Cancer treatment targeting cancer stem cell

Abstract

To provide a compound that forces differentiation of cancer stem cells and inhibits signaling pathways (the same pathways used by embryonic stem cells during differentiation and development) required for metastasis.SOLUTION: The disclosed compound is a compound of Formula (0), or pharmaceutically acceptable salts thereof, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 667,412, filed on May 4, 2018, and U.S. Provisional Patent Application No. 62 / 815,251, filed on Mar. 7, 2019, the entire contents of each of which are incorporated herein by reference.

Background Art

[0002] Cancer is prevalent everywhere and remains a leading cause of death worldwide despite medical advancements. In 2017, an estimated 1.7 million new cancer cases were diagnosed, and 600,000 people died from the disease. 1 Cancer is the second leading cause of death globally, 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. The total annual economic cost of cancer in 2010 was estimated to be approximately $1.16 trillion. 2

[0003] Cancer is a general term for a large group of diseases that can affect all parts of the body. Among others, the terms malignant tumor and neoplasm are also used. Cancer results from the transformation of normal cells into tumor cells in a multi-step process, generally progressing from pre-cancerous lesions to malignant tumors. One of the defining characteristics of cancer is the rapid creation of abnormal cells that grow beyond normal boundaries and can invade adjacent parts of the body and spread to other organs. The latter process is called metastasis. Metastasis is the main cause of death from cancer. The most common causes of death from cancer are cancers of the lung, liver, colorectal, stomach, and breast.

[0004] Some progress has been made in the treatment of subsets of cancer types, but the average cancer mortality rate remains extremely high, and little overall improvement is seen in the ongoing cancer crisis. Almost all current cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on tumor reduction and do not target cancer stem cells, the most dangerous cells within the tumor. 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 Since current treatment methods do not target cancer stem cell populations, they often lead to an increase in resistant tumors and continuous 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 an effective and non-toxic therapy can be achieved through a strategy called cancer containment therapy by targeting the embryonic properties of cancer stem cells, which are the factors that make cancer very dangerous, namely the basis for cancer growth, spread, and resistance. A therapy that can reduce the tumor mass and destroy cancer stem cells will revolutionize cancer treatment. 7

[0006] Described herein are compounds that force the differentiation of cancer stem cells and inhibit the 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, so they 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. Also, since the reactivation of embryonic properties is a characteristic common to many types of tumors, cancer containment therapy is expected to be effective against many different types of cancer, including colon, stomach, prostate, testicular, and breast cancer.

[0008] Compounds, methods, compositions, uses, and kits for treating proliferative disorders, benign neoplasms, and cancer are disclosed herein.

[0009] In one aspect, the compounds of the present disclosure are compounds of formula (0):

Chemical formula

[0010] In one aspect, the compounds of the present disclosure are compounds of formula (0'):

Chemical formula

[0011] In one aspect, the compounds of the present disclosure are compounds of formula (I): [Chem.] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof (the variables described in formula (I) are as described herein). In another aspect, the present disclosure provides a method for treating cancer, the method 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, isotope-labeled derivative, or prodrug thereof (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 present disclosure provides a method comprising contacting a cell with an effective amount of a compound of formula (0) or (0’), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

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

[0015] In certain embodiments, the compound of formula (I) is a compound of formula (I-A):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[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, 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.

[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, cocrystal, 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0019] In a further embodiment, the present disclosure provides a kit 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] Details of certain embodiments of the invention are set forth in the detailed description, which follows, of the mode(s) for carrying out the invention. Other features, objects, and advantages of the invention will be apparent from the definition, drawings, examples, and claims.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

[0022] Definitions For the sake of convenience, certain terms used in this specification, the examples, and the appended claims are summarized herein.

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

[0024] The phrases "in some embodiments" and "in certain embodiments" are used interchangeably.

[0025] The following definitions apply to the more general terms used throughout this application.

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

[0027] Except as otherwise indicated in the examples or elsewhere, all numbers expressing amounts of ingredients or reaction conditions used in this specification are to be understood as being modified in all instances by the term "about." "About" and "approximately" generally mean an acceptable degree of error for the measured quantity, taking into account the nature and precision of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%, 4%, 3%, 2%, or 1%.

[0028] The definitions of specific functional groups and chemical terms are further described below. Chemical elements are those of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thIdentified according to Ed. (front and back cover), specific functional groups are generally defined as described in the literature. Further, for general principles of organic chemistry and specific functional moieties and reactivity, see Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March 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 can contain one or more asymmetric centers and, accordingly, can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can take the form of individual enantiomers, diastereomers, or geometric isomers, or can take the form of mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from the 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 the 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, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. 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 the compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0030] In the formula,

Chem.

Chem.

Chem.

[0031] Unless otherwise specified, the formulas shown in this specification include compounds that do not contain atoms enriched in isotopes, and also include compounds that contain atoms enriched in isotopes. Compounds that contain atoms enriched in isotopes can be useful, for example, as analytical tools and / or as probes for 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, the aliphatic group is optionally substituted with one or more functional groups (e.g., halo such as fluorine). As will be understood by those skilled in the art, "aliphatic" is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0033] When a range of values ("range") is recited, this is intended to include each value and sub-range within the range. The range includes the values at both ends of the range unless otherwise indicated. For example, "integers between 1 and 4" means 1, 2, 3, and 4. For example, "C 1-6 alkyl" is intended to include 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.

[0034] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20means "alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 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-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, for example, unsubstituted ( "unsubstituted alkyl") or substituted with one or more substituents ( "substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-12 alkyl (e.g., -CH3 (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 iso-butyl (i-Bu)). In certain embodiments, the alkyl group is substituted C 1-12 alkyl (e.g., substituted C 1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)). The point of attachment of the alkyl can be a single bond (e.g., like -CH3), a double bond (e.g., like =CH2), or a triple bond (e.g., like ≡CH). Moieties such as =CH2 and ≡CH are also alkyls.

[0035] In some embodiments, the alkyl group is substituted with one or more halogens. "Perhaloalkyl" is a substituted alkyl group as defined herein in which all hydrogen atoms are independently substituted by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ( "C 1-8"perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 6 carbon atoms ("C 1-6 "perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 4 carbon atoms ("C 1-4 "perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 3 carbon atoms ("C 1-3 "perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 2 carbon atoms ("C 1-2 "perhaloalkyl"). In some embodiments, all hydrogen atoms are substituted with fluoro. In some embodiments, all hydrogen atoms are substituted with chloro. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0036] "Alkenyl" means a 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 as permitted by valence) carbon-carbon double bonds and no triple bonds ("C 2-20 "alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 "alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 "alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 "alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 "alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 "alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 "alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4"(alkenyl)". In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl)". In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may 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. C 2-6 Examples of alkenyl groups include the aforementioned C 2-4 In addition to the alkenyl group, pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like can be mentioned. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each instance of the alkenyl group is independently optionally substituted, for example, unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2-10 alkenyl. In the alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.,

Chemical formula

[0037] "Alkynyl" means a 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 as valence permits) carbon-carbon triple bonds, optionally having one or more double bonds ("C 2-20 alkynyl)". In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2-10(alkynyl). In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, the alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C2 alkynyl”). One or more carbon-carbon triple bonds may 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. C 2-6 Examples of alkenyl groups include, in addition to the aforementioned C 2-4 alkynyl groups, 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 (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In certain embodiments, the alkynyl group is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2-10 alkynyl.

[0038] "Carbocyclic" or "carbocyclic ring" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 13 ring carbon atoms ("C 3-13 arbocyclic"), meaning a radical having no heteroatoms within the non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 arbocyclic"). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms ("C 3-7 arbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 arbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 arbocyclic"). Exemplary C 3-6 arbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 arbocyclic groups include, in addition to the aforementioned C 3-6 arbocyclic groups, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 arbocyclic groups include, in addition to the aforementioned C 3-8 arbocyclic groups, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10) and the like. As shown in the above examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or includes a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclic")). The carbocyclic may be saturated, and a saturated carbocyclic is referred to as "cycloalkyl". In some embodiments, the carbocyclic is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C 3-6 cycloalkyl groups include, in addition to the aforementioned C 5-6 alkyl groups, cyclopropyl (C3) and cyclobutyl (C4). Examples of C 3-8 cycloalkyl groups include, in addition to the aforementioned C 3-6 cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of the cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3-10It is cycloalkyl. The carbocyclic ring may be partially unsaturated. The carbocyclic ring can contain zero, one, or more (e.g., two, three, or four as valence permits) C═C double bonds in all rings of a carbocyclic ring system that is neither aromatic nor heteroaromatic. A carbocyclic ring containing one or more (e.g., two or three as valence permits) C═C double bonds in the carbocyclic ring is referred to as a "cycloalkenyl". A carbocyclic ring containing one or more (e.g., two or three as valence permits) C≡C triple bonds in the carbocyclic ring is referred to as a "cycloalkynyl". The carbocyclic ring contains aryl. Also, "carbocyclic ring" includes a ring system in which the carbocyclic ring defined above is fused with one or more aryl or heteroaryl groups having a bonding point on the carbocyclic ring. In such a case, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclic ring system. Unless otherwise specified, each instance of the carbocyclic ring group is independently optionally substituted, e.g., unsubstituted ("unsubstituted carbocyclic ring") or substituted with one or more substituents ("substituted carbocyclic ring"). In certain embodiments, the carbocyclic ring group is unsubstituted C 3-10 is a carbocyclic ring. In certain embodiments, the carbocyclic ring group is substituted C 3-10 is a carbocyclic ring. In certain embodiments, the carbocyclic ring is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, the carbocyclic ring is substituted or unsubstituted, 5- to 13-membered, and bicyclic.

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

[0040] "Heterocyclyl" or "heterocyclic" means a 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"). In the case of a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or can be any of fused, bridged, or spiro ring systems (e.g., bicyclic system ("bicyclic heterocyclyl")). The heterocyclic group can be saturated or partially unsaturated. Heterocyclyl can contain zero, 1, or more (e.g., 2, 3, or 4 as valence permits) double bonds in all rings of a heterocyclic ring system that is neither aromatic nor heteroaromatic. Partially unsaturated heterocyclyl groups include heteroaryl. The bicyclic heterocyclyl ring system can contain one or more heteroatoms in one or both rings. Also, "heterocyclyl" includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclic groups having a point of attachment either on the carbocyclic ring or on the heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups having a point of attachment on the heterocyclyl ring. In such cases, the ring member count continues to indicate the ring member count within 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, heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.

[0041] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 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 pyrrol-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" means a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided by an aromatic ring system (e.g., a ring system having 6, 10, or 14 π electrons shared in a cyclic arrangement) (「C 6-14 aryl」). In some embodiments, the aryl group has 6 ring carbon atoms (「C6 aryl」, e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (「C 10 aryl」, e.g., naphthyl (e.g., 1-naphthyl and 2-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms (「C 14 aryl」, e.g., anthracyl). Also, "aryl" includes ring systems in which the aryl ring defined above is fused with one or more carbocyclic or heterocyclic groups having a radical or a point of attachment 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 the aryl group is independently optionally substituted, e.g., unsubstituted (「unsubstituted aryl」) or substituted with one or more substituents (「substituted aryl」). In certain embodiments, the aryl group is unsubstituted C 6-14 aryl. In certain embodiments, the aryl group is substituted C 6-14 aryl.

[0044] "Heteroaryl" means 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) provided by an aromatic ring system and having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom being independently selected from nitrogen, oxygen, and sulfur) ("5- to 10-membered heteroaryl"). In the case of a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as the valence permits. The bicyclic heteroaryl ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocyclic or heterocyclic groups having a point of attachment on the heteroaryl ring, and in such cases, the ring member count continues to indicate the ring member count within the heteroaryl ring system. Also, "heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups having a point of attachment on either the aryl ring or the heteroaryl ring, and in such cases, the ring member count continues to indicate the ring member count within the fused (aryl / heteroaryl) ring system. The point of attachment of a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) is on either ring, e.g., on the ring having a heteroatom (e.g., 2-indolyl)) or on the ring not containing a heteroatom (e.g., 5-indolyl).

