Cancer therapy targeting cancer stem cells

Abstract

For example, compounds, methods, compositions, and kits are disclosed that enable the treatment of cancer by targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in this disclosure are of formulas (0), (O'), and (I).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Nos. USSN 62 / 667,412 (filed May 4, 2018) and USSN 62 / 815,251 (filed March 7, 2019), the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Cancer is ubiquitous and, despite medical advances, remains a leading cause of death worldwide. In 2017, an estimated 1.7 million new cases of cancer were diagnosed and 600,000 people died from the disease. 1 Cancer is the second leading cause of death worldwide, accounting for nearly one in six deaths. The number of new cases is expected to increase by approximately 70% over the next 20 years. The economic impact of cancer is significant and growing: in 2010, the total annual economic cost of cancer was estimated to be approximately US$1.16 trillion. 2

[0003] Cancer is a general term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumor and neoplasm. Cancer results from the transformation of normal cells into tumor cells in a multistep process, which generally progresses from a precancerous lesion to a malignant tumor. One of the defining characteristics of cancer is the rapid creation of abnormal cells, which can grow beyond their normal boundaries and invade adjacent parts of the body, spreading to other organs. This latter process is called metastasis. Metastasis is the leading cause of cancer death. The most common causes of cancer death are cancer of the lung, liver, colorectum, stomach, and breast.

[0004] While some progress has been made in treating a subset of cancer types, average cancer mortality rates remain extremely high, and little overall improvement has been made in the ongoing cancer crisis. Nearly all modern cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on tumor debulking and do not target the most dangerous cells within tumors: cancer stem cells. Cancer stem cells are responsible for the spread of cancer cells throughout the body, tumor growth, cancer resistance to chemotherapy, and tumor recurrence after treatment or surgical removal. 3、4 Current treatments do not target cancer stem cell populations, often leading to the proliferation of resistant tumors and continued cancer spread. Summary of the Invention

[0005] The discovery of cancer stem cells provides an opportunity to integrate the fields of oncology and embryonic stem cell biology. 5、6 The development of effective, non-toxic therapies can be achieved through a strategy called cancer containment therapy by targeting what makes cancer so dangerous: the embryonic properties of cancer stem cells that form the basis for cancer growth, spread, and resistance. Therapies that can simultaneously debulk tumors and destroy cancer stem cells would revolutionize cancer treatment. 7

[0006] Described herein are compounds that force cancer stem cells to differentiate and inhibit signaling pathways required for metastasis (the same pathways used by embryonic stem cells during differentiation and development). 8、9 These properties occur only in embryonic stem cells and not in healthy adult tissues, and therefore can be safely targeted.

[0007] These compounds are more effective than conventional cancer treatments in reducing tumor growth, extending lifespan, and preventing metastasis and recurrence. Furthermore, because reactivation of embryonic characteristics is a common property of many tumor types, cancer containment therapy is expected to be effective against many different types of cancer, including colon, stomach, prostate, testicular, and breast cancers.

[0008] Disclosed herein are compounds, methods, compositions, uses, and kits that allow for the treatment of proliferative diseases, benign neoplasms, and cancer.

[0009] In one embodiment, the compound of the present disclosure is a compound of formula (0): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (0) are as described herein. In another aspect, the disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound of Formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (0) are as described herein.

[0010] In one embodiment, the compound of the present disclosure is a compound of formula (0'): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0') are as described herein. In another aspect, the disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound of formula (0') or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0') are as described herein.

[0011] In one embodiment, the compound of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (I) are as described herein. In another aspect, the disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (I) are as described herein.

[0012] In certain embodiments, the cancer comprises cancer stem cells. In certain embodiments, the cancer comprises or is associated with cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, or prostate cancer. In certain embodiments, the cancer is liver cancer or endometrial cancer. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the subject is in need of regenerative medicine or therapy.

[0013] In yet another aspect, the disclosure provides a method comprising contacting a cell with an effective amount of Formula (0) or (0'), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0014] In yet another aspect, the disclosure provides methods and uses comprising contacting a cell with an effective amount of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0015] In certain embodiments, the compound of formula (I) is a compound of formula (IA): [ka] In certain embodiments, formula (I) is a compound of formula (IB): [ka] (IB), wherein R 7 is substituted or unsubstituted 3-pyridinyl. In certain embodiments, Formula (I) is a compound of Formula (IC): [ka] wherein: [ka] is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Formula (I) comprises a compound of Formula (IC): [ka] wherein: [ka] is imidazolyl, oxazolyl, azetidinyl, -C≡C-, or [ka] In certain embodiments, formula (I) is a compound of formula (ID): [ka] where R 7is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0016] In some embodiments, the present disclosure provides a composition comprising a compound of Formula (0) or (0'), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the composition further comprises an additional pharmaceutical agent.

[0017] In some embodiments, the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the composition further comprises an additional pharmaceutical agent.

[0018] In certain embodiments, the present disclosure provides a kit comprising a compound of Formula (0) or (0'), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition described herein, and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0019] In further embodiments, the present disclosure provides kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition described herein, and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0020] The details of certain embodiments of the invention are set forth in the detailed description set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, drawings, examples, and claims. [Brief explanation of the drawings]

[0021] [Figure 1] It is shown that compound I-1 depleted the population of embryonic-like gastric cells in gastric cancer. [Figure 2] It shows that compound I-1 reduced oct4 expression in gastric cancer cells. [Figure 3] It shows that compound I-1 reduced nanog expression in gastric cancer cells. [Figure 4] This indicates that compound I-1 was not toxic to healthy liver cells. [Figure 5] It shows that compound I-1 inhibited the growth of gastric cancer cells. [Figure 6] The in vitro properties (eg, solubility, microsomal stability, and plasma stability) of compound I-1 are shown. [Figure 7] 1 shows the pharmacokinetics of compound I-1 in mice. [Figure 8] 1 shows the results of the mouse tolerability of compound I-1.

[0022] definition For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0023] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0024] The phrases "in some embodiments" and "in one particular embodiment" are used interchangeably.

[0025] The following definitions are of more general terms used throughout this application.

[0026] The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0027] Except in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." "About" and "approximately" are generally intended to refer to the degree of error acceptable for the measured quantity given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0028] Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th(ed.) (back cover), and specific functional groups are generally defined as described therein. Further information regarding general principles of organic chemistry and specific functional moieties and reactivities is available in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0029] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELS Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0030] In the formula: [ka] is a single bond with no specified stereochemistry at the directly attached moiety, [ka] is absent or a single bond, [ka] is a single or double bond.

[0031] Unless otherwise specified, formulas set forth herein include compounds that do not contain isotopically enriched atoms and also include compounds that contain isotopically enriched atoms, which may be useful, for example, as analytical tools and / or as probes in biological assays.

[0032] The term "aliphatic" includes both saturated and unsaturated, non-aromatic, straight-chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, aliphatic groups are optionally substituted with one or more functional groups (e.g., halo, such as fluorine). As one of ordinary skill in the art would understand, "aliphatic," as used herein, is intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0033] When a range of values ​​("range") is listed, it is intended to encompass each value and subrange within the range. A range includes the values ​​at both ends of the range unless otherwise indicated. For example, "an integer between 1 and 4" means 1, 2, 3, and 4; for example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0034] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-12 Alkyl (e.g., —CH(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, e.g., unsubstituted N-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-12 Alkyl (e.g., substituted C 1-6 Alkyl, for example, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, or benzyl (Bn). The point of attachment of the alkyl can be a single bond (e.g., as in -CH), a double bond (e.g., as in =CH), or a triple bond (e.g., as in ≡CH). Moieties such as =CH and ≡CH are also alkyls.

[0035] In some embodiments, an alkyl group is substituted with one or more halogens. A "perhaloalkyl" is a substituted alkyl group, as defined herein, in which all hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C 1-8In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all hydrogen atoms are replaced with fluoro. In some embodiments, all hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include -CF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0036] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., 2, 3, or 4, valences permitting) carbon-carbon double bonds and no triple bonds ("C 2-20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 In addition to alkenyl groups, examples include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 In alkenyl groups, a C=C double bond with no specified stereochemistry (e.g., [ka] ) can be in the (E) or (Z) configuration.

[0037] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., two, three, or four, valences permitting) carbon-carbon triple bonds, and optionally one or more double bonds ("C 2-20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkynyl group include the above-mentioned C 2-4 In addition to alkynyl groups, examples include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0038] "Carbocyclyl" or "carbocyclic" means a radical of a non-aromatic cyclic hydrocarbon group having 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 As the carbocyclyl group, the aforementioned C 3-6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 As the carbocyclyl group, the aforementioned C 3-8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10As the preceding examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"). A carbocyclyl can be saturated, and saturated carbocyclyls are referred to as "cycloalkyls." In some embodiments, a carbocyclyl is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 In addition to alkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are included. 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10It is a cycloalkyl. A carbocyclyl may be partially unsaturated. A carbocyclyl may contain zero, one, or more (e.g., two, three, or four, valences permitting) C=C double bonds in all rings of a carbocyclic ring system that is neither aromatic nor heteroaromatic. A carbocyclyl containing one or more (e.g., two or three, valences permitting) C=C double bonds in a carbocyclic ring is referred to as a "cycloalkenyl." A carbocyclyl containing one or more (e.g., two or three, valences permitting) C≡C triple bonds in a carbocyclic ring is referred to as a "cycloalkynyl." Carbocyclyl includes aryl. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring; in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 In certain embodiments, the carbocyclyl is substituted or unsubstituted, 3-7 membered, and monocyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 5-13 membered, and bicyclic.

[0039] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 In addition to alkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are included. 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is cycloalkyl.

[0040] "Heterocyclyl" or "heterocyclic" means the radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclyl"). For heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")). Heterocyclic groups can be saturated or partially unsaturated. A heterocyclyl can contain zero, one, or more (e.g., two, three, or four, where valence allows) double bonds in any ring of a heterocyclic ring system that is neither aromatic nor heteroaromatic. Partially unsaturated heterocyclyl groups include heteroaryl. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring defined above is fused to one or more carbocyclyl groups, with the point of attachment either on the carbocyclyl ring or on the heterocyclyl ring, or in which the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment on the heterocyclyl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.

[0041] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0042] Exemplary 3-membered heterocyclyl groups containing one heteroatom include aziridinyl, oxiranyl, or thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0043] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl," for example, naphthyl (e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the radical or point of attachment being on the aryl ring; in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0044] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., a ring system having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5- to 10-membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, as valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups with points of attachment on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl ring or the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the fused (aryl / heteroaryl) ring system. The point of attachment of bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be on either ring, for example, on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0045] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0046] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0047] "Partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0048] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents at each position can be the same or different. Unless otherwise specified, substituents on a polycyclic ring can be at any substitutable position of any single monocyclic ring in the polycyclic ring. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, and with any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates all such combinations to arrive at stable compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0049] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )Rbb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa, -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is a counter ion), Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group), R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2Raa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is a counter ion), R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group), R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(Rff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents are linked to form =O or =S, and X - is a counter ion; R ee Each instance of C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group), R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may be linked to form =O or =S (wherein X - is the counterion).

[0050] In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bbIn certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb )2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2, where R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or nitrogen protecting groups.

[0051] As used herein, a "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. Anionic counterions can be monovalent (i.e., containing one formal negative charge). Anionic counterions can also be polyvalent (i.e., containing multiple formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid ions, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid ions, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4- , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylate, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0052] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0053] Nitrogen atoms may be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc, -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined above.

[0054] In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group.

[0055] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroalkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and Rdd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0056] Amide nitrogen protecting groups (e.g., -C(=O)R aa ) include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0057] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl Ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0058] Sulfonamide nitrogen protecting groups (e.g., -S(=O)R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts ), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0059] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilyla. 1,3-Dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) Amines, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthio Methyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0060] In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0061] In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or oxygen protecting group.

[0062] In certain embodiments, the substituent present on the oxygen atom is a nitrogen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0063] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), and the like. ), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4 -Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formyl Benzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate Examples of suitable amines include nitrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0064] In certain embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0065] In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or sulfur protecting group.

[0066] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(Rcc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0067] The "molecular weight" of -R (where -R is any monovalent moiety) is calculated by subtracting the atomic weight of the hydrogen atom from the molecular weight of the molecule RH. The "molecular weight" of -L- (where -L- is any divalent moiety) is calculated by subtracting the combined atomic weight of the two hydrogen atoms from the molecular weight of the molecule HLH.

[0068] In certain embodiments, the molecular weight of the substituent is less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, less than 50 g / mol, or less than 25 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, and / or fluorine atoms. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond donors. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond acceptors.

[0069] The suffix "ene" when added to a group indicates that the group is a multivalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In certain embodiments, the suffix "ene" when added to a group indicates that the group is a divalent moiety.

[0070] The terms "hydroxyl" or "hydroxy" refer to an --OH group.

[0071] The terms "thiol" or "thio" refer to an --SH group.

[0072] The term "amine" or "amino" refers to the group --NH-- or --NH.sub.2.

[0073] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, and -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, wherein R X1 is hydrogen, halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or diarylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc. (each of which may or may not be further substituted)).

[0074] The term "salt" refers to an ionic compound resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), and therefore is electrically neutral (has no net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lanthanide, thiazolinone ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0075] The term "pharmaceutically acceptable salt" means a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response, or the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, 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 the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts. + (C 1-4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate ions.

[0076] The term "solvent" refers to a substance that dissolves one or more solutes to form a solution. A solvent can function as a medium for any reaction or transformation described herein. A solvent can dissolve one or more reactants or reagents in a reaction mixture. A solvent can facilitate mixing of one or more reagents or reactants in a reaction mixture. A solvent can also function to increase or decrease the rate of a reaction compared to a reaction in a different solvent. A solvent can be polar or nonpolar, protic or aprotic. Common solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, Examples of suitable solvents include hexane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.

[0077] The term "solvate" refers to a compound or a salt form thereof that is associated with a solvent, usually by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, solvates may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0078] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including monohydrates (x is 1), hypohydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0079] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0080] The term "co-crystal" refers to a crystal structure that includes at least two different components (e.g., a compound of Formula (I) and an acid), where each component is independently an atom, ion, or molecule. In certain embodiments, neither component is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound of Formula (I) and an acid is different from a salt formed from a compound of Formula (I) and an acid. Co-crystals can be useful in improving the properties of a compound of Formula (I), such as solubility, stability, and ease of formulation.

[0081] Additionally, the term "co-crystal" refers to a crystal structure that includes at least two different components (e.g., a compound of Formula (0) and an acid), where each component is independently an atom, ion, or molecule. In certain embodiments, neither component is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound of Formula (0) or (0') and an acid is different from a salt formed from a compound of Formula (0) or (0') and an acid. Co-crystals can be useful in improving the properties (e.g., solubility, stability, and ease of formulation) of a compound of Formula (0) or (0').

[0082] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction resulting in a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0083] It should also be understood that compounds that have the same molecular formula but differ in the nature or bonding order of their atoms or the spatial arrangement of their atoms are referred to as "isomers." Isomers that differ in the spatial arrangement of their atoms are referred to as "stereoisomers." In certain embodiments, if a phenyl group contains two substituents that are each attached to adjacent carbons, the compound can be referred to as an ortho isomer. In certain embodiments, if a phenyl group contains two substituents that are each attached to carbons separated by one ring carbon, the compound can be referred to as a meta isomer. In certain embodiments, if a phenyl group contains two substituents that are each attached to carbons separated by two ring carbons, the compound can be referred to as a para isomer.

[0084] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center and is bonded to, for example, four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0085] As used herein, the term "agent" refers to a molecule, group of molecules, complex, or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a preventative agent). In certain embodiments, the compositions disclosed herein include an agent(s), e.g., a first therapeutic agent (e.g., at least one (e.g., at least two, including at least three)). In some embodiments, the composition further includes a second therapeutic agent, a targeting moiety, a diagnostic moiety, as described herein.

