,250 cP, about 1,250 cP to about 2,500 cP, about 1,500 cP to about 1,750 cP, about 1,500 cP to about 2,000 cP, about 1,500 cP to about 2,250 cP, about 1,500 cP to about 2,500 cP, about 1,750 cP to about 2,000 cP, about 1,750 cP to about 2,250 cP, about 1,750 cP to about 2,500 cP, about 2,000 cP to about 2,250 cP, about 2,000 cP to about 2,500 cP, or about 2,250 cP to about 2,500 cP. In some embodiments, the nasal spray has a viscosity of about 100 cP, about57260921.164Attorney Docket No.: 272050-553087 PCT APPLICATION 250 cP, about 500 cP, about 750 cP, about 1,000 cP, about 1,250 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, or about 2,500 cP.

[0275] In some embodiments, the pharmaceutical composition comprises a tablet, capsule, or oral suspension.

[0276] III. METHODS OF TREATMENT

[0277] A. Compound of Formula (I)

[0278] 1. Method of Treating Cancer

[0279] The present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0280] In some implementations, the cancer is a cancer of epithelial origin. For example, in some implementations, the cancer of epithelial origin is selected from the group consisting of brain cancer, breast cancer, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, such as squamous cell and basal cell cancers (e.g., basal cell carcinoma), prostate cancer, renal cell carcinoma, cystadenomas, and endometrial cancer.

[0281] In other implementations, the cancer is a central nervous system (CNS) cancer. For example, in some implementations, the CNS cancer is selected from the group consisting of acoustic neuroma, adenoma, astrocytoma, glioblastoma, brain stem glioma, breast cancer and metastatic brain tumors, chondroma, chondrosarcoma, chordoma, colon cancer and metastatic brain tumors, convexity meningioma, encephaloceles, ependymoma, esthesioneuroblastoma, fibrillary astrocytoma, fibrous dysplasia, giant cell tumor, germ cell tumor, gliomas, gliomatosis cerebri, oligodendroglioma, optic nerve glioma, hemangiopericytoma, kidney cancer and metastatic brain tumors, lung cancer and metastatic brain tumors, medulloblastoma, melanoma (skin cancer) and metastatic brain tumors, meningioma, metastatic brain tumors, mixed glioma, nasopharyngeal angiofibroma, neurofibroma, neurofibromatosis, olfactory neuroblastoma (esthesioneuroblastoma), oligoastrocytoma,57260921.165Attorney Docket No.: 272050-553087 PCT APPLICATION oligodendroglioma, optic glioma, osteoma, paranasal sinus cancer, pituitary adenoma, Rathke's cleft cyst, rhabdomyosarcoma, and schwannoma.

[0282] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in cancer cells. In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in cancer cells. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in cancer cells.

[0283] The compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, that modulate BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A function may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5,57260921.166Attorney Docket No.: 272050-553087 PCT APPLICATION LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A. Without wishing to be bound by theory, it is believed that the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in cancer cells and thereby exhibits cytotoxicity towards cancer cells.

[0284] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0285] In some implementations, the method further comprises administering to the subject an additional therapeutic candidate. For example, the additional therapeutic agent may be an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, abiraterone Acetate, afatinib, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide anagrelide, anastrozole, arsenic trioxide, asparaginase, azacitidine, azathioprine, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cemiplimab, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, denileukin diftitox, decitabine, docetaxel, dexamethasone, dostarlimab, doxifluridine, doxorubicin, enzalutamide, epirubicin, epoetin alpha, epothilones, erlotinib, erubulin, estramustine, etinostat, etoposide, everolimus, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, folate linked alkaloids, gefitinib, gemcitabine, gemtuzumab ozogamicin, GM-CT-01, goserelin, hexamethylmelamine, hydroxyureas, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alpha, interferon beta, irinotecan, ixabepilone, lapatinib, latrunculin, leucovorin,57260921.167Attorney Docket No.: 272050-553087 PCT APPLICATION leuprolide, lenalidomide, letrozole, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nelarabine, nilotinib, nilutamide, nivolumab, octreotide, ofatumumab, omacetaxine mepesuccinate, oprelvekin, oxaliplatin, paclitaxel, panitumumab, pembrolizumab, pemetrexed, pentostatin, polysaccharide galectin inhibitors, procarbazine, proscillaridin A, raloxifene, retinoic acids, rituximab, romiplostim, sargramostim, sorafenib, streptozocin, sunitinib, tamoxifen, temsirolimus, temozolomide, teniposide, thalidomide, thioguanine, thiotepa, tioguanine, topotecan, toremifene, tositumomab, trametinib, trastuzumab, tretinoin, valrubicin, VEGF inhibitors and traps, vinblastine, vincristine, vindesine, vinorelbine, vintafolide (EC145), and vorinostat.

[0286] In some implementations, the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti-cancer agents, or any combination thereof. For example, the anti-cancer agent is temozolomide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is ixabepilone, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is cladribine, or a pharmaceutically acceptable salt thereof. In some examples, the anti- cancer agent is enzalutamide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is omacetaxine mepesuccinate, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is epothilones, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is erubulin, or a pharmaceutically acceptable salt thereof. And, in some examples, the anti- cancer agent is latrunculin, or a pharmaceutically acceptable salt thereof.

[0287] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered concurrently. In other implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered sequentially. For example, the additional therapeutic agent may be administered prior to or subsequent to the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these57260921.168Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0288] In some implementations, the method further comprises administering to the subject a radiation therapy. In other words, radiation therapy may be administered during the treatment course wherein a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0289] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 5057260921.169Attorney Docket No.: 272050-553087 PCT APPLICATION mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0290] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically (i.e., “chronic administration”). Chronic administration refers to administration the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition thereof, over an extended period of time (e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.), or indefinitely (e.g., for the rest of the subject's life. In some examples, the chronic administration is intended to provide a constant level of the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, in the blood (e.g., within the therapeutic window over the extended period of time).

