Cancer treatment targeting cancer stem cells

Abstract

The invention relates to cancer therapy targeting cancer stem cells. Disclosed are compounds, methods, compositions, and kits that allow for the treatment of cancer by, for example, targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. Compounds used in the present disclosure have formulae (0), (0 ') and (I): # imgabs0 #

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: May 3, 2019; application number: 201980039988.3 (international application number: PCT / US2019 / 030664); invention title: cancer treatment targeting cancer stem cells).

[0002] Related applications

[0003] This application claims priority under Title 35, Section 119(e) of the United States Code to U.S. Provisional Applications filed May 4, 2018, USSN 62 / 667,412 and March 7, 2019, USSN 62 / 815,251, the disclosures of which are each incorporated herein by reference. Background Technology

[0004] Cancer is ubiquitous, and despite medical advancements, it remains a leading cause of death worldwide. In 2017, an estimated 1.7 million new cases of cancer were diagnosed, and 600,000 people died from the disease. 1 Cancer is the second leading cause of death worldwide, accounting for nearly one in six deaths. The number of new cases is projected to increase by approximately 70% over the next 20 years. The economic impact of cancer is enormous and is increasing. It was estimated that the total annual economic cost of cancer in 2010 was approximately US$1.16 trillion. 2

[0005] Cancer is a general term for a large class of diseases that can affect any part of the body. Other terms used are malignant tumors and growths. Cancer is caused by normal cells transforming into tumor cells in a multi-stage process, typically progressing from precancerous lesions to malignant tumors. A defining characteristic of cancer is the rapid production of abnormal cells that grow beyond their normal boundaries and can then invade adjacent parts of the body and spread to other organs; this latter process is called metastasis. Metastasis is a leading cause of cancer death. The most common causes of cancer death are lung cancer, liver cancer, colorectal cancer, stomach cancer, and breast cancer.

[0006] Despite some progress in treating subsets of cancer types, the average cancer mortality rate remains very high, with little overall improvement in the ongoing cancer crisis. Almost all modern cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on eliminating the tumor rather than targeting the most dangerous cells within it: cancer stem cells. Cancer stem cells are responsible for the spread of cancer cells throughout the body, tumor growth, cancer resistance to chemotherapy, and tumor recurrence after treatment or surgical removal. 3,4 Because current treatments do not target cancer stem cell populations, they often lead to the development of drug-resistant tumors and continued cancer spread. Summary of the Invention

[0007] The discovery of cancer stem cells has provided an opportunity for the convergence of oncology and embryonic stem cell biology. 5,6 The development of effective and non-toxic therapies that target the very reasons cancer is so dangerous—the embryonic characteristics of cancer stem cells that form the basis of cancer growth, spread, and drug resistance—can be achieved through strategies called cancer-suppressing therapies. Therapies that can both reduce tumor size and destroy cancer stem cells will revolutionize cancer treatment. 7

[0008] This article describes compounds that induce cancer stem cells to differentiate and inhibit metastasis through signaling pathways that are identical to those used by embryonic stem cells during differentiation and development. 8,9 These properties can be safely targeted because they are found only in embryonic stem cells, not in healthy adult tissue.

[0009] These compounds are expected to be more effective than traditional cancer treatments in reducing tumor growth, prolonging life, and preventing metastasis and recurrence. Furthermore, since the reactivation of embryonic characteristics is a common feature of many tumors, cancer suppression therapy holds promise for effectiveness against many different types of cancer, including colon cancer, stomach cancer, prostate cancer, testicular cancer, and breast cancer.

[0010] This article discloses compounds, methods, compositions, uses, and kits that allow for the treatment of proliferative disorders, benign growths, and cancers.

[0011] In one respect, the compounds disclosed herein have formula (0):

[0012]

[0013] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0) are as described herein. In another aspect, this disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0) are as described herein.

[0014] In one respect, the compounds disclosed herein have formula (0′):

[0015]

[0016] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0′) are as described herein. In another aspect, this disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (0′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0′) are as described herein.

[0017] In one respect, the compounds disclosed herein have formula (I):

[0018]

[0019] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (I) are as described herein. In another aspect, this 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (I) are as described herein.

[0020] In some implementations, the cancer includes cancer stem cells. In some implementations, the cancer involves or is related to cancer stem cells. In some implementations, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, or prostate cancer. In some implementations, the cancer is liver cancer or endometrial cancer. In some implementations, the cancer is leukemia. In some implementations, the cancer is lymphoma. In some implementations, the cancer is multiple myeloma. In some implementations, the subject requires regenerative medicine or a therapy.

[0021] In another aspect, this disclosure provides a method for contacting cells with an effective amount of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug of formula (0) or (0′) or thereof.

[0022] In another aspect, this disclosure provides methods and uses comprising contacting cells with an effective amount of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug of formula (I) or thereof.

[0023] In some embodiments, the compound of formula (I) is of formula (IA):

[0024] In some implementations, equation (I) is equation (IB), where: Where R 7 The 3-pyridyl group may be substituted or unsubstituted. In some embodiments, formula (I) is formula (IC), wherein:

[0025] in It is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, formula (I) is formula (IC), wherein:

[0026] in It is imidazole, oxazolyl, azacyclic butyl, -C≡C- or In some implementations, equation (I) is equation (ID), where:

[0027] Where R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group.

[0028] In some embodiments, this disclosure provides compositions 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 some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises additional pharmaceutical agents.

[0029] In some embodiments, this disclosure provides compositions 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 some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises additional pharmaceutical agents.

[0030] In some embodiments, this 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 the composition described herein; and instructions for use of said compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0031] In a further embodiment, this disclosure provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or the composition described herein; and instructions for use of said compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0032] Details of certain embodiments of the present invention are set forth in the detailed description below. Other features, objectives, and advantages of the invention will become apparent from the definitions, drawings, embodiments, and claims. Attached Figure Description

[0033] Figure 1 Compound I-1 was shown to deplete the embryonic-like gastric cell population in gastric cancer.

[0034] Figure 2 Compound I-1 showed that it reduced oct4 expression in gastric cancer cells.

[0035] Figure 3 Compound I-1 showed that it reduced nanog expression in gastric cancer cells.

[0036] Figure 4 Compound I-1 showed no toxicity to healthy liver cells.

[0037] Figure 5 Compound I-1 was shown to inhibit the growth of gastric cancer cells.

[0038] Figure 6 The in vitro properties of compound I-1 (e.g., solubility, microsomal stability, and plasma stability) were shown.

[0039] Figure 7 The pharmacokinetics of compound I-1 in mice were shown.

[0040] Figure 8 The mouse tolerance results for compound I-1 are shown.

[0041] definition

[0042] For convenience, certain terms used herein in the specification, embodiments and appended claims are included.

[0043] Unless the context otherwise requires, singular terms should include plural terms and plural terms should include singular terms.

[0044] The phrase "in some implementations" and the phrase "in certain implementations" are used interchangeably.

[0045] The following definitions are the more general terms used in this application:

[0046] Unless the context clearly indicates otherwise, the singular terms “a,” “an,” and “the” include plural referents. Similarly, the word “or” is intended to include “and,” unless the context clearly indicates otherwise.

[0047] Except as illustrated in the examples or otherwise stated, all figures used herein to represent amounts of components or reaction conditions should be understood to be modified by the term “about” in all cases. Given the nature or precision of the measurement, “about” and “approximately” generally mean an acceptable degree of error for the measured quantity. Exemplary degrees of error are within 20% (%) of a given value or range, typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1%.

[0048] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the periodic table of elements on the inner cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0049] The compounds described herein may include one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (Ell. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also covers compounds as single isomers substantially free of other isomers, as well as mixtures of various isomers, alternatively.

[0050] In the formula, It is a single bond, where the stereochemistry of the portion directly bonded to it is unspecified—either it does not exist or it is a single bond, and It is either a single bond or a double bond.

[0051] Unless otherwise specified, the formulas described herein include compounds excluding isotopically enriched atoms as well as compounds including isotopically enriched atoms. Compounds including isotopically enriched atoms can be used as analytical tools and / or probes, for example, in biological assays.

[0052] The term "aliphatic" includes 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., halogens, such as fluorine). As will be understood by those skilled in the art, "aliphatic" herein is intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0053] When listing a range of values ​​(“range”), it is intended to encompass every value within that range and its subranges. Unless otherwise provided, a range includes the values ​​at both ends of the range. For example, “integers between 1 and 4” means 1, 2, 3, and 4. For example, “C…” 1-6 "Alkyl" is intended to encompass 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.

[0054] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 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 (“C1 alkyl”). 2-6 Alkyl group). 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), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-12 Alkyl groups (e.g., -CH3(Me), unsubstituted ethyl groups (Et), unsubstituted propyl groups (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl groups (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C 1-12 Alkyl groups (such as substituted C4 groups) 1-6 Alkyl groups, such as -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)). The linkage of an alkyl group can be a single bond (e.g., in -CH3), a double bond (e.g., in =CH2), or a triple bond (e.g., in ≡CH). Parts =CH2 and ≡CH are also alkyl groups.

[0055] In some embodiments, the alkyl group is substituted with one or more halogens. A “holohaloalkyl” is a substituted alkyl group as defined herein, wherein all hydrogen atoms are independently substituted with a halogen (e.g., fluorine, bromine, chlorine, or iodine). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms (“C…”). 1-8 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C6”). 1-6 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms (“C4”). 1-4 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C10"). 1-3 (Fully halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C10”). 1-2(Perhaloalkyl). In some embodiments, all hydrogen atoms are replaced by fluorine. In some embodiments, all hydrogen atoms are replaced by chlorine. Examples of perhaloalkyl include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[0056] "Alkenyl" refers to a straight-chain or branched hydrocarbon group ("C-alkenyl") having 2 to 20 carbon atoms, one or more (e.g., two, three, or four, depending on valence) carbon-carbon double bonds, and no triple bonds. 2-20 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-10 Alkenyl group. In some embodiments, the alkenyl group is a substituted C-group. 2-10 Alkenyl. In alkenyl groups, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3, ...). It can be in (E)- or (Z)- configuration.

[0057] "Alkyne" refers to a straight-chain or branched hydrocarbon group ("C-H") having 2 to 20 carbon atoms, one or more (e.g., two, three, or four, depending on valence) carbon-carbon triple bonds, and optionally one or more double bonds. 2-20 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of the alkynyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-10 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-10 Alkyne group.

[0058] "Carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 13 ring carbon atoms ("C"). 3-13 The carbocyclic group has 3 to 8 cyclic carbon atoms (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”). The carbocyclic group may be saturated, and saturated carbocyclic groups are referred to as “cycloalkyl”. In some embodiments, the carbocyclic group is a monocyclic saturated carbocyclic group (“C”) having 3 to 10 ring carbon atoms. 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C14 groups. 3-6Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C- group. 3-10 Cycloalkyl. The carbocyclic group may be partially unsaturated. The carbocyclic group may include zero, one or more (e.g., two, three, or four, depending on the valence) C=C double bonds in all rings of a non-aromatic or heteroaromatic carbocyclic system. A carbocyclic group that includes one or more (e.g., two or three, depending on the valence) C=C double bonds in the carbocyclic group is called a “cycloalkenyl”. A carbocyclic group that includes one or more (e.g., two or three, depending on the valence) C≡C triple bonds in the carbocyclic group is called a “cycloynyl”. Carbocyclic groups include aryl groups. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaromatic groups, wherein the bonding point is on the carbocyclic ring, and in this case, the number of carbons continues to indicate the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently and optionally substituted, e.g., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is substituted or unsubstituted, 3 to 7 members and monocyclic. In some embodiments, the carbocyclic group is substituted or unsubstituted, 5 to 13 members and bicyclic.