[0086] As used herein, the term "therapeutic agent" includes an agent capable of producing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. For example, a therapeutic agent can control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and enhance bone growth, among other functions. Other suitable therapeutic agents can include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active upon administration but are converted by metabolism or some other mechanism into a biologically active agent upon administration to a subject.

[0087] Agents (e.g., therapeutic agents) include a wide variety of different compounds, including chemical compounds and mixtures of chemical compounds (e.g., organic or inorganic small molecules), such as compounds such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)); targeting agents; isotopically labeled chemical compounds; agents useful in bioprocessing; carbohydrates; saccharin; monosaccharides; oligosaccharides; polysaccharides; biopolymers (e.g., peptides, proteins, and peptide analogs and derivatives); peptidomimetics; antibodies and antigen-binding fragments thereof; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucoproteins; lipoproteins; synthetic polypeptides or proteins; small molecules bound to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunological agents; extracts made from biological materials such as bacteria, plants, fungi, animal cells, and the like; animal tissue; natural or synthetic compositions; and any combination thereof.

[0088] In some embodiments, the drug is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, e.g., by solvolysis, reduction, oxidation, or under physiological conditions, to yield a pharmaceutically active compound, e.g., in vivo. Prodrugs include derivatives of pharmaceutically active compounds, such as esters formed by reaction of the acid, anhydride, or mixed anhydride portion of the prodrug moiety with a hydroxyl moiety of the pharmaceutically active compound, or amides prepared by reaction of the acid, anhydride, or mixed anhydride portion of the prodrug moiety with a substituted or unsubstituted amine of the pharmaceutically active compound. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups may comprise prodrugs. In some embodiments, the compositions described herein incorporate one therapeutic agent or a prodrug thereof. In some embodiments, the compositions described herein incorporate two or more therapeutic agents or prodrugs.

[0089] In some embodiments, the agent (e.g., a therapeutic agent) is a small molecule. As used herein, the term "small molecule" can refer to a compound that is "natural product-like." However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, small molecules are typically characterized by containing several carbon-carbon bonds and have a molecular weight of less than 5,000 daltons (5 kDa), preferably less than 3 kDa, even more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases, it is preferred that the molecular weight of a small molecule be 700 daltons or less.

[0090] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those listed in Harrison's Principles of Internal Medicine, 13th Edition, Eds. TR Harrison et al., McGraw-Hill NY, NY; Physicians' Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics; and the latest edition of The Merck Index, the entire contents of all of which are incorporated herein by reference.

[0091] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more of the agents listed in paragraph

[0148] of U.S. Pat. No. 9,381,253 (incorporated herein by reference).

[0092] In other embodiments, exemplary therapeutic agents in the compositions include, but are not limited to, one or more of the therapeutic agents listed in WO2013 / 169739 (incorporated herein by reference), including antihypertensive agents and / or collagen modifying agents ("AHCMs") (e.g., as disclosed in paragraphs 40-49, 283, 286-295), microenvironment modulators (e.g., as disclosed in paragraphs 113-121 of WO2013 / 169739). In some embodiments, a composition comprising AHCM and / or a microenvironment modulator causes one or more of the following in a subject: a reduction in solid stress (e.g., tumor growth-induced solid stress); a reduction in tumor fibrosis; a reduction in interstitial hypertension or interstitial fluid pressure (IFP); an increase in interstitial tumor transport; an increase in tumor or vascular perfusion; an increase in vascular diameter and / or dilation of compressed or collapsed blood vessels; a reduction or depletion of one or more of cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); an increase in extracellular matrix components, such as fibers (e.g., collagen, procollagen), and reducing the levels or production of tumor cells and / or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid); reducing the levels or production of collagen or procollagen; reducing the levels or production of hyaluronic acid; increasing tumor oxygenation; reducing tumor hypoxia; reducing tumor acidosis; enabling immune cell infiltration; reducing immunosuppression; increasing anti-tumor immunity; reducing the production of cancer stem cells (also referred to herein as tumor-initiating cells); or enhancing the effectiveness (e.g., penetration or spread) of a therapy, e.g., a cancer therapy (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy) in the tumor or tumor vasculature.

[0093] Agents, e.g., therapeutic agents, include the categories and specific examples disclosed herein. It is not intended that the category be limited by the specific examples. Those of skill in the art will recognize numerous other compounds that fall within this category and are useful according to the present disclosure.

[0094] Examples of therapeutic agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, counterirritants, coagulation modifiers, diuretics, sympathomimetics, appetite suppressants, antacids and other gastrointestinal agents, anthelmintics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetics, dopaminergic agents, antiemetics, muscle relaxants, parasympathomimetics, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast media, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antivirals, and agents with antineoplastic or cytostatic or other anti-cancer properties, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Still other examples include anti-infectives, e.g., antibiotics and antivirals; analgesics and analgesic combinations; appetite suppressants; antiheimintics; anti-arthritics; anti-asthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; antiemetics; antineoplastics; anti-Parkinson's drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations (e.g., calcium channel blockers and beta blockers (e.g., antihypertensives; diuretics; vasodilators (including general coronary, peripheral, and cerebrovascular); central nervous system stimulants; cough and cold preparations (including decongestants); hormones, such as estradiol and other steroids (including corticosteroids); hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally occurring or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0095] "Composition" and "formulation" are used interchangeably.

[0096] A "subject" to which administration is contemplated means a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey)), a commercially important mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal.

[0097] The terms "administer," "administering," or "administration" mean implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0098] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of a disease have occurred or are observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of a disease. For example, treatment can be administered to a susceptible subject before symptoms develop (e.g., based on a history of treatment for the condition). Treatment can also be continued after symptoms have resolved to delay and / or prevent the recurrence of a disease or disorder.

[0099] The terms "prevent," "preventing," or "prevention" refer to prophylactic treatment of a subject who does not currently have or has not previously had the disease but is at risk of developing the disease, or who has previously had the disease but does not currently have the disease but is at risk of relapse. In certain embodiments, the subject is at higher risk of developing or relapsing from the disease than the average healthy member of a population of subjects.

[0100] The terms "condition," "disease," and "disorder" are used interchangeably.

[0101] "Proliferative disease" refers to a disease caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with 1) pathological proliferation of normally quiescent cells; pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis-related diseases, inflammatory diseases, and autoimmune diseases.

[0102] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue whose growth exceeds and is out of step with that of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. Benign neoplasms are generally well differentiated, characteristically slower growing than malignant neoplasms, and remain localized at the site of origin. In addition, benign tumors lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors may subsequently give rise to malignant neoplasms. This may result from additional genetic alterations in a subpopulation of the tumor's neoplastic cells; such tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, a "malignant neoplasm" is generally poorly differentiated (anaplastic) and characteristically fast-growing, with progressive invasion, infiltration, and destruction of surrounding tissue. Furthermore, a malignant neoplasm generally has the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, typically distinguishable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor, rather than the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is considered metastatic prostate cancer, and includes cancerous prostate cancer cells growing within bone tissue.

[0103] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct adenocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, carcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, neuroblastoma, thyroid cancer ... Glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., , esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); lung cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma); hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL), as well as non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkina Fascia, lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; mixed leukemia / lymphoma of one or more of the above; and multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma (also known as Wilms' tumor), renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis ( Myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myelofibrosis (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic endocrine tumors (GEP-NETs), carcinoid tumors), osteosarcomas (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma) chromoma, basal cell carcinoma (BCC); small intestine cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva);

[0104] Cancer cells exhibit properties similar to those of embryonic stem cells. As used herein, cancer stem cells (CSCs) are embryonic cancer cells that have one or more embryonic characteristics. CSCs are generally considered problematic cancer cells because of their ability to metastasize to other sites in the body and form tumors. As used herein, "embryonic characteristics" refers to gene and / or miRNA expression and / or biological properties similar to those of embryonic cells. Undifferentiated cancer cells with embryonic characteristics have the ability to metastasize, are resistant to chemotherapy and radiotherapy, and have the ability to regrow tumors after surgery and / or additional cancer therapeutic treatments have removed or reduced the majority of the tumor.

[0105] In some embodiments, cancer stem cells are characterized by expression of genes and / or miRNAs associated with an embryonic state, hi some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes or miRNAs associated with an embryonic state.

[0106] In some embodiments, cancer stem cells are characterized by one or more embryonic characteristics, including, but not limited to, cellular self-renewal properties, hyperproliferative activity, multipotency, pluripotency, expression of embryonic markers, lack of differentiation markers, resistance to chemotherapy, motility, and the ability to give rise to different cell lineages.

[0107] As used herein, the term "regenerative medicine" or "regenerative therapy" refers to promoting the regenerative capacity of cells, tissues, and / or organs. Regenerative medicine encompasses the manipulation of cells and / or tissues to replace, manipulate, or regenerate cells, tissues, and / or organs, and / or to repair or improve one or more biological functions of dysfunctional or abnormal cells, tissues, and / or organs, as well as tissue engineering and organ regeneration. As used herein, "regenerative capacity" refers to the conversion of cells, such as stem cells, into dividing progenitor cells and differentiated tissue-specific cells. Regenerative capacity can additionally or alternatively refer to the ability of cells, tissues, and / or organs to replicate, proliferate, restore function, and / or regenerate.

[0108] An "effective amount" of a composition described herein means an amount sufficient to elicit a desired biological response. The effective amount of a composition described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount in a single administration of a composition or pharmaceutical composition described herein. In certain embodiments, the effective amount is the total amount in multiple administrations of a composition or pharmaceutical composition described herein.

[0109] A "therapeutically effective amount" of a composition described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with that condition. A therapeutically effective amount of a composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or conditions, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0110] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0111] The term "gene" refers to a nucleic acid fragment that provides a template that can be used to produce a gene product. In certain embodiments, the nucleic acid fragment includes regulatory sequences that precede and follow the coding sequence. "Native gene" refers to a gene found in nature with its own regulatory sequences. "Chimeric gene" or "chimeric construct" refers to any gene or construct that is not a natural gene, containing regulatory and coding sequences that are not found together in nature. Thus, a chimeric gene or chimeric construct can contain regulatory and coding sequences that are derived from different sources, or regulatory and coding sequences that are derived from the same source but that are arranged in a manner different from that found in nature. "Endogenous gene" refers to a native gene in its natural location within the genome of an organism. "Foreign" gene refers to a gene that is not normally found in a host organism but that is introduced into the host organism by gene transfer. A foreign gene can include a native gene inserted into a non-native organism, or a chimeric gene. A "transgene" is a gene that has been introduced into a genome by a transformation procedure.

[0112] The terms "nucleic acid," "nucleic acid sequence," "nucleic acid molecule," "nucleic acid fragment," or "polynucleotide" are used interchangeably. A polynucleotide molecule is a biopolymer composed of nucleotide monomers covalently linked in a chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two strands of a polynucleotide, each in the form of a helix. RNA is more frequently found in nature as a single strand folded back on itself. Exemplary RNA types include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin (shRNA), microRNA (miRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0113] The present disclosure is not intended to be limited in any manner by the above list of exemplary substituents. Additional terms may be defined in other sections of this disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0114] Before describing the disclosed systems, compounds, compositions, methods, uses, and kits in more detail, it is to be understood that the aspects described herein are not limited to specific embodiments, methods, devices, or configurations, which, as such, can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, such terms are not intended to be limiting.

[0115] The compounds of the present disclosure, as well as their compositions and kits, are useful for cancer therapy and the treatment of proliferative diseases. The compounds can differentiate embryonic-like cancer stem cells, inhibit their proliferation, and / or inhibit their ability to form new tumors. Embryonic-like characteristics, including embryonic gene expression patterns, are reactivated across a variety of different types of cancer. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. For example, embryonic-like characteristics have been found in cancer stem cells from solid tumors (e.g., colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer). 10 Embryonic-like properties have also been found in cancer stem cells from hematopoietic cancers (eg, leukemia and lymphoma). 14

[0116] compound In certain embodiments, the present disclosure provides compounds of formula (0) and (0').

[0117] The present disclosure describes compounds of formula (I) described herein.

[0118] In certain embodiments, the compound is a compound of formula (0): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L A is -N(R 2 )(L 1 R 1 ) or -C(=O)NR 1 R 2 and L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substitution C 1-6 Alkyl (substituents contain at least one double bond, triple bond, or heteroatom), substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1, Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are [ka] are meta or para to each other when they are phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L B is -N(R 6 )L 2 -or-L 2 N(R 6 )- and L 2 is -C(=O)-, [ka] or -S(=O)2-, Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; s is 0 or 1, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a, -N(R a )2, or -CN.

[0119] In certain embodiments, the compound of formula (0') is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substitution C 1-6 Alkyl (substituents contain at least one double bond, triple bond, or heteroatom), substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1, Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are [ka] are meta or para to each other when they are phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)-, [ka] or -S(=O)2-, Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; s is 0 or 1, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0120] In certain embodiments, the compound is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is a halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0121] In certain embodiments, L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is a halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0122] In certain embodiments, the compound is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is a halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0123] In certain embodiments, Formula (I) has Formula (IA): [ka] [ka] [ka] is.

[0124] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0125] In certain embodiments, Formula (I) has Formula (IB): [ka] where R 7 is a substituted or unsubstituted 3-pyridinyl.

[0126] In certain embodiments, Formula (I) has the formula (IC): [ka] and During the ceremony, [ka] is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is imidazolyl or oxazolyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is azetidinyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is -C≡C-. In certain embodiments, formula (I) is formula (IC), wherein: [ka] teeth [ka] is.

[0127] In certain embodiments, the compound of formula (I) is a compound of formula (IC): [ka] and During the ceremony, [ka] is thiazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is thiazolyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In certain embodiments, Formula (I) is Formula (IC), wherein: [ka] is piperazinyl.

[0128] In certain embodiments, formula (I) has formula (ID): [ka] where R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0129] In certain embodiments, Formula (I) has the formula: [ka] where R 7 is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl (eg, substituted or unsubstituted 3-pyridinyl).

[0130] In certain embodiments, Formula (I) has the formula: [ka] wherein: R 1 is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 alkyl), R 2 is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-3 alkyl), R 7 is a substituted or unsubstituted pyridinyl (eg, substituted or unsubstituted 3-pyridinyl).

[0131] In certain embodiments, Formula (I) has the formula: [ka] [ka] and In the formula, R 2 is a substituted or unsubstituted C 1-6 Alkyl (eg, Me).

[0132] In certain embodiments, Formula (I) has the formula (I-1A): [ka] is.

[0133] In certain embodiments, Formula (I) has the formula (I-1B): [ka] where R 7 is a substituted or unsubstituted 3-pyridinyl.

[0134] In certain embodiments, Formula (I) has the formula (I-1C): [ka] and During the ceremony, [ka] is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Formula (I) is Formula (I-1C): During the ceremony, [ka] is imidazolyl, oxazolyl, azetidinyl, -C≡C-, or [ka] is.

[0135] In certain embodiments, Formula (I) has the formula (I-1C): [ka] and During the ceremony, [ka] is thiazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0136] In certain embodiments, Formula (I) has the formula (I-1D): [ka] where R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0137] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0138] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0139] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0140] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0141] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0142] In certain embodiments, Formula (I) has the formula: [ka] [ka] is.

[0143] In certain embodiments, q is 0 or 1. In some embodiments, q is 1. In certain embodiments, q is 0.

[0144] In certain embodiments, L A is -C(=O)NR 1 R 2 In certain embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, q is 0 or 1. In some embodiments, q is 1. In certain embodiments, q is 0.

[0145] In some embodiments, L A is -N(R 2 )(L 1 R 1 In certain embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, q is 0 or 1. In some embodiments, q is 1. In certain embodiments, q is 0. In certain embodiments, L 1 is a single bond. In some embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, L 1 is —C(═O)—. In certain embodiments, the compound of formula (0) has the formula: [ka] is a compound of

[0146] In certain embodiments, L 1 is a single bond. In certain embodiments, L 1 is -C(=O)-.