[0291] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically57260921.170Attorney Docket No.: 272050-553087 PCT APPLICATION acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0292] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a),57260921.171Attorney Docket No.: 272050-553087 PCT APPLICATION or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0293] In some implementations, the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences a reduced loss in bodyweight of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences a reduced loss in bodyweight of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences a reduced loss in bodyweight of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences a reduced loss in bodyweight of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the57260921.172Attorney Docket No.: 272050-553087 PCT APPLICATION compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0294] In some implementations, the subject experiences an increased life expectancy following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences an increased life expectancy of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences an increased life expectancy of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences an increased life expectancy of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences an increased life expectancy of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of57260921.173Attorney Docket No.: 272050-553087 PCT APPLICATION any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0295] In some implementations, the subject experiences a vacuolization of mitochondria in cancer cells following treatment onset. In other implementations, the subject experiences a depolarization of mitochondria in cancer cells following treatment onset.

[0296] Without wishing to be bound by theory, it is believed that treatment with the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, induces vacuolization of mitochondria in cancer cells (e.g., glioblastoma multiforme (GBM) cells). This vacuolization results in depolarization of mitochondria in cancer cells and, ultimately, cell death.

[0297] In some implementations, the subject is an animal. For example, the subject is a human.

[0298] 2. Method of Treating Brain Cancer

[0299] In one aspect, the present invention provides a method of treating brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0300] In some implementations, the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma (e.g., piloid astrocytoma, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytic astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme (GBM)), brain lymphoma, brain metastases, hypophyseal tumor (e.g., prolactinoma, HGH (human growth hormone) producing tumor, and ACTH-producing tumor (adrenocorticotrophic hormone)), craniopharyngiomas, medulloblastomas, meningiomas, and oligodendrogliomas.

[0301] In some implementations, the brain cancer is a glioma. In other implementations, the glioma is selected from the group consisting of an astrocytoma, an ependymoma, an oligodendroglioma, a brainstem glioma, an optic nerve glioma, and a mixed glioma. In some implementations, the glioma is an astrocytoma. Astroctyoma includes, by way of non- limiting example, pilocytic astrocytoma, subependymal giant cell astrocytoma, fibrillary astrocytoma, pleomorphic xanthoastrocytoma, mixed oligoastrocytoma, anaplastic57260921.174Attorney Docket No.: 272050-553087 PCT APPLICATION astrocytoma, and glioblastoma multiforme (GBM). And, in some implementations, the astrocytoma is GBM.

[0302] In some implementations, the glioma is ependymoma. Ependymoma includes, by way of non-limiting example, subependymoma, myxopapillary ependymoma, and anaplastic ependymoma.

[0303] In some implementations, the glioma is an oligodendroglioma. Oligodendroglioma includes, by way of non-limiting example, Grade II oligodendroglioma and Grade III oligodendroglioma (i.e., anaplastic oligodendrioglioma).

[0304] In some implementations, the glioma is a brainstem glioma. Brainstem glioma includes, by way of non-limiting example, tectal Glioma, diffuse intrinsic pontine glioma (DIPG), and cervicomedullary glioma.

[0305] In some implementations, the glioma is an optic nerve glioma. In some examples, the glioma is a mixed glioma (e.g., oligodendroglioma & oligoastrocytoma).

[0306] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in brain cancer cells. In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in brain cancer cells. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in brain cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in brain cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of57260921.175Attorney Docket No.: 272050-553087 PCT APPLICATION Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in brain cancer cells. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in brain cancer cells.

[0307] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0308] In some implementations, the method further comprises administering to the subject an additional therapeutic candidate. For example, the additional therapeutic agent may be an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, abiraterone Acetate, afatinib, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide anagrelide, anastrozole, arsenic trioxide, asparaginase, azacitidine, azathioprine, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cemiplimab, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, denileukin diftitox, decitabine, docetaxel, dexamethasone, dostarlimab, doxifluridine, doxorubicin, enzalutamide, epirubicin, epoetin alpha, epothilones, erlotinib, erubulin, estramustine, etinostat, etoposide, everolimus, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, folate linked alkaloids, gefitinib, gemcitabine, gemtuzumab ozogamicin, GM-CT-01, goserelin, hexamethylmelamine, hydroxyureas, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alpha, interferon beta, irinotecan, ixabepilone, lapatinib, latrunculin, leucovorin,57260921.176Attorney Docket No.: 272050-553087 PCT APPLICATION leuprolide, lenalidomide, letrozole, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nelarabine, nilotinib, nilutamide, nivolumab, octreotide, ofatumumab, omacetaxine mepesuccinate, oprelvekin, oxaliplatin, paclitaxel, panitumumab, pembrolizumab, pemetrexed, pentostatin, polysaccharide galectin inhibitors, procarbazine, proscillaridin A, raloxifene, retinoic acids, rituximab, romiplostim, sargramostim, sorafenib, streptozocin, sunitinib, tamoxifen, temsirolimus, temozolomide, teniposide, thalidomide, thioguanine, thiotepa, tioguanine, topotecan, toremifene, tositumomab, trametinib, trastuzumab, tretinoin, valrubicin, VEGF inhibitors and traps, vinblastine, vincristine, vindesine, vinorelbine, vintafolide (EC145), and vorinostat.

[0309] In some implementations, the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti-cancer agents, or any combination thereof. For example, the anti-cancer agent is temozolomide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is ixabepilone, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is cladribine, or a pharmaceutically acceptable salt thereof. In some examples, the anti- cancer agent is enzalutamide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is omacetaxine mepesuccinate, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is epothilones, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is erubulin, or a pharmaceutically acceptable salt thereof. And, in some examples, the anti- cancer agent is latrunculin, or a pharmaceutically acceptable salt thereof.

[0310] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered concurrently. In other implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered sequentially. For example, the additional therapeutic agent may be administered prior to or subsequent to the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these57260921.177Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0311] In some implementations, the method further comprises administering to the subject a radiation therapy. In other words, radiation therapy may be administered during the treatment course wherein a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0312] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 5057260921.178Attorney Docket No.: 272050-553087 PCT APPLICATION mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0313] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically.