[0059] In some implementations, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 10 ring carbon atoms. 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8Examples of cycloalkyl groups include the aforementioned C14 groups. 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C12. 3-10 Cycloalkyl.

[0060] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 13-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclic groups"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"). Heterocyclic groups can be saturated or partially unsaturated. Heterocyclic groups can include zero, one or more (e.g., two, three, or four, where the valence allows) double bonds in all rings of a non-aromatic or heteroaromatic heterocyclic system. Partially unsaturated heterocyclic groups include heteroaryl groups. Heterocyclic bicyclic systems can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or includes ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise indicated, each instance of a heterocyclic group is independently and optionally substituted, for example, unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is substituted or unsubstituted, 3 to 7-membered, and monocyclic. In some embodiments, the heterocyclic group is substituted or unsubstituted, 5 to 13-membered, and bicyclic.

[0061] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0062] Exemplary 3-membered heterocyclic groups containing one heteroatom include aziridinyl, ethylene oxide, or cyclothioethane. Exemplary 4-membered heterocyclic groups containing one heteroatom include azirrobutyl, oxetyl, and thiobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxolanecycloyl, oxetyl, dithioalkyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0063] "Aryl" refers to a group ("C") having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons common to the ring array) that provides 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system. 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each instance of an aryl is independently and optionally substituted, for example, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0064] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic -4n+2 aromatic ring system (e.g., having 6 or -10 π electrons common to the ring array) of a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl, where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the connection point can be on either ring, for example, a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0065] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0066] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrole, furanyl, and phenylthio. 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 tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azazolyl. basic, oxygen thia Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazole, benzotriazolyl, benzobenzylthio, isobenzobenzylthio, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Examples of 6,6-bicyclic heteroaryl groups include naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0067] "Partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl) as defined herein. Similarly, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains all single bonds.

[0068] In some embodiments, 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). Generally, the term "substituted," whether preceded by "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a usable substituent, such that, for example, the substitution yields a stable compound, which is a compound that does not spontaneously undergo transformation, such as through rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a “substituted” group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. Unless otherwise provided, substituents on a polycyclic ring can be at any substituted position on any monocyclic ring of the polycyclic ring. The term “substituted” is contemplated to include substitution with all available substituents of an organic compound (any substituent described herein that causes the formation of a stable compound). This disclosure contemplates any and all such combinations to obtain a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or satisfy the valence of the heteroatom and cause the formation of a stable moiety with any suitable substituent as described herein.

[0069] Exemplary carbon substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2Raa 、-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)(ORcc )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 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0070] Or two hydrogen atom on a carbon atom are surrounded by =O, =S, =NN(R) groups. bb )2、=NNR bb C(=O)Raa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc Substitute;

[0071] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0072] R bb Each instance is independently selected from 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) 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 All-halogenated alkyl, C 2-10alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0073] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0074] R dd Each instance is independently selected from halogens, -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(Rff )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(R) ff )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 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groupsdd Substituents can be linked to form =O or =S; where X - It is a counter ion;

[0075] R ee Each instance is independently selected from C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0076] R ff Each instance is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff Groups are linked to form 3-10 membered heterocyclic groups or 5-10 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0077] R gg Each instance is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3+ X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl, -P(=O)(OC) 1-6 Alkyl)2、-P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two geminal Rs gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0078] In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by 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. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb )2, -CN, -SCN, -NO2, -C(=O)R aa -CO2R aa-C(=O)N(R) bb )2、-OC(=O)R aa -OCO2R aa -OC(=O)N(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(R bb )2, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl group, oxygen-protecting group attached to an oxygen atom, or sulfur-protecting group attached to a sulfur atom (e.g., acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl); each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen-protecting group. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb 2. -CN, -SCN, or -NO2. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., partially substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb )2, -CN, -SCN or -NO2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl group, oxygen-protecting group attached to an oxygen atom, or sulfur-protecting group attached to a sulfur atom (e.g., acetamoxymethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl); and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group.

[0079] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one form of negative charge). Anionic counterions can also be polyvalent (i.e., comprising more than one form of negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F). - Cl - ,Br - I - NO3 - ClO4 - OH - H2PO4 - HCO3 - HSO4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - PF4 - PF6 - AsF6 - SbF6 - B[3,5-(CF3)2C6H3]4] - B(C6F5)4 - BPh4 - Al(OC(CF3)3)4 - and carborane anions (e.g., CB) 11 H 12 - or (HCB) 11 Me5Br6) - Exemplary multivalent counterions include CO3. 2- HPO4 2- PO4 3- B4O7 2- SO4 2- S2O3 2- Carboxylate anions (such as tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0080] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0081] Where valence permits, the nitrogen atom may be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include hydrogen, -OH, and -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 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, or two R groups bonded to a N atom cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As defined above.

[0082] In some embodiments, the nitrogen substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C atom. 1-6 Alkyl, -C(=O)Raa -CO2R aa -C(=O)N(R) bb )2 or nitrogen protecting group. In some embodiments, the nitrogen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or nitrogen protecting group, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the nitrogen substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C atom. 1-6 Alkyl or nitrogen protecting group.

[0083] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). 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, heteroaralkyl), C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Base substitution, and where R aa R bb R cc and R dd As defined herein, nitrogen protecting groups are those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0084] Amide nitrogen protecting group (e.g., -C(=O)R) aa This includes formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0085] Carbamate nitrogen protecting groups (e.g., -C(=O)OR) aaThis includes methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiopheneyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), and 1-(1-adamantyl)-1-methylethyl carbamate (Adpo). c) 1,1-Dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-diphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylcarbamate)ethylcarbamate, tert-butyl carbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc) ), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, 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-anthraylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-dithiaalkyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonoethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromone methylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylethylene carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl Carbamates, isobornyl carbamate, isobutyl carbamate, isonicoyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamates, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0086] sulfonamide nitrogen protecting group (e.g., -S(=O)2R) aa This includes 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-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethylsulfonamide.

[0087] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazopentanyl adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluoreneamine (PhF), N-2,7 -Dichloro-9-fluorenylmethyleneamine, N-ferrocene-methylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosamine, amine N-oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkyl aminophosphate, dibenzyl aminophosphate, diphenyl aminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

[0088] In some embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0089] In some embodiments, the oxygen substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C atom. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group. In some embodiments, the nitrogen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the oxygen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

[0090] In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to herein as "hydroxyl protecting groups"). 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 As defined herein. Oxygen protecting groups are those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0091] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyl dimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silanoxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromo Tetrahydropyranyl, 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-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylbridged benzofuran-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-(phenylhydroselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxyphenyl, 3,4-dimethoxyphenyl, o-nitrophenyl, p-nitrophenyl, p-halophenylmethyl, 2,6-dichlorophenylmethyl, p-cyanophenylmethyl, p-phenylphenylmethyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenyl Methyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorobenzoyliminophenyl)methyl, 4,4',4”-tris(acetylpropionyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)oxanthraceneyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithio-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triphenylmethylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methyl Oxyethyl acetate, triphenylmethoxyethyl acetate, phenoxyethyl acetate, p-chlorophenoxyethyl acetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionyl dithioacetal), neovalerate, adamantane ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Ps) ec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzenemethyl carbonate, 3,4-dimethoxybenzenemethyl carbonate, o-nitrobenzenemethyl carbonate, p-nitrobenzenemethyl carbonate, S-benzenemethyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-( (Methiomethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, alkyl N,N,N',N'-tetramethylphosphinodiacamide, N-phenylcarbamate, borate, dimethylphosphino, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, methanesulfonate (methanesulfonate), benzylmethylsulfonate, and toluenesulfonate (Ts).

[0092] In some embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, neopentanoyl, or benzoyl.

[0093] In some embodiments, the sulfur atom substituent is either independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or sulfur protecting group. In some embodiments, the sulfur atom substituent is an independently substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or sulfur protecting group, wherein R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the sulfur substituent is an independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or sulfur protecting group.

[0094] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). 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(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 R aa R bb , and R cc As defined herein, a sulfur protecting group is those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In some embodiments, the sulfur protecting group is acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl.

[0095] The molecular weight of -R (where -R is any monovalent part) is calculated by subtracting the atomic weight of hydrogen atoms from the molecular weight of the molecule RH. The molecular weight of -L- (where -L- is any divalent part) is calculated by subtracting the combined atomic weight of two hydrogen atoms from the molecular weight of the molecule HLH.

[0096] In some embodiments, the molecular weight of the substituent is less than 200, less than 150, less than 100, less than 50, or less than 25 g / mol. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the substituent is composed of carbon, hydrogen, and / or fluorine atoms. In some embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond donors. In some embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond acceptors.

[0097] Adding the suffix "ene" to a group indicates that the group is a polyvalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In some embodiments, adding the suffix "ene" to a group indicates that the group is a divalent moiety.

[0098] The term "hydroxyl group" refers to the -OH group.

[0099] The term "thiol" or "thio" refers to the -SH group.

[0100] The term "amine" or "amino" refers to the group -NH- or -NH2.

[0101] The term "acyl" refers to a group having the following general formula: -C(=O)R X1 -C(=O)OR X1 -C(=O)-OC(=O)R X1 -C(=O)SR X1 -C(=O)N(R) X1 )2、-C(=S)R X1 -C(=S)N(R) X1 )2, and -C(=S)S(R X1 -C (=NR) X1 )R X1 -C(=NR) X1 OR X1 -C(=NR) X1 )SR X1 and -C(=NR) X1 )N(R X1 )2, where R X1 Hydrogen; halogen; substituted or unsubstituted hydroxyl group; substituted or unsubstituted thiol; substituted or unsubstituted amino group; substituted or unsubstituted acyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl group; 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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkyl sulfoxy, heteroalkyl sulfoxy, aryl sulfoxy, heteroaryl sulfoxy, mono- or dialiphatic amino, mono- or dialkylamino, mono- or diheteroalkylamino, mono- or diarylamino or mono- or diheteroarylamino; or two R X1The groups together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any substituents described herein that lead to the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkyl sulfoxy, heteroalkyl sulfoxy, aryl sulfoxy, heteroaryl sulfoxy, acyloxy, etc., each of which may or may not be further substituted).

[0102] The term "salt" refers to an ionic compound produced by the neutralization reaction of an acid and a base. A salt consists of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (has no net charge). Salts of the compounds disclosed herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0103] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 - Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0104] The term "solvent" refers to a substance that dissolves one or more solutes to produce a solution. Solvents can be used as the medium for any reaction or transformation described herein. Solvents can dissolve one or more reactants or reagents in the reaction mixture. Solvents can promote the mixing of one or more reagents or reactants in the reaction mixture. Solvents can also be used to increase or decrease the reaction rate relative to reactions in different solvents. Solvents can be polar or nonpolar, protons or aprotons. Common solvents that can be used in the methods described herein include, but are not limited to, acetone, acetonitrile, benzyl nitrile, 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, ethanol, ethylene glycol, dimethyl ether, heptane, n-hexane, and hexane. Alkane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, ethyl 2-methoxyethyl acetate, methanol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidone, 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.