[0147] In certain embodiments, L 1 is a single bond, and R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl. 1 is a substituted or unsubstituted C 1-6 In certain embodiments, R 1 is the unsubstituted C 1-6 In certain embodiments, R 1 is unsubstituted C alkyl. In certain embodiments, R 1 is an unsubstituted C alkyl. In certain embodiments, R 1 is an unsubstituted C alkyl. In certain embodiments, R 1 is unsubstituted C4 alkyl. In certain embodiments, R 1 is unsubstituted C5 alkyl. In certain embodiments, R 1 is unsubstituted C alkyl. In certain embodiments, R 1 is a substitution C 1-6 In certain embodiments, R 1 is a substituted C alkyl. In certain embodiments, R 1 is a substituted C alkyl. In certain embodiments, R 1 is a substituted C alkyl. In certain embodiments, R 1 is a substituted C4 alkyl. In certain embodiments, R 1is a substituted C alkyl. In certain embodiments, R 1 is a substituted C alkyl. In certain embodiments, R 1 is fluorinated C 1-6 alkyl (e.g., —CF). In certain embodiments, R 1 is a substituted or unsubstituted C 2-6 In certain embodiments, R is alkenyl. 1 is a substituted or unsubstituted C 2-6 In certain embodiments, R is alkenyl. 1 is a substituted or unsubstituted C 2-6 In certain embodiments, R 1 is a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl. 1 is a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl. 1 is a substituted or unsubstituted 5-11 membered monocyclic or bicyclic heteroaryl.

[0148] In certain embodiments, L 1 is -C(=O)- and R 1 is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl. 1 is a substituted C containing at least one heteroatom 1-6 In certain embodiments, R 1 is a substituted C containing at least one double bond 1-6 In certain embodiments, R 1is a substituted C containing at least one triple bond 1-6 It is alkyl.

[0149] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is not hydrogen. In certain embodiments, R 2 is a substituted or unsubstituted C 1-6 In certain embodiments, R 2 is the unsubstituted C 1-6 In certain embodiments, R 2 is Me. In certain embodiments, R 2 is Et, Pr, or Bu. In certain embodiments, R 2 is fluorinated C 1-6 alkyl (e.g., fluorinated methyl such as —CF). In certain embodiments, R 2 is a nitrogen protecting group.

[0150] In certain embodiments, R 2 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl. 2 is a substituted or unsubstituted 3- to 5-membered monocyclic carbocyclyl. 2 is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl. 2 is a substituted or unsubstituted 3-5 membered monocyclic heterocyclyl. 2 is substituted or unsubstituted phenyl. In certain embodiments, R 2 is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl.

[0151] In some embodiments, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN. In some embodiments, R3 is hydrogen.

[0152] In certain embodiments, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , N(R a )2, or -CN. In certain embodiments, R 3 is a halogen, substituted or unsubstituted C 1-6 Alkyl, or -OR a In certain embodiments, R 3 is -N(R a )2 or -CN. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 3 is Me. In certain embodiments, R 3 is Et, Pr, or Bu. In certain embodiments, R 3 is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 3 HA-OR a In certain embodiments, R 3 is —OH. In certain embodiments, R 3 is -O (substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 3 -N(R a )2. In certain embodiments, R 3 is —NH. In certain embodiments, R 3 Ha-NHR a (e.g., -NH(substituted or unsubstituted C 1-6alkyl), for example, -NHMe). In certain embodiments, R 3 is -N(substituted or unsubstituted C 1-6 alkyl)2, for example, —N(Me)2). In certain embodiments, R 3 is -CN.

[0153] In certain embodiments, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom. a Each instance of R is hydrogen. a In certain embodiments, R a At least one instance of 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R a At least one instance of R is Me. a At least one instance of R is Et, Pr, or Bu. a At least one instance of fluorinated C 1-6 Alkyl (eg, fluorinated methyl, eg, -CF3).

[0154] In certain embodiments, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl. In certain embodiments, R 2 and R 3 are joined with their intervening atoms to form an unsubstituted 5-membered monocyclic heterocyclyl. In certain embodiments, R 2 and R 3 are joined with their intervening atoms to form a substituted 5-membered monocyclic heteroaryl. [ka] teeth [ka] In certain embodiments, [ka] teeth [ka] In certain embodiments, [ka] teeth [ka] (for example, [ka] ,for example, [ka] In certain embodiments, [ka] teeth [ka] In certain embodiments, [ka] teeth [ka] In certain embodiments, [ka] teeth [ka] (for example, [ka] ,for example, [ka] In certain embodiments, R 2 and R 3 are joined with their intervening atoms to form a substituted 5-membered monocyclic heteroaryl. [ka] teeth, [ka] is.

[0155] In certain embodiments, at least one instance of Y is CR 4 In certain embodiments, each instance of Y is CR 4 In certain embodiments, at least one instance of Y is N. In certain embodiments, each instance of Y is N.

[0156] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is.

[0157] In certain embodiments, R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN. In certain embodiments, R 4 At least one instance of R is hydrogen. 4 Each instance of R is hydrogen. 4 At least one instance of R is not hydrogen. 4 In certain embodiments, R 4 At least one instance of 1-6 In certain embodiments, R 4 At least one instance of R is halogen. 4 At least one instance of R is F. In certain embodiments, 4 At least one instance of R is Cl. 4 At least one instance of 1-6 Alkyl (e.g., unsubstituted C1-6 In certain embodiments, R 4 At least one instance of R is Me. 4 At least one instance of R is Et, Pr, or Bu. 4 At least one instance of fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 4 At least one instance of -OR a In certain embodiments, R 4 At least one instance of R is —OH. 4 At least one instance of -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 4 At least one instance of -N(R a )2. In certain embodiments, R 4 At least one instance of is -NH. In certain embodiments, R 4 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), for example, -NHMe). In certain embodiments, R 4 At least one instance of -N (substituted or unsubstituted C 1-6 alkyl)2, for example, —N(Me)2). In certain embodiments, R 4 At least one instance of is -CN.

[0158] In certain embodiments, [ka] is a 6-membered monocyclic aryl or heteroaryl. In certain embodiments, [ka] is phenyl. In certain embodiments, [ka] teeth [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is. In certain embodiments, [ka] is imidazolyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is. In certain embodiments, [ka] is oxazolyl. In certain embodiments, [ka] In certain embodiments, [ka] [ka] In certain embodiments, [ka] is azetidinyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is -C≡C-. In certain embodiments, [ka] In certain embodiments, [ka] is.

[0159] In certain embodiments, bond b and bond c are para to each other. In certain embodiments, bond b and bond c are meta to each other.

[0160] In certain embodiments, [ka] When is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are para to each other. [ka] When is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are meta to each other.

[0161] In certain embodiments, [ka] is thiazolyl. In certain embodiments, [ka] In certain embodiments, [ka] is.

[0162] In certain embodiments, [ka] is a 6-membered monocyclic carbocyclyl or heterocyclyl. [ka] is piperazinyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] [ka] In certain embodiments, [ka] is.

[0163] In certain embodiments, [ka] is piperidinyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is.

[0164] In some embodiments, [ka] is molformyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is.

[0165] In some embodiments, [ka] is thiomorpholinyl. In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] In certain embodiments, [ka] is.

[0166] In certain embodiments, R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN. In certain embodiments, R 5 At least one instance of R is hydrogen. 5 Each instance of R is hydrogen. 5 At least one instance of R is not hydrogen. 5 In certain embodiments, R 5 At least one instance of R is halogen. 5 At least one instance of R is F. In certain embodiments, 5 At least one instance of R is Cl. 5 At least one instance of 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R5 At least one instance of R is Me. 5 At least one instance of R is Et, Pr, or Bu. 5 At least one instance of fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 5 At least one instance of -OR a In certain embodiments, R 5 At least one instance of R is —OH. 5 At least one instance of -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 5 At least one instance of -N(R a )2. In certain embodiments, R 5 At least one instance of is -NH. In certain embodiments, R 5 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), for example, -NHMe). In certain embodiments, R 5 At least one instance of -N (substituted or unsubstituted C 1-6 alkyl)2, for example, —N(Me)2. In certain embodiments, R 5 At least one instance of R is -CN. 5 At least one instance of 1-6 Alkyl, or -OR a is.

[0167] In some embodiments, L B -N(R 6 )L 2 In some embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, L 2 is C=O. In certain embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, L 2 is S(=O)2. In certain embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, L 2 teeth [ka] In some embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, each R 6 are independently hydrogen. In some embodiments, one R 6 is methyl and one R 6 is hydrogen.

[0168] In certain embodiments, L B Ha-L 2 N(R 6 In some embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, L 2 is C=O. In certain embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, L 2 is S(=O)2. In certain embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, L 2 teeth [ka] In some embodiments, the compound of formula (0) has the formula: [ka] In certain embodiments, each R 6 is hydrogen. In some embodiments, one R 6 is methyl and one R 6 is hydrogen. In some embodiments, the compound of formula (0) has the formula: [ka] is a compound of

[0169] In certain embodiments, the compound of formula (0) has the formula (0'): [ka] In certain embodiments, the compound of formula (0') is a compound of the formula: [ka] [ka] is a compound of

[0170] In certain embodiments, L 2 is —C(═O)—. In certain embodiments, L 2 is -S(=O)2-.

[0171] In certain embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] and R 6 is hydrogen. In some embodiments, L 2 teeth [ka] and R 6 is methyl.

[0172] In certain embodiments, each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group. 6 are independently substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl. 6is independently hydrogen. In certain embodiments, each R 6 are independently substituted or unsubstituted C 1-6 alkyl (e.g., Me). In certain embodiments, R 6 Each instance of R is the same. 6 Each case is different.

[0173] In certain embodiments, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group. 6 is a substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl. 6 is hydrogen. In certain embodiments, R 6 is a substituted or unsubstituted C 1-6 Alkyl (eg, Me).

[0174] In certain embodiments, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl. 7 is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl. 7 is substituted or unsubstituted phenyl. In certain embodiments, R 7 is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In certain embodiments, R 7is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 7 is substituted or unsubstituted 3-pyridinyl. In certain embodiments, R 7 is unsubstituted 3-pyridinyl. In certain embodiments, R 7 teeth, [ka] In certain embodiments, R 7 teeth, [ka] In certain embodiments, R 7 teeth [ka] In certain embodiments, R 7 teeth, [ka] [ka] In certain embodiments, R 7 teeth [ka] In certain embodiments, R 7 is substituted or unsubstituted 2-pyridinyl or 4-pyridinyl. In certain embodiments, R 7 is substituted or unsubstituted 2-pyridinyl. In certain embodiments, R 7 is unsubstituted 2-pyridinyl. In certain embodiments, R 7 teeth, [ka] In certain embodiments, R 7 teeth, [ka] In certain embodiments, R 7 teeth, [ka] In certain embodiments, R 7 teeth [ka] is.

[0175] In certain embodiments, R 8 Each case is independently -OR a , -N(R a )2, or -CN. In certain embodiments, R 8 Each instance of R is hydrogen. 8 At least one instance of 1-6 In certain embodiments, R 8 At least one instance of 1-6 alkyl (e.g., Me). In certain embodiments, R 8 at least one instance of C substituted with at least one instance of halogen (e.g., F) 1-6 It is alkyl.

[0176] R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN. In certain embodiments, R 9At least one instance of R is hydrogen. 9 Each instance of R is hydrogen. 9 At least one instance of R is not hydrogen. 9 In certain embodiments, R 9 At least one instance of R is halogen. 9 At least one instance of R is F. In certain embodiments, 9 At least one instance of R is Cl. 9 At least one instance of 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 9 At least one instance of R is Me. 9 At least one instance of R is Et, Pr, or Bu. 9 At least one instance of fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 9 At least one instance of -OR a In certain embodiments, R 9 At least one instance of R is —OH. 9 At least one instance of -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 9 At least one instance of -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH. In certain embodiments, R 9 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), for example, -NHMe). In certain embodiments, R9 At least one instance of -N (substituted or unsubstituted C 1-6 alkyl)2, for example, —N(Me)2). In certain embodiments, R 9 At least one instance of R is -CN. 9 At least one instance of 1-6 Alkyl, or -OR a is.

[0177] In some embodiments, s is 1. In certain embodiments, s is 0.

[0178] In certain embodiments, s is 1. In some embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, s is 0. In certain embodiments, the compound of formula (0) has the formula: [ka] In some embodiments, s is 0 and the compound of formula (0) is [ka] [ka] The compound is selected from the group of formulas consisting of:

[0179] In certain embodiments, s is 1. In some embodiments, the compound of formula (0') has the formula: [ka] In some embodiments, s is 0. In certain embodiments, the compound of formula (0') has the formula: [ka] In some embodiments, s is 0 and the compound of formula (0') is [ka] The compound is selected from the group of formulas consisting of:

[0180] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0181] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0182] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0183] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0184] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0185] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0186] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Z is hydrogen or a substituted or unsubstituted C 1-6 is alkyl, m is 1, 2, 3, 4, 5, or 6.

[0187] In certain embodiments, the compound is a compound of the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0188] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0189] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0190] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0191] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0192] In certain embodiments, the compound is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0193] In certain embodiments, a compound of the present disclosure (a compound described herein) is a compound of formula (0) or (0'), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound of the present disclosure is a compound of formula (0) or (0'), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a compound of the present disclosure is a compound of formula (0) or (0'), or a pharmaceutically acceptable salt thereof.

[0194] In certain embodiments, a compound of the present disclosure (a compound described herein) is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound of the present disclosure is a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a compound of the present disclosure is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0195] The compounds of the present disclosure may have a safe in vitro pharmacological profile. The compounds of the present disclosure may have a safer in vitro pharmacological profile (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% safer) than a certain similar known compound.

[0196] The compounds of the present disclosure may have high water solubility. The compounds of the present disclosure may have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) water solubility than certain similar known compounds.

[0197] The compounds of the present disclosure may have high microsomal stability. The compounds of the present disclosure may have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) microsomal stability compared to certain similar known compounds.

[0198] Exemplary compounds of the present disclosure include those in Table A, Table 5, and the following compounds: [ka]

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[0199]

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 19

[0200] Compositions and Kits The present disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure and an excipient (e.g., a pharmaceutically acceptable excipient). In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the excipient is a pharmaceutically acceptable excipient.

[0201] The compositions described herein can be prepared by any method known in the art. Generally, such preparation methods include bringing the disclosed compounds described herein into association with an excipient, and may also include one or more pharmaceutical or accessory ingredients, and, as necessary and / or desired, shaping and / or packaging the product into a desired single-dose or multi-dose unit. In certain embodiments, the pharmaceutical agent is a pharmaceutical agent.

[0202] In certain embodiments, compounds of the present disclosure are in the form of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0203] The compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of the composition comprising a predetermined amount of a drug. The amount of drug is approximately equal to the dose of the drug that would be administered to a subject and / or a convenient fraction of such a dose (e.g., one-half or one-third of such a dose).

[0204] The relative amounts of the compounds of the present disclosure, excipients, drugs, and / or any additional components in the compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is administered. The compositions may contain between 0.1% and 100% (w / w) of drug.

[0205] Excipients and auxiliary ingredients used in the preparation of the provided compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients and auxiliary ingredients such as cocoa butter, PEGylated lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavorings, and fragrances may also be present in the compositions.

[0206] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0207] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0208] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., Polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters ( For example, polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate,Examples of suitable anti-inflammatory agents include sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0209] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Chorizoides extract, Panwa gum, Gahatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0210] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative can be an antioxidant. In other embodiments, the preservative can be a chelating agent.