[0314] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is57260921.179Attorney Docket No.: 272050-553087 PCT APPLICATION administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0315] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0316] In some implementations, the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these57260921.180Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences a reduced loss in bodyweight of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences a reduced loss in bodyweight of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences a reduced loss in bodyweight of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences a reduced loss in bodyweight of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0317] In some implementations, the subject experiences an increased life expectancy following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA),57260921.181Attorney Docket No.: 272050-553087 PCT APPLICATION (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences an increased life expectancy of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences an increased life expectancy of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences an increased life expectancy of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences an increased life expectancy of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds.

[0318] In some implementations, the subject experiences a vacuolization of mitochondria in cancer cells following treatment onset. In other implementations, the subject experiences a depolarization of mitochondria in cancer cells following treatment onset.

[0319] In some implementations, the subject is an animal. For example, the subject is a human.57260921.182Attorney Docket No.: 272050-553087 PCT APPLICATION

[0320] 3. Method of Inducing Vacuolization

[0321] Another aspect of the present invention provides a method of inducing vacuolization of mitochondria in a glioblastoma multiforme (GBM) cell, comprising administering to the cell an effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0322] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in the cell. In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a),57260921.183Attorney Docket No.: 272050-553087 PCT APPLICATION or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in the cell.

[0323] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0324] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 157260921.184Attorney Docket No.: 272050-553087 PCT APPLICATION year. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0325] In some implementations, the cell experiences a depolarization of mitochondria following treatment onset.

[0326] In some implementations, the cell is an animal cell. For example, the cell is a human cell.

[0327] 4. Method of Depolarizing Mitochondria

[0328] Another aspect of the present invention provides a method of depolarizing a mitochondrion in a glioblastoma multiforme (GBM) cell, comprising administering to the cell an effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0329] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in the cell. In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these57260921.185Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA- 1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in the cell. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in the cell.

[0330] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0331] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically57260921.186Attorney Docket No.: 272050-553087 PCT APPLICATION acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0332] In some implementations, the cell experiences a vacuolization of mitochondria following treatment onset.

[0333] In some implementations, the cell is an animal cell. For example, the cell is a human cell.

[0334] 5. Method of Modulating

[0335] Another aspect of the present invention provides a modulating activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in a cancer cell, comprising administering to the cancer cell an effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier. In one aspect, the present invention provides method of modulating activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in a cancer cell, comprising administering to the cancer cell an effective amount of a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these57260921.187Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0336] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0337] In some implementations, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 157260921.188Attorney Docket No.: 272050-553087 PCT APPLICATION year. And, in some examples, the compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (I), (IA), (IA-1), or (IA-1a), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0338] In some implementations, the cell experiences a vacuolization of mitochondria following treatment onset. In some implementations, the cell experiences a depolarization of mitochondria following treatment onset.

[0339] In some implementations, the cell is an animal cell. For example, the cell is a human cell.

[0340] B. Compound of Formula (II)

[0341] 1. Method of Treating Cancer

[0342] The present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier, wherein the cancer is selected from brain cancer, breast cancer, pancreatic cancer, lung cancer, or any combination thereof.

[0343] In some implementations, the cancer is brain cancer. Examples of brain cancer include, but are not limited to, acoustic neuroma, astrocytoma (e.g., piloid astrocytoma, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytic astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme (GBM)), brain lymphoma, brain metastases, hypophyseal tumor (e.g., prolactinoma, HGH (human growth hormone) producing tumor, and ACTH-producing tumor (adrenocorticotrophic hormone)), craniopharyngiomas, medulloblastomas, meningiomas, and oligodendrogliomas. In some examples, the brain cancer is glioblastoma multiforme (GBM).

[0344] In some implementations, the cancer is breast cancer. Examples of breast cancer include, but are not limited to, mammary carcinoma, ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenoid cystic carcinoma, and papillary carcinoma.57260921.189Attorney Docket No.: 272050-553087 PCT APPLICATION

[0345] In some implementations, the cancer is pancreatic cancer. Examples of pancreatic cancer include, but are not limited to, exocrine (nonendocrine) pancreatic cancer and neuroendocrine pancreatic cancer.

[0346] In some implementations, the cancer is lung cancer. Examples of lung cancer include, but are not limited to, bronchial carcinoma, small cell lung cancer, and non-small cell lung cancer (e.g., squamous epithelium carcinoma, lung adenocarcinoma, and large-cell bronchial carcinoma).

[0347] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in cancer cells. In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in cancer cells. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in cancer cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in cancer cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in cancer cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in cancer cells.

[0348] The compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, that modulates BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1,57260921.190Attorney Docket No.: 272050-553087 PCT APPLICATION ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A function may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, and / or ZNF75A. Without wishing to be bound by theory, it is believed that the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in cancer cells and thereby exhibits cytotoxicity towards cancer cells.

[0349] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0350] In some implementations, the method further comprises administering to the subject an additional therapeutic candidate. For example, the additional therapeutic agent may be an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, abiraterone Acetate, afatinib, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide anagrelide, anastrozole, arsenic trioxide, asparaginase, azacitidine, azathioprine, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cemiplimab, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, denileukin diftitox, decitabine, docetaxel, dexamethasone, dostarlimab, doxifluridine, doxorubicin, enzalutamide, epirubicin, epoetin alpha, epothilones, erlotinib, erubulin, estramustine, etinostat, etoposide, everolimus, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, folate linked alkaloids, gefitinib, gemcitabine, gemtuzumab ozogamicin, GM-CT-01, goserelin, hexamethylmelamine, hydroxyureas, ibritumomab, idarubicin, ifosfamide, imatinib,57260921.191Attorney Docket No.: 272050-553087 PCT APPLICATION interferon alpha, interferon beta, irinotecan, ixabepilone, lapatinib, latrunculin, leucovorin, leuprolide, lenalidomide, letrozole, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nelarabine, nilotinib, nilutamide, nivolumab, octreotide, ofatumumab, omacetaxine mepesuccinate, oprelvekin, oxaliplatin, paclitaxel, panitumumab, pembrolizumab, pemetrexed, pentostatin, polysaccharide galectin inhibitors, procarbazine, proscillaridin A, raloxifene, retinoic acids, rituximab, romiplostim, sargramostim, sorafenib, streptozocin, sunitinib, tamoxifen, temsirolimus, temozolomide, teniposide, thalidomide, thioguanine, thiotepa, tioguanine, topotecan, toremifene, tositumomab, trametinib, trastuzumab, tretinoin, valrubicin, VEGF inhibitors and traps, vinblastine, vincristine, vindesine, vinorelbine, vintafolide (EC145), and vorinostat.