[0105] The term "solvent" refers to a compound or its salt that typically associates with a solvent via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, as well as stoichiometric and non-stoichiometric solvates. In some cases, solvates will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvent" includes both the solution phase and the separable solvate. Representative solvates include hydrates, ethanolides, and methanolides.

[0106] The term "hydrate" refers to a compound that associates with water. Typically, the number of water molecules in a hydrate of a compound is in a definite 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 more than one hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0107] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0108] The term "eutectic" refers to a crystal structure comprising at least two distinct components (e.g., a compound of formula (I) and an acid), wherein each component is independently an atom, ion, or molecule. In some embodiments, none of the components are solvents. In some embodiments, at least one component is a solvent. A eutectic of a compound of formula (I) and an acid is different from a salt formed from a compound of formula (I) and an acid. Eutectic can be used to improve the properties of the compound of formula (I) (e.g., solubility, stability, and ease of formulation).

[0109] Furthermore, the term "eutectic" refers to a crystal structure comprising at least two different components (e.g., a compound of formula (0) and an acid), wherein each component is independently an atom, ion, or molecule. In some embodiments, none of the components are solvents. In some embodiments, at least one component is a solvent. A eutectic of a compound of formula (0) or (0′) with an acid is different from a salt formed by a compound of formula (0) or (0′) with an acid. Eutectic can be used to improve the properties of a compound of formula (0) or (0′) (e.g., solubility, stability, and ease of formulation).

[0110] The term "tautomer" or "tautomerizing" refers to two or more interconvertible compounds resulting from at least one formal migration of hydrogen atoms and at least one change in valence (e.g., single to double, triple to single, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone-to-enol, amide-to-imide, lactam-to-lactamimide, enamine-to-imide, and enamine-to-(different enamines) tautomerization.

[0111] It should also be understood that compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of their atoms, are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." In some embodiments, if the phenyl group contains two substituents, each bonded to an adjacent carbon, the compound may be called an ortho isomer. In some embodiments, if the phenyl group contains two substituents, each bonded to a carbon separated by a ring carbon, the compound may be called a meta isomer. In some embodiments, if the phenyl group contains two substituents, each bonded to a carbon separated by two ring carbons, the compound may be called a para isomer.

[0112] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, it may have a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or by rotating the molecule in a plane of polarized light and specifying it as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0113] As used herein, the term "pharmaceutical" refers to a molecule, group of molecules, complex, or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. In some embodiments, a pharmaceutical agent is a pharmaceutical agent (e.g., a therapeutic agent, diagnostic agent, or preventative agent). In some embodiments, the compositions disclosed herein comprise one or more pharmaceutical agents, such as a first therapeutic agent (e.g., at least one, including, for example, at least two or at least three). In some embodiments, the composition may also comprise a second therapeutic agent, a targeting portion, or a diagnostic portion as described herein.

[0114] As used herein, the term "therapeutic agent" includes agents capable of providing local or systemic biological, physiological, or therapeutic effects in the biological system to which they are administered. For example, therapeutic agents can be used to control tumor growth, control infection or inflammation, act as analgesics, promote anti-cell adhesion, and enhance bone growth. Other suitable therapeutic agents may include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active at the time of administration but are converted into biologically active agents through metabolism or some other mechanism after administration to a subject.

[0115] Pharmaceutical agents (e.g., therapeutic agents) can include a wide variety of compounds, including chemical compounds and mixtures of chemical compounds (e.g., small organic or inorganic molecules), such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use as defined in the Code of Federal Regulations (CFR)); targeting agents; isotopically labeled compounds; pharmaceutical agents suitable for bioprocessing; carbohydrates; saccharin; monosaccharides; oligosaccharides; polysaccharides; biological macromolecules (e.g., peptides, proteins, and peptide analogs and derivatives); peptide mimics; antibodies and their antigen-binding fragments; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucins; lipoproteins; synthetic polypeptides or proteins; small molecules linked to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunizing agents; extracts made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combination thereof.

[0116] In some embodiments, the pharmaceutical agent is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, for example, through solvent decomposition, reduction, oxidation, or under physiological conditions, to provide, for example, a pharmaceutically active compound in vivo. Prodrugs may include derivatives of pharmaceutically active compounds, such as esters formed by the reaction of an acid or anhydride or mixed anhydride portion of the prodrug moiety with a hydroxyl portion of the pharmaceutically active compound, or amides prepared by the reaction of an acid or anhydride or mixed anhydride portion of the prodrug moiety with a substituted or unsubstituted amine of the pharmaceutically active compound. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups may contain prodrugs. In some embodiments, the compositions described herein incorporate a therapeutic agent or a prodrug thereof. In some embodiments, the compositions described herein incorporate more than one therapeutic agent or prodrug.

[0117] In some embodiments, the agent (e.g., a therapeutic agent) is a small molecule. As used herein, the term "small molecule" can refer to a "natural product-like" compound. However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, a small molecule is 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, more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases, the molecular weight of the small molecule is preferably equal to or less than 700 Daltons.

[0118] Exemplary pharmaceutical agents (e.g., therapeutic agents) in the composition include, but are not limited to, those found in the following literature: Harrison's Principles of Internal Medicine, 13th edition, TR. Harrison et al., McGraw-Hill NY, NY; Physicians' Desk Reference, 50th edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics; and the latest edition of the Merck Index, all of which are incorporated herein by reference.

[0119] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more therapeutic agents listed in paragraph 1 of U.S. Patent No. 9,381,253, which is incorporated herein by reference.

[0120] In other embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more therapeutic agents listed in WO 2013 / 169739, including, for example, antihypertensive drugs and / or collagen modifiers (“AHCM”) disclosed in paragraphs 40-49, 283, 286-295; and, for example, microenvironment modifiers disclosed in paragraphs 113-121 of WO 2013 / 169739, which are incorporated herein by reference. In some embodiments, compositions comprising AHCM and / or microenvironment modifiers induce one or more of the following in a subject: reduction of solid stress (e.g., growth-induced solid stress in tumors); 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 vascular diameter and / or dilation of compressed or collapsed vessels; reduction or depletion of one or more of the following: cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); reduction of extracellular matrix components (such as fibers (e.g., collagen, etc.)). The levels or production of procollagen and / or polysaccharides (such as glycosaminoglycans like hyaluronic acid or hyaluronic acid) may be reduced; the levels or production of collagen or procollagen may be decreased; the levels or production of hyaluronic acid may be decreased; tumor oxygenation may be increased; tumor hypoxia may be reduced; tumor acidosis may be reduced; immune cell infiltration may be increased; immunosuppression may be reduced; antitumor immunity may be increased; the production of cancer stem cells (also referred to herein as tumor-initiating cells) may be decreased; or the efficacy of therapies may be enhanced (e.g., penetration or spread), such as cancer therapies in the tumor or tumor vascular system (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy).

[0121] Pharmaceuticals, such as therapeutic agents, include the categories and specific examples disclosed herein. This is not intended to limit the categories by specific examples. Those skilled in the art will also recognize many other compounds that belong to this category and are applicable under this disclosure.

[0122] Examples of therapeutic agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, anti-irritants, coagulation modifiers, diuretics, sympathomimetic agents, anorexia nervosa, antacids, and other gastrointestinal agents; antiparasitic agents, antidepressants, antihypertensive agents, anticholinergic agents, stimulants, antihormonal agents, central and respiratory stimulants, drug antagonists, lipid regulators, uric acid excretion agents, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, sympathomimetic agents, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast agents, radiopharmaceuticals, antiallergics, sedatives, vasodilators, antiviral agents, and antitumor agents or cell growth inhibitors or other agents with anticancer effects, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Other examples include anti-infective agents, such as antibiotics and antiviral agents; analgesics and combinations of analgesics; anorexia; antihistamines; antiarthritis drugs; antiasthmatic drugs; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory drugs; anti-migraine preparations; antinausea drugs; antitumor drugs; anti-Parkinson's disease drugs; antipruritics; antipsychotics; antipyretics and antispasmodics; anticholinergics; sympathomimetic drugs; xanthine derivatives; and cardiovascular preparations, including calcium channel blockers and beta-blockers. Body blocking agents, such as indole and antiarrhythmic drugs; antihypertensive drugs; diuretics; vasodilators, including those for the coronary, peripheral, and cerebral systems; central nervous system stimulants; cough and cold medicines, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic drugs; psychostimulants; sedatives; and tranquilizers; as well as naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0123] The terms “composition” and “formulation” are used interchangeably.

[0124] The intended "subject" refers to a human (i.e., a male or female of any age, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly person)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey), a commercially relevant 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 developmental stage. The non-human animal can be a transgenic or genetically engineered animal.

[0125] The terms “administer,” “administering,” or “administration” mean the implantation, absorption, ingestion, injection, inhalation, or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0126] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., based on a history of symptoms). Treatment may also continue after symptom relief, for example, to delay and / or prevent recurrence of the disease or disorder.

[0127] The terms "prevent," "preventing," or "prevention" refer to preventive treatment for subjects who currently do not have or have not had any disease but are at risk of developing it, or who have had a disease in the past but are currently not at risk of remission. In some implementations, subjects have a higher risk of developing a disease or a higher risk of disease remission compared to the average healthy member of the subject population.

[0128] The terms “symptom,” “disease,” and “disorder” are used interchangeably.

[0129] "Proliferative disorders" are diseases caused by abnormal growth or spread due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press, Cambridge, 1990). Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant tumors"), benign tumors, diseases related to angiogenesis, inflammatory diseases, and autoimmune diseases.

[0130] The terms “vesicle” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and incongruous with the growth of normal tissue. A vegetation 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. “Benign vegetations” are typically well-differentiated, characterized by slower growth than malignant vegetations, and remain confined to the site of origin. Furthermore, benign vegetations do not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign vegetations include, but are not limited to, lipomas, chondromas, adenomas, acanthomas, senile hemangiomas, seborrheic keratosis, nevi, and sebaceous hyperplasia. In some cases, certain “benign” tumors may later give rise to malignant vegetations, possibly due to other genetic changes in a subset of tumor vegetation cells, and these tumors are referred to as “malignant pre-vesicles.” An exemplary malignant pre-vesicle is a teratoma. In contrast, "malignant growths" are typically poorly differentiated (dysplastic) and characterized by rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, and are usually identified by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type in which the primary or original tumor is located, rather than by the presence of a "secondary tumor" or "secondary cell mass" of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to bone is called metastatic prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0131] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal human tissues. See, for example, Stedman's Medical Dictionary, 25th edition; edited by Hensyl; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial cell sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct cancer); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); chordoma; craniopharyngioma. Colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma)). Cancers include: pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic system cancers (e.g., leukemia, such as 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's lymphoma (HL) (e.g., B-cell HL). T-cell lymphomas (HL) and non-Hodgkin lymphomas (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e. 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, Sezary 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-mentioned leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha-1 ... Chain disease, gamma chain disease, μ chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastoma; immune cell amyloidosis; renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., generalized mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), amyelometaplasia of unknown etiology (AMM)). Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibroma type 1 or 2, schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor. Tumors (PNT); plasmacytoma; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), corneal acanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testis carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer;And vulvar cancer (e.g., Paget's vulvary disease).