[0211] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0212] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0213] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0214] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0215] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0216] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0217] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0218] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0219] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea Cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0220] In certain embodiments, the composition further comprises a drug and is useful for delivery of the drug (e.g., to a subject or a cell). In certain embodiments, the composition is a pharmaceutical composition useful for treating a disease in a subject in need thereof. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer). In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is gastrointestinal stromal tumor. In certain embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In certain embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is pancreatic cancer (e.g., pancreatic cancer or pancreatic adenocarcinoma). In certain embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In certain embodiments, the cancer is testicular cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In certain embodiments, the cancer is a lymphoma, e.g., a non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma). In certain embodiments, the cancer is a B-cell lymphoma (e.g., Burkitt's B-cell lymphoma, large B-cell lymphoma). In certain embodiments, the cancer is a T-cell lymphoma. In certain embodiments, the cancer is a Burkitt's lymphoma (e.g., Burkitt's B-cell lymphoma). In certain embodiments, the cancer is a large cell immunoblastic lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is acute monocytic leukemia or acute lymphocytic leukemia (e.g., B-cell acute lymphocytic leukemia). In certain embodiments, the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia). In certain embodiments, the cancer is multiple myeloma (e.g., B-cell myeloma).

[0221] The compositions described herein can be administered in combination with one or more additional agents. In certain embodiments, the agent is an organic molecule. In certain embodiments, the agent is an inorganic molecule. In certain embodiments, the agent is a targeting agent. In certain embodiments, the agent is an isotopically labeled chemical compound. In certain embodiments, the agent is an agent useful in bioprocessing. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutically and / or prophylactically active agent). Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunological agents, and cells.

[0222] In certain embodiments, the compound of the present disclosure described herein is provided in an effective amount in the composition.In certain embodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need of cancer treatment.In certain embodiments, the effective amount is an amount effective for inhibiting the signal transduction pathway required for metastasis in a subject or cell.

[0223] In certain embodiments, the cells are in vitro. In certain embodiments, the cells are ex vivo.

[0224] The composition can be formulated into a liquid dosage form for oral and parenteral administration, including pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the drug, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, oral compositions may contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents. In certain embodiments of parenteral administration, the compositions described herein are mixed with a solubilizing agent, such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0225] Injectable preparations, for example, aqueous or oily sterile injectable suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents (for example, as a solution in 1,3-butanediol). Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable solutions.

[0226] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0227] In order to prolong the effect of the compound of the present disclosure, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the compound depends on its dissolution rate, which may depend on crystal size and crystalline form.Alternatively, the absorption of parenterally administered drug forms can be delayed by dissolving or suspending the compound in an oil vehicle.

[0228] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the compositions described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax. Such excipients or carriers are solid at ambient temperature but liquid at body temperature and will melt in the rectum or vaginal cavity and release the compounds of the present disclosure.

[0229] Composition can be formulated into the solid dosage form for oral administration, including capsule, tablet, pill, powder and granule.In this solid dosage form, the compound of the present disclosure is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectant, such as glycerol, (d) disintegrant, such as agar, calcium carbonate, Potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can contain buffering agents.

[0230] Solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmacological arts. These dosage forms can optionally contain opacifying agents and can also be of a composition that releases the compounds of the present disclosure only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0231] The compounds of the present disclosure may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as 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 formulation art. In such solid dosage forms, the compounds of the present disclosure may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. These dosage forms may optionally contain opacifying agents and may be of a composition that releases the compounds of the present disclosure only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0232] Dosage forms for topical and / or transdermal administration of the compositions described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the compounds of the present disclosure are admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as may be required.

[0233] Suitable devices for use in delivering the intradermal compositions described herein include short needle devices. The intradermal compositions can be administered using a device that limits the effective penetration length of the needle into the skin. Alternatively or additionally, a conventional syringe may be used for classical Mantoux intradermal administration. Jet injection devices are suitable, delivering liquid formulations to the dermis via a liquid jet injector and / or via a needle that creates a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder / particle delivery devices are suitable, using compressed gas to accelerate a powdered polymer through the outer layer of the skin to the dermis.

[0234] Formulations suitable for topical administration include liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations can contain, for example, about 1% to about 100% (w / w) of a compound of the present disclosure, although the concentration of the compound of the present disclosure can be as high as the solubility limit of the compound in the solvent. Formulations for topical administration can further include one or more of the additional ingredients described herein.

[0235] The compositions described herein can be prepared, packaged, and / or sold in formulations suitable for pulmonary administration via the oral cavity. Such formulations can include dry particles containing a compound of the present disclosure. Such compositions are conveniently in the form of a dry powder and administered using a device equipped with a dry powder reservoir capable of directing a flow of propellant to disperse the powder, and / or using a self-propelling solvent / powder dispensing container (e.g., a device containing the drug dissolved and / or suspended in a low-boiling propellant in a sealed container). Dry powder compositions can include a solid fine powder diluent, such as sugar, and are conveniently provided in unit dosage form.

[0236] Low-boiling propellants generally include liquid propellants having a boiling point at atmospheric pressure below 65° F. Generally, the propellant comprises 50-99.9% (w / w) of the composition, and the compound of the present disclosure can comprise 0.1-100% (w / w) of the composition. The propellant can further comprise additional components, such as a liquid nonionic and / or solid anionic surfactant and / or a solid diluent.

[0237] The compositions described herein formulated for pulmonary delivery can provide the compounds of the present disclosure in the form of droplets of solution and / or suspension. Such formulations can be prepared, packaged, and / or sold in aqueous and / or dilute alcoholic solutions and / or suspensions (optionally sterilized) containing the compounds of the present disclosure, and can be conveniently administered using any spray and / or atomization device. Such formulations can further include one or more additional ingredients, including flavoring agents (e.g., saccharin sodium), volatile oils, buffers, surfactants, and / or preservatives (e.g., methyl hydroxybenzoate).

[0238] The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein.Another formulation suitable for intranasal administration is a coarse powder comprising the compounds of the present disclosure.This formulation is administered by rapid inhalation through the nasal cavity from a powder container held near the nostrils.

[0239] Formulations for nasal administration can contain, for example, from as little as about 0.1% (w / w) to 100% (w / w) of a compound of the present disclosure and can include one or more of the additional ingredients described herein. The pharmaceutical compositions described herein can also be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations can take the form of, for example, tablets and / or lozenges made using conventional methods and contain, for example, 0.1-20% (w / w) of the drug, with the remainder comprising an orally dissolvable and / or disintegrable composition, and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration can include a powder and / or an aerosolized and / or atomized solution and / or suspension containing a compound of the present disclosure.

[0240] The compositions described herein can be prepared, packaged, and / or sold in formulations for ophthalmic administration. Such formulations can take the form of, for example, eye drops, comprising, for example, a 0.1-100% (w / w) solution and / or suspension of a compound of the present disclosure in an aqueous or oily liquid carrier or excipient. Such drops can further comprise buffers, salts, and / or one or more of the additional ingredients described herein. Other useful ophthalmically administrable formulations include formulations comprising a compound of the present disclosure in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of the present disclosure.

[0241] While the description of compositions provided herein is primarily directed to compositions suitable for administration to humans, those skilled in the art will understand that such compositions are also broadly suitable for administration to all types of animals. Modifications to compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and such modifications can be designed and / or implemented by a veterinary pharmacologist of ordinary skill, using routine experimentation.

[0242] The compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it should be understood that the total daily amount of the compositions described herein is determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the cancer to be treated and the severity of the cancer, the activity of the specific compound of the present disclosure used, the specific composition used, the subject's age, weight, general health, sex and diet, administration time, administration route, excretion rate of the specific compound of the present disclosure used, duration of treatment, drugs used in combination with or simultaneously with the specific compound of the present disclosure used, and similar factors well known in the medical field.

[0243] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or drop), transmucosal, nasal, buccal, sublingual, by intratracheal instillation, bronchial instillation, and / or inhalation, and / or by oral spray, nasal spray, and / or aerosol. Specifically, contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via the blood and / or lymphatic supply, and / or direct administration to the affected site. Generally, the most appropriate administration route depends on various factors, including the properties of the disclosed compounds (e.g., their stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compositions described herein are suitable for topical administration to the subject's eye.

[0244] In some embodiments, administration of any of the compositions described herein occurs at least 1 hour before treatment with another cancer therapy.

[0245] The compositions can be administered in combination with additional agents that improve their activity (e.g., potency and / or efficacy), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution within a subject or cell in treating a disease or disorder (e.g., cancer) in a subject in need thereof and / or inhibit a signal transduction pathway in a subject or cell. It will also be understood that the therapies used may achieve the desired effect on the same disease and / or may achieve different effects. In certain embodiments, compositions described herein that include a compound of the present disclosure and an agent described herein exhibit a synergistic effect that is not present in compositions that include either a compound of the present disclosure or an agent, but not both.

[0246] The composition may be administered simultaneously with, before, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy, separate from the composition. Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may be administered together with each other and / or with the compounds of the present disclosure or compositions described herein in a single dose or separately in different doses. The particular combination to be used in the regimen will take into account the compatibility of the compounds of the present disclosure and the additional pharmaceutical agent(s) described herein and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0247] Additional pharmaceutical agents include antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, and analgesics. In certain embodiments, the additional pharmaceutical agent is an antiproliferative agent. In certain embodiments, the additional pharmaceutical agent is an anticancer agent. In certain embodiments, the additional pharmaceutical agent is a chemotherapeutic agent. In certain embodiments, the additional pharmaceutical agent is an antiviral agent. In certain embodiments, the additional pharmaceutical agent is a protein kinase binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), inhibitors of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the disclosed compounds or pharmaceutical compositions described herein can be administered in combination with anti-cancer therapies (including surgery, radiation therapy, transplantation (e.g., stem cell transplant, bone marrow transplant), immunotherapy, and chemotherapy). In some embodiments, the subject is administered one or more additional agents (e.g., one or more additional cancer therapies) simultaneously with, before, or after the administration of the one or more additional agents. In some embodiments, the one or more additional cancer therapies include immunotherapy. Generally, immunotherapy (also called biological therapy) is a type of cancer treatment that boosts the natural defense of the subject to treat cancer.In certain embodiments, immunotherapy utilizes compounds that are biologically produced by the subject.In certain embodiments, immunotherapy utilizes compounds that are not biologically produced by the subject.In certain embodiments, immunotherapy utilizes cells from the subject.In certain embodiments, the immunotherapy utilizes cells that are not from the subject. In certain embodiments, the immunotherapy utilizes a compound biologically produced by an organism that is not the subject. In certain embodiments, the immunotherapy utilizes cells biologically produced by an organism that is not the subject. In certain embodiments, the immunotherapy includes at least one chemical modification to a compound or cell from the subject. In certain embodiments, the immunotherapy includes at least one chemical modification to a compound or cell that is not from the subject.

[0248] In some embodiments, immunotherapy may involve one or more of the following steps: preventing or inhibiting the growth of cancer cells; preventing cancer from spreading to other parts of the body; and improving the immune system's ability and activity to kill cancer cells. Non-limiting examples of immunotherapy include monoclonal antibodies, checkpoint inhibitors, non-specific immunotherapy, oncolytic virus therapy, T-cell therapy, and cancer vaccines.

[0249] In certain embodiments, immunotherapy utilizes monoclonal antibodies, which in some embodiments target (bind to) and / or block abnormal proteins on cancer cells.

[0250] In certain embodiments, immunotherapy utilizes checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitor is a monoclonal antibody. Immune checkpoints are regulators of immune activation by maintaining immune homeostasis and preventing autoimmunity. In cancer cells, immune checkpoint mechanisms are often activated to suppress nascent anti-cancer immune responses. In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-L1 (programmed death-ligand 1). In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Examples of immune checkpoint inhibitors include, but are not limited to, ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0251] In certain embodiments, the immunotherapy is a non-specific immunotherapy (e.g., interferon or interleukin). In certain embodiments, the immunotherapy is an oncolytic virus therapy.

[0252] In certain embodiments, the immunotherapy is T cell therapy. In some embodiments, the T cell therapy is chimeric antigen receptor (CAR) T cell therapy.

[0253] In certain embodiments, the immunotherapy is an anti-cancer vaccine.

[0254] Anti-cancer agents include biotherapeutic anti-cancer agents and chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon alpha, interferon gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulatory and / or immunomodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF), and antibodies (e.g., Hercptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporphine (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfones, and the like. amides (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents), docosahexaenoic acid-conjugated paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrugs (TAPs), ANG1005 (Angiopep-2 linked to three paclitaxel molecules),Paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1) and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloroisothiazolinone, ... methotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, thiazophrenia, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®) , imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), (trademark), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (NIR-1111), nivolumab ... Nib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosin, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine.

[0255] In some embodiments, the composition is substantially soluble in water (e.g., hydrophilic). In some embodiments, the composition is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the composition is substantially insoluble in water, requiring more than about 10,000 parts water to dissolve 1 part of a compound of the present disclosure.

[0256] In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 1 to about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of the composition comprising a compound of the present disclosure is less than about 50%, e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 25%, or about 5% to about 20%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 5% to about 90%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 5% to about 75%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 5% to about 50%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is about 10% to about 25%.

[0257] In some embodiments, the total amount of compounds of the present disclosure present in the composition is greater than about 1% of the total size or weight of the composition (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30%, or more). In some embodiments, the total amount of compounds of the present disclosure present in the composition is greater than about 10% of the total size or weight of the composition (e.g., about 12%, about 15%, about 20%, about 25%, about 30%, or more).

[0258] Without being bound by theory, the compositions disclosed herein can improve the efficacy of the compounds of the present disclosure by one or more of: increasing the localization and / or release (e.g., preferential release) of the compounds of the present disclosure to target cells (e.g., cancer or fibrocytes; cells associated with a hypoxic environment); or increasing the half-life of the compounds of the present disclosure, resulting in significantly greater amounts of the compounds of the present disclosure released at the target site (e.g., tumor or liver (e.g., cirrhotic cells)). Thus, the compositions disclosed herein can be more therapeutically effective than the free compounds (e.g., due to enhanced drug uptake in the target tissue) and / or allow for lower therapeutic doses of the compounds of the present disclosure, e.g., without substantially compromising the drug concentration achieved in the target tissue. In some embodiments, the compositions disclosed herein can reduce adverse effects associated with systemic administration of the compounds in their free form.

[0259] In some embodiments, a compound of the present disclosure is incorporated into a composition at a dose or amount that is lower than the dose or amount of the compound in free form to achieve a desired effect (e.g., a desired therapeutic effect). In certain embodiments, the composition delivers an increased amount of the compound of the present disclosure to tissues or cells in need thereof compared to the free compound, and reduces the amount of the compound of the present disclosure exposed to non-target tissues or cells compared to the free compound.

[0260] In another aspect, a kit is provided that includes a compound of the present disclosure, or a pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition of the present disclosure.

[0261] In certain embodiments, the kit instructions may also include information required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for delivery of a compound of the present disclosure. In certain embodiments, the kit and instructions provide for delivery of a composition. In certain embodiments, the kit and instructions provide for treatment of cancer in a subject in need thereof. In certain embodiments, the kit and instructions provide for inhibition of a signal transduction pathway in a subject or cell.

[0262] Treatment and Prevention Methods and Uses Some aspects of the present invention relate to methods, uses, compositions, and kits for administering to a subject in need thereof. In some embodiments, the subject is a subject who has, is suspected of having, or is at risk of developing a disease or disorder (e.g., cancer). As used herein, "subject," "individual," and "patient" can be used interchangeably. In some embodiments, the subject is a mammalian subject, including, but not limited to, a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, or primate. In some embodiments, the subject is a human subject, e.g., a patient. The human subject can be a pediatric or adult subject.

[0263] As used herein, "treating" includes remission, cure, prevention of deterioration, slowing the rate of progression, prevention of recurrence of the disorder (i.e., prevention of relapse), or prevention or slowing the rate of metastasis. An effective amount of a composition means the amount of the composition that produces a therapeutic effect. For example, in a method or use for treating cancer in a subject, an effective amount of a chemotherapeutic agent is any amount that produces an anti-cancer effect (e.g., reduces or prevents the proliferation of cancer cells, or is cytotoxic to cancer cells).