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

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

[0048] In some embodiments, the aliphatic, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). Generally, the term "substituted" means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom), whether or not preceded by the term "optionally", is replaced with an acceptable substituent, e.g., a substituent that results in a stable compound (e.g., a compound that is not spontaneously converted by rearrangement, cyclization, elimination, or other reactions) when substituted. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when a plurality of positions in any given structure are substituted, the substituents at each position are the same or different. Unless otherwise specified, a substituent on a polycyclic ring may be at any substitutable position of any monocyclic ring in the polycyclic ring. The term "substituted" is intended to include substitution by any of the substituents described herein that results in substitution by substituents of all acceptable organic compounds and formation of a stable compound. The present disclosure contemplates any such combinations to reach a stable compound. For the purposes of the present disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results 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, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclic, 3 - 14 membered heterocyclic, C 6-14Aryl, and 5- to 14-membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 R dd groups, and X - is a counterion), or two geminal hydrogens on a carbon atom are replaced by =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 , Each instance of R aa is independently 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 R dd groups), Each instance of R bb 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and X - is a counterion), R cc in each case 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14Selected from 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, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups). R dd in each case is independently 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, HeteroC 1-6 Alkyl, HeteroC 2-6 Alkenyl, HeteroC 2-6 Alkynyl, C 3-10 Carbocyclic, 3 - 10 membered heterocyclic, C 6-10 Aryl, 5 - 10 membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents are linked to form =O or =S, and X - is a counterion), selected from R ee in each case is independently, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, HeteroC 1-6 Alkyl, HeteroC 2-6 Alkenyl, HeteroC 2-6 Alkynyl, C 3-10 Carbocyclic, C 6-10Aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups) are selected from, R ff in each instance 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 carbocyclic, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl are selected from, or two R ff groups are linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups), R gg in each instance is independently 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 1-6(alkyl), -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 1-6(alkyl), 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, heteroC 1-6 (alkyl, heteroC 2-6 (alkenyl, heteroC 2-6 (alkynyl, C 3-10 (carbocyclic, C 6-10 (aryl, 3 - to 10 - membered heterocyclyl, 5 - to 10 - membered heteroaryl, or two geminal R gg (substituents may be linked to form =O or =S (wherein X - (is a 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 bb) It is 2. 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 bb )2, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. 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, wherein R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when bonded to a sulfur atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.

[0051] As used herein, "counterion" or "anionic counterion" refers to a negatively charged group that associates with a positively charged group to maintain electrical neutrality. The anionic counterion may be monovalent (i.e., including one formal negative charge). Also, the anionic counterion may be polyvalent (i.e., including a plurality of formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - 、Cl - 、Br - 、I - ), NO3 - 、ClO4 - 、OH - 、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 a carborane anion (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - ) are included. Exemplary counterions that can be polyvalent include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylic acid 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 ions, etc.), and carboranes are included.

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

[0053] The nitrogen atom may be substituted or unsubstituted as long as its valence permits, and primary, secondary, tertiary, and quaternary nitrogen atoms are included. 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl are included, or two R cc groups bonded to the N atom are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and at this time, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd are 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 1-6An alkyl, or when attached to an oxygen atom, an oxygen protecting group, each R bb is independently hydrogen, a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl or a 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). Examples of 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and Rdd is as defined herein. Nitrogen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (which is hereby incorporated by reference herein).

[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'-dithiobenzyl-oxyacylamino)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)fluorenylmethyl 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-trimethylsilylethyl 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-Bumeoc), 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-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, 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)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acetyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 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-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,Examples include 6-trimethylbenzylcarbamate.,

[0058] Sulfonamide nitrogen protecting groups (e.g., -S(=O)2R 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, N-1,1,4,4-tetramethyldisilazacyclopentane adduct (STABASE), 5-substituted 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)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberlylamine, 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-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-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 derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (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 an oxygen protecting group when attached to an oxygen atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 is an alkyl or a nitrogen 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 is an alkyl or an 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"). Examples of 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, where X - , R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd rd edition, John Wiley & Sons, 1999 (which is incorporated herein by reference).

[0063] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyl oxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 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-trichloroethyl, 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), dimethyltexylsilyl, 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, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkylethyl 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-formylbenzenesulfonate, 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, (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 an oxygen protecting group when attached to an oxygen atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen 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 or a 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"). Examples of 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 are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd rd edition, John Wiley & Sons, 1999 (which is hereby incorporated by reference). In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

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

[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] When the suffix “ene” is attached to a group, it indicates that the group is a polyvalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In certain embodiments, when the suffix “ene” is attached to a group, it indicates that the group is a divalent moiety.

[0070] The term “hydroxyl” or “hydroxy” means an -OH group.

[0071] The term “thiol” or “thio” means an -SH group.

[0072] The term “amine” or “amino” means an -NH- group or -NH2.

[0073] The term “acyl” has the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-O-C(=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, where 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, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or dialiphatic amino, mono- or diheteroaliphatic amino, mono- or dialkylamino, mono- or diheteroalkylamino, mono- or diarylamino, or mono- or diheteroarylamino, or two Rs X1The bases combine to form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehyde (-CHO), carboxylic acid (-CO2H), ketone, acyl halide, ester, amide, imine, carbonate, carbamate, and urea. Acyl substituents include, but are not limited to, those that result in the formation of stable moieties (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc. (each of which may or may not be further substituted)) as described herein.

[0074] The term "salt" means an ionic compound resulting from the neutralization reaction of an acid and a base. Since a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), a salt is electrically neutral (has no net charge). The 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 by 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-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Examples of the (alkyl)4 salts include salts of alkali metals or alkaline earth metals. Representative examples of the salts of alkali metals or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and the like. Further examples of the salts include ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acid ions).

[0075] The term "pharmaceutically acceptable salt" means a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference) describe pharmaceutically acceptable salts in detail. 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 by 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl)4 -Salts are included. Representative salts of alkali metals or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acid ions).

[0076] The term "solvent" means a substance that dissolves one or more solutes to yield a solution. The solvent can function as a medium for any reaction or transformation described herein. The solvent can dissolve one or more reactants or reagents into the reaction mixture. The solvent can facilitate the mixing of one or more reagents or reactants in the reaction mixture. Also, the solvent can function to increase or decrease the reaction rate compared to the reaction in different solvents. The 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, 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" usually means a compound or its salt form that associates with a solvent through solvolysis reaction. 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 can be prepared, for example, in crystalline form and can also be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both the solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0078] The term "hydrate" means a compound that associates with water. Typically, the number of water molecules contained in a hydrate of a compound takes a certain ratio to the number of compound molecules in the hydrate. Therefore, 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, for example, monohydrate (x is 1), low hydrate (x is greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)), and polyhydrate (x is greater than 1, for example, dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0079] The term "polymorph" means the crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stabilities, and solubilities. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may be dominant. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0080] The term "cocrystal" means 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, none of the components are a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound of formula (I) and an acid is different from a salt formed from the compound of formula (I) and the acid. Cocrystals can be useful in improving the properties of the compound of formula (I) (e.g., solubility, stability, and ease of formulation).

[0081] Furthermore, the term "cocrystal" means 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, none of the components are a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound of formula (0) or (0') and an acid is different from a salt formed from the compound of formula (0) or (0') and the acid. Cocrystals can be useful in improving the properties of the compound of formula (0) or (0') (e.g., solubility, stability, and ease of formulation).

[0082] The term "tautomer" or "tautomerism" means two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, from 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 that results in a tautomeric pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include the tautomerization from keto to enol, from amide to imide, from lactam to lactim, from enamine to imine, and from enamine to (a different enamine).

[0083] It should also be understood that compounds having the same molecular formula but different in the nature of atoms or bond order, or in the spatial arrangement of atoms, are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers". In certain embodiments, when a phenyl group contains two substituents each bonded to adjacent carbons, this compound can be called an ortho isomer. In certain embodiments, when a phenyl group contains two substituents each bonded to carbons separated by one ring carbon, this compound can be called a meta isomer. In certain embodiments, when a phenyl group contains two substituents each bonded to carbons separated by two ring carbons, this compound can be called a para isomer.

[0084] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". For example, when a compound has an asymmetric center, e.g., is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the Cahn and Prelog R- and S-rules, or by the way the molecule rotates the plane of polarization, 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" means a molecule, group of molecules, complex, or substance that is administered to a living being for purposes of diagnosis, therapy, prophylactic medicine, or veterinary medicine. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent). In certain embodiments, the compositions disclosed herein comprise an agent(s), e.g., a first therapeutic agent (e.g., at least one (e.g., including at least two, at least three)). In some embodiments, the composition can further comprise 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 a biological system to which it is applied. For example, a therapeutic agent can, among other functions, control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and act to enhance bone growth. 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 to a biologically active agent in the subject by metabolism or some other mechanism.

[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 in accordance with the provisions of the Code of Federal Regulations (CFR)); targeted agents; isotope-labeled chemical compounds; agents useful for 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, etc.; animal tissues; natural or synthetic compositions; and any combination thereof are included.

[0088] In some embodiments, the agent takes the form of a prodrug. The term "prodrug" means, for example, a compound that becomes active, for example in vivo, to provide a pharmaceutically active compound by solvolysis, reduction, oxidation, or under physiological conditions. Prodrugs include derivatives of pharmaceutically active compounds, for example, esters can be formed by reaction of an acid, or acid anhydride, or mixed anhydride moiety of the prodrug moiety with a hydroxyl moiety of the pharmaceutically active compound, or amides prepared by an acid, or acid anhydride, or mixed anhydride moiety of the prodrug moiety and a substituted or unsubstituted amine of the pharmaceutically active compound can be formed. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups can include 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 mean 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 having a molecular weight of less than 5000 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 the small molecule is 700 Daltons or less.

[0090] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those described in Harrison’s Principles of Internal Medicine, 13th Edition, Eds. T.R. Harrison et al., McGraw-Hill N.Y., 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, and the entire contents of all of these documents 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. Patent No. 9,381,253 (incorporated herein by reference).

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

[0093] Agents, such as therapeutic agents, include the categories and specific examples disclosed herein. This category is not intended to be limited by the specific examples. One of ordinary skill in the art will recognize many other compounds that fall within the scope of this category and are useful in accordance with this disclosure.

[0094] Examples of therapeutic agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, counterirritants, coagulation modifiers, diuretics, sympathomimetic agents, anorectics, antacids and other gastrointestinal agents, anthelmintics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormonal agents, central and respiratory stimulants, drug antagonists, lipid regulators, uricosuric agents, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, soporifics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, parasympathomimetic agents, anticonvulsants, antihistamines, beta blockers, cathartics, antiarrhythmics, contrast agents, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antiviral agents, and antineoplastic or cytostatic or other anti-cancer agents, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Still other examples include anti-infective agents, such as antibiotics and antiviral agents; analgesics and combinations of analgesics; anorectics; anthelmintics; anti-arthritis agents; anti-asthma agents; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine formulations; antiemetics; antineoplastic agents; anti-Parkinson's disease agents; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetic agents; xanthine derivatives; cardiovascular formulations (including calcium channel blockers and beta blockers (e.g., pindolol and antiarrhythmics)); antihypertensives; diuretics; vasodilators (including general coronary, peripheral, and cerebral blood vessels); central nervous system stimulants; cough and cold formulations (including expectorants); hormones, such as estradiol and other steroids (including corticosteroids); soporifics; immunosuppressants; muscle relaxants; parasympathetic blockers; psychostimulants; sedatives; and psychotropics; as well as proteins, polysaccharides, glycoproteins, or lipoproteins of natural origin or genetically engineered.

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

[0096] The "subject" for which administration is contemplated means a human (i.e., a male or female of any age group, 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 monkey 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 can be male or female at any stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal.

[0097] The terms "administer", "administering", or "administration" mean introducing the compounds or compositions thereof described herein into a subject or onto a subject by implantation, absorption, ingestion, injection, inhalation, or other means.

[0098] The terms "treat", "treating", and "treatment" mean effecting recovery, alleviation, delay in the onset, or inhibition of progression of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have occurred or been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject before the onset of symptoms (e.g., based on the subject's treatment history). Also, treatment can continue after the symptoms have resolved to delay and / or prevent recurrence of the disease or disorder.

[0099] The terms "prevent", "preventing", or "prevention" mean prophylactic treatment of a subject who does not currently have and has never had a disease but is at risk of developing the disease, or a subject who has had the disease in the past and does not currently have it but is at risk of the disease recurring. In certain embodiments, the subject has a higher risk of developing the disease or the disease recurring than the average healthy member of the population of subjects.