[0351] In some implementations, the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti-cancer agents, or any combination thereof. For example, the anti-cancer agent is temozolomide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is ixabepilone, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is cladribine, or a pharmaceutically acceptable salt thereof. In some examples, the anti- cancer agent is enzalutamide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is omacetaxine mepesuccinate, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is epothilones, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is erubulin, or a pharmaceutically acceptable salt thereof. And, in some examples, the anti- cancer agent is latrunculin, or a pharmaceutically acceptable salt thereof.

[0352] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered concurrently. In other implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered sequentially. For example, the additional therapeutic agent may be administered prior to or subsequent to the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical57260921.192Attorney Docket No.: 272050-553087 PCT APPLICATION composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.

[0353] In some implementations, the method further comprises administering to the subject a radiation therapy. In other words, radiation therapy may be administered during the treatment course wherein a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0354] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these57260921.193Attorney Docket No.: 272050-553087 PCT APPLICATION compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0355] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically (i.e., “chronic administration”). Chronic administration refers to administration the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, over an extended period of time (e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.), or indefinitely (e.g., for the rest of the subject's life. In some examples, the chronic administration is intended to provide a constant level of the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds in the blood (e.g., within the therapeutic window over the extended period of time).

[0356] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically57260921.194Attorney Docket No.: 272050-553087 PCT APPLICATION acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0357] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of57260921.195Attorney Docket No.: 272050-553087 PCT APPLICATION Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0358] In some implementations, the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences a reduced loss in bodyweight of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences a reduced loss in bodyweight of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences a reduced loss in bodyweight of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences a reduced loss in bodyweight of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.57260921.196Attorney Docket No.: 272050-553087 PCT APPLICATION

[0359] In some implementations, the subject experiences an increased life expectancy following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences an increased life expectancy of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences an increased life expectancy of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences an increased life expectancy of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences an increased life expectancy of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.

[0360] In some implementations, the subject experiences a vacuolization of mitochondria in cancer cells following treatment onset. In other implementations, the subject experiences a depolarization of mitochondria in cancer cells following treatment onset.57260921.197Attorney Docket No.: 272050-553087 PCT APPLICATION

[0361] Without wishing to be bound by theory, it is believed that treatment with the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt thereof, induces vacuolization of mitochondria in cancer cells (e.g., glioblastoma multiforme (GBM) cells). This vacuolization results in depolarization of mitochondria in cancer cells and, ultimately, cell death.

[0362] In some implementations, the subject is an animal. For example, the subject is a human.

[0363] 2. Method of Treating Glioma

[0101] Another aspect of the present invention provides a method of treating glioma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0364] In some implementations, the glioma is selected from the group consisting of an astrocytoma, an ependymoma, an oligodendroglioma, a brainstem glioma, an optic nerve glioma, and a mixed glioma. For example, the glioma is an astrocytoma. Astroctyoma includes, by way of non-limiting example, pilocytic astrocytoma, subependymal giant cell astrocytoma, fibrillary astrocytoma, pleomorphic xanthoastrocytoma, mixed oligoastrocytoma, anaplastic astrocytoma, and glioblastoma multiforme (GBM). In some implementations, the astrocytoma is GBM.

[0365] In some implementations, the glioma is ependymoma. Ependymoma includes, by way of non-limiting example, subependymoma, myxopapillary ependymoma, and anaplastic ependymoma.

[0366] In some implementations, the glioma is an oligodendroglioma. Oligodendroglioma includes, by way of non-limiting example, Grade II oligodendroglioma and Grade III oligodendroglioma (i.e., anaplastic oligodendrioglioma).

[0367] In some implementations, the glioma is a brainstem glioma. Brainstem glioma includes, by way of non-limiting example, tectal Glioma, diffuse intrinsic pontine glioma (DIPG), and cervicomedullary glioma.

[0368] In some implementations, the glioma is an optic nerve glioma. In some examples, the glioma is a mixed glioma (e.g., oligodendroglioma & oligoastrocytoma).57260921.198Attorney Docket No.: 272050-553087 PCT APPLICATION

[0369] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in glioma cells (e.g., GBM cells). In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in glioma cells (e.g., GBM cells). For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in glioma cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in glioma cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in glioma cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in glioma cells.