[0264] The methods and uses disclosed herein involve administering an effective amount of any of the disclosed compounds or compositions described herein to a subject with a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is a benign neoplasm.

[0265] The methods and uses disclosed herein involve administering an effective amount of any of the disclosed compounds or compositions described herein to a subject having or at risk of having cancer. In some embodiments, the cancer is characterized by the presence of cancer stem cells. In some embodiments, the cancer includes, involves, or is associated with stem cells. In some embodiments, the subject has undergone or is currently undergoing cancer therapy (e.g., chemotherapy, immunotherapy, surgery, radiation). Whether a subject is considered "at risk" of having a disease or disorder (e.g., cancer) can be determined by a skilled practitioner.

[0266] In certain embodiments, the cancer is colorectal cancer. Colorectal cancer is cancer that develops in the colon or rectum. These cancers are sometimes referred to as colon cancer or rectal cancer depending on where the cancer originates. Colon cancer and rectal cancer are often classified together because they share several common characteristics. Most colorectal cancers begin as growths on the lining of the colon or rectum. The Colorectal Cancer (CRC) Subtyping Consortium integrated six independent molecular classification systems into a single consensus system with four distinct groups, known as Consensus Molecular Subtypes (CMS), based on gene expression data. CMS were determined and associated with epigenomic, transcriptomic, microenvironmental, genetic, prognostic, and clinical characteristics. The CMS1 subtype is immunogenic and hypermutable. CMS2 tumors are activated by the WNT-β-catenin pathway and are generally associated with higher overall survival rates. CMS3 is characterized by a metabolic cancer phenotype. CMS4 cancers are associated with the poorest survival rates and have a strong stromal gene signature. The molecular subtypes CMS2 and CMS4 exhibit the highest levels of embryonic signaling. 11

[0267] In certain embodiments, the cancer is gastric cancer. Gastric cancer is cancer that begins in the stomach. Gastric cancer tends to develop slowly over many years. Before true cancer develops, precancerous changes often occur in the stomach lining (mucosa). These early changes rarely cause symptoms and therefore often go undetected. Types of gastric cancer include adenocarcinoma, lymphoma, gastrointestinal stromal tumor (GIST), carcinoid tumor, squamous cell carcinoma, small cell carcinoma, and leiomyosarcoma. Recently, the Cancer Genome Atlas (TCGA) project identified four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomic stable (GS), and chromosomal instability (CIN). The GS (genomically stable) and CIN (chromosomal instability) molecular subtypes exhibit the highest levels of germline signaling, as measured by comprehensive analysis of gene expression patterns across gastric cancer subtypes.12,13

[0268] In certain embodiments, the subject is receiving an additional therapy. In certain embodiments, the subject is further administered (co-administered) an additional therapy (e.g., before, simultaneously with, and / or after administration of a compound or composition described herein). The additional therapy is different from the compound or composition described herein. In certain embodiments, the additional therapy is ineffective when administered alone or is less effective than when co-administered with (e.g., before, simultaneously, and / or after) a compound or composition described herein in a method or use described herein.

[0269] The exact amount of a compound of the present disclosure required to achieve an effective dose will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of the side effect or disorder, the identity of the particular compound of the present disclosure, the mode of administration, etc.

[0270] An effective amount can be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses contain different or substantially the same amounts of an agent described herein.

[0271] In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cells is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose per 2 days, 1 dose per 3 days, 1 dose per week, 1 dose per 2 weeks, 1 dose per 3 weeks, or 1 dose per 4 weeks or more.In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, the period between the first and last administration of multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifetime of a subject, tissue, or cell.In certain embodiments, the period between the first and last administration of multiple doses is 3 months, 6 months, or 1 year. In certain embodiments, the period between the first and last administration of multiple doses is the lifetime of the subject, tissue, or cell.

[0272] Any of the compositions described herein can be administered in a therapeutically effective amount. In some embodiments, the methods and uses include administering a composition comprising any of the compounds described herein to a subject to achieve a desired amount (e.g., a therapeutically effective amount) of the compound at a specific site. In some embodiments, the methods and uses include administering a composition comprising any of the compounds described herein to a subject to achieve a desired amount (e.g., a therapeutically effective amount) of the compound at a tumor site.

[0273] Dosage can be adjusted appropriately to achieve desired local levels of the compound.

[0274] The terms "dose" and "dosage" are used interchangeably herein. In some embodiments, the amount of compound administered to a subject is about 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g, inclusive, of a compound of the present disclosure described herein. In certain embodiments, the doses described herein independently comprise 1 mg to 3 mg, inclusive, of a compound of the present disclosure described herein. In certain embodiments, the doses described herein independently comprise 3 mg to 10 mg, inclusive, of a compound of the present disclosure described herein. In certain embodiments, the doses described herein independently comprise between 10 mg and 30 mg (inclusive) of a compound of the present disclosure described herein. In certain embodiments, the doses described herein independently comprise between 30 mg and 100 mg (inclusive) of a compound of the present disclosure described herein.

[0275] In some embodiments, a subject is administered an initial dose of any one of the compositions described herein, followed by one or more additional doses of any of the compositions described herein. In some embodiments, the initial dose can contain a different amount of any of the compounds described herein compared to the one or more additional doses. In some embodiments, the initial dose is a higher dose (e.g., contains a higher amount of any one of the compounds described herein) than the one or more additional doses.

[0276] The dosage ranges described herein provide guidelines for administering provided compositions to adults.For example, the dosage that is administered to children or adolescents can be determined by medical practitioners or those skilled in the art, and this amount may be less than or equal to the amount that is administered to adults.In certain embodiments, the dosage provided herein is the dosage for an adult with a body weight of 70 kg.

[0277] Effectiveness in treating cancer can be measured, for example, by determining the growth, replication, proliferation, metastasis, and / or gene expression profile of one or more cancer cells. Thus, an effective amount is one that is deemed toxicologically acceptable and effective by a clinician.

[0278] Without being bound by any particular theory, it is believed that the compounds disclosed herein induce differentiation of embryonic cells and / or cells exhibiting embryonic cell characteristics. In some embodiments, the methods and uses disclosed herein involve administering an effective amount of any of the compositions described herein to a subject in need of regenerative medicine or therapy. In some embodiments, the subject is in need of restoration or improvement of one or more biological functions in dysfunctional or abnormal cells, tissues, and / or organs. In some embodiments, the subject is in need of tissue engineering and organ regeneration. In some embodiments, the compositions described herein regenerate or differentiate potentially damaged cells, tissues, and / or organs. In some embodiments, the subject has experienced brain trauma (e.g., trauma or injury to brain tissues or cells) and / or central nervous system injury (e.g., trauma or injury to central nervous system tissues or cells) and is in need of repair of the tissues or cells. In some embodiments, the subject has experienced cardiac trauma (e.g., trauma or injury to cardiac tissues or cells) and is in need of repair of the tissues or cells.

[0279] In some embodiments, administration of any of the compositions described herein is by oral administration, intravenous administration (e.g., systemic intravenous injection), parenteral administration, subcutaneous administration, intramuscular administration, transmucosal administration, transdermal administration, intradermal administration, intravaginal administration, intraperitoneal administration, topical administration, nasal administration, buccal administration, sublingual administration; intratracheal topical administration via the blood and / or lymphatic supply, and / or direct administration to the affected area.

[0280] The present disclosure provides a method of treating cancer, comprising administering to a subject a compound of formula (0): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L A is -N(R 2 )(L 1 R 1 ) or -C(=O)NR 1 R 2 and L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1, Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are [ka] are meta or para to each other when they are phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L B is -N(R 6 )L 2 -or-L 2 N(R 6 )- and L 2 is -C(=O)-, [ka] or -S(=O)2-, Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; s is 0 or 1, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -ORa , -N(R a )2, or -CN.

[0281] In certain embodiments, the present disclosure further provides a method of treating cancer, comprising administering to a subject a compound of formula (0'): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1, Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are [ka] are meta or para to each other when they are phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)-, [ka] or -S(=O)2-, Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; s is 0 or 1, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0282] The present disclosure also provides a method of treating cancer, comprising administering to a subject a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R aeach instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, azetidinyl, -C≡C-, or [ka] and Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0283] In certain embodiments of the "methods of treatment and prevention," L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0284] In certain embodiments, the present disclosure provides a method of treating cancer, comprising administering to a subject a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: L 1 is a single bond or -C(=O)-, L 1 If is a single bond, R 1 is hydrogen, substituted or unsubstituted C1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; L 1 When is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1-6 is an alkyl or nitrogen protecting group, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, R a each instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Alternatively, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl or heteroaryl; Each instance of Y is independently N or CR 4 and R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(Ra )2, or -CN, [ka] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Bond b and bond c are meta or para to each other; R 5 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R 5 There is no case where is bonded to a nitrogen atom, L 2 is -C(=O)- or -S(=O)2-, R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , -N(R a )2, or -CN.

[0285] In certain embodiments of the "Methods of Treatment and Prevention and Uses" section, L 1 , R 1 , R 2 , R 3 , R a , R 4 ,Y, [ka] , bond b and bond c, R 5 , n, L 2 , R 6 , R 7 , and R 8 is as described in the Compounds section.

[0286] In certain embodiments of the "Methods of Treatment and Prevention and Uses" section, L 1 is a single bond, R 1 is hydrogen. In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, L 1 When is -C(=O)-, R 1 is a substitution C 1-6 In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, L 1 When is -C(=O)-, R 1 is unsubstituted C 1-6 Alkyl (eg, Me or Et).

[0287] In certain embodiments of the "Methods of Treatment and Prevention and Uses" section, R 3 is hydrogen.

[0288] In certain embodiments of the "Methods of Treatment and Prevention and Uses" section, R 2 and R 3 are joined with their intervening atoms to form a substituted or unsubstituted 6-membered monocyclic heterocyclyl or heteroaryl. In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, R 2 and R 3are joined with their intervening atoms to form an unsubstituted 6-membered monocyclic heterocyclyl. In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, [ka] is.

[0289] In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0290] In certain embodiments in the "Methods of Treatment and Prevention and Uses" section, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0291] Additional methods The present disclosure also provides methods for contacting a cell with an effective amount of a compound of the present disclosure.The present disclosure also provides uses for contacting a cell with an effective amount of a compound of the present disclosure.

[0292] In some embodiments, any compound described herein is contacted with cells in vivo, e.g., within an organism. In some embodiments, any compound described herein is contacted with cells in vitro, e.g., in cell culture. In some embodiments, any compound described herein is contacted with cells ex vivo, meaning that the cells are removed from the organism prior to contacting. As will be apparent to one of skill in the art, the term cell can be used to refer to both single cells and populations of cells. In some embodiments, a cell population is contacted with any compound described herein to regenerate or differentiate one or more cells in the cell population. In some embodiments, a cell population is contacted with any compound described herein for use in personalized medicine, e.g., for diagnostic and / or therapeutic purposes.

[0293] Generally, any cell known in the art can be used in the methods and uses described herein. In some embodiments, the cell is a cell of a cell line. In some embodiments, the cell is obtained from an organism (e.g., a subject). In some embodiments, the cell is a cancer cell (e.g., a cancer stem cell). In some embodiments, the cell is a stem cell. In some embodiments, the cell is an embryonic stem cell. In some embodiments, the cell is an induced pluripotent stem cell. In some embodiments, the cell is a neural cell (e.g., a neural stem cell). In some embodiments, the cell is an adult stem cell (e.g., a gastric stem cell or an intestinal stem cell).

[0294] In some embodiments, the methods and uses further include inhibiting cell growth. In other embodiments, the methods and uses include killing the cell. In some embodiments, the cell is a stem cell. In some embodiments, the cell is selected from the group consisting of cancer stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, or adult stem cells. In certain embodiments, the cell is a cancer stem cell. In certain embodiments, the cell is an embryonic stem cell. In certain embodiments, the present disclosure provides methods and uses for inhibiting cell growth and / or killing cells with an effective amount of a compound of the present disclosure. In certain aspects, inhibiting cell growth and / or killing cells is useful for treating proliferative diseases, including cancer.

[0295] In some embodiments, the methods and uses further include measuring or assessing the level of one or more embryonic characteristics of the cells. In some embodiments, the level of one or more embryonic characteristics of the cells is assessed after contacting the cells with any of the compositions described herein. In some embodiments, the level of one or more embryonic characteristics after contacting the cells with any of the compositions described herein is compared to the level of a reference sample or the one or more embryonic characteristics before contacting the cells with the composition. In some embodiments, contacting the cells with any of the compositions described herein reduces one or more embryonic characteristics of the cells. In some aspects, the methods and uses described herein can be used to determine whether a cell is suspectable for treatment with a composition described herein. In some embodiments, if the level of one or more embryonic characteristics is reduced after contacting the cells with any of the compositions described herein, the cell is determined to be suspectable for treatment with the composition. In some embodiments, if the level of one or more embryonic characteristics is reduced after contacting the cells with any of the compositions described herein, the composition is determined to be a candidate for a cell-related disease or disorder.

[0296] In some embodiments, the methods and uses described herein can be used in regenerative medicine. In some embodiments, contacting cells with any of the compositions described herein promotes differentiation and / or loss of one or more embryonic characteristics of the cells. In some embodiments, contacting cells with any of the compositions described herein promotes the regenerative capacity of the cells. In some embodiments, contacting cells with any of the compositions described herein enhances the regenerative capacity of the cells. In some embodiments, contacting cells with any of the compositions described herein regenerates a cell population (e.g., a tissue or organ). In some embodiments, the regenerated cell population (e.g., a tissue or organ) can be administered or transplanted into a subject. In some embodiments, the subject is the same subject as the source of the cells. In some embodiments, the subject is a different subject from the source of the cells (e.g., autologous transplant). In some embodiments, the subject is a subject of the same species as the source of the cells but different from the source of the cells (e.g., allogeneic transplant). In some embodiments, the subject is a subject of a different species than the source of the cells and different from the source of the cells (e.g., xenogeneic transplant). [Example]

[0297] In order that this disclosure 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, methods, and uses provided herein, and are not to be construed in any way as limiting the scope thereof.

[0298] Example 1. Kinetic cell viability in AGS cells Approximately 50,000 AGS cells were seeded per well of a 96-well plate in media containing NanoLuc luciferase and MT Cell Viability Substrate, provided in PROMEGA's RealTime Glo MT Cell Viability Assay Kit. Four hours after plating, cells were treated with DMSO alone (no drug treatment) or decreasing concentrations of compounds of the present disclosure to achieve final concentrations of 20, 10, 5, and 2.5 μM. Luminescence units (RLU) were measured every 16–20 hours using a Synergy HTX plate reader with 30 ms integration (see Figure 1).

[0299] Example 2. Human microarray study AGS human gastric adenocarcinoma cells were treated with compound I-1 or DMSO alone (as a negative control) for two days. After two days, RNA was isolated in duplicate from compound I-1-treated and DMSO-treated cells and subjected to microarray analysis using an AFFYMETRIX CLARIOM S microarray. Data are expressed as fold changes relative to compound I-1-treated cells, with negative values ​​representing genes that were higher in compound I-1-treated cells than in DMSO-treated cells, and positive values ​​representing genes that were higher in DMSO-treated cells than in compound I-1-treated cells. Values ​​are averaged across duplicate samples. Genes whose expression changed more than three-fold, either upward or downward, in response to compound I-1 were included in the data.