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

[0101] "Proliferative disease" means 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) the pathological proliferation of cells that are normally quiescent; 2) the pathological movement of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the 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 neoplasm"), benign neoplasm, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

[0102] The terms "neoplasm" and "tumor" are used interchangeably herein and mean an abnormal mass of tissue that grows beyond and is uncoordinated with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A "benign neoplasm" is generally well-differentiated, characteristically grows more slowly than a malignant neoplasm, and remains localized to its site of origin. In addition, a benign tumor does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile angioma, seborrheic keratosis, nevus, and sebaceous hyperplasia. In some cases, a particular "benign" tumor may later give rise to a malignant neoplasm. This can result from additional genetic changes in a subpopulation of the neoplastic cells of the tumor, and such tumors are referred to as "premalignant neoplasms". An exemplary premalignant neoplasm is dysplasia. In contrast, a "malignant neoplasm" is generally poorly differentiated (anaplastic), characteristically grows rapidly, and is associated with progressive invasion, infiltration, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the ability to metastasize to distant sites. The terms "metastasis", "metastatic", or "metastasize" mean that cancer cells spread or move from the primary tumor or original tumor to another organ or tissue, and are typically distinguishable by the presence of a "secondary tumor" or "secondary mass" of the tissue type of the primary tumor or original tumor, rather than the organ or tissue where the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to the bone is considered metastatic prostate cancer and includes cancerous prostate cancer cells that grow within the bone tissue.

[0103] The term "cancer" means 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 cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., adenocarcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; epithelioma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett 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 cancer; head and neck cancer (e.g., squamous cell carcinoma of the head and neck, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic system cancer (e.g., leukemia, e.g., acute lymphoblastic 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 lymphoma (HL) (e.g., B-cell HL, T-cell HL), and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large B-cell lymphoma (DLBCL) (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, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (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); mixtures of one or more of the above leukemias / lymphomas; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocytic 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), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); rhabdomyosarcoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine carcinoma (e.g., gastroenteropancreatic endocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian fetal cancer, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; tumor associated syndrome; intraepithelial neoplasm; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small intestine cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, testicular fetal cancer); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid cancer (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).;

[0104] Cancer cells exhibit characteristics similar to those of embryonic stem cells. As used herein, cancer stem cell (CSC) refers to an embryoid cancer cell having one or more embryonic features. CSCs are generally regarded as problematic cancer cells because of their ability to metastasize to other sites in the body and form tumors. As used herein, "embryonic features" means gene and / or miRNA expression and / or biological characteristics similar to those of embryonic cells. Undifferentiated cancer cells having embryonic characteristics have the ability to metastasize, are resistant to chemotherapy and radiation therapy, and have the ability to regrow tumors after surgery and / or additional cancer therapeutic treatments have removed or reduced most of the tumor.;

[0105] In some embodiments, cancer stem cells are characterized by the expression of genes and / or miRNAs associated with an embryonic state. In 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 features. Examples of embryonic features include, but are not limited to, cell self-renewal properties, hyperproliferative activity, multipotency, pluripotency, expression of embryonic markers, absence of differentiation markers, resistance to chemotherapy, motility, and the ability to give rise to different cell lineages.

[0107] As used herein, the terms "regenerative medicine" or "regenerative therapy" mean promoting the regenerative capacity of cells, tissues, and / or organs. Regenerative medicine includes 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 cells, tissues, and / or organs that are dysfunctional or abnormal, as well as the manipulation of tissues and the regeneration of organs. As used herein, "regenerative capacity" means converting cells such as stem cells into progenitor cells or differentiated tissue-specific cells. Regenerative capacity can additionally or alternatively mean the ability of cells, tissues, and / or organs to replicate, proliferate, recover function, and / or regenerate.

[0108] An "effective amount" of a composition described herein means an amount sufficient to induce 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 status 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] The "therapeutically effective amount" of the compositions 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 the condition. The therapeutically effective amount of a composition means the 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 include an amount that improves the overall therapy, reduces or avoids symptoms, signs, or conditions, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0110] The "preventively effective amount" of the compounds described herein is an amount sufficient to prevent a condition or one or more symptoms associated with the condition or to prevent its recurrence. The preventively effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of a condition. The term "preventively effective amount" can include an amount that improves the overall prevention or enhances the preventive effectiveness of another preventive agent.

[0111] The term "gene" means 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 before and after the coding sequence. A "native gene" means a gene found in nature with its own regulatory sequences. A "chimeric gene" or "chimeric construct" means any gene or construct that is not a native gene and includes regulatory and coding sequences that are not found together in nature. Thus, a chimeric gene or chimeric construct can include regulatory and coding sequences from different sources, or regulatory and coding sequences from the same source but arranged in a manner different from that found in nature. An "endogenous gene" means a native gene in its natural position within an organism's genome. A "foreign" gene means a gene that is not normally found within a host organism but is introduced into the host organism by genetic transformation. 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 the 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 bonded within the strand. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two strands of polynucleotides, each strand taking a helical form. RNA is more frequently found in nature as a single strand folded upon 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 way by the above exemplary list of substituents. Additional terms may be defined in other sections of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

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

[0115] The compounds of the present disclosure, as well as their compositions and kits, are useful for the treatment of cancer and 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 in various different types of cancer as a whole. 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 Also, embryonic-like characteristics have been found in cancer stem cells from hematopoietic cancers (e.g., leukemia and lymphoma). 14

[0116] Compound In certain aspects, the present disclosure provides compounds of formula (0) and (0’).

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

[0118] In certain embodiments, the compound is a compound of formula (0): [Chemical formula] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-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 when L 1 is a single bond, R 1-6 is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, when L 1 is -C(=O)-, R 1-6 is substituted C 2-6 alkyl (the substituent contains at least one double bond, triple bond, or heteroatom), substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C R 2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6An alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic ring, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic ring, a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group, R 3 is hydrogen, a halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, R a in each case is independently hydrogen, a substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or, R 2 and R 3 are linked with the intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclic ring or heteroaryl, q is 0 or 1, each case of Y is independently N or CR 4 , R 4 in each case is independently hydrogen, a halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0119] In certain embodiments, the compound of formula (0’) is a compound of the following formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0120] In certain embodiments, the compound is a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof, wherein L 1 is a single bond or -C(=O)-, L 1 when L is a single bond, R 1 is 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, L 1 when L is -C(=O)-, R 1 is substituted C 1-6 alkyl containing 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, 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 or a nitrogen protecting group, R 3 is halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, R a in each case is independently hydrogen, substituted or unsubstituted C 1-6an alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or R 2 and R 3 are linked with the intervening atoms thereof to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl, each instance of Y is independently N or CR 4 and each instance of R 4 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN,

Chemical formula

Chemical formula

[0121] In certain embodiments, L 1 is a single bond or -C(=O)-, L 1 When L is a single bond, R 1 is a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic ring, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic ring, or a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, L 1 When L is -C(=O)-, R 1 is a substituted C 1-6 alkyl containing at least one double bond, triple bond, or heteroatom, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, and R 2 is hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group, and R 3 is halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, and R a in each case is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or alternatively, R 2 and R 3 are linked with the intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclic or heteroaryl, and in each case Y is independently N or CR 4 , and R 4 in each case is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, and

Chemical formula

[0122] In certain embodiments, the compound is a compound of formula (I):

Chemical formula

[0123] In certain embodiments, formula (I) is formula (I-A): [Chemical formula] [Chemical formula] [Chemical formula] is as follows.

[0124] In certain embodiments, formula (I) is of the formula: [Chemical formula] [Chemical formula] is as follows.

[0125] In certain embodiments, formula (I) is of the formula (I-B): [Chemical formula] wherein R 7 is substituted or unsubstituted 3-pyridinyl.

[0126] In certain embodiments, formula (I) is of the formula (I-C): [Chemical formula] is as follows, wherein [Chemical formula] is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, formula (I) is of the formula (I-C), wherein [Chemical formula] is imidazolyl or oxazolyl. In certain embodiments, formula (I) is formula (I-C), wherein,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0127] In certain embodiments, the compound of formula (I) is a compound of formula (I-C):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0128] In certain embodiments, formula (I) is formula (I-D):

Chemical formula

[0129] In certain embodiments, formula (I) is the formula:

Chemical formula

[0130] In certain embodiments, formula (I) is the formula:

Chemical formula

[0131] In certain embodiments, formula (I) is the formula:

Chemical formula

Chemical formula

[0132] In certain embodiments, formula (I) is formula (I-1A):

Chemical formula

[0133] In certain embodiments, formula (I) is formula (I-1B):

Chemical formula

[0134] In certain embodiments, formula (I) is formula (I-1C):

Chemical formula

Chemical formula

Chemical formula

Chem.

[0135] In certain embodiments, formula (I) is formula (I-1C):

Chem.

Chem.

[0136] In certain embodiments, formula (I) is formula (I-1D):

Chem.

[0137] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[0138] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[0139] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[0140] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[0141] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[0142] In certain embodiments, formula (I) is the formula:

Chem.

Chem.

[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) is of the formula:

Chemical formula

[0145] In some embodiments, L A is -N(R 2 )(L 1 R 1 ) In certain embodiments, the compound of formula (0) is of the formula:

Chemical formula

Chemical formula

Chemical formula

[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 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. In certain embodiments, R 1 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C1 alkyl. In certain embodiments, R 1 is unsubstituted C2 alkyl. In certain embodiments, R 1 is unsubstituted C3 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 C6 alkyl. In certain embodiments, R 1 is substituted C 1-6 alkyl. In certain embodiments, R 1 is substituted C1 alkyl. In certain embodiments, R 1 is substituted C2 alkyl. In certain embodiments, R 1 is substituted C3 alkyl. In certain embodiments, R 1 is substituted C4 alkyl. In certain embodiments, R 1is a substituted C5 alkyl. In certain embodiments, R 1 is a substituted C6 alkyl. In certain embodiments, R 1 is fluorinated C 1-6 alkyl (e.g., -CF3). In certain embodiments, R 1 is a substituted or unsubstituted C 2-6 alkenyl. In certain embodiments, R 1 is a substituted or unsubstituted C 2-6 alkenyl. In certain embodiments, R 1 is a substituted or unsubstituted C 2-6 alkynyl. In certain embodiments, R 1 is a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic ring. In certain embodiments, R 1 is a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic ring. In certain embodiments, R 1 is a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl.

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

[0149] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is not hydrogen. In certain embodiments, R 2 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted C 1-6 alkyl. 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 -CF3). In certain embodiments, R 2 is a nitrogen protecting group.

[0150] In certain embodiments, R 2 is substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl. In certain embodiments, R 2 is substituted or unsubstituted 3- to 5-membered monocyclic carbocyclyl. In certain embodiments, R 2 is substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl. In certain embodiments, R 2 is substituted or unsubstituted 3- to 5-membered monocyclic heterocyclyl. In certain embodiments, R 2 is substituted or unsubstituted phenyl. In certain embodiments, R 2 is 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 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 substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). 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., -CF3). In certain embodiments, R 3 is -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 is -N(R a )2. In certain embodiments, R 3 is -NH2. In certain embodiments, R 3 is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6is -NHMe). In certain embodiments, R 3 is -N(substituted or unsubstituted C 1-6 alkyl)2, e.g., -N(Me)2). In certain embodiments, R 3 is -CN.

[0153] In certain embodiments, each instance of R a 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. In certain embodiments, each instance of R a is hydrogen. In certain embodiments, there is no instance where R a is hydrogen. In certain embodiments, at least one instance of R a is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, at least one instance of R a is Me. In certain embodiments, at least one instance of R a is Et, Pr, or Bu. In certain embodiments, at least one instance of R a is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF3).

[0154] In certain embodiments, R 2 and R 3 are linked 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 linked with their intervening atoms to form an unsubstituted 5 - membered monocyclic heterocyclyl. In certain embodiments, R 2 and R 3 are linked with their intervening atoms to form a substituted 5 - membered monocyclic heteroaryl. In certain embodiments,

Chemical Structure

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0156] In certain embodiments,

Chemical formula

[0157] In certain embodiments, each instance of R 4 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN. In certain embodiments, at least one instance of R 4 is hydrogen. In certain embodiments, each instance of R 4 is hydrogen. In certain embodiments, at least one instance of R 4 is not hydrogen. In certain embodiments, there is no instance where R 4 is hydrogen. In certain embodiments, at least one instance of R 4 is halogen or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4 is halogen. In certain embodiments, at least one instance of R 4 is F. In certain embodiments, at least one instance of R 4 is Cl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C1-6 is (alkyl). In certain embodiments, R 4 in at least one instance is Me. In certain embodiments, R 4 in at least one instance is Et, Pr, or Bu. In certain embodiments, R 4 in at least one instance is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF3). In certain embodiments, R 4 in at least one instance is -OR a . In certain embodiments, R 4 in at least one instance is -OH. In certain embodiments, R 4 in at least one instance is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 4 in at least one instance is -N(R a )2. In certain embodiments, R 4 in at least one instance is -NH2. In certain embodiments, R 4 in at least one instance is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R 4 in at least one instance is -N(substituted or unsubstituted C 1-6 alkyl)2, e.g., -N(Me)2). In certain embodiments, R 4 in at least one instance is -CN.