[0370] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (II) or57260921.199Attorney Docket No.: 272050-553087 PCT APPLICATION (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0371] In some implementations, the method further comprises administering to the subject an additional therapeutic candidate. For example, the additional therapeutic agent may be an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, abiraterone Acetate, afatinib, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide anagrelide, anastrozole, arsenic trioxide, asparaginase, azacitidine, azathioprine, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cemiplimab, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, denileukin diftitox, decitabine, docetaxel, dexamethasone, dostarlimab, doxifluridine, doxorubicin, enzalutamide, epirubicin, epoetin alpha, epothilones, erlotinib, erubulin, estramustine, etinostat, etoposide, everolimus, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, folate linked alkaloids, gefitinib, gemcitabine, gemtuzumab ozogamicin, GM-CT-01, goserelin, hexamethylmelamine, hydroxyureas, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alpha, interferon beta, irinotecan, ixabepilone, lapatinib, latrunculin, leucovorin, leuprolide, lenalidomide, letrozole, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nelarabine, nilotinib, nilutamide, nivolumab, octreotide, ofatumumab, omacetaxine mepesuccinate, oprelvekin, oxaliplatin, paclitaxel, panitumumab, pembrolizumab, pemetrexed, pentostatin, polysaccharide galectin inhibitors, procarbazine, proscillaridin A, raloxifene, retinoic acids, rituximab, romiplostim, sargramostim, sorafenib, streptozocin, sunitinib, tamoxifen, temsirolimus, temozolomide, teniposide, thalidomide, thioguanine, thiotepa, tioguanine, topotecan, toremifene, tositumomab, trametinib, trastuzumab, tretinoin, valrubicin, VEGF inhibitors and traps, vinblastine, vincristine, vindesine, vinorelbine, vintafolide (EC145), and vorinostat.

[0372] In some implementations, the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti-cancer agents, or any combination thereof. For example, the anti-cancer agent is temozolomide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is ixabepilone, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is cladribine, or a pharmaceutically acceptable salt thereof. In some examples, the anti-57260921.1100Attorney Docket No.: 272050-553087 PCT APPLICATION cancer agent is enzalutamide, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is omacetaxine mepesuccinate, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is epothilones, or a pharmaceutically acceptable salt thereof. In some examples, the anti-cancer agent is erubulin, or a pharmaceutically acceptable salt thereof. And, in some examples, the anti- cancer agent is latrunculin, or a pharmaceutically acceptable salt thereof.

[0373] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered concurrently. In other implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and the additional therapeutic agent are administered sequentially. For example, the additional therapeutic agent may be administered prior to, or subsequent to, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.

[0374] In some implementations, the method further comprises administering to the subject a radiation therapy. In other words, radiation therapy may be administered during the treatment course wherein a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0375] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage57260921.1101Attorney Docket No.: 272050-553087 PCT APPLICATION amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0376] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically.

[0377] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of57260921.1102Attorney Docket No.: 272050-553087 PCT APPLICATION treatment for a duration of at least about 2 days. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0378] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or57260921.1103Attorney Docket No.: 272050-553087 PCT APPLICATION (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0379] In some implementations, the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences a reduced loss in bodyweight of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences a reduced loss in bodyweight of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences a reduced loss in bodyweight of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences a57260921.1104Attorney Docket No.: 272050-553087 PCT APPLICATION reduced loss in bodyweight of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.

[0380] In some implementations, the subject experiences an increased life expectancy following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. For example, the subject experiences an increased life expectancy of at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In other examples, the subject experiences an increased life expectancy of at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. In some examples, the subject experiences an increased life expectancy of at least about 20% (e.g., at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, or at least about 29%) following treatment onset as compared to a subject not administered the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds. And, in some examples, the subject experiences an increased life expectancy of at least about 30% to about 99% (e.g., from about 30% to about 85%, from about 30% to about 80%, from about 30% to about 75%, and the like) following treatment onset as compared to a subject not administered the compound of57260921.1105Attorney Docket No.: 272050-553087 PCT APPLICATION Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds.

[0381] In some implementations, the subject experiences a vacuolization of mitochondria in glioma cells (e.g., GBM cells) following treatment onset. In other implementations, the subject experiences a depolarization of mitochondria in glioma cells (e.g., GBM cells) following treatment onset.

[0382] In some implementations, the subject is an animal. For example, the subject is a human.

[0383] 3. Method of Inducing Vacuolization

[0384] Another aspect of the present invention provides a method of inducing vacuolization of mitochondria in glioblastoma multiforme (GBM) cells of a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0385] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in GBM cells. In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in GBM cells. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a57260921.1106Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in GBM cells.

[0386] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0387] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples,57260921.1107Attorney Docket No.: 272050-553087 PCT APPLICATION the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0388] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically.

[0389] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a57260921.1108Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0390] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the57260921.1109Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0391] In some implementations, the subject experiences a depolarization of mitochondria in GBM cells following treatment onset.

[0392] In some implementations, the subject is an animal. For example, the subject is a human.

[0393] 4. Method of Depolarizing Mitochondria

[0394] Another aspect of the present invention provides a method of depolarizing mitochondria in glioblastoma multiforme (GBM) cells of a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

[0395] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, CARD1, ETV2L, HMGN5, LYSMD4, PLA2G7, TAF11, TDRD5, UTP23, UGP2, WT1P, ZNF75A, or any combination thereof in GBM cells. In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in GBM cells. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of BMPR1A in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a57260921.1110Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutically acceptable salt of any of these compounds, modulates activity of UTP23 in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ARHGAP33 in GBM cells. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, modulates activity of ITSN1 in GBM cells.

[0396] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once per day. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once or twice per day. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered once per day.

[0397] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 2,000 mg. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 1,000 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 1 mg to about 900 mg, 1 mg to about 800 mg, 1 mg to about 700 mg, 1 mg to about 600 mg, 1 mg to about 500 mg, 1 mg to about 400 mg, 1 mg to about 300 mg, 1 mg to about 200 mg, 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 500 mg. In some examples,57260921.1111Attorney Docket No.: 272050-553087 PCT APPLICATION the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 500 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 50 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 100 mg to about 300 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of from about 75 mg to about 150 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 50 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 75 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 100 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 200 mg. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 300 mg. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered in a dosage amount of about 400 mg.

[0398] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered chronically.

[0399] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 days. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a57260921.1112Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, or 60 days. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7, months, 8 months, 9 months, 10 months, or 11 months. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 1 year. And, in some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered at least once a day from onset of treatment for a duration of at least about 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0400] In some implementations, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally or intranasally. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered orally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a tablet, capsule, or oral suspension. In some examples, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the57260921.1113Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered intranasally. For example, the compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, or the pharmaceutical composition comprising a compound of Formula (II) or (IIA), or a pharmaceutically acceptable salt of any of these compounds, is administered as a nasal spray.