[0300] Table 1 shows a list of genes upregulated upon treatment of the AGS human gastric cancer cell line with compound I-1 (see below). Negative numbers indicate fold upregulation upon drug treatment. Positive numbers indicate fold downregulation upon drug treatment. Overall, these data represent the reactivation of tumor suppressor genes and the reduction of tumor-promoting gene expression. For example, DUSP10, NR1D1, and Per1 have all been shown to have tumor-suppressing activity that prevents uncontrolled cell proliferation, and the expression of all three genes was significantly increased by compound I-1 treatment. In addition, Chac1, PCK2, and SLC7A11 have all been shown to have tumor-promoting activity and are associated with more dangerous and lethal forms of cancer, and these three genes were the three most strongly downregulated genes measured in this analysis. While other examples of data exist to support this model, the overall model is that compound I-1 increases the expression of tumor suppressor genes and decreases the expression of tumor-promoting genes. [ka]

[0301] [Table 30] [Table 31]

[0302] Table 2 shows a list of genes that are down-regulated upon treatment of the AGS human gastric cancer cell line with compound I-1.

[0303] [Table 32] [Table 33] [Table 34] [Table 35]

[0304] Example 3. Kinetic cell viability in AGS cells Compound I-1 was tested for its ability to inhibit the growth of 12 additional cell lines derived from various different types of human cancer. In addition to potently inhibiting the growth of gastric adenocarcinoma and gastrointestinal stromal cells (gastric adenocarcinoma data shown in Example 1, gastrointestinal stromal tumor data shown in Table 3), compound I-1 also exerted the most potent effects on non-Hodgkin's lymphoma, small cell lung cancer, pancreatic cancer, gastrointestinal stromal, and ovarian adenocarcinoma cells. Exemplary results are shown in Table 3. The results are expressed as IC , the lowest concentration of compound I-1 that inhibited cancer cell growth by 50%. 50 are listed as values.

[0305] [Table 36]

[0306] General Method Used in Examples 4-10 and 11 Unless otherwise specified, Examples 4-10 and 11 were carried out according to the general methods described in this subsection.

[0307] RT-qPCR Approximately 2.5 x 10 5 AGS cells were treated with DMSO alone (no drug treatment) or 10 μM compound I-1 in DMSO for 4 days. Cells were lysed and RNA was extracted using Zymo's Quick RNA-Microprep according to the manufacturer's instructions. 100 ng of RNA was reverse transcribed using MuLV reverse transcriptase (New England Biolabs, USA). qPCR was performed using 2 μl of cDNA and NEB's Luna Universal qPCR Master Mix in a Stratagene Mx3005P.

[0308] Hepatotoxicity assay Fresh primary CD-1 mouse hepatocytes were obtained from XenoTech in 96-well plates the day after perfusion. After 24 hours of recovery at 37°C using OptiCulture Hepatocyte Media, media containing either DMSO alone (no drug treatment) or 10 μM Compound I-1 was replaced daily for 4 days. Cell viability was measured using the CellTiter Glo 2.0 Kit from PROMEGA according to the manufacturer's instructions. Luminescence was measured using a Synergy HTX plate reader with a 1-second integration.

[0309] Kinetic cell viability Approximately 50,000 AGS cells were seeded per well of a 96-well plate in medium containing NanoLuc luciferase and MT Cell Viability Substrate, provided in PROMEGA's RealTime Glo MT Cell Viability Assay Kit. Four hours after plating, cells were treated with DMSO alone (no drug treatment) or decreasing concentrations of compound I-1 to achieve final concentrations of 20, 10, 5, and 2.5 μM. Luminescence units (RLU) were measured every 16–20 hours using a Synergy HTX plate reader with 30 ms integration.

[0310] Absorption, Distribution, Metabolism, and Excretion (ADME) Profiling Plasma stability was determined by the QuintaraBio stability assay using samples supplied in DMSO solution. Briefly, compounds at a final concentration of 1 μM were incubated in duplicate in the presence of mouse plasma at 37°C. At four different time points, 300 μL of quench solution (50% acetonitrile, 50% methanol, and 0.05% formic acid, warmed to 37°C) containing an internal standard was added to each well. The plate was sealed, vortexed, and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was transferred to a new plate for LC / MS / MS analysis. All samples were analyzed by LC / MS / MS using an AB Sciex API 4000 instrument connected to a Shimadzu LC-20AD LC Pump system. The extent of metabolism was calculated as the disappearance of the test compound compared to a 0-minute control reaction incubation. Initial rates were calculated versus compound concentration, and the t 1 / 2 was used to determine the value.

[0311] Microsomal Stability. Microsomal stability was determined using the QuintaraBio stability assay with samples supplied in DMSO solution. Briefly, the assay was performed in a 96-well microtiter plate at 37°C. Reaction mixtures (25 μL) containing 1 μM final test compound, 0.5 mg / mL liver microsomal protein, and 1 mM NADPH and / or 1 mM uridine 5'-diphospho-α-D-glucuronic acid (UDPGA) (containing alamethicin) in 100 mM potassium phosphate pH 7.4 buffer containing 3 mM MgCl2 were incubated. At each time point (0.25, 0.5, 1, 2, 4, 6, 8, and 24 minutes), 150 μL of quench solution (100% acetonitrile and 0.1% formic acid) containing an internal standard was transferred to each well. The plate was sealed and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was transferred to a new plate for LC / MS / MS analysis. All samples were analyzed by LC / MS / MS using an AB Sciex API 4000 instrument connected to a Shimadzu LC-20AD LC Pump system. The extent of metabolism was calculated as the disappearance of the test compound relative to the 0 minute incubation time. Initial rates were calculated versus compound concentration, and t 1 / 2 value, followed by determination of the intrinsic clearance CLint = (0.693)(1 / t 1 / 2 (min) (g liver / kg body weight) (mL incubation / mg microsomal protein) (45 mg microsomal protein / g liver weight) was used to determine the saturation.

[0312] Kinetic solubility. Solubility was determined by QuintaraBio's solubility assay using samples provided in DMSO solution. Briefly, 10 mM compound I-1 was diluted with an appropriate amount of buffer (PBS, pH 7.4) and mixed by shaking for 1.5 hours, followed by vacuum filtration. Samples were then assayed via reverse-phase HPLC with UV detection. Quantification was achieved by reference to a three-point standard curve constructed with serial dilutions of the drug substance dissolved in 100% DMSO.

[0313] Pharmacokinetic profile The pharmacokinetic profile of compound I-1 was determined using a newly prepared formulation after oral gavage at 100 mg / kg in male CD1 mice (n=3). Approximately 0.025 mL of blood was collected from the dorsal metatarsal vein at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The plasma concentration of the drug was analyzed by LC / MS / MS.

[0314] Maximum Tolerated Dose Test The maximum tolerated dose profile of compound I-1 was determined using a newly prepared formulation after oral gavage of either vehicle control (n=3) or compound I-1 (n=9) to female BALB / c nude mice. Animals were dosed at 50 mg / kg (n=3), 25 mg / kg (n=3), or 12 mg / kg (n=3) for 5 consecutive days, followed by clinical observation for an additional 5 days.

[0315] Example 4. AGS gastric cancer cells were treated with either DMSO alone (no drug treatment) or 10 μM of compound I-1 for 4 days. RNA was isolated and oct4 RNA levels were measured by RT-qPCR. Exemplary results are shown in Figure 2.

[0316] Example 5. AGS gastric cancer cells were treated with either DMSO alone (no drug treatment) or 10 μM of compound I-1 for 4 days. RNA was isolated and nanog RNA levels were measured by RT-qPCR. Exemplary results are shown in Figure 3.

[0317] Example 6 Normal, healthy mouse hepatocytes were treated with DMSO alone (no drug treatment) or 10 μM of compound I-1 for 4 days. Cell health was measured using the CELLTITER GLO reagent, which provides a luminescent readout as a measure of total ATP concentration. Exemplary results are shown in Figure 4.

[0318] Example 7 AGS gastric cancer cells were treated with either DMSO alone (no drug treatment) or various concentrations of compound I-1 (including 2.5 μM, 5 μM, 10 μM, and 20 μM) for 4 days. Cell health and replication were measured using the REALTIME-GLO MT Cell Viability Assay, which provides a luminescence readout as a measure of cell number and health. Exemplary results are shown in Figure 5.

[0319] Example 8 Selected chemical properties of compound I-1 were measured. Solubility was measured in aqueous solution at either pH 1.2 or 7.4. Mouse liver microsome stability was measured by the half-life (t 1 / 2 The plasma stability is listed as the percentage of compound I-1 remaining in mouse plasma after 4 hours. Exemplary results are shown in FIG.

[0320] Example 9. After a single PO (oral) injection of 100 mg / kg into mice, the concentration of compound I-1 in plasma was measured over 24 hours. Exemplary results are shown in Figure 7. The half-life was approximately 6 hours.

[0321] Example 10. Nude BALB / c mice were treated (orally) once daily with either vehicle control or 50 mg / kg of Compound I-1, 25 mg / kg of Compound I-1, or 12.5 mg / kg of Compound I-1 for 5 days. Three mice were treated with vehicle control and three mice with Compound I-1. Mice were monitored for a total of 10 days and weighed to assess overall health. Exemplary results are shown in Figure 8.

[0322] Example 11. Kinetic cell viability in AGS cells Compound I-1 was tested for its ability to inhibit the growth of an additional 11 cell lines derived from a variety of different types of human cancer. Exemplary results are shown in Table 4. The results are expressed as IC , the lowest concentration of compound I-1 that inhibited cancer cell growth by 50%. 50 are listed as values.

[0323] [Table 37]

[0324] Example 12. Preparation of exemplary compounds Compounds I-152, I-156, I-157, I-160, I-168, I-171, I-174, I-175, I-176, I-178, I-179, I-180, and I-181 were purchased from commercial vendors.

[0325] The following LC-MS method (analytical) was used in the preparation of compounds I-215, I-224, I-225, I-227, I-228, I-230, I-231, I-232, I-241, I-246, I-248, I-252, I-257, I-258, I-260, I-263, I-264, I-271, I-272, I-284, I-285, and I-296.

[0326] Method 1 (LC-MS) 2min_low_3_97_BEH: LC / MS system: Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter); Mobile phase A: 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 3% A, 97% B, flow rate 0.9 ml / min; 1.9 min 3% A, 97% B, flow rate 0.9 ml / min; 2.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1000 AMU.

[0327] Method 2 (LC-MS): 2min_high_3_97_BEH: LC / MS system: Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter); Mobile phase A: 10 mM aqueous ammonium bicarbonate (adjusted to pH 10 with ammonia); Mobile phase B: acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 3% A, 97% B, flow rate 0.9 ml / min; 1.9 min 3% A, 97% B, flow rate 0.9 ml / min; 2.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0328] Method 5 (LC-MS): 12min_low_3_97_BEH: LC / MS system: Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7µm packing diameter); Mobile phase A: 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 0.9ml / min; 1.5 min 97% A, 3% B, flow rate 0.9ml / min; 11.5 min 3% A, 97% B, flow rate 0.9ml / min; 12.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0329] Method 6 (LC-MS): 12min_high_3_97_BEH: LC / MS system: Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter); Mobile phase A: 10 mM aqueous ammonium bicarbonate (adjusted to pH 10 with ammonia); Mobile phase B: acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 97% A, 3% B, flow rate 0.9 ml / min; 11.5 min 3% A, 97% B, flow rate 0.9 ml / min; 12.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0330] Synthesis of 4-(1-acetylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (compound I-42)

[0331] Preparation of tert-butyl 5-bromoindoline-1-carboxylate [ka]

[0332] Procedure A: To a mixture of 5-bromoindoline (10.0 g, 50.8 mmol) in DCM (80 mL) was added a solution of di-tert-butyl dicarbonate (11.2 g, 51.3 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give tert-butyl 5-bromoindoline-1-carboxylate as a yellow oil (18.0 g, quantitative yield). LC-MS (ESI): m / z (M) + = 297.12 / 299.33.

[0333] Preparation of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate [ka]

[0334] Procedure B: To a mixture of tert-butyl 5-bromoindoline-1-carboxylate (18.0 g, 50.8 mmol) in dioxane / HO (135 mL) was added (4-(methoxycarbonyl)phenyl)boronic acid (13.2 g, 76.2 mmol), Pd(dppf)Cl (4.2 g, 5.1 mmol), and CsCO (49.4 g, 152 mmol). The reaction mixture was stirred at 80 °C for 20 h, then diluted with DCM and washed with brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (PE / EA 4:1 (v / v)) to give tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate as a yellow solid (11.2 g, 62%). LC-MS (ESI): m / z (M-56) + = 298.14.

[0335] Preparation of 4-(1-(tert-butoxycarbonyl)indolin-5-yl)benzoic acid [ka]

[0336] Procedure C: To a mixture of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate (5.0 g, 14.2 mmol) in 1:1 MeOH / THF (60 mL) was added LiOH (1N, 30 ml). The reaction mixture was stirred at 70° C. for 3 h. It was then concentrated in vacuo and acidified with aqueous HCl (1N). After filtration, the solid was dried to give 4-(1-(tert-butoxycarbonyl)indolin-5-yl)benzoic acid as a white solid (5.6 g, quantitative yield). LC-MS (ESI): m / z (M-56) + = 284.09.

[0337] Preparation of tert-butyl 5-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)indoline-1-carboxylate [ka]

[0338] Procedure D: To a mixture of 4-(1-(tert-butoxycarbonyl)indolin-5-yl)benzoic acid (3.0 g, 8.8 mmol) in DMF, pyridin-3-ylmethanamine (1.1 g, 10.6 mmol), HATU (5.0 g, 13.2 mmol), and DIPEA (3.4 g, 26.4 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. It was then diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (DCM / MeOH 9:1 (v / v)) to give tert-butyl 5-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)indoline-1-carboxylate as a solid (3.2 g, 85%). LC-MS (ESI): m / z (M+1) + = 430.28.

[0339] Preparation of 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide [ka]

[0340] Procedure E: To a mixture of tert-butyl 5-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)indoline-1-carboxylate (2.0 g, 4.7 mmol) in DCM (5 mL) was added HCl in dioxane (4 N, 20 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give a red solid (2.4 g). The residue (100 mg) was purified by preparative HPLC (C18, 40-100% MeCN in HO with 0.1% formic acid) to give 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid (27 mg, 35%).

[0341] Preparation of 4-(1-acetylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (compound I-42) [ka]

[0342] Procedure D was followed, starting with 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (200 mg, 0.5 mmol) and HOAc (36 mg, 0.6 mmol). In this case, the reagents were added at 0° C. and the reaction mixture was allowed to warm to room temperature. (1-acetylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide was isolated as a white solid (47 mg, 25%). LC-MS (ESI): m / z (M+H) + = 372.21. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J = 5.9 Hz, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.46 (dd, J = 4.7, 1.5 Hz, 1H), 8.15 - 8.06 (m, J = 8.4 Hz, 1H), 7.98 - 7.92 (m, J = 8.4 Hz, 2H), 7.78 - 7.71 (m, J = 9.0, 5.1 Hz, 3H), 7.63 (s, 1H), 7.57 - 7.52 (m, J = 8.4 Hz, 1H), 7.39 - 7.34 (m, J = 7.8, 4.8 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 4.14 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.5 Hz, 2H), 2.18 (s, 3H).

[0343] Synthesis of 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-43)

[0344] 3.4.1 Preparation of 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-43) [ka]

[0345] Following general procedure D, starting from 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (1.5 g, 5.0 mmol) and propionic acid (340 mg, 6.0 mmol), 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide was isolated as a white solid (690 mg, 36%). LC-MS (ESI): m / z (M+H) + = 386.23. 1H NMR (400 MHz, DMSO-d6) δ 9.17 - 9.09 (m, J = 5.9 Hz, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.47 (dd, J = 4.7, 1.5 Hz, 1H), 8.22 - 8.11 (m, 1H), 7.99 - 7.92 (m, 2H), 7.80 - 7.71 (m, 5.2 Hz, 3H), 7.63 (s, 1H), 7.58 - 7.53 (m, 1H), 7.40 - 7.31 (m, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.12 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 2.50 - 2.44 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).