[0158] In certain embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[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,

Chemical Formula

Chemical Formula

[0161] In certain embodiments,

Chemical Formula

Chemical Formula

Chemical Formula

[0162] In certain embodiments,

Chemical Formula

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0163] In certain embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0164] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0165] In some embodiments,

Chemical formula

[0166] In certain embodiments, each instance of R 5 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN. In certain embodiments, at least one instance of R 5 is hydrogen. In certain embodiments, each instance of R 5 is hydrogen. In certain embodiments, at least one instance of R 5 is not hydrogen. In certain embodiments, there is no instance where R 5 is hydrogen. In certain embodiments, at least one instance of R 5 is halogen. In certain embodiments, at least one instance of R 5 is F. In certain embodiments, at least one instance of R 5 is Cl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, R5 At least one instance of is Me. In certain embodiments, R 5 At least one instance of is Et, Pr, or Bu. In certain embodiments, R 5 At least one instance of is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF3). In certain embodiments, R 5 At least one instance of is -OR a . In certain embodiments, R 5 At least one instance of is -OH. In certain embodiments, R 5 At least one instance of is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 5 At least one instance of is -N(R a )2. In certain embodiments, R 5 At least one instance of is -NH2. In certain embodiments, R 5 At least one instance of is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R 5 At least one instance of is -N(substituted or unsubstituted C 1-6 alkyl)2, e.g., -N(Me)2. In certain embodiments, R 5 At least one instance of is -CN. In certain embodiments, R 5 At least one instance of is halogen, substituted or unsubstituted C 1-6 alkyl, or -OR a .

[0167] In some embodiments, L B is -N(R 6 )L 2 -. In some embodiments, the compound of formula (0) has the formula:

Chemical formula

[0168] In certain embodiments, L B is -L 2 N(R 6 )-. In some embodiments, the compound of formula (0) has the formula: [Chemical formula] is a compound of. In some embodiments, L 2 is C=O. In certain embodiments, the compound of formula (0) has the formula: [Chemical formula] is a compound. In some embodiments, L 2 is S(=O)2. In certain embodiments, the compound of formula (0) is of the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0169] In certain embodiments, the compound of formula (0) is of formula (0’):

Chemical formula

Chemical formula

Chemical formula

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

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

[0172] In certain embodiments, each R 6 is 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, 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. In certain embodiments, each R 6 is 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. In certain embodiments, each R 6is independently hydrogen. In certain embodiments, each R 6 is independently a substituted or unsubstituted C 1-6 alkyl (e.g., Me). In certain embodiments, each instance of R 6 is the same. In some embodiments, each instance of R 6 is different.

[0173] In certain embodiments, R 6 is hydrogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, a substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group. In certain embodiments, R 6 is a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, or a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl. In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is a substituted or unsubstituted C 1-6 alkyl (e.g., Me).

[0174] In certain embodiments, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic. In certain embodiments, R 7 is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic. In certain embodiments, R 7 is a substituted or unsubstituted phenyl. In certain embodiments, R 7 is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. In certain embodiments, R 7is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R 7 is a substituted or unsubstituted 3-pyridinyl. In certain embodiments, R 7 is unsubstituted 3-pyridinyl. In certain embodiments, R 7 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

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

[0176] Each instance of R 9 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 is hydrogen. In certain embodiments, R 9 Each instance of is hydrogen. In certain embodiments, R 9 At least one instance of is not hydrogen. In certain embodiments, R 9 There is no instance where R is hydrogen. In certain embodiments, R 9 At least one instance of is a halogen. In certain embodiments, R 9 At least one instance of is F. In certain embodiments, R 9 At least one instance of is Cl. In certain embodiments, R 9 At least one instance of is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, R 9 At least one instance of is Me. In certain embodiments, R 9 At least one instance of is Et, Pr, or Bu. In certain embodiments, R 9 At least one instance of is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF3). In certain embodiments, R 9 At least one instance of is -OR a In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 9 At least one instance of is -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH2. In certain embodiments, R 9 At least one instance of is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R9 At least one instance of is -N(substituted or unsubstituted C 1-6 alkyl)2, for example, -N(Me)2). In certain embodiments, R 9 At least one instance of is -CN. In certain embodiments, R 9 At least one instance of is halogen, substituted or unsubstituted C 1-6 alkyl, or -OR a .

[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) is of the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0179] In certain embodiments, s is 1. In some embodiments, the compound of formula (0’) is of the formula:

Chemical formula

Chemical formula

Chemical formula

[0180] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

[0181] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

[0182] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

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

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

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

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

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

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

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

[0190] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

[0191] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

[0192] In certain embodiments, the compound is a compound of the following formula:

Chemical formula

[0193] In certain embodiments, the compounds of the present disclosure (the compounds described herein) are compounds 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, the compounds of the present disclosure are compounds of formula (0) or (0’), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, the compounds of the present disclosure are compounds of formula (0) or (0’), or a pharmaceutically acceptable salt thereof.

[0194] In certain embodiments, the compounds of the present disclosure (the compounds described herein) are compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotope-labeled derivatives, or prodrugs thereof. In certain embodiments, the compounds of the present disclosure are compounds of formula (I), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In certain embodiments, the compounds of the present disclosure are compounds of formula (I), or pharmaceutically acceptable salts 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 (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) in vitro pharmacological profile compared to certain similar known compounds.

[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 compared to 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 the compounds of Table A, Table 5, and the following compounds.

Chemical formula

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Chem.

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Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

Chem.

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Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

Chem.

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Chem.

Chem.

Chem.

Chem.

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Chem.

Chem.

Chem.

Chem.

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Chem.

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Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

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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 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

[0200] Compositions and Kits The present disclosure provides compositions (e.g., pharmaceutical compositions) 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 a preparation method involves associating a compound of the present disclosure described herein with an excipient, and may also include one or more agents or auxiliary components, and, if necessary and / or desired, shaping and / or packaging the product into the desired single-dose or multi-dose units. In certain embodiments, the agent is a pharmaceutical agent.

[0202] In certain embodiments, the compound of the present disclosure takes the form of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0203] The composition can be prepared, packaged, and / or sold in large quantities as a single unit dose and / or as multiple single unit doses. A "unit dose" is an individual quantity of a composition containing a predetermined amount of the agent. The amount of the agent is generally equal to the dosage of the agent that is considered to be administered to the subject and / or a convenient fraction of such a dosage (e.g., half or one-third of such a dosage).

[0204] The relative amounts of the compounds, excipients, agents, and / or any additional components of the present disclosure 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 of administration of the composition. The composition can contain from 0.1% to 100% (w / w) of the agent.

[0205] Excipients and auxiliary components used in the manufacture of the provided compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Also, excipients and auxiliary components such as cocoa butter, PEGylated lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and fragrances may be present in the composition.

[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, dried starch, corn starch, powdered sugar, and mixtures thereof.

[0207] Exemplary granulating agents and / or dispersants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, crosslinked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked carboxymethyl cellulose (croscarmellose) sodium, methyl cellulose, pregelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, 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, lanolin, 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 polymer, and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), 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 (e.g., 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,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, doxart sodium, and / or mixtures thereof may be mentioned.

[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, tragacanth extract, panwa gum, ghatti gum, isapol husk mucilage, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, 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, ascorbyl 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., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, 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 butyl paraben, methyl paraben, ethyl paraben, propyl paraben, 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, hydroxybenzoate, 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, tocopherol acetate, detroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip® , methylparaben, Germall® 115, Germaben® II, Neolone® , Kathon® , and Euxyl® .

[0217] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, 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 mixture, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixture, 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 oil, 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, caraway oil, carrot 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, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, marula oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange raffia oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, peony oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana 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 malt 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 an agent that is useful for the delivery of the agent (e.g., delivery to a subject or cell). In certain embodiments, the composition is a pharmaceutical composition useful for the treatment of 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., prostatic 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 lymphoma, e.g., non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma). In certain embodiments, the cancer is B-cell lymphoma (e.g., Burkitt B-cell lymphoma, large cell type B-cell lymphoma). In certain embodiments, the cancer is T-cell lymphoma. In certain embodiments, the cancer is Burkitt lymphoma (e.g., Burkitt's B-cell lymphoma). In certain embodiments, the cancer is large cell type immunoblastic lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute monocytic leukemia or acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic 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 isotope-labeled chemical compound. In certain embodiments, the agent is an agent useful for 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. Examples of pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use in accordance with the provisions of the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules conjugated 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 compounds of the present disclosure described herein are 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 the treatment of cancer in a subject in need of cancer treatment. In certain embodiments, the effective amount is an amount effective for inhibiting a signaling pathway required for metastasis in a subject or cell.

[0223] In certain embodiments, the cell is in vitro. In certain embodiments, the cell is ex vivo.

[0224] The composition can be formulated into liquid dosage forms for oral and parenteral administration, which include pharmaceutically acceptable emulsifiers, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the drug, the liquid dosage forms may include 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 (such as 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. Oral compositions may, in addition to the inert diluent, include adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In certain embodiments of parenteral administration, the compositions described herein are mixed with solubilizers such as Cremophor® (registered trademark), alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0225] Injectable preparations, such as aqueous or oleaginous sterile injectable suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be made into sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent (such as a solution in 1,3 - butanediol). Acceptable vehicles and solvents that can be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally 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 formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

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

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

[0229] The composition can be formulated into a solid dosage form for oral administration, including capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the present disclosure are combined with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) dissolution retardants, such as paraffin, (f) absorption promoters, 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 include a buffering agent.

[0230] Solid compositions of the same type can be used as fillers within soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, along with high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. These dosage forms can optionally include opacifying agents and can also be compositions that release the compounds of the present disclosure in a delayed manner, either limitedly or preferentially, in a specific part of the intestinal tract. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of the same type can be used as fillers within soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, along with high molecular weight polyethylene glycol.

[0231] The compounds of the present disclosure can take a microencapsulated form having one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In the case of such solid dosage forms, the compounds of the present disclosure can be mixed with at least one inert diluent, for example, sucrose, lactose, or starch. Such dosage forms may, as is customary, contain additional substances other than the inert diluent, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can contain buffering agents. These dosage forms may optionally contain opacifying agents and may also optionally be compositions that release the compounds of the present disclosure in a delayed manner, limitedly or preferentially, in a particular part of the intestinal tract. 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 mixed, under sterile conditions, with a pharmaceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffering agents as required.

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

[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, from about 1% to about 100% (w / w) of the compounds of the present disclosure, although the concentration of the compounds of the present disclosure can be on the order of the solubility limit of the compounds of the present disclosure in the solvent. Formulations for topical administration can further contain one or more of the additional components described herein.

[0235] The compositions described herein can be prepared, packaged, and / or sold in formulations suitable for pulmonary administration via the oral vestibule. Such formulations can contain dry particles containing the compounds of the present disclosure. Such compositions are conveniently in the form of a dry powder and are administered using a device equipped with a dry powder reservoir that can direct the flow of a propellant to disperse the powder and / or using an auto-propelled solvent / powder dispensing container (e.g., a device containing a drug dissolved and / or suspended in a low-boiling propellant in a sealed container). The dry powder compositions can contain solid fine powder diluents such as sugars and are conveniently provided in unit dosage forms.

[0236] Low-boiling propellants generally include liquid propellants having a boiling point of less than 65°F at atmospheric pressure. Generally, the propellant constitutes 50 to 99.9% (w / w) of the composition, and the compounds of the present disclosure can constitute 0.1 to 100% (w / w) of the composition. The propellant can further include additional components, such as liquid nonionic and / or solid anionic surfactants and / or solid diluents.

[0237] The compositions described herein formulated for pulmonary delivery can deliver the compounds of the present disclosure in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcohol solutions and / or suspensions (optionally sterilized) containing the compounds of the present disclosure and can be conveniently administered using any spraying and / or atomizing device. Such formulations can further include one or more additional components including flavoring agents (such as sodium saccharin), volatile oils, buffering agents, surfactants, and / or preservatives (such as methyl hydroxybenzoate).