[0132] Cancer cells exhibit properties similar to embryonic stem cells. As used herein, cancer stem cells (CSCs) are embryonic-like cancer cells that possess one or more embryonic characteristics. CSCs are generally considered problematic cancer cells due to their ability to metastasize and form tumors in other parts of the body. As used herein, “embryonic characteristics” refers to gene and / or miRNA expression and / or biological properties similar to those of embryonic cells. Undifferentiated cancer cells with embryonic characteristics are metastatic, resistant to chemotherapy and radiation therapy, and capable of regrowth after most tumors have been removed or shrunk following surgery and / or other cancer treatments.

[0133] In some embodiments, cancer stem cells are characterized by the expression of genes and / or miRNAs associated with 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 embryonic state.

[0134] In some implementations, cancer stem cells are characterized by one or more embryonic characteristics. Examples of embryonic characteristics include, but are not limited to, cell self-renewal properties, excessive proliferative activity, pluripotency, multipotency, expression of embryonic markers, lack of differentiation markers, resistance to chemotherapy, motility, and the ability to generate different cell lineages.

[0135] As used herein, the terms “regenerative medicine” or “regenerative therapy” refer to the ability to promote the regeneration of cells, tissues, and / or organs. Regenerative medicine includes cell and / or tissue engineering to replace, engineer, or regenerate cells, tissues, and / or organs; and / or restore or improve one or more biological functions of dysfunctional or damaged cells, tissues, and / or organs; as well as tissue engineering and organ regeneration. As used herein, “regenerative capacity” refers to the ability of cells, such as stem cells, to transform into dividing progenitor cells and differentiated tissue-specific cells. Regenerative capacity may additionally or alternatively refer to the ability of cells, tissues, and / or organs to replicate, proliferate, restore function, and / or regenerate.

[0136] The term "effective amount" for the compositions described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of the compositions described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the route of administration, and the age and health status of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic effective amount. In some embodiments, the effective amount is the amount of the composition or pharmaceutical composition described herein in a single dose. In some embodiments, the effective amount is the combined amount of the composition or pharmaceutical composition described herein in multiple doses.

[0137] The "therapeuticly effective amount" of the compositions described herein is an amount sufficient to provide therapeutic benefit in the treatment of a condition or sufficient to delay or minimize one or more symptoms associated with the condition. Therapeuticly effective amount of a composition refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a condition. The term "therapeuticly effective amount" can include amounts that improve overall therapy; reduce or avoid symptoms, signs, or causes of the condition; and / or enhance the therapeutic efficacy of another therapeutic agent.

[0138] The “preventatively effective amount” of a compound described herein is an amount sufficient to prevent the disease or one or more symptoms associated with the disease, or to prevent its recurrence. The preventatively effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides preventative benefit in preventing the disease. The term “preventatively effective amount” may also include amounts that improve overall prevention or enhance the preventative efficacy of another preventative agent.

[0139] The term "gene" refers to a nucleic acid fragment that provides a template for producing a gene product. In some embodiments, the nucleic acid fragment includes regulatory sequences preceding and following the coding sequence. "Natural gene" refers to a gene found in nature that has its own regulatory sequences. "Chimeric gene" or "chimeric construct" refers to any gene or construct that contains regulatory and coding sequences not found in nature, rather than a natural gene. Therefore, a chimeric gene or chimeric construct may contain regulatory and coding sequences derived from different sources, or regulatory and coding sequences derived from the same source but arranged differently from those found in nature. "Endogenous gene" refers to a natural gene located at its natural position in the genome of an organism. "Exogenous" gene refers to a gene that is not normally found in a host organism but is introduced into a host organism through gene transfer. Exogenous genes may include natural genes or chimeric genes inserted into non-natural organisms. "Transgenic" is a gene introduced into the genome through a transformation procedure.

[0140] The terms “nucleic acid” or “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 together in a chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two polynucleotide chains, each helical. In nature, RNA typically occurs as a single-stranded fold. Exemplary types of RNA include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0141] This disclosure is not intended to be limited in any way by the exemplary list of substituents provided above. Additional terms may be defined in other parts of this disclosure. Detailed Implementation

[0142] Before describing the disclosed systems, compounds, compositions, methods, uses, and kits in more detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, apparatus, or constructions, and therefore are subject to variation. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting unless specifically defined herein.

[0143] The compounds, compositions thereof, and kits disclosed herein can be used for the treatment of cancer and proliferative diseases. The compounds can differentiate embryonic-like cancer stem cells, disrupt their proliferation, and / or inhibit their ability to form new tumors. Embryonic-like characteristics, including embryonic gene expression patterns, are reactivated in a variety of different types of cancer. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. For example, embryonic-like characteristics have been found in cancer stem cells derived from solid tumors, such as colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer. 10 Embryonic-like characteristics have also been found in cancer stem cells derived from hematopoietic system cancers such as leukemia and lymphoma. 14

[0144] compound

[0145] In some respects, this disclosure provides compounds of formulas (0) and (0′).

[0146] This disclosure describes the compound of formula (I) described herein.

[0147] In some embodiments, the compound is a compound of formula (0):

[0148]

[0149] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0150] L A -N(R) 2 (L) 1 R 1 ) or -C(=O)NR 1 R 2 ;

[0151] L 1 It is a single bond or -C (=O)-;

[0152] When L 1 When it is a single bond, R 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0153] When L 1 When R is -C(=O)-, 1 To replace C 1-6 Alkyl groups, wherein the substituents comprise at least one double bond, triple bond, or heteroatom; substituted or unsubstituted C atoms 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group.

[0154] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0155] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0156] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0157] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups;

[0158] q is 0 or 1;

[0159] Each instance of Y is independently N or CR 4 ;

[0160] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0161] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacyclic butyl, -C≡C- or

[0162] when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in the meta or para position relative to each other;

[0163] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0164] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0165] L B -N(R) 6 )L 2 -or-L 2 N(R 6 )-;

[0166] L 2 -C(=O)-、 Or -S(=O)2-;

[0167] Each R 6 Independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0168] s is 0 or 1;

[0169] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0170] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0171] In some embodiments, the compound of formula (0′) has the following formula:

[0172]

[0173] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0174] L 1 It is a single bond or -C (=O)-;

[0175] When L 1 When it is a single bond, R 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0176] When L 1 When R is -C(=O)-, 1 To replace C 1-6 Alkyl groups, wherein the substituents comprise at least one double bond, triple bond, or heteroatom; substituted or unsubstituted C atoms 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group.

[0177] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0178] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0179] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0180] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups;

[0181] q is 0 or 1;

[0182] Each instance of Y is independently N or CR 4 ;

[0183] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0184] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacyclic butyl, -C≡C- or

[0185] when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in the meta or para position relative to each other;

[0186] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0187] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0188] L 2 -C(=O)-、 Or -S(=O)2-;

[0189] Each R 6 Independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0190] s is 0 or 1;

[0191] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0192] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0193] In some embodiments, the compound is a compound of formula (I):

[0194]

[0195] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0196] L 1 It is a single bond or -C (=O)-;

[0197] When L 1 When it is a single bond, R 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0198] When L 1When it is -C(=O)-, R 1 It 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 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group.

[0199] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen-protecting groups;

[0200] R 3 It is a halogenated, substituted, or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2, or -CN;

[0201] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0202] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups;

[0203] Each instance of Y is independently N or CR 4 ;

[0204] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0205] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, aziridine, -C≡C- or

[0206] Keys b and c are either interpositional or opposite to each other;

[0207] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0208] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0209] L 2 It is -C(=O)- or -S(=O)2-;

[0210] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0211] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0212] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0213] In some implementation schemes:

[0214] L 1 It is a single bond or -C (=O)-;

[0215] When L 1 When it is a single bond, R 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0216] When L 1 When it is -C(=O)-, R 1 It is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6 Alkyl; substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group.

[0217] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen-protecting groups;

[0218] R 3 It is a halogenated, substituted, or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2, or -CN;

[0219] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0220] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups;

[0221] Each instance of Y is independently N or CR 4 ;

[0222] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0223] It can be phenyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl;

[0224] Keys b and c are either interpositional or opposite to each other;

[0225] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0226] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0227] L2 It is -C(=O)- or -S(=O)2-;

[0228] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0229] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0230] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0231] In some embodiments, the compound is a compound of formula (I):

[0232]

[0233] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0234] L 1 It is a single bond or -C (=O)-;

[0235] When L 1 When it is a single bond, R 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0236] When L 1 When it is -C(=O)-, R 1 It is a substituted C containing at least one double bond, triple bond, or heteroatom. 1-6Alkyl; substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group.

[0237] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen-protecting groups;

[0238] R 3 It is a halogenated, substituted, or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2, or -CN;

[0239] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0240] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups;

[0241] Each instance of Y is independently N or CR 4 ;

[0242] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0243] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl;

[0244] Keys b and c are either interpositional or opposite to each other;

[0245] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0246] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0247] L 2 It is -C(=O)- or -S(=O)2-;

[0248] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0249] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0250] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0251] In some implementations, equation (I) is equation (IA):

[0252]

[0253] (For example,

[0254] ).

[0255] In some implementations, equation (I) is as follows:

[0256]

[0257] (For example,

[0258]

[0259] ).

[0260] In some implementations, equation (I) is equation (IB):

[0261] Where R 7 It is either substituted or unsubstituted 3-pyridyl.

[0262] In some implementations, formula (I) is formula (IC):

[0263]

[0264] in It is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, formula (I) is formula (IC), wherein... It is an imidazole group or an oxazolyl group. In some embodiments, formula (I) is formula (IC), wherein... It is a nitrogen-containing heterocyclic butyl group. In some embodiments, formula (I) is formula (IC), wherein... For -C≡C-. In some embodiments, equation (I) is equation (IC), where for

[0265] In some embodiments, the compound of formula (I) has formula (IC):

[0266]

[0267] in It is thiazolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In some embodiments, formula (I) is formula (IC), wherein... It is a thiazolyl group. In some embodiments, formula (I) is formula (IC), wherein... It is piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In some embodiments, formula (I) is formula (IC), wherein... It is piperazine group.

[0268] In some implementations, equation (I) is equation (ID):

[0269] Where R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group.

[0270] In some implementations, equation (I) is as follows:

[0271] Where R 7 It is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group (e.g., a substituted or unsubstituted 3-pyridyl group).

[0272] In some implementations, equation (I) is as follows:

[0273] in:

[0274] R 1C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6 alkyl);

[0275] R 2 C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-3 Alkyl); and

[0276] R 7 It is a substituted or unsubstituted pyridinyl group (e.g., a substituted or unsubstituted 3-pyridinyl group).

[0277] In some implementations, equation (I) is as follows:

[0278]

[0279] (For example,

[0280] ), where R 2 C is either substituted or not substituted. 1-6 Alkyl group (e.g., Me). In some embodiments, formula (I) is formula (I-1A):

[0281]

[0282] In some implementations, equation (I) is equation (I-1B):

[0283] Where R 7 It is either substituted or unsubstituted 3-pyridyl.

[0284] In some implementations, equation (I) is equation (I-1C):

[0285]

[0286] in It is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, formula (I) is formula (I-1C), wherein... It is imidazole, oxazolyl, azacyclic butyl, -C≡C- or

[0287] In some implementations, equation (I) is equation (I-1C):

[0288]

[0289] in It is thiazolyl, piperidinyl, piperazine, morpholino, or thiomorpholino.