[0346] Synthesis of 4'-propionamido-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (Compound I-44) [ka]

[0347] To a solution of methyl 4-iodobenzoate (3.0 g, 11.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.03 g, 13.8 mmol), and KCO (3.2 g, 23.0 mmol) in dioxane / HO (25 / 5 mL) was added Pd(PPh) (1.33 g, 1.15 mmol) in one portion. The mixture was stirred at 100 °C for 10 h. It was then extracted with EA, and the combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give methyl 4'-amino-[1,1'-biphenyl]-4-carboxylate as a white solid (2.5 g, quantitative yield). LC-MS (ESI): m / z (M+H) + = 220.19.

[0348] Following general procedure D, starting from methyl 4'-amino-[1,1'-biphenyl]-4-carboxylate (2.4 g, 10.6 mmol) and propionic acid (1.18 g, 15.9 mmol), methyl 4'-propionamido-[1,1'-biphenyl]-4-carboxylate was isolated as a white solid (2.1 g, 70%). LC-MS (ESI): m / z (M+H) = 284.14.

[0349] To a solution of methyl 4'-propionamido-[1,1'-biphenyl]-4-carboxylate (200 mg, 0.7 mmol) in MeOH / THF (2 / 2 mL) was added NaOH (3.5 mL, 3.5 mmol). The mixture was stirred at room temperature for 12 hours. It was acidified with HCl 4N and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to give 4'-propionamido-[1,1'-biphenyl]-4-carboxylic acid as a white solid (150 mg, 79%). LC-MS (ESI): m / z (M+H) = 270.09.

[0350] Compound I-44 was prepared according to general procedure D starting from 4'-propionamido-[1,1'-biphenyl]-4-carboxylic acid (150 mg, 0.56 mmol) and pyridin-3-ylmethanamine (91 mg, 0.84 mmol). Purification by preparative HPLC afforded 4'-propionamido-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide as a white solid (32 mg, 16%). LC-MS (ESI): m / z (M+H) + = 360.25. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.13 (t, J = 5.9 Hz, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H),7.81-7.65 (m, 7H), 7.40-7.33 (m, 1H), 4.52 (d, J = 5.8 Hz, 2H), 2.35 (q, J = 7.5 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H).

[0351] Synthesis of 4'-(N-methylpropionamido)-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (Compound I-45) [ka]

[0352] To a solution of methyl 4'-propionamido-[1,1'-biphenyl]-4-carboxylate (500 mg, 1.77 mmol) and CsCO (1.36 g, 3.54 mmol) in MeCN (10 mL) was added MeI (0.22 mL, 3.54 mmol) in one portion. The mixture was stirred at 80 °C for 10 h. It was then extracted with EA, and the combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give methyl 4'-(N-methylpropionamido)-[1,1'-biphenyl]-4-carboxylate as a white solid (475 mg, 90%). LC-MS (ESI): m / z (M+H) + = 298.14.

[0353] To a solution of methyl 4'-(N-methylpropionamido)-[1,1'-biphenyl]-4-carboxylate (200 mg, 0.68 mmol) in MeOH / THF (2 / 2 mL) was added NaOH (3.4 mL, 3.4 mmol) in one portion. The mixture was stirred at room temperature for 12 hours. It was then acidified with HCl 4N and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to give 4'-(N-methylpropionamido)-[1,1'-biphenyl]-4-carboxylic acid as a white solid (140 mg, 73%). LC-MS (ESI): m / z (M+H) + = 284.14.

[0354] Following general procedure D and starting from 4'-(N-methylpropionamido)-[1,1'-biphenyl]-4-carboxylic acid (140 mg, 0.50 mmol) and pyridin-3-ylmethanamine (82 mg, 0.75 mmol), 4'-(N-methylpropionamido)-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide was isolated as a white solid (30 mg, 16%). LC-MS (ESI): m / z (M+H) + = 374.30. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (t, 1H), 8.58 (s, 1H), 8.47 (d, J = 3.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.90-7.66 (m, 5H), 7.44 (d, J = 8.3 Hz,2H), 7.40-7.31 (m, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.20 (s, 3H), 2.32-1.89 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

[0355] Synthesis of 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-46) [ka]

[0356] To a solution of 1,2,3,4-tetrahydroquinoline (2.0 g, 15.0 mmol) in DMF (20 mL) was added NBS (2.67 g, 15.0 mmol) in one portion. The mixture was stirred at 0 °C for 1 h. It was then extracted with EA, and the combined organic layers were washed with brine, dried over Na SO , concentrated, and purified by flash chromatography to give 6-bromo-1,2,3,4-tetrahydroquinoline as a yellow oil (3.1 g, 97%). LC-MS (ESI): m / z (M+H) = 212.08 / 214.08.

[0357] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (13.1 g, 14.6 mmol) and DIPEA (6.5 mL, 36.5 mmol) in DCM (30 mL) at 0 °C, AcCl (1.72 g, 21.9 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 4 h and then quenched with water. It was extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one as a pale yellow oil (3.33 g, 90%). LC-MS (ESI): m / z (M+H) + = 254.06 / 256.06.

[0358] To a solution of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (1.0 g, 4.0 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.08 g, 6.0 mmol), and NaCO (850 mg, 8.0 mmol) in dioxane / HO (10 mL / 2 mL) was added Pd(PPh) (466 mg, 0.4 mmol). The mixture was stirred at 100 °C for 10 hours. It was then extracted with EA, and the combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give methyl 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a white solid (1.25 g, 100%). LC-MS (ESI): m / z (M+H) + = 310.13.

[0359] Procedure F: To a solution of methyl 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (500 mg, 1.62 mmol) in MeOH (10 mL) was added NaOH (2.1 mL, 8.1 mmol). The mixture was stirred at 50° C. for 12 h, acidified with HCl (4 N), and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to give 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid as a white solid (445 mg, 93%). LC-MS (ESI): m / z (M+H) + = 296.15.

[0360] Following general procedure D and starting from 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (150 mg, 0.51 mmol) and pyridin-3-ylmethanamine (66 mg, 0.61 mmol), 4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(pyridin-3-ylmethyl)benzamide was isolated as a white solid (53 mg, 27%). LC-MS (ESI): m / z (M+H) + = 386.25. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.9 Hz, 1H), 8.51 (d, J = 5.5 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.66-7.48 (m, 3H),7.32 (d, J = 5.5 Hz, 2H), 4.52 (d, J = 5.8 Hz, 2H), 3.71 (t, J = 6.3 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.21 (s, 3H), 1.94-1.87 (m, 2H).

[0361] Synthesis of 4-(1-(2-hydroxyacetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-47)

[0362] Preparation of 4-(1-(2-(benzyloxy)acetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide [ka]

[0363] Following general procedure D, starting from 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (150 mg, 0.45 mmol) and 2-(benzyloxy)acetic acid (60 mg, 0.54 mmol), 4-(1-(2-(benzyloxy)acetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide was obtained as a white solid (140 mg, 65%). LC-MS (ESI): m / z (M-56) + = 478.32.

[0364] Preparation of 4-(1-(2-hydroxyacetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (compound I-47) [ka]

[0365] To a solution of 4-(1-(2-(benzyloxy)acetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (100 mg, 0.209 mmol) in DCM (5 mL) was added BBr3 (262 mg, 1.05 mmol). The reaction mixture was stirred under N2 at 0 °C for 2 h. After quenching with aqueous NaHCO3, the mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 40-100% MeCN in HO with 0.1% formic acid) to give 4-(1-(2-hydroxyacetyl)indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid (15 mg, 18%). LC-MS (ESI): m / z (M+H) + = 388.61. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (t, J = 5.9 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.82 - 7.70 (m, 3H), 7.65 (s, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 7.7, 4.8 Hz, 1H), 4.94 (s, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.21 (s, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.3 Hz, 2H).

[0366] Synthesis of 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide (Compound I-48)

[0367] Preparation of 1-(5-bromoindolin-1-yl)propan-1-one [ka]

[0368] General procedure D was followed, starting with 5-bromoindoline (3.0 g, 15.2 mmol) and propionic acid (1.37 g, 18.3 mmol). In this case, the reagents were added at 0° C. and the reaction mixture was allowed to warm to room temperature. 1-(5-bromoindolin-1-yl)propan-1-one was isolated as a white solid (3.0 g, 78%). LC-MS (ESI): m / z (M) + = 253.01, 255.52.

[0369] Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)propan-1-one [ka]

[0370] Procedure G: To a mixture of 1-(5-bromoindolin-1-yl)propan-1-one (1.5 g, 5.9 mmol) in dioxane (15 mL), B2Pin2 (1.65 g, 6.5 mmol), Pd(dppf)Cl (240 mg, 0.3 mmol), and KOAc (1.7 g, 17.7 mmol) were added. The reaction mixture was stirred at 80 °C for 20 h. It was then diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (PE / EA 4:1 (v / v)) to give 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)propan-1-one as a yellow solid (800 mg, 45%). LC-MS (ESI): m / z (M-56) + = 254.20.

[0371] Preparation of 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide [ka]

[0372] To a mixture of 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (200 mg, 0.783 mmol) in THF (5 mL) was added pyridin-3-ylmethanamine (92.9 mg, 0.861 mmol) and DIPEA (303.1 mg, 2.349 mmol). The reaction mixture was stirred at room temperature for 2 hours. It was quenched with water, washed with brine, and extracted with EA. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (PE / EA 4:1 (v / v)) to give 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide as a yellow solid (140 mg, 55%). LC-MS (ESI): m / z (M) + = 326.02, 328.33.

[0373] Preparation of 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide (Compound I-48) [ka]

[0374] Procedure B was followed, starting from 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (100 mg, 0.31 mmol) and 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)propan-1-one. In this case, the reaction mixture was stirred in a microwave at 80 °C for 1 h. Purification by preparative HPLC (C18, 40-100% MeCN in HO with 0.1% formic acid) gave 4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide as a white solid (18 mg, 13%). LC-MS (ESI): m / z (M+1) + = 422.23. 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.40 (m, 2H), 8.31 - 8.25 (m, J = 15.9 Hz, 1H), 8.21 - 8.13 (m, J = 8.3 Hz, 1H), 7.83 (s, 4H), 7.68 - 7.61 (m, J = 11.3, 3.2 Hz, 2H), 7.59 - 7.54 (m, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, J = 7.8, 4.8 Hz, 1H), 4.15 (t, J = 8.5 Hz, 2H), 4.07 (d, J = 3.5 Hz, 2H), 3.23 (t, J = 8.4 Hz, 3H), 2.50 - 2.46 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H).

[0375] Synthesis of 4-(1-propionylindolin-5-yl)-N-(pyridin-4-ylmethyl)benzamide (Compound I-49)

[0376] Preparation of methyl 4-(indolin-5-yl)benzoate [ka]

[0377] Following procedure E gave methyl 4-(indolin-5-yl)benzoate as a solid (1.5 g, 95%). LC-MS (ESI): m / z (M-56) + = 254.14.

[0378] Preparation of methyl 4-(1-propionylindolin-5-yl)benzoate [ka]

[0379] General procedure D was followed, starting with methyl 4-(indolin-5-yl)benzoate (4.8 g, 19.0 mmol) and propionic acid (1.7 g, 22.7 mmol). In this case, the reagents were added at 0° C. and the reaction mixture was allowed to warm to room temperature. Methyl 4-(1-propionylindolin-5-yl)benzoate was isolated as a solid (4.4 g, 75%). LC-MS (ESI): m / z (M+1) + = 310.14.

[0380] Preparation of 4-(1-propionylindolin-5-yl)benzoic acid [ka]

[0381] Following procedure C, methyl 4-(1-propionylindolin-5-yl)benzoate (1.8 g, 5.8 mmol) gave 4-(1-propionylindolin-5-yl)benzoic acid (Intermediate B) as a white solid (1.3 g, 76%). LC-MS (ESI): m / z (M+1) + = 296.09.

[0382] Preparation of 4-(1-propionylindolin-5-yl)-N-(pyridin-4-ylmethyl)benzamide (compound I-49) [ka]

[0383] Following general procedure D, starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and pyridin-4-ylmethanamine (44 mg, 0.41 mmol), 4-(1-propionylindolin-5-yl)-N-(pyridin-4-ylmethyl)benzamide was isolated as a white solid (70 mg, 53%). LC-MS (ESI): m / z (M+H) + = 386.22. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 6.0 Hz, 1H), 8.55 - 8.45 (m, J = 4.5, 1.6 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.02 - 7.93 (m, J = 8.5 Hz, 2H), 7.81 - 7.73 (m, J = 8.5 Hz, 2H), 7.64 (s, 1H), 7.60 - 7.54 (m, J = 8.4 Hz, 1H), 7.32 (d, J = 5.9 Hz, 2H), 4.52 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H).

[0384] Synthesis of 4-(1-propionylindolin-5-yl)-N-(pyrimidin-5-ylmethyl)benzamide (Compound I-51) [ka]

[0385] To a solution of pyrimidine-5-carbaldehyde (500 mg, 4.6 mmol) in MeOH (10 mL) at 0 °C, NaBH (262 mg, 6.9 mmol) was added in one portion. The mixture was stirred at room temperature for 4 h. It was then washed with brine and extracted with EA. The combined organic layers were washed with brine, dried over NaSO, and concentrated to give pyrimidin-5-ylmethanol as a white solid (456 mg, 89%). LC-MS (ESI): m / z (M+H) = 111.13.

[0386] To a solution of pyrimidin-5-ylmethanol (410 mg, 3.7 mmol) in THF (10 mL) at 0 °C, SOCl (1.33 g, 11.1 mmol) was added in one portion. The mixture was stirred at room temperature for 4 h. It was then quenched with NaCO, and the mixture was extracted with EA. The combined organic layers were washed with brine, dried over NaSO, and concentrated to give 5-(chloromethyl)pyrimidine as a white solid (456 mg, 95%). LC-MS (ESI): m / z (M+H) = 129.02 / 131.07.

[0387] To a solution of 5-(chloromethyl)pyrimidine (200 mg, 1.56 mmol) in THF was added NH₃·H₂O (4 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and purified by flash chromatography to give pyrimidin-5-ylmethanamine as a white solid (130 mg, 38%). LC-MS (ESI): m / z (M+H) = 110.13.

[0388] Following general procedure D, starting from 4-(1-propionylindolin-5-yl)benzoic acid (238 mg, 0.8 mmol) and pyrimidin-5-ylmethanamine (130 mg, 1.2 mmol), 4-(1-propionylindolin-5-yl)-N-(pyrimidin-5-ylmethyl)benzamide was isolated as a white solid (38 mg, 12%). LC-MS (ESI): m / z (M+H) = 387.24. 1 H NMR (400 MHz, DMSO-d6) δ 9.21-9.06 (m, 2H), 8.80 (s, 2H), 8.16 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 6.6 Hz, 2H), 7.76 (d, J = 6.4 Hz, 2H), 7.67-7.52(m, 2H), 4.61-4.48 (m, 2H), 4.19-4.06 (m, 2H), 3.28-3.14 (m, 2H), 2.50-2.39 (m, 2H), 1.13- 1.02 (m, 3H).

[0389] Synthesis of 4-(1-propionylindolin-5-yl)-N-(pyridazin-4-ylmethyl)benzamide (Compound I-52) [ka]

[0390] Following general procedure D, starting from 4-(1-propionylindolin-5-yl)benzoic acid (106 mg, 0.36 mmol) and pyridazin-4-ylmethanamine (50 mg, 0.33 mmol), 4-(1-propionylindolin-5-yl)-N-(pyridazin-4-ylmethyl)benzamide was isolated as a white solid (59 mg, 42%). LC-MS (ESI): m / z (M+H) + = 387.22. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 - 9.24 (m, 1H), 9.22 (s, 1H), 9.16 (dd, J = 5.3, 1.0 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.01 - 7.96 (m, 2H), 7.80 - 7.75 (m, 2H), 7.64 (s, 1H), 7.60 - 7.54 (m, 2H), 4.55 (d, J = 5.8 Hz, 2H), 4.13 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.3 Hz, 2H), 2.50 - 2.44 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).