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

[0239] Formulations for nasal administration can, for example, contain from about 0.1% (w / w) to 100% (w / w) of the compounds of the present disclosure and can contain one or more of the additional ingredients described herein. The pharmaceutical compositions described herein can be prepared, packaged, and / or sold as formulations for buccal administration. Such formulations can, for example, take the form of tablets and / or lozenges prepared using conventional methods, contain, for example, 0.1 to 20% (w / w) of the drug, and the remainder can contain a composition that is orally soluble and / or decomposable and, optionally, one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration can contain powders and / or aerosolized and / or micronized solutions and / or suspensions containing the compounds of the present disclosure.

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

[0241] The descriptions of the compositions provided herein are primarily directed to compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are also widely suitable for administration to all kinds of animals. It is well understood that modifications can be made to compositions suitable for administration to humans to render them suitable for administration to various animals, and a veterinary pharmacologist of ordinary skill can design and / or carry out such modifications using routine experimentation.

[0242] The compositions described herein are typically formulated in dosage unit form for ease of administration and to provide a uniform dosage. However, it should be understood that the total daily usage of the compositions described herein will be decided by the physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject or organism depends upon a variety of factors including the cancer to be treated and its severity, the activity of the specific compound of the disclosure being used, the specific composition employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the excretion rate of the specific compound of the disclosure being used, the duration of the treatment, drugs used in combination with or concurrently with the specific compound of the disclosure being used, as well as similar factors well known in the medical arts.

[0243] The compositions provided herein can be administered by any route including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (by powder, ointment, cream, and / or droplet), transmucosal, nasal, buccal, sublingual, by endotracheal instillation, bronchial instillation, and / or inhalation, and / or by oral spray, nasal spray, and / or aerosol. Specifically, the intended routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via the blood and / or lymph supply, and / or direct administration to the site of affliction. Generally, the most appropriate route of administration depends upon a variety of factors including the nature of the compound of the disclosure (e.g., stability within the gastrointestinal tract 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 eyes of a subject.

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

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

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

[0247] Additional pharmaceutical agents include anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergy agents, contraceptives, and analgesics. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer 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 binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is an epigenetic or transcriptional modulator (e.g., a DNA methyltransferase inhibitor, a histone deacetylase inhibitor (HDAC inhibitor), a lysine methyltransferase inhibitor), an anti-mitotic agent (e.g., a taxane and a vinca alkaloid), a hormone receptor modulator (e.g., an estrogen receptor modulator and an androgen receptor modulator), a cell signaling pathway inhibitor (e.g., a tyrosine protein kinase inhibitor), an inhibitor of protein stability (e.g., a proteasome inhibitor), an Hsp90 inhibitor, a glucocorticoid, all-trans retinoic acid, and other agents that promote differentiation, selected from the group consisting of. In certain embodiments, the compounds or pharmaceutical compositions of the present disclosure described herein can be administered in combination with anti-cancer therapies (including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), 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, prior to, or after the compound or pharmaceutical composition of the present disclosure. 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 subject's natural defenses 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 compounds that are biologically produced by an organism that is not the subject. In certain embodiments, the immunotherapy utilizes cells that are biologically produced by an organism that is not the subject. In certain embodiments, the immunotherapy comprises at least one chemical modification to a compound or cell from the subject. In certain embodiments, the immunotherapy comprises at least one chemical modification to a compound or cell that is not from the subject.

[0248] In some embodiments, the immunotherapy can involve one or more of the following steps: preventing or inhibiting the growth of cancer cells; preventing the cancer from spreading to other parts of the body; and improving the ability and activity of the immune system 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, the immunotherapy utilizes monoclonal antibodies. In some embodiments, the monoclonal antibodies target (bind to) and / or block abnormal proteins on cancer cells.

[0250] In certain embodiments, the 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 the case of cancer cells, the immune checkpoint mechanism is often activated to suppress the anti-cancer immune response during the development stage. 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 non-specific immunotherapy (e.g., interferon or interleukin). In certain embodiments, the immunotherapy is 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] Anticancer agents include biotherapy anticancer agents and chemotherapeutic agents. Exemplary biotherapy anticancer agents include, but are not limited to, interferon, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulants, and / or immunomodulators (e.g., IL-1, 2, 4, 6, or 12), immunocyte 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 leuprorelin), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (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 (TAP), ANG1005 (Angiopep-2 conjugated to three paclitaxel molecules),Paclitaxel-EC-1 (paclitaxel conjugated to erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, for example, 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllin (for example, etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (for example, methotrexate, dichloromethotrexate, trimethoprim, edatrexate), IMP dehydrogenase inhibitors (for example, mycophenolic acid, thiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (for example, hydroxyurea and deferoxamine), uracil analogs (for example, 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (for example, cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (for example, mercaptopurine and thioguanine), vitamin D3 analogs (for example, EB 1089, CB 1093, and KH 1060), prenylation inhibitors (for example, lovastatin), dopamine-acting neurotoxins (for example, 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (for example, staurosporine), actinomycin (for example, actinomycin D, dactinomycin), bleomycin (for example, bleomycin A2, bleomycin B2, peplomycin), anthracyclines (for example, daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (for example, verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN (trademark), AZD2171), dasatinib (SPRYCEL (registered trademark), BMS-354825), erlotinib (TARCEVA (registered trademark)), gefitinib (IRESSA (registered trademark)), imatinib (Gleevec (registered trademark), CGP57148B, STI-571), lapatinib (TYKERB (registered trademark), TYVERB (registered trademark)), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA (registered trademark)), semaxanib (semaxinib, SU5416), sunitinib (SUTENT (registered trademark), SU11248), toceranib (PALLADIA (registered trademark)), vandetanib (ZACTIMA (registered trademark), ZD6474), batatinib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN (registered trademark)), bevacizumab (AVASTIN (registered trademark)), rituximab (RITUXAN (registered trademark)), cetuximab (ERBITUX (registered trademark)), panitumumab (VECTIBIX (registered trademark)), ranibizumab (Lucentis (registered trademark)), nilotinib (TASIGNA (registered trademark)), sorafenib (NEXAVAR (registered trademark)), everolimus (AFINITOR (registered trademark)), alemtuzumab (CAMPATH (registered trademark)), gemtuzumab ozogamicin (MYLOTARG (registered trademark)), temsirolimus (TORISEL (registered trademark)), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK (trademark)), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF (registered trademark)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, Tibosutinib (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), Lidaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), Oblimersen, Gemcitabine, Calminomycin, Leucovorin, Pemetrexed, Cyclophosphamide, Dacarbazine, Procarbazine, Prednisolone, Dexamethasone, Campathecin, Plicamycin, Asparaginase, Aminopterin, Methopterin, Porfiromycin, Melphalan, Leurosidine, Leurosine, Chlorambucil, Trabectedin, Procarbazine, Discodermolide, Calminomycin, Aminopterin, and Hexamethylmelamine are included.

[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 and requires more than about 10,000 parts of water to dissolve 1 part of the compound of the present disclosure.

[0256] In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from 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 the 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 the compound of the present disclosure is from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 25%, or from about 5% to about 20%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 5% to 90%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 5% to about 75%. In some embodiments, the composition comprising the compound of the present disclosure is from about 5% to about 50%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 10% to about 25%.

[0257] In some embodiments, the total amount of the compound 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 the compound 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] Although not bound by theory, the compositions disclosed herein can improve the efficacy of the compounds of the present disclosure by increasing the localization and / or release (e.g., preferential release) of the compounds of the present disclosure to target cells (e.g., cancer or fibrotic cells; cells associated with a hypoxic environment), or by increasing the half-life of the compounds of the present disclosure to result in a significantly greater amount of the released compounds of the present disclosure at the target site (e.g., a tumor or the liver (e.g., cirrhotic cells)). Accordingly, the compositions disclosed herein can be more therapeutically effective than the free compound (e.g., because drug uptake is enhanced within the target tissue), and / or can allow for a lower therapeutic dose of the compounds of the present disclosure without substantially compromising the drug concentration obtained in the target tissue. In some embodiments, the compositions disclosed herein can reduce the adverse effects associated with systemic administration of the free form of the compound.

[0259] In some embodiments, the compounds of the present disclosure are incorporated into the composition at a lower dose than the dose or amount of the free form of the compound to achieve the desired effect (e.g., the desired therapeutic effect). In certain embodiments, the composition increases the amount of the compound of the present disclosure delivered to the tissue or cells to which the compound of the present disclosure needs to be delivered and reduces the amount of the compound of the present disclosure exposed to non-target tissues or cells as compared to the case of the free compound.

[0260] In another aspect, there is provided a kit comprising 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 US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit and instructions effect delivery of the compounds of the present disclosure. In certain embodiments, the kit and instructions effect delivery of a composition. In certain embodiments, the kit and instructions effect treatment of cancer in a subject in need thereof. In certain embodiments, the kit and instructions effect inhibition of a signaling pathway in a subject or cell.

[0262] Methods of treatment and prevention and uses Some aspects of the invention relate to methods, uses, compositions, and kits for administering to a subject in need thereof. In some embodiments, the subject is a subject having, suspected of having, or 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 dogs, cats, horses, cows, pigs, sheep, goats, chickens, rodents, or primates. 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 exacerbation, slowing of the rate of progression, prevention of recurrence of a disorder (i.e., prevention of relapse), or prevention of metastasis or slowing of the rate of metastasis. An effective amount of a composition means an 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 growth 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 compounds of the present disclosure or the compositions described herein to a subject having 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 compounds of the present disclosure or the compositions described herein to a subject having cancer 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 comprises, is associated with, or is related to stem cells. In some embodiments, the subject has received or is currently receiving cancer therapy (e.g., chemotherapy, immunotherapy, surgery, radiation). Whether a subject is considered to be "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 occurs in the colon or rectum. These cancers may also be referred to as colon cancer or rectal cancer depending on the location of the cancer. Colon cancer and rectal cancer are often grouped together because they share several common characteristics. Most colorectal cancers begin as growths on the inner lining of the colon or rectum. The Colorectal Cancer (CRC) Subtyping Consortium integrated six independent molecular classification systems into one consensus system with four distinct groups known as Consensus Molecular Subtypes (CMS) based on gene expression data. CMS was determined and associated with epigenomic, transcriptomic, microenvironmental, genetic, prognostic, and clinical characteristics. The CMS1 subtype is immunogenic and hypermutated. 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 lowest 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. Premalignant changes often occur in the inner lining (mucosa) of the stomach before true cancer develops. Such early changes rarely cause symptoms and are often not detected. 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 stability (GS), and chromosomal instability (CIN). The GS (genomic stability) and CIN (chromosomal instability) molecular subtypes exhibit the highest levels of embryonic signaling as measured by a comprehensive analysis of gene expression patterns across gastric cancer subtypes.12,13

[0268] In certain embodiments, the subject is receiving additional therapy. In certain embodiments, the subject is further administered (co-administered) additional therapy (e.g., before, at the same time as, and / or after administration of the compounds or compositions described herein). The additional therapy is different from the compounds or compositions described herein. In certain embodiments, the additional therapy is ineffective alone or has lower efficacy when co-administered (e.g., before, at the same time as, and / or after) with the compounds or compositions described herein in the methods or uses described herein.

[0269] The exact amount of the disclosed compounds required to achieve an effective amount will vary depending on the subject, e.g., the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the particular compound of the disclosure, the mode of administration, and the like.

[0270] The effective amount can be included 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 amount of the agent described herein.

[0271] In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject, or the frequency of applying the multiple doses to the tissue or cell, is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every 2 days, 1 dose every 3 days, 1 dose per week, 1 dose every 2 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks or more. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the period between the first and last administrations of the 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 the subject, tissue, or cell. In certain embodiments, the period between the first and last administrations of the multiple doses is 3 months, 6 months, or 1 year. In certain embodiments, the period between the first and last administrations of the multiple doses is the lifetime of the subject, tissue, or cell.

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

[0273] The dosage can be appropriately adjusted to achieve the desired local level in the compound.

[0274] "Dosage" and "drug dosage" are used interchangeably herein. In some embodiments, the amount of the 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 (including both end values) of the compounds of the disclosure described herein. In certain embodiments, the dosages described herein independently include 1 mg to 3 mg (including both end values) of the compounds of the disclosure described herein. In certain embodiments, the dosages described herein independently include 3 mg to 10 mg (including both end values) of the compounds of the disclosure described herein. In certain embodiments, the dosages described herein independently include 10 mg to 30 mg (including both end values) of the compounds of the disclosure described herein. In certain embodiments, the dosages described herein independently include 30 mg to 100 mg (including both end values) of the compounds of the disclosure described herein.

[0275] In some embodiments, a subject is administered an initial dosage of any one of the compositions described herein, and then one or more additional dosages of any one of the compositions described herein are administered. In some embodiments, the initial dosage can include a different amount of any of the compounds described herein compared to one or more additional dosages. In some embodiments, the initial dosage is a higher dosage than one or more additional dosages (e.g., contains more of any one of the compounds described herein).