[0401] In some implementations, the subject experiences a vacuolization of mitochondria in GBM cells following treatment onset.

[0402] In some implementations, the subject is an animal. For example, the subject is a human.

[0403] IV. EXAMPLES

[0404] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0405] A. General Synthetic Schemes

[0406] Scheme 1:

[0407] General compounds of formula G-2, wherein m, n,R2are defined herein, can be synthesized by exposure of compounds of Formula G-1 to a reducing agent such as sodium borohydride, lithium aluminum hydride, or the like.

[0408] Scheme 2:57260921.1114Attorney Docket No.: 272050-553087 PCT APPLICATIONknown to those having skill in the art, can be functionalized by an SN2 reaction with an alkylating agent of Formula G-4, wherein X is a leaving group, such as halogen or activated oxygen, such as a tosyl, mesyl, or triflate moiety, and y is a lower integer. Compounds of Formula G-5 can then be reacted with an appropriate reagent to convert the hydroxyl group to the leaving group, X, to produce compounds of Formula G-6. Alternatively, compounds of Formula G-3 can also be converted to compounds of Formula G-8, by reaction with an acylating agent of Formula G-7, using amide coupling chemistry well known to those having skill in the art. Amide compounds of Formula G-8 can then be deprotected under appropriate conditions based on the protecting group, and exposed to reducing conditions, such as lithium aluminum hydride, optionally in the presence of a Lewis acid, or the like. Amine compounds of Formula G-9 can then be functionalized to compounds of Formula G-10 analogously to the conversion of compounds of Formula G-3 to compounds of Formula G-6. R4, R5, and p are defined herein.

[0410] Scheme 3:57260921.1115Attorney Docket No.: 272050-553087 PCT APPLICATION (R4)p(R1)m(R4)pX O R5

[0411] of Formula G-10 with compounds of Formula G-2. Alternatively, compounds of Formula G- 11 can be produced by Sn-2 reaction of compounds of Formula G-6 with compounds of Formula G-2, followed or preceded by deprotection of the protecting group, Pr. Sn-2 conditions for the transformations in Scheme 3 are well known to those having skill in the art, for example favorable conditions may include a strong base, such as sodium hydride and a polar aprotic solvent, such as dimethyl formamide, dimethylacetamide, or dimethylsulfoxide.

[0412] B. Specific Synthetic Examples

[0413] Example 1: Synthesis of 1-(2-((4- chlorophenyl)(phenyl)methoxy)ethyl)piperazine (Compound 4).57260921.1Attorney Docket No.: 272050-553087 PCT APPLICATION Br HO 4a

[0415] To a stirred solution of compound 1a (5.0 g, 23 mmol) in methanol (50 mL) was added NaBH4(0.87 g, 23 mmol) at 0oC under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0oC and quenched with ammonium chloride solution, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 2a (4.5 g, 90%) as an off-white solid.

[0416] Step 2: tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5a)

[0417] To a stirred solution of compound 3a (10.0 g, 53.7 mmol) in acetonitrile (150 mL) was added 2-bromoethan-1-ol 4a (4.5 mL, 64.5 mmol) and K2CO3(11.2 g, 86.0 mmol) and the reaction mixture was stirred at 80oC for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over anhydrous57260921.1117Attorney Docket No.: 272050-553087 PCT APPLICATION Na2SO4, filtered and concentrated under reduced pressure to obtain crude material. This crude material was purified by silica gel (100-200) column chromatography using 5% MeOH / DCM to afford compound 5a (6 g, 48%) as colorless liquid.

[0418] Step 3: tert-butyl 4-(2-(tosyloxy)ethyl)piperazine-1-carboxylate (6a)

[0419] To a stirred solution of compound 5a (6.00 g, 26.0 mmol) in dichloromethane (120 mL) was added triethylamine (5.40 mL 39.0 mmol) followed by tosyl chloride (4.00 mL, 31.0 mmol) at 0oC under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. This crude material was purified by silica gel (100-200) column chromatography using 30% EtOAc / hexanes to afford compound 6a (4.8 g, 48%) as a semi-solid.

[0420] Step 4: tert-butyl 4-(2-((4-chlorophenyl)(phenyl)methoxy)ethyl)piperazine-1- carboxylate (7a)

[0421] To a stirred solution of (4-chlorophenyl)(phenyl)methanol 2a (1.00 g, 4.50 mmol) in DMF (10 mL) was added NaH (0.36 g, 9.10 mmol) followed by the addition of compound 6a (2.55 g, 6.60 mol) and the reaction mixture was stirred at 50oC for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extract was dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to obtain crude material. This crude material was purified by silica gel (100-200) column chromatography using 25% EtOAc / hexanes to afford compound 7a (0.32 g, 30%) as a viscous liquid; LC-MS (ESI): m / z 431.0 [M + H]+.

[0422] Step 5: 1-(2-((4-chlorophenyl)(phenyl)methoxy)ethyl)piperazine (Compound 4)

[0423] To a stirred solution of compound 7a (0.30 g, 697 mmol) in 1,4-dioxane (12 mL) was added 4 M HCl in 1,4-dioxane (0.35 mL, 1.39 mmol) at 0oC under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude material. This crude material was purified by basic alumina column chromatography using 25% EtOAc / hexanes to afford Compound 4 (30 mg, 14%) as a viscous liquid.1H NMR (400 MHz, DMSO-d6#1 P .&*0%.&*+ (m, 8H), 7.28-7.22 (m, 1H), 5.48 (s, 1H), 3.47 (t, J = 4.0 Hz, 2H), 2.66-2.63 (m, 4H), 2.5 (m, 2H), 2.32-2.3 (m, 4H); LC-MS (ESI): m / z 330.9 [M + H]+.57260921.1118Attorney Docket No.: 272050-553087 PCT APPLICATION

[0424] Example 2: Synthesis of 1-(2-(di-p-tolylmethoxy)ethyl)-4-(3-phenylpropyl)

[0426] To a stirred solution of compound 1b (4.00 g, 19.0 mmol) in methanol (40 mL) was added NaBH4 (0.72 g, 19.0 mmol) at 0oC under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0oC and quenched with ammonium chloride solution and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 2b (3.5 g, 85%) as an off-white solid.