[0391] Synthesis of 4-(1-propionylindolin-5-yl)-N-(1-(pyridin-3-yl)ethyl)benzamide (Compound I-57) [ka]

[0392] Following general procedure D and starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and 1-(pyridin-3-yl)ethan-1-amine (38 mg, 0.31 mmol), 4-(1-propionylindolin-5-yl)-N-(1-(pyridin-3-yl)ethyl)benzamide was isolated as a white solid (50 mg, 40%). LC-MS (ESI): m / z (M+H) + = 400.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 7.8 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 4.7, 1.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.83 - 7.78 (m, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 - 7.34 (m, 1H), 5.26 - 5.18 (m, 1H), 4.13 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.3Hz, 2H), 2.50 - 2.44 (m, 2H), 1.53 (d, J = 7.1 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H).

[0393] Synthesis of 4-(1-propionylindolin-5-yl)-N-(2-(pyridin-3-yl)propan-2-yl)benzamide (compound I-58) [ka]

[0394] Following general procedure D and starting from 4-(1-propionylindolin-5-yl)benzoic acid (80 mg, 0.271 mmol) and 2-(pyridin-3-yl)propan-2-amine (40 mg, 0.298 mmol), 4-(1-propionylindolin-5-yl)-N-(2-(pyridin-3-yl)propan-2-yl)benzamide was isolated as a white solid (63 mg, 56%). LC-MS (ESI): m / z (M+H) + = 414.32. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.2 Hz, 1H), 8.56 (s, 1H), 8.39 (dd, J = 4.7, 1.4 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.77 - 7.71(m, 3H), 7.62 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.33 - 7.29 (m, 1H), 4.13 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.5 Hz, 2H), 2.50 - 2.46 (m, 2H), 1.71 (s, 6H), 1.08 (t, J = 7.3 Hz, 3H).

[0395] Synthesis of N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (Compound I-59)

[0396] Preparation of (6-methylpyridin-3-yl)methanamine [ka]

[0397] Procedure H: To a mixture of 6-methylnicotinonitrile (300 mg, 2.54 mmol) in MeOH / NH (7N, 10 mL) was added Raney Ni (50 mg). The reaction mixture was stirred under H at room temperature for 3 hours. It was then filtered, and the filtrate was concentrated in vacuo to give 6-methylpyridin-3-yl)methanamine as a yellow oil (280 mg, 90%). LC-MS (ESI): m / z (M+1) + = 123.30.

[0398] Preparation of N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (compound I-59) [ka]

[0399] Following general procedure D and starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and (6-methylpyridin-3-yl)methanamine (50 mg, 0.41 mmol), N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide was isolated as a white solid (50 mg, 36%). LC-MS (ESI): m / z (M+H) + = 400.32. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (t, J = 5.8 Hz, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4Hz, 2H), 7.65 - 7.59 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 4.13 (t, J = 8.4 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 2.50 - 2.47(m, 2H), 2.44 (s, 3H), 1.07 (t, J = 7.3 Hz, 3H).

[0400] Synthesis of N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (Compound I-60)

[0401] Preparation of 2,6-dimethylnicotinonitrile [ka]

[0402] Procedure I: To a mixture of 3-bromo-2,6-dimethylpyridine (500 mg, 2.69 mmol) in DMF (5 mL) was added CuCN (480 mg, 5.38 mmol). The reaction mixture was stirred at 150 °C for 12 h. It was then diluted with DCM and washed with aqueous NH4Cl (85%) / NH3.H2O (15%), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (DCM / MeOH 10:1 (v / v)) to give 2,6-dimethylnicotinonitrile as a yellow solid (210 mg, 59%). LC-MS (ESI): m / z (M+1) + = 133.17.

[0403] Preparation of (2,6-dimethylpyridin-3-yl)methanamine [ka]

[0404] Following procedure H, 2,6-dimethylnicotinonitrile (100 mg, 0.176 mmol) gave (2,6-dimethylpyridin-3-yl)methanamine as a yellow oil (60 mg, 58%). LC-MS (ESI): m / z (M+1) + = 137.20.

[0405] Preparation of N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (Compound I-60) [ka]

[0406] Following general procedure D and starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and (2,6-dimethylpyridin-3-yl)methanamine (50 mg, 0.41 mmol), N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide was isolated as a white solid (41 mg, 29%). LC-MS (ESI): m / z (M+H) + = 414.32. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.5 Hz, 1H), 8.18 - 8.14 (m, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H),7.49 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 4.13 (t, J = 8.4 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 2.50 - 2.45 (m, 5H), 2.39 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H).

[0407] Synthesis of N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (Compound I-61)

[0408] Preparation of 2-methylnicotinonitrile [ka]

[0409] Following procedure I, 3-bromo-2-methylpyridine (500 mg, 2.9 mmol) gave 2-methylnicotinonitrile as a yellow solid (110 mg, 32%). LC-MS (ESI): m / z (M+1) + = 119.20.

[0410] Preparation of (2-methylpyridin-3-yl)methanamine [ka]

[0411] Following procedure H, 2-methylnicotinonitrile (100 mg, 0.85 mmol) gave (2-methylpyridin-3-yl)methanamine as a yellow solid (80 mg, 77%). LC-MS (ESI): m / z (M+1) + = 123.71.

[0412] Preparation of N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide (Compound I-61) [ka]

[0413] Following general procedure D and starting from 4-(1-propionylindolin-5-yl)benzoic acid (145 mg, 0.49 mmol) and (2-methylpyridin-3-yl)methanamine (60 mg, 0.49 mmol), N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindolin-5-yl)benzamide was obtained as a white solid (41 mg, 29%). LC-MS (ESI): m / z (M+H) + = 400.31. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 3.9 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H),7.65 - 7.52 (m, 3H), 7.20 (dd, J = 7.5, 4.9 Hz, 1H), 4.49 (d, J = 5.5 Hz, 2H), 4.13 (t, J = 8.4 Hz, 2H), 3.21 (t, J = 8.3 Hz, 3H), 2.53 (s, 3H), 2.48 (t, 2H), 1.08 (t, J = 7.2 Hz, 3H).

[0414] Synthesis of N-methyl-4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-62)

[0415] Preparation of N-(pyridin-3-ylmethyl)formamide [ka]

[0416] A mixture of pyridin-3-ylmethanamine (1.0 g, 9.2 mmol) in ethyl formate (10 mL) was stirred at 60° C. for 4 hours. It was then concentrated under reduced pressure to give N-(pyridin-3-ylmethyl)formamide as a colorless oil (1.0 g, 79%). LC-MS (ESI): m / z (M+1) + = 137.06.

[0417] Preparation of N-methyl-1-(pyridin-3-yl)methanamine [ka]

[0418] To a solution of N-(pyridin-3-ylmethyl)formamide (500 mg, 3.6 mmol) in THF (20 mL) was added BH3·MeS in THF (10 N, 3 mL). The reaction mixture was stirred at 60 °C for 4 h. It was then diluted with DCM and washed with aqueous NH4Cl and brine. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, 40-100% MeCN in HO with 0.1% formic acid) to give N-methyl-1-(pyridin-3-yl)methanamine as a yellow oil (600 mg, quantitative yield). LC-MS (ESI): m / z (M+H) + = 151.31.

[0419] Preparation of N-methyl-4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (compound I-62) [ka]

[0420] Following general procedure D, starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and N-methyl-1-(pyridin-3-yl)methanamine (62 mg, 0.41 mmol), N-methyl-4-(1-propionylindolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide was obtained as a yellow solid (36 mg, 26%). LC-MS (ESI): m / z (M+H) + = 400.31. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.68 (m, 2H), 8.44 - 8.25 (m, 1H), 8.18 - 8.13 (m, 1H), 7.92 - 7.81 (m, 1H), 7.72 (d, J = 7.2 Hz, 2H),7.66 - 7.47 (m, 4H), 4.89 - 4.71 (m, 2H), 4.13 (t, J = 8.2 Hz, 2H), 3.21 (t, J = 8.2 Hz, 2H), 2.99 (s, 3H), 2.49 - 2.45 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H).

[0421] Synthesis of N-(piperidin-3-ylmethyl)-4-(1-propionylindolin-5-yl)benzamide (compound I-63)

[0422] Preparation of piperidin-3-ylmethanamine [ka]

[0423] 4 To a solution of piperidine-3-carboxamide (500 mg, 3.9 mmol) in THF (20 mL) at 0 °C was added LiAlH (300 mg, 7.8 mmol). The reaction mixture was then stirred at 70 °C for 12 h. Water (0.3 mL) was added, followed by NaOH (10%, 0.3 mL). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give piperidin-3-ylmethanamine as a colorless oil (200 mg, 44%). LC-MS (ESI): m / z (M+H) + = 115.20.

[0424] Preparation of N-(piperidin-3-ylmethyl)-4-(1-propionylindolin-5-yl)benzamide (compound I-63) [ka]

[0425] Following general procedure D, starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and piperidin-3-ylmethanamine (43 mg, 0.38 mmol), N-(piperidin-3-ylmethyl)-4-(1-propionylindolin-5-yl)benzamide was isolated as a white solid (31 mg, 23%). LC-MS (ESI): m / z (M+H) + = 392.33. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 4.13 (t, J = 8.5 Hz,2H), 3.21 (t, J = 8.4 Hz, 2H), 3.12 (t, J = 6.3 Hz, 2H), 2.96 - 2.90 (m, 1H), 2.86 - 2.80 (m, 1H), 2.48 - 2.40 (m, 3H), 2.24 - 2.16 (m, 1H), 1.79 - 1.26 (m, 6H), 1.08 (t, J = 7.3 Hz, 3H).

[0426] Synthesis of 4-(1-propionylindolin-5-yl)-N-((1,2,3,6-tetrahydropyridin...

Claims

1. Compound: 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. (In the formula, 【Chemistry 2】 teeth 【Chemistry 3】 and R ａ Each instance of is independently hydrogen, substituted or unsubstituted C １－６ an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; q is 0; Each case of Y is CR ４ and R ４ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN, 【Chemistry 4】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and Bond b and bond c are meta or para to each other; R ５ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN, n is 0, 1, 2, 3, or 4, as permitted by valence, and when n is 1, 2, 3, or 4, R ５ There is no case where it is bonded to a nitrogen atom. Each R ６ are independently hydrogen, substituted or unsubstituted C １－６ is an alkyl or nitrogen protecting group, s is 1, R ７ is a substituted or unsubstituted pyridinyl, a substituted or unsubstituted pyrimidinyl, or a substituted or unsubstituted pyridazinyl; R ８ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN, each nitrogen protecting group is independently selected from benzyl (Bn), t-butyl carbamate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbamate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, and tosylate (Ts); and The oxygen protecting groups are each independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxylmethyl (MOM), tetrahydropyranyl (THP), tert-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, and benzoyl.

2. The compound has the formula 【Chemistry 5】 2. The compound of claim 1 ,

3. The compound has the formula 【Chemistry 6】 (In the formula, R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -ORa, -N(Ra) ２ or -CN.

4. The compound has the formula 【Chemistry 7】 2. The compound of claim 1, wherein each instance of R9 is independently hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -ORa, -N(Ra)2, or -CN.

5. R ４ A compound according to any one of claims 1 to 4, wherein each instance of is hydrogen; or

6. R ４ At least one instance of １－６ The compound according to any one of claims 1 to 4, which is alkyl. 【Request 7】 【Chemical 8】 The compound according to any one of claims 1 and 5-6, wherein is phenyl. 【Request 8】 【Chemistry 9】 The compound of any one of claims 1, 5, and 6, wherein is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

9. The compound according to any one of claims 1 and 5 to 8, wherein bond b and bond c are para to each other.

10. The compound of claim 1 , wherein bond b and bond c are meta to each other.

11. 【Catalog 10】 The compound according to any one of claims 1 to 7,

12. R ５ The compound of any one of claims 1 to 11, wherein each instance of is hydrogen.

13. R ５ At least one instance of １－６ Alkyl, or -OR ａ The compound according to any one of claims 1 to 11,

14. R ６ The compound according to any one of claims 1 and 4 to 13, wherein is hydrogen.

15. R ６ is a substituted or unsubstituted C １－６ The compound according to any one of claims 1 and 5 to 13, wherein said compound is alkyl.

16. R ７ The compound according to any one of claims 1 to 2 and 5 to 15, wherein is substituted or unsubstituted pyridazinyl.

17. R ７ The compound according to any one of claims 1 to 2 and 5 to 15, wherein is substituted or unsubstituted pyrimidinyl.

18. R ７ The compound according to any one of claims 1 to 2 and 5 to 15, wherein is substituted or unsubstituted pyridinyl.

19. R ７ The compound of any one of claims 1-2 and 5-15, wherein is substituted or unsubstituted 3-pyridinyl.

20. R ７ The compound of any one of claims 1-2 and 5-15, wherein is unsubstituted 3-pyridinyl.

21. R ７ but, 【Chemistry 11】 and R ９ is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN.

22. R ８ 22. The compound of any one of claims 1-3 and 5-21, wherein each instance of is hydrogen.

23. R ８ At least one instance of １－６ The compound according to any one of claims 1 to 3 and 5 to 21, which is alkyl.

24. R ９ 22. The compound of any one of claims 3-4 and 21, wherein each instance of is hydrogen.

25. R ９ At least one instance of １－６ Alkyl, or -OR ａ 22. The compound according to any one of claims 3 to 4 and 21,

26. The compound is a compound of the formula: 【Chemistry 12】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

27. The compound is a compound of the formula: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

28. A compound as defined in any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof; 13. A pharmaceutical composition comprising:

29. 30. The pharmaceutical composition of claim 28, further comprising a pharma- ceutically acceptable excipient.

30. 30. The pharmaceutical composition of claim 28 or 29, further comprising an additional pharmaceutical agent.

31. 31. The pharmaceutical composition of claim 30, wherein the additional pharmaceutical agent is a chemotherapeutic agent.

32. A pharmaceutical composition for treating cancer, the composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27.

33. (a) the cancer comprises cancer stem cells, and / or (b) Cancer (i) Gastric cancer (ii) gastric cancer subtype GS or gastric cancer subtype CIN (iii) Colorectal cancer (iv) colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4 (v) testicular cancer (vi) liver cancer (vii) Uterine cancer (viii) lymphoma (ix) non-Hodgkin's lymphoma (x) B-cell lymphoma, Burkitt's lymphoma, or large cell immunoblastic lymphoma (xi) large B-cell lymphoma (xii) Burkitt B-cell lymphoma (xiii) Leukemia (xiv) acute monocytic leukemia, acute lymphoblastic leukemia, or B-cell acute lymphoblastic leukemia. (xv) chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia (xvi) acute lymphoblastic leukemia (xvii) B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia (xviii) multiple myeloma, or (xix) B-cell myeloma (xx) endometrial cancer, (xxi) gastrointestinal stromal tumor, (xxii) ovarian cancer, (xxiii) lung cancer; (xxiv) breast cancer, (xxv) pancreatic cancer, or (xxvi) prostate cancer 33. The pharmaceutical composition of claim 32, wherein

34. 28. A pharmaceutical composition for contacting a cell comprising a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

35. (a) the cells are characterized by one or more embryonic or pluripotent properties; (b) the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, or an adult stem cell; (c) the contacting reduces one or more embryonic characteristics of the cell; (d) the contacting is carried out in vitro or ex vivo; (e) the contacting reduces cell viability; and / or (f) the contacting kills the cell; 35. The pharmaceutical composition of claim 34.

36. 28. A pharmaceutical composition for killing a cell comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

37. (a) the cells are characterized by one or more embryonic or pluripotent properties; (b) the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, or an adult stem cell; (c) the contacting reduces one or more embryonic characteristics of the cell; (d) the contacting is carried out in vitro or ex vivo; 37. The pharmaceutical composition of claim 36.

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