[0276] The dosage ranges described herein provide guidance for administering the provided compositions to adults. For example, the amount to be administered to a pediatric or adolescent can be determined by a medical practitioner or one of ordinary skill in the art, and this amount may be less than or the same as the amount administered to an adult. In certain embodiments, the dosages provided herein are for adults weighing 70 kg.

[0277] The effectiveness in the treatment of cancer can be measured, for example, by determining the growth, replication, proliferation, metastasis, and / or gene expression profile of one or more cancer cells. Therefore, an effective amount is an amount that is toxicologically acceptable to a clinician and is considered effective.

[0278] Without being bound by a particular theory, the compounds disclosed herein are believed to induce the differentiation of embryonic cells and / or cells exhibiting characteristics of embryonic cells. In some embodiments, the methods and uses disclosed herein involve administering to a subject in need of regenerative medicine or regenerative therapy an effective amount of any of the compositions described herein. 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 manipulation and organ regeneration. In some embodiments, the compositions described herein regenerate or differentiate cells, tissues, and / or organs that are at risk of damage. In some embodiments, the subject has experienced a traumatic brain injury (e.g., trauma or damage to brain tissue or cells) and / or an injury to the central nervous system (e.g., trauma or damage to central nervous system tissue or cells) and requires repair of the tissue or cells. In some embodiments, the subject has experienced a cardiac trauma (e.g., trauma or damage to cardiac tissue or cells) and requires repair of the tissue or cells.

[0279] In some embodiments, the 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 lymph supply, and / or direct administration to the affected area.

[0280] The present disclosure is a method for treating cancer, comprising administering to a subject a compound of formula (0): [Chemical formula] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof, comprising administering a therapeutically effective amount, 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 when L 1 is a single bond, R 1-6 is hydrogen, substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C L 1 when L 1 is -C(=O)-, R 1-6 is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C R 2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6An alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group, R 3 is hydrogen, halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, R a in each case is independently hydrogen, a substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or, R 2 and R 3 are linked with the intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic or heteroaryl, q is 0 or 1, each case of Y is independently N or CR 4 , R 4 in each case is independently hydrogen, halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, [Chemical formula] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or [Chemical formula] , bond b and bond c are [Chemical formula] When it is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, they are meta or para to each other, R 5 In each case 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 long as the valence permits, and when n is 1, 2, 3, or 4, there is no case where R 5 is bonded to a nitrogen atom, L B is -N(R 6 )L 2 - or -L 2 N(R 6 )-, L 2 is -C(=O)-,

Chemical formula

[0281] In certain embodiments, the present disclosure further provides a method of treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (0’): [Chemical formula] 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 when L 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, L 1 when L is -C(=O)-, R 1 is 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, 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 2-6An alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group, R 3 is hydrogen, halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, R a in each case is independently hydrogen, a substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or, R 2 and R 3 are linked with the intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic or heteroaryl, q is 0 or 1, each case of Y is independently N or CR 4 , R 4 in each case is independently hydrogen, halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0282] Also provided is a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I): [Chemical Formula] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof, wherein L 1 is a single bond or -C(=O)-, L 1 when L 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, L 1 when L is -C(=O)-, R 1 is 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 carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, 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 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 aEach instance of is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or, R 2 and R 3 are linked with the 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 wherein, R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN, [Chemical formula] is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, azetidinyl, -C≡C-, or [Chemical formula] wherein, 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 long as the valence permits, provided that when n is 1, 2, 3, or 4, there is no instance where R 5 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 An alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, a substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl, a 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 carbocyclic, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, R 8 In each case of which is independently hydrogen, halogen, a substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN.

[0283] In certain embodiments of "Methods of Treatment and Prevention", L 1 is a single bond or -C(=O)-, L 1 When L is a single bond, R 1 is hydrogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, a substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, or a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, L 1 When L is -C(=O)-, R 1 is a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic, 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 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 in each case is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, or, R 2 and R 3 are linked with the intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic or heteroaryl, in each case Y is independently N or CR 4 , R 4 in each case is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , -N(R a )2, or -CN,

Chemical formula

[0284] In certain embodiments, the disclosure provides a method of treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I):

Chemical formula

Chemical formula

[0285] In certain embodiments having a "Methods of Treatment and Prevention and Use" section, L 1 , R 1 , R 2 , R 3 , R a , R 4 , Y, [Chemical Formula] , bond b and bond c, R 5 , n, L 2 , R 6 , R 7 , and R 8 are as described in the "Compound" section.

[0286] In certain embodiments having a "Methods of Treatment and Prevention and Use" section, when L 1 is a single bond, R 1 is hydrogen. In certain embodiments having a "Methods of Treatment and Prevention and Use" section, when L 1 is -C(=O)-, R 1 is substituted C 1-6 alkyl. In certain embodiments having a "Methods of Treatment and Prevention and Use" section, when L 1 is -C(=O)-, R 1 is unsubstituted C 1-6 alkyl (e.g., Me or Et).

[0287] In certain embodiments having a "Methods of Treatment and Prevention and Use" section, R 3 is hydrogen.

[0288] In certain embodiments having a "Methods of Treatment and Prevention and Use" section, R 2 and R 3 , when linked to the intervening atoms, form a substituted or unsubstituted 6-membered monocyclic heterocyclyl or heteroaryl. In certain embodiments having a "Methods of Treatment and Prevention and Use" section, R 2 and R 3It is linked to those intervening atoms to form an unsubstituted 6-membered monocyclic heterocyclyl. In certain embodiments having a "Methods of Treatment and Prevention and Uses" section,

Chemical formula

[0289] In certain embodiments having a "Methods of Treatment and Prevention and Uses" section, the compound of formula (I) is a compound of the formula

Chemical formula

[0290] In certain embodiments having a "Methods of Treatment and Prevention and Uses" section, the compound of formula (I) is a compound of the formula

Chemical formula

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

[0292] In some embodiments, any of the compounds described herein are contacted with cells in vivo, for example, within an organism. In some embodiments, any of the compounds described herein are contacted with cells in vitro, for example, within a cell culture. In some embodiments, any of the compounds described herein are contacted with cells ex vivo. This means removing the cells from an organism prior to contacting. As will be apparent to those skilled in the art, the term cell can be used to mean a single cell as well as a population of cells. In some embodiments, a population of cells is contacted with any of the compounds described herein to regenerate or differentiate one or more cells in the population of cells. In some embodiments, a population of cells is contacted with any of the compounds described herein for use in personalized medicine, for example, for diagnostic and / or therapeutic purposes.

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

[0294] In some embodiments, the method and use further comprise inhibiting cell growth. In other embodiments, the method and use comprise killing cells. In some embodiments, the cells are stem cells. In some embodiments, the cells are 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 cells are cancer stem cells. In certain embodiments, the cells are embryonic stem cells. 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 the treatment of proliferative diseases including cancer.

[0295] In some embodiments, the method and use further comprise 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 evaluated 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 one or more embryonic characteristics of a reference sample or of the cells prior to 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 susceptible to 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 cells are determined to be susceptible to 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 treating a disease or disorder associated with the cells.

[0296] In some embodiments, the methods and uses described herein can be used in regenerative medicine. In some embodiments, cells are contacted with any of the compositions described herein to promote differentiation and / or loss of one or more embryonic characteristics of the cells. In some embodiments, cells are contacted with any of the compositions described herein to promote 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 an organ). In some embodiments, the regenerated cell population (e.g., a tissue or an organ) can be administered or transplanted into a subject. In some embodiments, the subject is the same subject from whom the cells were obtained. In some embodiments, the subject is a different subject from whom the cells were obtained (e.g., autotransplantation). In some embodiments, the subject is a different subject from whom the cells were obtained but belongs to the same species (e.g., allotransplantation). In some embodiments, the subject is a different subject from whom the cells were obtained and belongs to a different species (e.g., xenotransplantation).

Example

[0297] To better understand the present disclosure, the following examples are provided. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, methods, and uses provided herein and should not be construed as limiting their scope in any way.

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

[0299] Example 2. Human Microarray Assay AGS human gastric adenocarcinoma cells were treated with Compound I-1 or DMSO only (as a negative control) for 2 days. After 2 days, RNA was isolated in duplicate from Compound I-1-treated cells and DMSO-treated cells and subjected to microarray analysis using an AFFYMETRIX CLARIOM S microarray. The data are presented as fold change 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. The values are the average of duplicate samples. Genes whose expression changed by more than 3-fold either up or down in response to Compound I-1 were included in the data.

[0300] Table 1 shows a list of genes that are upregulated when the AGS human gastric cancer cell line is treated with compound I-1 (see below). Negative numbers indicate the fold increase in upregulation upon drug treatment. Positive numbers indicate the fold decrease in downregulation upon drug treatment. Overall, these data represented the reactivation of tumor suppressor genes and the decreased expression of tumor promoting genes. For example, DUSP10, NR1D1, and Per1 have all been shown to have tumor suppressor activity that prevents uncontrolled cell proliferation, and the expression of all three of these genes was significantly increased by treatment with compound I-1. In addition, Chac1, PCK2, and SLC7A11 have all been shown to have tumor promoting activity and to be associated with more aggressive and lethal cancer forms, and these three genes were the three most strongly suppressed genes in this analysis' measurements. There are other examples in the data that support this model, but the overall model was that compound I-1 increased the expression of tumor suppressor genes and decreased the expression of tumor promoting genes.

Chem.

[0301]

Table 30

Table 31

[0302] Table 2 shows a list of genes that are downregulated when the AGS human gastric cancer cell line is treated with compound I-1.

[0303]

Table 32

Table 33

Table 34

Table 35

[0304] Example 3. Kinetic cell viability in AGS cells In compound I-1, the ability to inhibit the growth of an additional 12 cell lines derived from various different types of human cancers was tested. In addition to strongly inhibiting the growth of gastric adenocarcinoma and gastrointestinal stromal cells (data on gastric adenocarcinoma shown in Example 1, data on gastrointestinal stromal tumors shown in Table 3), compound I-1 also had the most potent effect on non-Hodgkin lymphoma, small cell lung cancer, pancreatic cancer, gastrointestinal stroma, and ovarian adenocarcinoma cells. Exemplary results are shown in Table 3. The results are listed as the IC 50 value, which is the lowest concentration of compound I-1 that inhibited the growth of cancer cells by 50%.

[0305]

Table 36

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

[0307] RT-qPCR Approximately 2.5×10 5 individual AGS cells were treated with DMSO only (no drug treatment) or 10 μM of compound I-1 in DMSO for 4 days. The 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 on a Stratagene Mx3005P.

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

[0309] Kinetic cell viability Approximately 50,000 AGS cells per well of a 96-well plate were seeded into a medium containing NanoLuc luciferase and MT Cell Viability Substrate provided by the RealTime Glo MT Cell Viability Assay Kit from PROMEGA. Four hours after plating, the cells were treated with either DMSO only (no drug treatment) or Compound I-1 at decreasing concentrations to achieve final concentrations of 20, 10, 5, and 2.5 μM. Luminescence units (RLU) were measured every 16 - 20 hours using a SynergyHTX plate reader with 30-millisecond integration.

[0310] Absorption, distribution, metabolism, and excretion (ADME) profiling Plasma stability. Plasma stability was determined by QuintaraBio's stability assay using samples supplied in DMSO solution. Briefly, a compound at a final concentration of 1 μM was incubated in duplicate at 37 °C in the presence of mouse plasma. At four different time points, 300 μL of a 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 the control reaction incubation at 0 minutes. The initial rate was calculated with respect to the compound concentration and used for the determination of the t 1 / 2 value.

[0311] Microsomal stability. Microsomal stability was determined by QuintaraBio's stability assay using samples supplied in DMSO solution. Briefly, the assay was performed in a 96-well microtiter plate at 37 °C. A reaction mixture (25 μL) containing the test compound at a final concentration of 1 μM, 0.5 mg / mL of liver microsomal protein, and 1 mM of NADPH and / or 1 mM of uridine 5'-diphospho-α-D-glucuronic acid (UDPGA) (including alamethicin) in 100 mM potassium phosphate pH 7.4 buffer containing 3 mM of MgCl2 was incubated. At each time point (0.25, 0.5, 1, 2, 4, 6, 8, and 24 minutes), 150 μL of a 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 compared to the 0-minute incubation. The initial rate was calculated with respect to the compound concentration, and t 1 / 2 value determination, followed by determination of intrinsic clearance CLint = (0.693)(1 / t 1 / 2 (min))(liver g / body weight kg)(mL incubation / microsomal protein mg)(microsomal protein 45 mg / liver weight g) was used.