[0290] In some implementations, equation (I) is equation (I-1D):

[0291] Where R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group.

[0292] In some implementations, equation (I) is as follows:

[0293]

[0294] (For example,

[0295]

[0296] In some implementations, equation (I) is as follows:

[0297]

[0298] (For example,

[0299]

[0300] In some implementations, equation (I) is as follows:

[0301]

[0302] (For example,

[0303]

[0304] In some implementations, equation (I) is as follows:

[0305]

[0306] (For example,

[0307]

[0308] In some implementations, equation (I) is as follows:

[0309]

[0310] (For example,

[0311]

[0312] In some implementations, equation (I) is as follows:

[0313]

[0314] (For example,

[0315]

[0316]

[0317] ).

[0318] In some implementations, q is 0 or 1. In some implementations, q is 1. In some implementations, q is 0.

[0319] In some implementations, L A -C(=O)NR 1 R 2 In some embodiments, the compound of formula (0) has the following formula: In some implementations, q is 0 or 1. In some implementations, q is 1. In some implementations, q is 0.

[0320] In some implementations, L A -N(R) 2 (L) 1 R 1 In some embodiments, the compound of formula (0) has the following formula: In some implementations, q is 0 or 1. In some implementations, q is 1. In some implementations, q is 0. In some implementations, L 1 It is a single bond. In some embodiments, the compound of formula (0) has the following formula: In some implementations, L 1 For -C(=O)-. In some embodiments, the compound of formula (0) has the following formula:

[0321] In some implementations, L 1 It is a single bond. In some implementations, L 1 It is -C(=O)-.

[0322] In some implementations, L 1 It is a single bond, and R 1 C is either substituted or not substituted. 1-6 Alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group. In some embodiments, R 1 For C that is replaced or not replaced 1-6 Alkyl group. In some embodiments, R 1 For the unreplaced C 1-6 Alkyl group. In some embodiments, R 1 It is an unsubstituted C1 alkyl group. In some embodiments, R 1 It is an unsubstituted C2 alkyl group. In some embodiments, R 1 It is an unsubstituted C3 alkyl group. In some embodiments, R 1 It is an unsubstituted C4 alkyl group. In some embodiments, R 1 It is an unsubstituted C5 alkyl group. In some embodiments, R 1 It is an unsubstituted C6 alkyl group. In some embodiments, R 1 To replace C 1-6 Alkyl group. In some embodiments, R 1 The substituted C1 alkyl group. In some embodiments, R 1 The C2 alkyl group is substituted. In some embodiments, R 1 The substituted C3 alkyl group. In some embodiments, R 1 The substituted C4 alkyl group. In some embodiments, R 1 The substituted C5 alkyl group. In some embodiments, R 1 The substituted C6 alkyl group. In some embodiments, R 1 C for fluorination 1-6 Alkyl group (e.g., -CF3). In some embodiments, R 1 For C that is replaced or not replaced 2-6 Alkenyl. In some embodiments, R 1 For C that is replaced or not replaced 2-6 Alkenyl. In some embodiments, R 1 For C that is replaced or not replaced 2-6 Alkyne group. In some embodiments, R 1 The substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group. In some embodiments, R 1 For substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic groups. In some embodiments, R 1 It consists of 5 to 11 member monocyclic or bicyclic heteroaryl groups, whether substituted or unsubstituted.

[0323] In some implementations, L 1 It is -C(=O)-; and R 1 C 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 Alkyne group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group; substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group. In some embodiments, R 1 C that is substituted with at least one heteroatom 1-6 Alkyl group. In some embodiments, R 1 For C-substituted compounds containing at least one double bond 1-6 Alkyl group. In some embodiments, R 1 For C-type substitutions containing at least one triple bond 1-6 alkyl.

[0324] In some implementations, R 2 It is hydrogen. In some implementations, R 2 It is not hydrogen. In some implementations, R 2 For C that is replaced or not replaced 1-6 Alkyl group. In some embodiments, R 2 For the unreplaced C 1-6 Alkyl group. In some embodiments, R 2 For Me. In some implementations, R 2 For Et, Pr, or Bu. In some implementations, R 2 C for fluorination 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 2 It is a nitrogen-protecting group.

[0325] In some implementations, R 2 The substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group. In some embodiments, R 2 The substituted or unsubstituted 3- to 5-membered monocyclic carbocyclic group. In some embodiments, R 2 For substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic groups. In some embodiments, R 2 For substituted or unsubstituted 3- to 5-membered monocyclic heterocyclic groups. In some embodiments, R 2 The phenyl group may be substituted or unsubstituted. In some embodiments, R... 2 It is a 5- to 6-membered monocyclic heteroaryl group that may or may not be substituted.

[0326] In some implementation schemes, R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN. In some implementations, R 3 It is hydrogen.

[0327] In some implementations, R 3 Halogenated, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN. In some implementations, R 3 Halogenated, substituted or unsubstituted C 1-6 Alkyl or -OR a In some implementations, R 3 -N(R) a )2 or -CN. In some implementations, R 3 It is a halogen. In some embodiments, R 3 For F. In some implementations, R 3 For Cl. In some implementations, R 3 For C that is replaced or not replaced 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6 Alkyl). In some embodiments, R 3 For Me. In some implementations, R 3 For Et, Pr, or Bu. In some implementations, R 3 C for fluorination 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 3 For -OR a In some implementations, R 3 For -OH. In some embodiments, R 3 -O (substituted or unsubstituted C) 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 3 -N(R) a 2. In some implementations, R 3 For -NH2. In some implementations, R 3 -NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 3 -N (substituted or unsubstituted C) 1-6Alkyl group (e.g., -N(Me)2). In some embodiments, R 3 For -CN.

[0328] In some implementations, R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, an oxygen-protecting group when attached to an oxygen atom, or a nitrogen-protecting group when attached to a nitrogen atom. In some embodiments, R a Each instance is hydrogen. In some implementations, R a The instance is not hydrogen. In some implementations, R a At least one instance of C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6 Alkyl). In some embodiments, R a At least one instance of R is Me. In some implementations, R a At least one instance is Et, Pr, or Bu. In some implementations, R a At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, e.g., -CF3).

[0329] In some implementations, R 2 and R 3 They are linked with their inserted atoms to form substituted or unsubstituted 5-membered monocyclic heterocyclic groups or heteroaryl groups. In some embodiments, R 2 and R 3 They are linked with their inserted atoms to form an unsubstituted 5-membered monocyclic heterocyclic group. In some embodiments, R 2 and R 3 They are linked to their insert atoms to form substituted 5-membered monocyclic heteroaryl groups. In some embodiments, for In some implementations, for In some implementations, for (For example, For example, In some implementations, for In some implementations, for In some implementations, for (For example, For example, In some implementations, R 2 and R 3They are linked to their insert atoms to form substituted 5-membered monocyclic heteroaryl groups. In some embodiments, for

[0330] In some implementations, at least one instance of Y is CR 4 In some implementations, each instance of Y is a CR. 4 In some implementations, at least one instance of Y is N. In some implementations, each instance of Y is N.

[0331] In some implementations, for In some implementations, (For example, )for In some implementations, (For example, )for In some implementations, (For example, )for In some implementations, (For example, )for

[0332] In some implementations, R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN. In some implementations, R 4 At least one instance is hydrogen. In some embodiments, R 4 Each instance is hydrogen. In some implementations, R 4 At least one instance of it is not hydrogen. In some implementations, R 4 The instance is not hydrogen. In some implementations, R 4 At least one instance is a halogenated or substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R 4 At least one instance is a halogen. In some embodiments, R 4 At least one instance of R is F. In some implementations, R 4 At least one instance is Cl. In some implementations, R 4 At least one instance of C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6Alkyl). In some embodiments, R 4 At least one instance of R is Me. In some implementations, R 4 At least one instance is Et, Pr, or Bu. In some implementations, R 4 At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 4 At least one instance of -OR a In some implementations, R 4 At least one instance is -OH. In some embodiments, R 4 At least one instance is -O (substituted or unsubstituted C). 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 4 At least one instance is -N(R) a 2. In some implementations, R 4 At least one instance is -NH2. In some implementations, R 4 At least one instance is -NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 4 At least one instance is -N (substituted or unsubstituted C) 1-6 Alkyl group (e.g., -N(Me)2). In some embodiments, R 4 At least one instance is -CN.

[0333] In some implementations, It is a 6-membered monocyclic aryl or heteroaryl. In some embodiments, It is phenyl. In some embodiments, for In some implementations, for In some implementations, for In some implementations, for In some implementations, for In some implementations,

[0334] for In some implementations, It is pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, for (For example, In some implementations, for (For example, In some implementations, for (For example,

[0335] In some implementations, for (For example, In some implementations,

[0336] for (For example, In some implementations, for (For example, ).

[0337] In some implementations, It is an imidazole group. In some embodiments, for (For example, In some implementations, for (For example, In some implementations, for (For example, In some implementations, for (For example, ).

[0338] In some implementations, It is an oxazolyl group. In some embodiments, for (For example, In some implementations, for (For example, ), (For example, ),or (For example, In some implementations, It is a nitrogen-containing heterocyclic butyl group. In some embodiments, for (For example, In some implementations, for (For example, In some implementations, For -C≡C--. In some implementations, for In some implementations, for (For example, ).

[0339] In some embodiments, keys b and c are aligned with each other. In other embodiments, keys b and c are spaced apart from each other.

[0340] In some implementations, when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in the para position relative to each other. In some embodiments, when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in a meta position relative to each other.

[0341] In some implementations, It is a thiazolyl group. In some embodiments, for (For example, In some implementations, for (For example, ), (For example, ),or (For example, ).

[0342] In some implementations, It is a 6-membered monocyclic carbocyclic or heterocyclic group. In some embodiments, It is piperazine-based. In some embodiments, for In some implementations, for In some implementations, for In some implementations, for In some implementations, for In some implementations, for In some implementations, for

[0343] In some implementations, It is piperidinyl. In some embodiments, for In some implementations, for In some implementations, for In some implementations, for

[0344] In some implementation schemes, It is morpholino. In some embodiments, for In some implementations, for In some implementations, for In some implementations, for

[0345] In some implementation schemes, It is a thiomorpholino group. In some embodiments, for In some implementations, for In some implementations, for In some implementations, for

[0346] In some implementations, R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN. In some implementations, R 5 At least one instance is hydrogen. In some embodiments, R 5 Each instance is hydrogen. In some implementations, R 5 At least one instance of it is not hydrogen. In some implementations, R 5 The instance is not hydrogen. In some implementations, R 5 At least one instance is a halogen. In some embodiments, R 5 At least one instance of R is F. In some implementations, R 5 At least one instance is Cl. In some implementations, R 5 At least one instance of C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6Alkyl). In some embodiments, R 5 At least one instance of R is Me. In some implementations, R 5 At least one instance is Et, Pr, or Bu. In some implementations, R 5 At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 5 At least one instance of -OR a In some implementations, R 5 At least one instance is -OH. In some embodiments, R 5 At least one instance is -O (substituted or unsubstituted C). 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 5 At least one instance is -N(R) a 2. In some implementations, R 5 At least one instance is -NH2. In some implementations, R 5 At least one instance is -NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 5 At least one instance is -N (substituted or unsubstituted C) 1-6 Alkyl)2, for example, -N(Me)2. In some embodiments, R 5 At least one instance is -CN. In some implementations, R 5 At least one instance is a halogenated, substituted or unsubstituted C 1-6 Alkyl or -OR a .