[0427] Step 2: tert-butyl 4-(3-phenylpropanoyl)piperazine-1-carboxylate (5b)

[0428] To a stirred solution of compound 3b (5.00 g, 33.0 mmol) in DMF (25 mL) were added HATU (15.2 g, 39.9 mmol), and N,N-diisopropylethylamine (17.4 mL, 0.10 mmol) followed by compound 4b (6.2 g, 33.0 mmol) at 0oC under argon atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. The reaction was57260921.1119Attorney Docket No.: 272050-553087 PCT APPLICATION monitored by TLC; after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 5b (4.00 g, 38%) as an off- white solid; LC-MS (ESI): m / z 319.0 [M + H]+.

[0429] Step 3: 3-phenyl-1-(piperazin-1-yl)propan-1-one (6b)

[0430] To a stirred solution of compound 5b (4.00 g, 12.0 mmol) in methylene chloride (40 mL) was added trifluoroacetic acid (12 mL) at 0oC and the reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. This crude material was purified by silica gel (100-200) column chromatography using 30% EtOAc / hexanes to afford compound 6b (2.60 g, 94%) as a viscous liqu...

Claims

Attorney Docket No.: 272050-553087 PCT APPLICATION WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically X is –O–, –S–, or –NR6–, wherein R6is –H or optionally substituted C1-6alkyl; each R1, R2, and R4is independently –H, halo, –CN, –OR, –SR, –NR2, –NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein each C1-6alkyl of R1, R2, and R4is independently optionally substituted with halo, –OH, or oxo, the C2-6 alkenyl, the C2-6 alkynyl, and the monocyclic ring of each R1, R2, and R4is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo, and wherein each R is independently –H or C1-6 alkyl; R3is –H or optionally substituted C1-6 alkyl; L is a bond or a C1-6 aliphatic chain optionally substituted with halo, unsubstituted C1-3alkyl, –OH, –CN, or oxo; R5is –H or a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or oxo; and each of m and n is independently 0, 1, 2, 3, 4, or 5; o is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4, provided that the compound is not a compound selected from57260921.1136Attorney Docket No.: 272050-553087 PCT APPLICATION or a pharmaceutically acceptab e sa t t ereo .

2. The compound or pharmaceutically acceptable salt of claim 1, wherein X is –O–, –S–, –NH–, or –N(CH3)–.

3. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein X is –O–.

4. The compound or pharmaceutically acceptable salt of any one of claims 1-3, wherein m is 1, 2, 3, 4, or 5; and each R1is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and monocyclic ring of R1is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl.57260921.1137Attorney Docket No.: 272050-553087 PCT APPLICATION 5. The compound or pharmaceutically acceptable salt of any one of claims 1-4, wherein each R1is independently halo, C1-6alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S.

6. The compound or pharmaceutically acceptable salt of any one of claims 1-5, wherein each R1is independently –F, –Cl, –Br, –CH3, or phenyl.

7. The compound or pharmaceutically acceptable salt of any one of claims 1-6, wherein m is 1.

8. The compound or pharmaceutically acceptable salt of any one of claims 1-3, wherein m is 0.

9. The compound or pharmaceutically acceptable salt of any one of claims 1-8, wherein n is 1, 2, 3, 4, or 5; and each R2is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, a 3-6 membered monocyclic cycloalkyl, or a 5-6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein each phenyl and heterocyclic ring of R2is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl.

10. The compound or pharmaceutically acceptable salt of any one of claims 1-9, wherein each R2is independently halo, C1-6alkyl, phenyl, or a 6 membered monocyclic, saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S.

11. The compound or pharmaceutically acceptable salt of any one of claims 1-10, wherein each R2is independently –F, –Cl, –Br, –CH3, or phenyl.

12. The compound or pharmaceutically acceptable salt of any one of claims 1-11, wherein n is 1.57260921.1138Attorney Docket No.: 272050-553087 PCT APPLICATION 13. The compound or pharmaceutically acceptable salt of any one of claims 1-8, wherein n is 0.

14. The compound or pharmaceutically acceptable salt of any one of claims 1-13, wherein p is 1, 2, 3, or 4; and each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

15. The compound or pharmaceutically acceptable salt of any one of claims 1-14, wherein each R4is independently halo, –CN, –OH, –SH, –NO2, –SCH3, –OCH3, –NCH3, or –CH .

16. The compound or pharmaceutically acceptable salt of any one of claims 1-15, wherein p is 1.

17. The compound or pharmaceutically acceptable salt of any one of claims 1-13, wherein p is 0.

18. The compound or pharmaceutically acceptable salt of any one of claims 1-17, wherein R3is –H or C1-3alkyl.

19. The compound or pharmaceutically acceptable salt of any one of claims 1-18, wherein R3is –H.

20. The compound or pharmaceutically acceptable salt of any one of claims 1-19, wherein L is a bond or a C1-3aliphatic chain optionally substituted with halo, methyl, –OH, –CN, or oxo.

21. The compound or pharmaceutically acceptable salt of any one of claims 1-20, wherein L is a bond, .57260921.1139Attorney Docket No.: 272050-553087 PCT APPLICATION 22. The compound or pharmaceutically acceptable salt of any one of claims 1-21, whereinacceptable salt of any one of claims 1-22, wherein R5is –H or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, – OH, –SH, –NO2, –SCH3, –OCH alkenyl, C2-6alkynyl, or oxo.

24. The compound or pharmaceutically acceptable salt of any one of claims 1-23, wherein R5is –H, phenyl, or a 3-6 membered monocyclic cycloalkyl, wherein the phenyl and monocyclic cycloalkyl of R are optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO , –NCH3, C1-6alkyl, C2-6alkenyl, or C2-6 alkynyl.