[0312] Kinetic solubility. Solubility was determined by QuintaraBio's solubility assay using samples supplied in DMSO solution. Briefly, 10 mM of Compound I-1 was diluted with an appropriate amount of buffer (PBS, pH 7.4), mixed by shaking for 1.5 hours, and then vacuum filtered. The samples were then assayed via reverse-phase HPLC equipped with UV detection. Quantification was achieved by reference to a 3-point standard curve constructed from 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 a single oral administration of 100 mg / kg to male CD1 mice (n = 3). Approximately 0.025 mL of blood was collected from the dorsal medial saphenous vein at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after dosing. Plasma drug concentrations were analyzed by LC / MS / MS method.

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

[0315] Example 4. AGS gastric cancer cells were treated with either DMSO only (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 only (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 and healthy mouse hepatocytes were treated with either DMSO only (no drug treatment) or 10 μM of Compound I-1 for 4 days. The health status of the cells was measured using the CELLTITER GLO reagent, which shows a luminescence readout as a measure of the total ATP concentration. Exemplary results are shown in Figure 4.

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

[0319] Example 8. The selective chemical properties of Compound I-1 were measured. Solubility was measured in aqueous solutions at either pH 1.2 or 7.4. Mouse liver microsomal stability is reported as the measured half-life (t 1 / 2 (minutes)), and plasma stability is listed as the percentage of Compound I-1 remaining in mouse plasma after 4 hours. Exemplary results are shown in Figure 6.

[0320] Example 9. After a single PO (oral) injection of 100 mg / kg to 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 a day for 5 days with either vehicle control or with 50 mg / kg of Compound I-1, 25 mg / kg of Compound I-1, or 12.5 mg / kg of Compound I-1. Three mice were used for vehicle control and three mice were used for Compound I-1. The mice were monitored for a total of 10 days and their body weights were measured to assess overall health. Exemplary results are shown in Figure 8.

[0322] Example 11. Kinetic cell viability in AGS cells In Compound I-1, the ability to inhibit the growth of an additional 11 cell lines derived from various different types of human cancers was tested. Exemplary results are shown in Table 4. The results are listed as the IC 50 value, which is the lowest concentration of Compound I-1 that inhibited cancer cell growth by 50%.

[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 (analysis) 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 connected to an SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm × 2.1 mm inner diameter, 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 - 1000 AMU.

[0327] Method 2 (LC-MS): 2min_high_3_97_BEH: LC / MS system: Acquity UPLC connected to an SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm × 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 10 mM aqueous solution of 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 - 1500 AMU.

[0328] Method 5 (LC-MS): 12min_low_3_97_BEH: LC / MS system: Acquity UPLC connected to an SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm × 2.1 mm inner diameter, 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 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 - 1500 AMU.

[0329] Method 6 (LC-MS): 12 min_high_3_97_BEH: LC / MS system: Acquity UPLC connected to an SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm × 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 10 mM aqueous solution of 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 - 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 - 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

Chem.

[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 h 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

Chem.

[0334] Procedure B: To a mixture of tert-butyl 5-bromoindoline-1-carboxylate (18.0 g, 50.8 mmol) in dioxane / H2O (135 mL) were added (4-(methoxycarbonyl)phenyl)boronic acid (13.2 g, 76.2 mmol), Pd(dppf)Cl2 (4.2 g, 5.1 mmol), and Cs2CO3 (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA 4:1 (v / v)) on silica gel to afford 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

Chemical Structure

[0336] Procedure C: To a mixture of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate (5.0 g, 14.2 mmol) in MeOH / THF 1:1 (60 mL) was added LiOH (1 N, 30 ml). The reaction mixture was stirred at 70 °C for 3 h. Then it was concentrated in vacuo and acidified with aqueous HCl (1 N). After filtration, the solid was dried to afford 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

Chem.

[0338] Procedure D: To a mixture of 4-(1-(tert-Butoxycarbonyl)indolin-5-yl)benzoic acid (3.0 g, 8.8 mmol) in DMF were added pyridin-3-ylmethanamine (1.1 g, 10.6 mmol), HATU (5.0 g, 13.2 mmol), and DIPEA (3.4 g, 26.4 mmol). The reaction mixture was stirred at room temperature for 20 h. 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 by flash column chromatography (DCM / MeOH 9:1 (v / v)) on silica gel to afford 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

Chem.

[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 (4N, 20 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to afford a red solid (2.4 g). The residue (100 mg) was purified by preparative HPLC (C18, 40 - 100% MeCN in H2O containing 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)

Chemical Structure

[0342] Starting from 4-(indolin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (200 mg, 0.5 mmol) and HOAc (36 mg, 0.6 mmol) according to Procedure D. In this case, the reagents were added at 0 °C and the reaction mixture was warmed 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. 11H 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)

Chemical Structure

[0345] 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) according to General Procedure D, 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. 11H 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) [Chemical formula]

[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 K2CO3 (3.2 g, 23.0 mmol) in dioxane / H2O (25 / 5 mL) was added Pd(PPh3)4 (1.33 g, 1.15 mmol) all at once. The mixture was stirred at 100 °C for 10 h. It was then extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, 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 h. It was acidified with 4N HCl 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 following 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 gave 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. 11H 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-methylpropionamide)-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (Compound I-45)

Chemical Structure

[0352] To a solution of methyl 4'-propionamido-[1,1'-biphenyl]-4-carboxylate (500 mg, 1.77 mmol) and Cs2CO3 (1.36 g, 3.54 mmol) in MeCN (10 mL) was added MeI (0.22 mL, 3.54 mmol) all at once. The mixture was stirred at 80 °C for 10 h. Then it was extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to give methyl 4'-(N-methylpropionamide)-[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-methylpropionamide)-[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) all at once. The mixture was stirred at room temperature for 12 h. It was then acidified with 4 N HCl 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-methylpropionamide)-[1,1'-biphenyl]-4-carboxylic acid as a white solid (140 mg, 73%). LC-MS (ESI): m / z (M+H) + = 284.14.

[0354] Starting from 4'-(N-methylpropionamide)-[1,1'-biphenyl]-4-carboxylic acid (140 mg, 0.50 mmol) and pyridin-3-ylmethanamine (82 mg, 0.75 mmol) according to General Procedure D, 4'-(N-methylpropionamide)-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)

Chemical Structure

[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) all at once. 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 Na2SO4, 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 0 °C 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) was added AcCl (1.72 g, 21.9 mmol) all at once. 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, 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] 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 Na2CO3 (850 mg, 8.0 mmol) in dioxane / H2O (10 / 2 mL) was added with Pd(PPh3)4 (466 mg, 0.4 mmol). The mixture was stirred at 100 °C for 10 h. Then it was extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to obtain 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 (4N), and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography to obtain 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] 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) according to General Procedure D, 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. 11H 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

Chem.

[0363] 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) according to General Procedure D, 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)

Chem.

[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 at 0 °C for 2 h under N2. 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 H2O containing 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

Chemical Structure

[0368] Starting from 5-bromoindoline (3.0 g, 15.2 mmol) and propionic acid (1.37 g, 18.3 mmol) according to General Procedure D. In this case, the reagents were added at 0 °C and the reaction mixture was warmed 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

Chemical formula

[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) were added B2Pin2 (1.65 g, 6.5 mmol), Pd(dppf)Cl2 (240 mg, 0.3 mmol), and KOAc (1.7 g, 17.7 mmol). 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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA 4:1 (v / v)) on silica gel 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

Chemical formula

[0372] To a mixture of 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (200 mg, 0.783 mmol) in THF (5 mL) were 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 h. 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 by flash column chromatography (PE / EA 4:1 (v / v)) on silica gel 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)

Chemical formula

[0374] 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 according to Procedure B. 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 H2O containing 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. 11H 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

Chemical Structure

[0377] Following Procedure E, methyl 4-(indolin-5-yl)benzoate was obtained 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

Chemical Structure

[0379] Starting from methyl 4-(indolin-5-yl)benzoate (4.8 g, 19.0 mmol) and propionic acid (1.7 g, 22.7 mmol) according to General Procedure D. In this case, the reagents were added at 0 °C and the reaction mixture was warmed 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

Chemical formula

[0381] According to Procedure C, 4-(1-propionylindolin-5-yl)benzoic acid (Intermediate B) was obtained as a white solid from methyl 4-(1-propionylindolin-5-yl)benzoate (1.8 g, 5.8 mmol) (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)

Chemical formula

[0383] Starting from 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and pyridin-4-ylmethanamine (44 mg, 0.41 mmol) according to General Procedure D, 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. 11H 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) [Chemical formula]

[0385] Sodium borohydride (262 mg, 6.9 mmol) was added in one portion to a solution of pyrimidine-5-carbaldehyde (500 mg, 4.6 mmol) in MeOH (10 mL) at 0 °C. 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 Na2SO4, 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 was added SOCl2 (1.33 g, 11.1 mmol) all at once. The mixture was stirred at room temperature for 4 h. It was then quenched with Na2CO3, the mixture was extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, 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 THF solution of 5-(chloromethyl)pyrimidine (200 mg, 1.56 mmol) was added NH3·H2O (4 mL). The mixture was stirred at room temperature for 30 min. 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] Starting from 4-(1-propionylindolin-5-yl)benzoic acid (238 mg, 0.8 mmol) and pyrimidin-5-ylmethanamine (130 mg, 1.2 mmol) according to General Procedure D, 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)

Chem.

[0390] Starting from 4-(1-propionylindolin-5-yl)benzoic acid (106 mg, 0.36 mmol) and pyridazin-4-ylmethanamine (50 mg, 0.33 mmol) according to General Procedure D, 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)

Chem.

[0392] Following the general procedure D, 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)

Chemical Structure

[0394] Following general procedure D, 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

Chemical Structure

[0397] Procedure H: Raney Ni (50 mg) was added to a mixture of 6-methylnicotinonitrile (300 mg, 2.54 mmol) in MeOH / NH3 (7N, 10 mL). The reaction mixture was stirred at room temperature for 3 h under H2. 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) [Chemical Struc...

Claims

1. Compound of formula (0): 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (In the formula, 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 When 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 (wherein the 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 ２－６ 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 2】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or 【Chemistry 3】 and Bond b and bond c are 【Chemistry 4】 are meta or para to each other when 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 it 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)-, 【Chemistry 5】 Or -S(=O) ２ - and 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)

2. The compound is a compound of formula (0'): 【Chemistry 6】 2. The compound of claim 1, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (In the formula, L １ is a single bond or -C(=O)-, L １ When 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 (wherein the 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 ２－６ 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 7】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or 【Chemistry 8】 and Bond b and bond c are 【Chemistry 9】 are meta or para to each other when 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 it is bonded to a nitrogen atom. L ２ is -C(=O)-, 【Chemistry 10】 Or -S(=O) ２ - and 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)

3. The compound is a compound of formula (I): 【Chemistry 11-1】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (In the formula, L １ is a single bond or -C(=O)-, L １ When 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 11-2】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, azetidinyl, -C≡C-, or 【Chemistry 12】 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. L ２ is -C(=O)- or -S(=O) ２ - and 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)

4. A compound according to any one of claims 3 to 4, comprising the formula: L １ is a single bond or -C(=O)-, L １ When 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 13】 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 valences, where n is 1, 2, 3, or 4, R ５ There is no case where it is bonded to a nitrogen atom. L ２ is -C(=O)- or -S(=O) ２ - and 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, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

5. A method of treating cancer comprising administering to a patient a compound of formula (0): 【Chemistry 14】 or a pharma- ceutical acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, to a subject. (In the formula, 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 When 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 ２－６ 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 15】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or 【Chemistry 16】 and Bond b and bond c are 【Chemistry 17】 are meta or para to each other when 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 it 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)-, 【Chemistry 18】 Or -S(=O) ２ - and 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)

6. The compound of formula (0) is a compound of formula (0'): 【Chemistry 19】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (In the formula, L １ is a single bond or -C(=O)-, L １ When 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 ２－６ 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 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 an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; Or, 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, 【Chemistry 20】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C-, or 【Chemistry 21】 and Bond b and bond c are 【Chemistry 22】 are meta or para to each other when 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 it is bonded to a nitrogen atom. L ２ is -C(=O)-, 【Chemistry 23】 Or -S(=O) ２ - and 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)

7. The compound is a compound of formula (I): 【Chemistry 24】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (In the formula, L １ is a single bond or -C(=O)-, L １ When 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 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; Or, 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, 【Chemistry 25】 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, azetidinyl, -C≡C-, or 【Chemistry 26】 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. L ２ is -C(=O)- or -S(=O) ２ - and 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)

8. The method according to any one of claims 5 to 7, comprising the steps of: L １ is a single bond or -C(=O)-, L １ When 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 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; Or, 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, 【Chemical 27】 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 valences, where n is 1, 2, 3, or 4, R ５ There is no case where it is bonded to a nitrogen atom. L ２ is -C(=O)- or -S(=O) ２ - and 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.