[0347] In some implementations, L B -N(R) 6 )L 2 - In some embodiments, the compound of formula (0) has the following formula: In some implementations, L 2 For C=O. In some embodiments, the compound of formula (0) has the following formula: In some implementations, L 2 The compound is S(=O)2. In some embodiments, the compound of formula (0) has the following formula: In some respects, L 2 for In some embodiments, the compound of formula (0) has the following formula: In some implementations, each R 6Independently hydrogen. In some implementations, an R 6 It is a methyl group, and one R 6 It is hydrogen.

[0348] In some implementations, L B -L 2 N(R 6 In some embodiments, the compound of formula (0) has the following formula: In some implementations, L 2 For C=O. In some embodiments, the compound of formula (0) has the following formula: In some implementations, L 2 The compound is S(=O)2. In some embodiments, the compound of formula (0) has the following formula: In some respects, L 2 for In some embodiments, the compound of formula (0) has the following formula: In some implementations, each R 6 For hydrogen. In some implementations, an R 6 It is a methyl group, and one R 6 It is hydrogen. In some embodiments, the compound of formula (0) has the following formula:

[0349] In some embodiments, the compound of formula (0) has formula (0′): In some embodiments, the compound of formula (0′) has the formula

[0350] In some implementations, L 2 For -C(=O)-. In some implementations, L 2 It is -S(=O)2-.

[0351] In some implementations, L 2 for In some implementations, L 2 for And R 6 It is hydrogen. In some implementations, L 2 for And R 6 It is a methyl group.

[0352] In some implementations, each R 6 Independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, or nitrogen protecting group. In some embodiments, each R 6 Independently for C, whether substituted or not. 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 some embodiments, each R 6 Independently hydrogen. In some implementations, each R 6 Independently for C, whether substituted or not. 1-6 Alkyl (e.g., Me). In some embodiments, R 6 Each instance of R is identical. In some implementations, R 6 Each instance is different.

[0353] In some implementations, R 6 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, or nitrogen protecting group. In some embodiments, R 6 For C that is replaced or not replaced 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 some embodiments, R 6 It is hydrogen. In some implementations, R 6 For C that is replaced or not replaced 1-6 Alkyl groups (e.g., Me).

[0354] In some implementations, R 7 The substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group. In some embodiments, R 7 For substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic groups. In some embodiments, R 7 The phenyl group may be substituted or unsubstituted. In some embodiments, R... 7 The substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group. In some embodiments, R 7The substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl groups. In some embodiments, R 7 The 3-pyridyl group may be substituted or unsubstituted. In some embodiments, R 7 It is an unsubstituted 3-pyridyl group. In some embodiments, R 7 for In some implementations, R 7 for In some implementations, R 7 for In some implementations, R 7 for In some implementations, R 7 for In some implementations, R 7 The 2-pyridyl or 4-pyridyl group may be substituted or unsubstituted. In some embodiments, R 7 The 2-pyridyl group may be substituted or unsubstituted. In some embodiments, R 7 It is an unsubstituted 2-pyridyl group. In some embodiments, R 7 for In some implementations, R 7 for In some implementations, R 7 for In some implementations, R 7 for

[0355] In some implementations, R 8 Each instance independently for -OR a -N(R) a )2 or -CN. In some implementations, R 8 Each instance is hydrogen. In some implementations, R 8 At least one instance is a halogenated or substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R 8 At least one instance of C is an unreplaced C 1-6 Alkyl (e.g., Me). In some embodiments, R 8 At least one instance of C is C substituted with at least one instance of a halogen (e.g., F). 1-6 alkyl.

[0356] R 9 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, ORa -N(R) a )2 or -CN. In some implementations, R 9 At least one instance is hydrogen. In some embodiments, R 9 Each instance is hydrogen. In some implementations, R 9 At least one instance of it is not hydrogen. In some implementations, R 9 The instance is not hydrogen. In some implementations, R 9 At least one instance is a halogen. In some embodiments, R 9 At least one instance of R is F. In some implementations, R 9 At least one instance is Cl. In some implementations, R 9 At least one instance of C is either substituted or not substituted. 1-6 Alkyl groups (e.g., unsubstituted C4 groups) 1-6 Alkyl). In some embodiments, R 9 At least one instance of R is Me. In some implementations, R 9 At least one instance is Et, Pr, or Bu. In some implementations, R 9 At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 9 At least one instance of -OR a In some implementations, R 9 At least one instance is -OH. In some embodiments, R 9 At least one instance is -O (substituted or unsubstituted C). 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 9 At least one instance is -N(R) a 2. In some implementations, R 9 At least one instance is -NH2. In some implementations, R 9 At least one instance is -NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 9 At least one instance is -N (substituted or unsubstituted C) 1-6 Alkyl group (e.g., -N(Me)2). In some embodiments, R 9 At least one instance is -CN. In some implementations, R 9 At least one instance is a halogenated, substituted or unsubstituted C 1-6 Alkyl or -ORa .

[0357] In some implementations, s is 1. In other implementations, s is 0.

[0358] In some embodiments, s is 1. In some embodiments, the compound of formula (0) has the following formula: In some embodiments, s is 0. In some embodiments, the compound of formula (0) has the following formula: In some implementations, s is 0, and compounds of formula (0) are selected from the group consisting of the following formulas:

[0359]

[0360] In some embodiments, s is 1. In some embodiments, the compound of formula (0′) has the following formula: In some embodiments, s is 0. In some embodiments, the compound of formula (0′) has the following formula: In some implementations, s is 0, and compounds of formula (0′) are selected from the group consisting of the following formulas:

[0361]

[0362] In some embodiments, the compound has the following formula:

[0363]

[0364] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0365] In some embodiments, the compound has the following formula:

[0366]

[0367] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0368] In some embodiments, the compound has the following formula:

[0369]

[0370] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0371] In some embodiments, the compound has the following formula:

[0372]

[0373] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0374] In some embodiments, the compound has the following formula:

[0375]

[0376] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0377] In some embodiments, the compound has the following formula:

[0378]

[0379] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0380] In some embodiments, the compound has the following formula:

[0381]

[0382] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug, wherein Z is hydrogen or substituted or unsubstituted C. 1-6 Alkyl; and

[0383] m can be 1, 2, 3, 4, 5, or 6.

[0384] In some embodiments, the compound has the following formula:

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0393] In some embodiments, the compound has the following formula:

[0394]

[0395] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0396] In some embodiments, the compound has the following formula:

[0397]

[0398] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0399] In some embodiments, the compound has the following formula:

[0400]

[0401] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0402] In some embodiments, the compound has the following formula:

[0403]

[0404] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0405] In some embodiments, the compound has the following formula:

[0406]

[0407] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0408] In some embodiments, the compounds of this disclosure (the compounds described herein) are compounds of formula (0) or (0′), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. In some embodiments, the compounds of this disclosure are compounds of formula (0) or (0′), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In some embodiments, the compounds of this disclosure are compounds of formula (0) or (0′), or pharmaceutically acceptable salts thereof.

[0409] In some embodiments, the compounds of this disclosure (the compounds described herein) are compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. In some embodiments, the compounds of this disclosure are compounds of formula (I), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In some embodiments, the compounds of this disclosure are compounds of formula (I), or pharmaceutically acceptable salts thereof.

[0410] The compounds disclosed herein may have a safe in vitro pharmacological profile. Compared with certain similar known compounds, the compounds disclosed herein may have a safer in vitro pharmacological profile (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% safer).

[0411] The compounds disclosed herein can have high water solubility. Compared with certain similar known compounds, the compounds disclosed herein can 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%) water solubility.

[0412] The compounds disclosed herein can have high microparticle stability. Compared with certain similar known compounds, the compounds disclosed herein can 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%) microparticle stability.

[0413] Exemplary compounds disclosed herein include those in Table A, Table 5, and the following compounds:

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565] Table A.

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596] Compositions and kits

[0597] This disclosure provides compositions (e.g., pharmaceutical compositions) comprising the compounds of this disclosure and excipients (e.g., pharmaceutically acceptable excipients). In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the excipient is a pharmaceutically acceptable excipient.

[0598] The compositions described herein can be prepared by any method known in the art. Typically, such preparation methods involve associating the disclosed compounds described herein with an excipient, and may include one or more pharmaceutical agents or auxiliary components, and then, if necessary and / or required, shaping and / or packaging the product into desired single-dose or multi-dose units. In some embodiments, the pharmaceutical agent is a pharmaceutically effective agent.

[0599] In some embodiments, the compounds disclosed herein are in the form of pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs.

[0600] The composition may be prepared, packaged, and / or sold as a single unit dose and / or in batches of multiple single unit doses. A “unit dose” is a discrete amount of a composition containing a predetermined amount of the pharmaceutical agent. The amount of the pharmaceutical agent is generally equal to the dose of the pharmaceutical agent to be administered to a subject and / or a suitable portion of that dose, such as half or one-third of the dose.

[0601] The relative amounts of the compounds, excipients, pharmaceutical agents, and / or any other components of this disclosure in the compositions described herein will vary depending on the identity, body type, and / or condition of the subject being treated, and also depending on the route of administration of the composition. The compositions may contain from 0.1% to 100% (w / w) of pharmaceutical agents.

[0602] Excipients and auxiliary ingredients used in the manufacture of the provided compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients and auxiliary ingredients such as cocoa butter, polyethylene glycol-modified lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavorings, and aromatizers may also be present in the compositions.

[0603] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0604] Exemplary granulating agents and / or dispersants include potato starch, corn starch, cassava starch, sodium glycolate starch, clay, alginate, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crosspovidone), sodium carboxymethyl starch (sodium glycolate starch), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), 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.

[0605] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, astragalus gum, chondrux, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, 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, glyceryl monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxyethylene polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), and sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol monolaurate). 20) Polyoxyethylene dehydrated sorbitol ( 60), Polyoxyethylene dehydrated sorbitan monooleate ( 80), sorbitol monopalmitate ( 40) Sorbitol monostearate ( 60), sorbitol tristearate ( 65), glyceryl monooleate, sorbitan monooleate [ 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate). 45) Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.) ), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether) 30), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl lauryl sulfate, sodium lauryl sulfate F-68, poloxamer P-188, hexadecyltrimethylammonium bromide, hexadecylpyridine chloride, benzalkonium chloride, sodium docusate and / or mixtures thereof.

[0606] Exemplary adhesives include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, carrageenan extract, panwar gum, agar, isapola shell adhesive, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), and magnesium aluminum silicate. (and larch arabinogalactan), alginate, polyoxyethylene, polyethylene glycol, inorganic calcium salts, silica, polymethyl methacrylate, wax, water, alcohol and / or mixtures thereof.

[0607] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0608] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbate palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0609] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium EDTA, disodium EDTA, trisodium EDTA, calcium disodium EDTA, dipotassium EDTA, 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, benzyl chloride, benzyl alcohol, bromonitrile glycol, cetrimonium bromide, hexadecylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexacodyl, imidazoline, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0610] Exemplary antifungal preservative packages include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0611] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0612] 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.

[0613] Other preservatives include tocopherol, tocopheryl acetate, ferric sulfate methanesulfonate, hexadecyltrimethylammonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, and potassium metabisulfite. Plus Methylparaben, 115. II. and

[0614] Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginate, pyrogen-free raw water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0615] 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.