25. The compound or pharmaceutically acceptable salt of any one of claims 1-24, wherein R5is –H, phenyl, or cyclohexyl.

26. The compound or pharmaceutically acceptable salt of any one of claims 1-25, wherein o is 1.

27. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of Formula (I) is a compound of Formula (or a pharmaceutically acceptable salt thereof.

28. The compound or pharmaceutically acceptable salt of claim 27, wherein the compound of Formula (IA) is a compound of Formula (IA-1):57260921.1140Attorney Docket No.: 272050-553087 PCT APPLICATION or a pharmaceutically29. The compound or pharmaceutically acceptable salt of claim 28, wherein R1is halo, C1-6alkyl, or phenyl; R2is –H, halo, or C1-6 L is a bond or C1-3aliphatic chain optionally substituted with halo, –OH, –CN, or oxo; and R5is –H or a 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O, or S, wherein the monocyclic ring of R5is optionally substituted with 1-3 groups independently selected from halo, –CN, –OH, –SH, –NO alkyl, C2-6 alkenyl, C2-6 alkynyl, or oxo.

30. The compound of pharmaceutically acceptable salt of claim 28, wherein the compound of Formula (IA-1 or a pharmaceutically31. A compound selected from57260921.1141Attorney Docket No.: 272050-553087 PCT APPLICATION Compound Structure No.57260921.1Attorney Docket No.: 272050-553087 PCT APPLICATION Compound Structure No.or a pharmaceutically acceptable salt thereof.57260921.1143Attorney Docket No.: 272050-553087 PCT APPLICATION 32. A compound selected from Compound No. Structure or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1-32 and a pharmaceutically acceptable excipient, pharmaceutically acceptable vehicle, or pharmaceutically acceptable carrier.

34. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-32, or a pharmaceutical composition of claim 33.

35. The method of claim 34, wherein the cancer is a cancer of epithelial origin.

36. The method of claim 34 or claim 35, wherein the cancer is a central nervous system (CNS) cancer.57260921.1144Attorney Docket No.: 272050-553087 PCT APPLICATION 37. The method of any one of claims 34-36, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in cancer cells.

38. A method of modulating activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in a cancer cell, comprising administering to the cancer cell an effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-32, or a pharmaceutical composition of claim 33.

39. A method of treating brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-32, or a pharmaceutical composition of claim 33.

40. The method of claim 39, wherein in the brain cancer is a glioma.

41. The method of claim 40, wherein in the glioma is selected from the group consisting of an astrocytoma, an ependymoma, an oligodendroglioma, a brainstem glioma, an optic nerve glioma, and a mixed glioma.

42. The method of claim 40, wherein in the glioma is an astrocytoma.

43. The method of claim 42, wherein in the astrocytoma is glioblastoma multiforme (GBM).

44. The method of any one of claims 39-43, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in brain cancer cells.

45. A method of inducing vacuolization of mitochondria in a glioblastoma multiforme (GBM) cell, comprising administering to the cell an effective amount of a compound or57260921.1145Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutically acceptable salt of any one of claims 1-32, or a pharmaceutical composition of claim 33.

46. The method of claim 45, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell.

47. A method of depolarizing a mitochondrion in a glioblastoma multiforme (GBM) cell, comprising administering to the cell an effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-32, or a pharmaceutical composition of claim 33.

48. The method of claim 47, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, modulates activity of BMPR1A, UTP23, ARHGAP33, ITSN1, or any combination thereof in the cell.

49. The method of any one of claims 34-48, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered at least once per day.

50. The method of any one of claims 34-37 or 39-44, further comprising administering an additional therapeutic agent.

51. The method of claim 50, wherein the additional therapeutic agent is an anti-cancer agent.

52. The method of claim 51, wherein the anti-cancer agent is selected from temozolomide, ixabepilone, cladribine, enzalutamide, omacetaxine mepesuccinate, epothilones, erubulin, latrunculin, a pharmaceutically acceptable salt of any of these anti- cancer agents, or any combination thereof.

53. The method of any one of claims 50-52, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, and the additional therapeutic agent are administered concurrently.57260921.1146Attorney Docket No.: 272050-553087 PCT APPLICATION 54. The method of any one of claims 50-52, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, and the additional therapeutic agent are administered sequentially.

55. The method of any one of claims 34-37, 39-44, or 50-54, further comprising administering a radiation therapy.

56. The method of any one of claims 34-37, 39-44, or 50-54, wherein compound or pharmaceutically acceptable salt of any one of claims 1-32 is administered in a dosage amount of from about 1 mg to about 1,000 mg.

57. The method of any one of claims 34-37, 39-44, or 50-54, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered chronically.

58. The method of any one of claims 34-37, 39-44, 50-54, or 55, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered orally, subcutaneously, intramuscularly, intravenously, intracranially, intrathecally, or intranasally.

59. The method of claim 58, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered orally.

60. The method of claim 59, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered as a tablet, capsule, or oral suspension.

61. The method of claim 58, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the pharmaceutical composition of claim 33, is administered intranasally.

62. The method of any one of claims 34-37, 39-44, 50-54, or 57-61, wherein the compound or pharmaceutically acceptable salt of any one of claims 1-32, or the57260921.1147Attorney Docket No.: 272050-553087 PCT APPLICATION pharmaceutical composition of claim 33, is administered at least once a day from onset of treatment for a duration of at least about one year.

63. The method of any one of claims 34-37, 39-44, 50-54, or 57-62, wherein the subject experiences a reduced loss in bodyweight following treatment onset as compared to a subject not administered the compound or pharmaceutically acceptable salt of any one of claims 1- 32, or the pharmaceutical composition of claim 33.

64. The method of any one of claims 34-37, 39-44, 50-54, or 57-63, wherein the subject experiences a vacuolization of mitochondria in cancer cells following treatment onset.

65. The method of any one of claims 34-37, 39-44, 50-54, or 57-64, wherein the subject is a human.57260921.1148

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