9. 112. The method of any one of claims 5-8 or 111, wherein the cancer comprises cancer stem cells.

10. 112. The method of any one of claims 5 to 9 or 111, wherein the cancer is gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, or prostate cancer.

11. The method of claim 10, wherein the cancer is gastric cancer subtype GS or gastric cancer subtype CIN.

12. 112. The method of any one of claims 5 to 9 or 111, wherein the cancer is colorectal cancer.

13. 13. The method of claim 12, wherein the cancer is colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4.

14. 112. The method of any one of claims 5 to 9 or 111, wherein the cancer is testicular cancer.

15. 112. The method of any one of claims 5 to 9 or 111, wherein the cancer is liver cancer or endometrial cancer (e.g., uterine cancer).

16. 112. The method of any one of claims 5-9 or 111, wherein the cancer is lymphoma (e.g., non-Hodgkin's lymphoma).

17. 112. The method of any one of claims 5-9 or 111, wherein the cancer is B cell lymphoma (e.g., large B cell lymphoma), Burkitt lymphoma (e.g., Burkitt B cell lymphoma), or large cell immunoblastic lymphoma.

18. 112. The method of any one of claims 5-9 or 111, wherein the cancer is leukemia (e.g., acute monocytic leukemia or acute lymphocytic leukemia (e.g., B-cell acute lymphocytic leukemia)).

19. 112. The method of any one of claims 5-9 or 111, wherein the cancer is chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia.

20. 112. The method of any one of claims 5-9 or 111, wherein the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia).

21. 112. The method of any one of claims 5-9 or 111, wherein the cancer is multiple myeloma (e.g., B-cell myeloma).

22. The method of any one of claims 5 to 21, wherein the subject has or is undergoing one or more additional cancer treatments.

23. The method of any one of claims 5 to 22, wherein the subject is in need of regenerative medicine.

24. 9. A method comprising contacting a cell with an effective amount of a compound of formula (I) as defined in any one of claims 5 to 8, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

25. 25. The method of claim 24, wherein the cells are characterized by one or more embryonic or pluripotent characteristics.

26. 26. The method of claim 24 or 25, wherein 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.

27. 27. The method of any one of claims 24 to 26, wherein said contacting reduces one or more embryonic characteristics of said cells.

28. The method of any one of claims 24 to 27, wherein the contacting is carried out in vitro or ex vivo.

29. The method of any one of claims 24 to 28, wherein said contacting reduces cell viability.

30. 30. The method of any one of claims 24 to 29, wherein the contacting kills the cell.

31. 9. A method comprising killing a cell with an effective amount of formula (I) as defined in any one of claims 5 to 8, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

32. 32. The method of claim 31 , wherein the cells are characterized by one or more embryonic characteristics.

33. The method of any one of claims 31 to 32, wherein the cells are cancer stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, or adult stem cells.

34. 34. The method of any one of claims 31 to 33, wherein said contacting reduces one or more embryonic characteristics of said cells.

35. The method of any one of claims 31 to 34, wherein the contacting is carried out in vitro or ex vivo.

36. 36. The compound or method of any one of claims 1 to 35, wherein formula (I) is formula (IA): 【Chemistry 28】

37. 37. The compound or method of claim 36, wherein formula (I) is: 【Chemical 29】 (In the formula, R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN)

38. 38. The compound or method of claim 37, wherein formula (I) is: 【Chemistry 30】 (In the formula, R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN)

39. The compound or method of any one of claims 1 to 35, wherein formula (I) is formula (IB): 【Chemistry 31】 (In the formula, R ７ is a substituted or unsubstituted 3-pyridinyl.

40. The compound or method of any one of claims 1 to 35, wherein formula (I) is formula (IC): 【Chemistry 32】 (In the formula, 【Chemical 33】 is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl)

41. The compound or method of any one of claims 1 to 35, wherein formula (I) is formula (IC): 【Chemical 34】 (In the formula, 【Chemistry 35】 is imidazolyl, oxazolyl, azetidinyl, -C≡C-, or 【Chemical Formula 36】 (It is)

42. 36. The compound or method of any one of claims 1 to 35, wherein formula (I) is formula (ID): 【Chemical 37】 (In the formula, R ７ is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

43. 36. The compound or method of any one of claims 1 to 35, wherein formula (I) is: 【Chemical Formula 38】 (In the formula, R ２ is a substituted or unsubstituted C １－６ is alkyl, R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN)

44. 44. The compound or method of claim 43, wherein formula (I) is: 【Chemical 39】

45. L Ａ -C(=O)NR １ R ２ 36. The compound or method of any one of claims 1 to 35, wherein

46. L Ｂ Ga-L ２ N (R ６ 46. ​​The compound or method of any one of claims 1 to 35 or 45, wherein

47. 47. The compound or method of any one of claims 1-35 or 45-46, wherein q is 1.

48. 48. The compound or method of any one of claims 1-35 or 45-47, wherein s is 0.

49. R １ is a substituted or unsubstituted C １－６ 49. The compound or method of any one of claims 1 to 48, wherein:

50. R １ is unsubstituted C １－６ 50. The compound or method of claim 49, wherein said alkyl is alkyl.

51. L １ The compound or method of any one of claims 1 to 50, wherein is a single bond.

52. L １ is a single bond, R １ 52. The method of claim 51 , wherein is hydrogen.

53. L １ The compound or method of any one of claims 1 to 50, wherein is -C(=O)-.

54. R ２ is hydrogen or a substituted or unsubstituted C １－６ 54. The compound or method of any one of claims 1 to 53, wherein:

55. R ２ is a substituted or unsubstituted C １－６ 55. The compound or method of claim 54, wherein said alkyl is alkyl.

56. R ３ is halogen, substituted or unsubstituted C １－６ Alkyl, or -OR ａ 56. The compound or method of any one of claims 1 to 55,

57. R ３ The method of any one of claims 5 to 55, wherein is hydrogen.

58. R ２ and R ３ 54. The compound or process of any one of claims 1-53, wherein: are linked with their intervening atoms to form a substituted or unsubstituted 5-membered monocyclic heterocyclyl or heteroaryl.

59. 【Catalogue 40】 54. The compound or method of any one of claims 1 to 53, wherein

60. 【Catalogue 41】 60. The compound or method of claim 59, wherein:

61. 【Catalogue 42】 54. The compound or method of any one of claims 1 to 53, wherein

62. R ２ and R ３ The method of any one of claims 5 to 53, wherein: are linked with their intervening atoms to form a substituted or unsubstituted 6-membered monocyclic heterocyclyl or heteroaryl. 【Request 63】 【Chemical 43】 63. The method of claim 62, wherein:

64. Each case of Y is CR ４ 64. The compound or method of any one of claims 1 to 63, wherein

65. 【Catalogue 44】 64. The compound or method of any one of claims 1 to 63, wherein

66. 64. The compound or method of any one of claims 1 to 63, wherein at least one Y is N.

67. R ４ 67. The compound or process of any one of claims 1 to 66, wherein each instance of is hydrogen.

68. R ４ At least one instance of １－６ 67. The compound or method of any one of claims 1 to 66, wherein:

69. 【Catalogue 45】 69. The compound or method of any one of claims 1 to 68, wherein is phenyl. 【Request 70】 【Chemical 46】 70. The compound or method of claim 69, wherein:

71. 【Catalogue 47】 69. The compound or method of any one of claims 1-68, wherein is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

72. 【Catalogue 48】 69. The compound or process of any one of claims 1 to 68, wherein is imidazolyl or oxazolyl. 【Request 73】 【Chemical 49】 69. The compound or method of any one of claims 1 to 68, wherein is azetidinyl. 【Request 74】 【Chemical 50】 The compound or process of any one of claims 1 to 68, wherein is -C≡C-.

75. 【Chemical 51】 69. The compound or method of any one of claims 1 to 68, wherein

76. 76. The compound or method of any one of claims 1 to 75, wherein bond b and bond c are para to each other.

77. 76. The compound or method of any one of claims 1 to 75, wherein bond b and bond c are meta to each other.

78. R ５ 78. The compound or process of any one of claims 1 to 77, wherein each instance of is hydrogen.

79. R ５ At least one instance of １－６ Alkyl, or -OR ａ 78. The compound or method of any one of claims 1 to 77, wherein

80. L ２ The compound or process of any one of claims 1 to 79, wherein is -C(=O)-.

81. L ２ -S (=O) ２ 80. The compound or method of any one of claims 1 to 79, wherein:

82. R ６ 82. The compound or process of any one of claims 1 to 81, wherein is hydrogen.

83. R ６ is a substituted or unsubstituted C １－６ 82. The compound or method of any one of claims 1-81, wherein R is alkyl, substituted or unsubstituted 6-11 membered monocyclic or bicyclic aryl, or substituted or unsubstituted 5-11 membered monocyclic or bicyclic heteroaryl.

84. R ７ 84. The compound or process of any one of claims 1 to 83, wherein is substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl.

85. R ７ 84. The compound or process of any one of claims 1 to 83, wherein is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl.

86. R ７ 86. The compound or method of claim 85, wherein is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl.

87. R ７ 86. The compound or method of claim 85, wherein is substituted or unsubstituted 3-pyridinyl.

88. R ７ 86. The compound or method of claim 85, wherein is unsubstituted 3-pyridinyl.

89. R ７ but, 【Chemistry 52】 and R ９ is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, -OR ａ , -N(R ａ ) ２ or -CN.

90. R ８ 90. The compound or process of any one of claims 1 to 89, wherein each instance of is hydrogen.

91. R ８ At least one instance of １－６ 90. The compound or method of any one of claims 1 to 89, wherein said alkyl is aryl.

92. R ９ 92. The compound or process of any one of claims 1 to 91, wherein each instance of is hydrogen.

93. R ９ At least one instance of １－６ Alkyl, or -OR ａ 92. The compound or method of any one of claims 1 to 91,

94. The compound is a compound of the formula: 【Chemistry 53】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

95. The compound is a compound of the formula: 【Chemical 54】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

96. The compound is a compound of the formula: 【Chemistry 55】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

97. The compound is a compound of the formula: 【Chemistry 56】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

98. The compound is a compound of the formula: 【Chemistry 57】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

99. The compound is a compound of the formula: 【Chemistry 58】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

100. The compound is a compound of the formula: 【Chemistry 59】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (Wherein, Z is hydrogen or substituted or unsubstituted C １－６ alkyl, and m is 1, 2, 3, 4, 5, or 6.

101. The compound is a compound of the formula: 【Chemistry 60】 【Chemistry 61】 【Chemistry 62】 【Chemistry 63】 【Chemistry 64】 【Chemistry 65】 【Chemistry 66】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

102. 36. The compound or method of any one of claims 1 to 35, wherein the compound is selected from the compounds listed in Table A.

103. The compound or method according to any one of claims 1 to 35, wherein the compound is selected from the compounds described in paragraph [0198].

104. 36. The compound or method of any one of claims 1 to 35, wherein the compound is selected from the compounds listed in Table 5.

105. The compound is a compound of the formula: 【Chemistry 67】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

106. The compound is a compound of the formula: 【Chemistry 68】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

107. The compound is a compound of the formula: 【Chemistry 69】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

108. A compound of formula (I) as defined in any one of claims 1 to 4, 36 to 51, 53 to 56, 58 to 62 and 64 to 105, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally A pharma- ceutically acceptable excipient; 13. A pharmaceutical composition comprising:

109. 109. The pharmaceutical composition of claim 108, further comprising an additional pharmaceutical agent.

110. 110. The pharmaceutical composition of claim 109, wherein the additional pharmaceutical agent is a chemotherapeutic agent.

111. 113. A method of treating cancer, comprising administering to a subject the pharmaceutical composition of claim 108, 109, or 110.

112. A compound of formula (I) as defined in any one of claims 1 to 4, 36 to 51, 53 to 56, 58 to 62, and 64 to 105, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition as defined in claim 89, 90, or 91; instructions for using said compound, pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition; Including the kit.

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