[0616] Exemplary natural oils include almonds, avocados, babassu, bergamot, blackcurrant seeds, borage, juniper, chamomile, canola, caraway, palm wax, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, citronellol, gourd, grapeseed, hazelnut, hyacinth, isopropyl myristate, jojoba, macadamia nuts, mixed lavender, lavender, lemon, litsea cubeba, macadamia nuts, mallow, mango seeds, meadowfoam seeds, mink, nutmeg, olives, citrus, orange barnacles, palm, palm kernels, peach kernels, peanuts, pumpkin seeds, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia, tamarisk, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, ailanthus, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include butyl stearate, octanoic acid triglyceride, caprylic acid triglyceride, cyclomethicone, diethyl sebacate, polydimethylsiloxane 360, isopropyl myristate, mineral oil, octyldodecanool, oleyl alcohol, silicone oil, and mixtures thereof.

[0617] In some embodiments, the composition further comprises a pharmaceutical agent and is available for delivery of said pharmaceutical agent (e.g., delivery to a subject or cells). In some embodiments, the composition is a pharmaceutical composition that can be used to treat a disease in a subject with this need. In some embodiments, the disease is cancer. In some embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer). In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is a gastrointestinal stromal tumor. In some embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In some embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic cancer or pancreatic adenocarcinoma). In some embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In some embodiments, the cancer is lymphoma, such as non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma). In some embodiments, the cancer is B-cell lymphoma (e.g., Burkitt B-cell lymphoma, large B-cell lymphoma). In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the cancer is Burkitt lymphoma (e.g., Burkitt B-cell lymphoma). In some embodiments, the cancer is large cell immunoblastic lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute monocytic leukemia or acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia). In some embodiments, the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia). In some embodiments, the cancer is multiple myeloma (e.g., B-cell myeloma).

[0618] As described herein, the composition may be administered in combination with one or more other pharmaceutical agents. In some embodiments, the pharmaceutical agent is an organic molecule. In some embodiments, the pharmaceutical agent is an inorganic molecule. In some embodiments, the pharmaceutical agent is a targeting agent. In some embodiments, the pharmaceutical agent is an isotopically labeled compound. In some embodiments, the pharmaceutical agent is a pharmaceutical agent that can be bioprocessed. In some embodiments, the pharmaceutical agent is a pharmaceutical agent (e.g., a therapeutic and / or preventive active agent). Pharmaceutical agents include therapeutic active agents. Pharmaceutical agents also include preventive active agents. Pharmaceutical agents include small organic molecules such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use as provided in U.S. Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunizing agents, and cells.

[0619] In some embodiments, the compounds of this disclosure described herein are provided in the composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is an amount that is effective in treating a subject's cancer in need. In some embodiments, the effective amount is an amount that is effective in inhibiting signaling pathways required for metastasis in a subject or cell.

[0620] In some embodiments, the cells are in vitro. In some embodiments, the cells are ex vivo.

[0621] The compositions can be formulated into liquid dosage forms for oral and parenteral administration, including pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to pharmaceutical preparations, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solvents, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters and mixtures thereof of sorbitol. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers. In some embodiments for parenteral administration, the compositions described herein are combined with a solvent such as... Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof are mixed.

[0622] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in parenteral acceptable non-toxic diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0623] Injectable formulations can be sterilized, for example, by filtration via a bacterial retention filter or by incorporation of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0624] To prolong the effects of the compounds disclosed herein, it is generally desirable to slow the absorption of compounds administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the compound in an oil medium.

[0625] Compositions for rectal or vaginal application are typically suppositories prepared by mixing the composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, and thus melt in the rectal or vaginal cavity and release the compounds disclosed herein.

[0626] The composition can be formulated into solid dosage forms for oral administration, including capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this disclosure are mixed with at least one pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (e) dissolution delayers, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; 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 may contain a buffer.

[0627] Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the field of pharmacology. They may optionally contain light-blocking agents and may have a composition in which they optionally release the compounds of this disclosure in a delayed manner, either only or preferably in a portion of the intestine. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0628] The compounds disclosed herein may be in a microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, lozenges, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the compounds of this disclosure may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may, according to conventional practice, contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may contain a buffer. They may optionally contain a light-blocking agent and may have a composition in which they optionally release the compounds of this disclosure in a delayed manner, either solely or preferentially, in a portion of the intestine. Examples of encapsulating agents that may be used include polymers and waxes.

[0629] Dosage forms for topical and / or transdermal application of the compositions described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, and / or patches. Typically, the compounds disclosed herein are mixed under aseptic conditions with pharmaceutically acceptable carriers or excipients and / or any desired preservatives and / or buffers that may be required.

[0630] Suitable devices for delivering the intradermal compositions described herein include short-needle devices. Intradermal compositions can be administered by devices that limit the effective length of the needle penetration into the skin. Alternatively or additionally, conventional syringes can be used in the classic Mantoux method for intradermal administration. Jet injection devices that deliver liquid formulations to the dermis via liquid jet syringes and / or via needles that puncture the stratum corneum and generate a jet stream reaching the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate polymers in powder form through the outer layer of skin to the dermis are suitable.

[0631] Formulations suitable for topical application include liquid and / or semi-liquid formulations 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 applicable formulations may, for example, contain from about 1% to about 100% (w / w) of the compounds disclosed herein, although the concentration of the compounds disclosed herein may be as high as the solubility limits of the compounds disclosed in solvents. Formulations for topical application may further contain one or more additional ingredients described herein.

[0632] The compositions described herein are suitable for preparation, packaging, and / or sale in formulations for intrabuccular administration to the lungs. Such formulations may comprise dried granules containing compounds disclosed herein. Such compositions are suitably available in the form of a dry powder for administration, which is administered using a device including a dry powder reservoir that directs the flow of propellant to its dispersed powder and / or using a self-propelled solvent / powder dispersion container, such as a device containing an agent dissolved and / or suspended in a low-boiling-point propellant in a sealed container. The dry powder composition may include a solid fine powder diluent such as sugar and is suitably provided in unit dosage forms.

[0633] Low-boiling-point propellants typically include liquid propellants with a boiling point below 65℉ at atmospheric pressure. Typically, the propellant may comprise 50% to 99.9% (w / w) of the composition, and the compounds disclosed herein may comprise 0.1% to 100% (w / w) of the composition. The propellant may further contain additional components such as liquid nonionic and / or solid anionic surfactants and / or solid diluents.

[0634] The compositions described herein for pulmonary delivery may be provided in the form of solutions and / or droplets of suspensions. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the compounds of this disclosure, and may be suitably administered using any spray and / or nebulizer. Such formulations may further comprise one or more additional ingredients, including flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methylparaben.

[0635] The formulations described herein, which can be used for pulmonary delivery, can be used for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the compounds disclosed herein. Such formulations are administered by rapid inhalation via the nasal passage from a container containing the powder, kept close to the nose.

[0636] Formulations for nasal application may, for example, contain as little as 0.1% (w / w) to as much as 100% (w / w) of the compounds disclosed herein, and may contain one or more of the additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in buccal application formulations. Such formulations may be available, for example, in tablet and / or lozenge form prepared using conventional methods, and may, for example, contain 0.1% to 20% (w / w) of the pharmaceutical agent, the remainder being an orally soluble and / or biodegradable composition and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal application may contain powders and / or aerosolized and / or nebulized solutions and / or suspensions containing the compounds disclosed herein.

[0637] The compositions described herein can be used to prepare, package, and / or market ophthalmic formulations. Such formulations may be present, for example, as eye drops, including, for example, 0.1%–100% (w / w) solutions and / or suspensions of the disclosed compounds in an aqueous or oily liquid carrier or excipient. Such drops may also contain buffers, salts, and / or one or more of the other ingredients described herein. Other useful ophthalmic formulations include those containing compounds of this disclosure in microcrystalline and / or liposome formulations. Ear drops and / or eye drops are also covered within the scope of this disclosure.

[0638] While the descriptions of the compositions provided herein primarily pertain to those intended for human administration, those skilled in the art will understand that such compositions are generally suitable for administration to all species of animals. Modifications to compositions intended for human administration to make them suitable for administration to a wide variety of animals are well known, and such modifications can be designed and / or performed by a general veterinary pharmacologist through routine experiments.

[0639] The compositions described herein are typically formulated in dosage units that facilitate administration and ensure uniform dosing. However, it will be understood that the total daily dosage of the compositions described herein will be determined by a physician within reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the type and severity of the cancer being treated; the activity of the specific compound used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0640] The compositions provided herein can be administered via any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullaryly, intrathecally, subcutaneously, intravenously, percutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and / or drops), mucosally, nasally, buccally, sublingually; by endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specifically, the intended routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topically administered via blood and / or lymphatic supply, and / or directly to the affected site. Generally, the most suitable route of administration will depend on a variety of factors, including the nature of the disclosed compounds (e.g., their stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compositions described herein are suitable for topically administering to the subject's eyes.

[0641] In some embodiments, the administration of any of the compositions described herein occurs at least one hour prior to treatment with another cancer therapy.

[0642] The composition may be administered in combination with other pharmaceutical agents that enhance their activity (e.g., potency and / or efficacy), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in the subject or cells in treating a disease or disorder (e.g., cancer) in a subject with this need and / or in inhibiting signaling pathways in the subject or cells. It should also be understood that the therapy employed may achieve the desired effect for the same condition, and / or it may achieve different effects. In some embodiments, the compositions described herein (including the compounds of this disclosure) and pharmaceutical agents exhibit a synergistic effect not present in compositions comprising one, but not both, of the compounds or pharmaceutical agents of this disclosure.

[0643] The composition may be administered simultaneously with, before, or after one or more other pharmaceutical agents, which are different from the composition and may be used as, for example, a combination therapy. Each additional pharmaceutical agent may be administered at a dose and / or schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compounds of this disclosure or the compositions described herein, either at a single dose or at different doses individually. Specific combinations employed in a regimen will take into account the compatibility of the compounds of this disclosure described herein with the additional pharmaceutical agents and / or the desired therapeutic and / or preventative effects to be achieved. Generally, the additional pharmaceutical agents in combination are intended to be used at levels not exceeding those used individually. In some embodiments, the level of combination use will be lower than that used individually.

[0644] Other pharmaceutical agents include antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, and analgesics. In some embodiments, the additional pharmaceutical agent is an antiproliferative agent. In some embodiments, the additional pharmaceutical agent is an anticancer agent. In some embodiments, the additional pharmaceutical agent is a chemotherapeutic agent. In some embodiments, the additional pharmaceutical agent is an antiviral agent. In some embodiments, the additional pharmaceutical agent is a protein kinase binder or inhibitor. In some embodiments, the additional pharmaceutical agents are selected from the group consisting of: epigenetic or transcriptional regulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other differentiation-promoting agents. In some embodiments, the compounds or pharmaceutical compositions of this disclosure described herein may be administered in combination with anticancer therapies, including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In some embodiments, the subject is given one or more additional agents, such as one or more additional cancer therapies, concurrently, before, or after the cancer. In some embodiments, one or more additional cancer therapies include immunotherapy. Typically, immunotherapy (also known as biotherapy) is a cancer treatment that strengthens the subject's natural defenses against cancer. In some embodiments, the immunotherapy utilizes a compound biologically generated by the subject. In some embodiments, the immunotherapy utilizes a compound not biologically generated by the subject. In some embodiments, the immunotherapy utilizes cells derived from the subject. In some embodiments, the immunotherapy utilizes cells not derived from the subject. In some embodiments, the immunotherapy utilizes a compound biologically generated by an organism not belonging to the subject. In some embodiments, the immunotherapy utilizes cells biologically generated by an organism not belonging to the subject. In some embodiments, the immunotherapy includes at least one chemical modification of the compound or cells derived from the subject. In some embodiments, the immunotherapy includes at least one chemical modification of the compound or cells not derived from the subject.

[0645] In some implementations, immunotherapy may include one or more of the following steps: preventing or inhibiting the growth of cancer cells; preventing the spread of cancer to other parts of the body; and enhancing the immune system's ability and activity to kill cancer cells. Non-limiting examples of immunotherapy include: monoclonal antibodies, checkpoint inhibitors, nonspecific immunotherapy, oncolytic virus therapy, T-cell therapy, and cancer vaccines.

[0646] In some implementations, immunotherapy utilizes monoclonal antibodies. In some implementations, monoclonal antibodies target (bind to) and / or block abnormal proteins on cancer cells.

[0647] In some embodiments, immunotherapy utilizes checkpoint inhibitors. In some embodiments, immune checkpoint inhibitors are monoclonal antibodies. Immune checkpoints are regulators of the immune system by maintaining immune homeostasis and preventing the activation of autoimmunity. In cancer cells, immune checkpoint mechanisms are typically activated to suppress nascent anticancer immune responses. In some embodiments, checkpoint inhibitors are inhibitors of PD-1 (programmed cell death protein 1). In some embodiments, checkpoint inhibitors are inhibitors of PD-L1 (programmed death ligand 1). In some embodiments, checkpoint inhibitors are inhibitors of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Examples of immune checkpoint inhibitors include, but are not limited to, Yervoy, Opdivo, Keytruda, Tecentriq, Bavencio, and Imfinzi.

[0648] In some implementations, the immunotherapy is a nonspecific immunotherapy (e.g., interferon or interleukin). In some implementations, the immunotherapy is an oncolytic virus therapy.

[0649] In some implementations, the immunotherapy is T-cell therapy. In some implementations, the T-cell therapy is chimeric antigen receptor (CAR) T-cell therapy.

[0650] In some implementations, immunotherapy is an anti-cancer vaccine.

[0651] Anticancer agents include biological therapeutic anticancer agents and chemotherapy agents. Exemplary biological therapeutic anticancer agents include, but are not limited to, interferons, 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), immune cell growth factors (e.g., GM-CSF), and antibodies (e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuzumab), Vectibix (perumumab), Rituxan (rituximab), Bexxar (tosimomab)). Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g., goserelin and leuprorelin), anti-androgens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-2-methylpyrazine (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trefophosphamide, chlorambucil, estradiol, and melphalan), and nitrosoureas (e.g., ...). Examples of alkaloids include carmustine (BCNU) and lomustine (CCNU), alkyl sulfonates (e.g., busulfan and triazine), triazene (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinblastine alkaloids (e.g., vincristine, vinblastine, vinorelbine), taxanes (e.g., paclitaxel or paclitaxel equivalents), docosahexaenoic acid conjugate paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate conjugate paclitaxel (PG-paclitaxel, polyglutamate paclitaxel). poliglumex), CT-2103, XYOTAX), tumor activation prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, such as 2'-paclitaxel methyl 2-pyranose glucosuccinate.Docetaxel, Taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, captopril, irinotecan, irinotecan, Krestor, mytomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethhotrexate, trimethotraxate, idatraxate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), nucleonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), fluorouracil, deoxyfluorouracil, raltitrexed, tegafuridine, capecitabine), cytosine analogs (e.g., cytarabine). C) Cytarabine and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB 1093 and KH 1060), isoprene inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium salt ion), cell cycle inhibitors (e.g., asteroidin), actinomycins (e.g., actinomycin D, styromycin), bleomycins (e.g., bleomycin A2, bleomycin B2, pepromycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, levorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca; 2+ ATPase inhibitors (e.g., carotenoids), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), besutinib (SKI-606), cediranib (RECENTIN) TM AZD2171), dasatinib ( BMS-354825), Erlotinib Gefitinib Imatinib CGP57148B, STI-571, and lapatinib Linatatinib (CEP-701), Linatinib (HKI-272), Nilotinib Semaxinib (SU5416), Sunitinib ( SU11248), toceranib, ), Vandetani ( ZD6474), Vatalani (PTK787, PTK / ZK), Trastuzumab bevacizumab Rituximab cetuximab Parmumab Ranibizumab Nilotinib Sorafenib Everolimus alenzusnezidine Gelatinumab Ozolmicin Sirolimus lipids ENMD-2076, PCI-32765, AC220, Dovirtinib Lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK) TM ), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647 and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, sirolimus ester (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi) Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI), oblimersen, gemcitabine, erythromycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, camptothecin, procainamide, asparaginase, aminopterin, methylfolate, methylmitromycin, melphalan, isovincrine, epoxyvincrine, chlorambucil, trabectedin, procarbizine, disccodermolide, erythromycin, aminopterin, and hexamethylmelamine.

[0652] 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 disclosed herein.

[0653] In some embodiments, the percentage of the composition comprising the compounds of this 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 compounds of this disclosure is less than about 50%, for example, 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 compounds of this 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 compounds of this disclosure is from about 5% to 90%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to about 75%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to about 50%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 10% to about 25%.

[0654] In some embodiments, the total amount of the disclosed compounds present in the composition is greater than about 1% of the total size or total 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 disclosed compounds present in the composition is greater than about 10% of the total size or total weight of the composition (e.g., about 12%, about 15%, about 20%, about 25%, about 30% or more).

[0655] Not bound by theory, the compositions disclosed herein can enhance the efficacy of the disclosed compounds by increasing one or more of the localization and / or release (e.g., preferential release) of the disclosed compounds to target cells (e.g., cancer or fibrotic cells; cells associated with hypoxia), or by increasing the half-life of the disclosed compounds, thereby resulting in a significantly higher amount of the released disclosed compounds at the target site (e.g., tumor or liver (e.g., cirrhotic cells)). Therefore, the compositions disclosed herein can be therapeutically more effective than the free compounds (e.g., due to enhanced drug absorption in the target tissue) and / or allow for lower therapeutic doses of the disclosed compounds, e.g., without substantially impairing the resulting drug concentration at the target tissue. In some embodiments, the compositions disclosed herein can reduce side effects associated with systemic administration of the free form of the compound.

[0656] In some embodiments, the compounds of this disclosure are incorporated into the composition at a dose or amount less than that of the compounds in their free form to achieve the desired effect (e.g., a desired therapeutic effect). In some embodiments, the composition increases the amount of the compounds of this disclosure delivered to the tissues or cells in need of it, and reduces the amount of the compounds of this disclosure exposed to non-target tissues or cells, compared to the free compound.

[0657] On the other hand, kits containing the compounds disclosed herein; or the pharmaceutical compositions described herein; and instructions for using the compounds or pharmaceutical compositions disclosed herein are provided.

[0658] In some embodiments, the kit's instructions may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions are used to deliver the disclosed compound. In some embodiments, the kit and instructions are used to deliver a composition. In some embodiments, the kit and instructions are used to treat cancer in a subject with this need. In some embodiments, the kit and instructions are used to inhibit signaling pathways in a subject or cells.

[0659] Treatment and prevention methods and uses

[0660] Some aspects of this invention relate to methods, uses, compositions, and kits for administration to subjects in need. In some embodiments, the subject is a subject who has, is suspected of having, or is at risk of developing a disease or disorder (e.g., cancer). As used herein, the terms "subject," "individual," and "patient" are 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, such as a patient. Human subjects can be pediatric or adult subjects.

[0661] As used herein, “treatment” includes improving, curing, preventing its worsening, slowing the rate of progression, preventing the recurrence of the barrier (i.e., preventing relapse), or preventing or slowing the rate of metastasis. An effective amount of a composition refers to the amount of the composition in which a therapeutic effect is achieved. For example, in a method or use for treating a subject's cancer, an effective amount of a chemotherapeutic agent is any amount that provides an anticancer effect, such as reducing or preventing the proliferation of cancer cells or having cytotoxic effects on cancer cells.

[0662] The methods and uses disclosed herein relate to administering an effective amount of any compound of this disclosure or the compositions described herein to a subject suffering from a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is a benign tumor.

[0663] The methods and uses disclosed herein involve administering an effective amount of any compound of this disclosure or the composition described herein to a subject who has cancer or is at risk of developing cancer. In some embodiments, the cancer is characterized by the presence of cancer stem cells. In some embodiments, the cancer includes, involves, or is related to stem cells. In some embodiments, the subject has received or is receiving cancer therapy (e.g., chemotherapy, immunotherapy, surgery, radiation). A skilled practitioner may determine whether a subject is considered to be at “risk” for a disease or disorder such as cancer.

[0664] In some implementations, the cancer is colorectal cancer. Colorectal cancer is cancer that originates in the colon or rectum. Depending on the location of the cancer, these cancers may also be called colon cancer or rectal cancer. Colon cancer and rectal cancer are often grouped together due to several common characteristics. Most colorectal cancers begin as growths on the inner wall of the colon or rectum. The Colorectal Cancer (CRC) Subtype Consortium unified six independent molecular classification systems into a single consensus system with four distinct groups, called Consensus Molecular Subtypes (CMS), based on gene expression data. CMSs were identified and associated with epigenomics, transcriptomics, microenvironment, genetics, prognosis, and clinical characteristics. The CMS1 subtype is immunogenic and hypermutagenic. CMS2 tumors are activated by the WNT-β-catenin pathway and are generally associated with higher overall survival. CMS3 is characterized by a metabolic cancer phenotype. CMS4 cancers are associated with the lowest survival rates and have a strong stromal genetic signature. Molecular subtypes CMS2 and CMS4 exhibit the highest levels of embryonic signaling. 11

[0665] In some implementations, the cancer is stomach cancer. Stomach cancer is cancer that begins in the stomach. Stomach cancer tends to develop slowly over many years. Before true cancer develops, precancerous changes often appear in the lining (mucosa) of the stomach. These early changes rarely cause symptoms and are therefore often undetected. Types of stomach cancer include adenocarcinoma, lymphoma, gastrointestinal stromal tumor (GIST), carcinoid tumor, squamous cell carcinoma, small cell carcinoma, and leiomyosarcoma. The Cancer Genome Atlas (TCGA) project recently identified four molecular subtypes of stomach 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 in stomach cancer subtypes. 12,13

[0666] In some embodiments, an additional therapy has already been administered to the subject. In some embodiments, an additional therapy is further administered (co-administered) to the subject (e.g., before, simultaneously with, and / or after administration of the compound or composition described herein). The additional therapy differs from the compound or composition described herein. In some embodiments, the additional therapy alone is ineffective or less effective compared to co-administration (e.g., before, simultaneously with, and / or after) with the compound or composition described herein in the methods or uses described herein.

[0667] The exact amount of the disclosed compound required to achieve an effective dose will vary depending on the subject, such as the type of subject, age and general condition, severity of side effects or illness, the identity of the specific compound of this disclosure, mode of administration, etc.

[0668] The effective amount may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, any two doses in the multiple doses contain different or substantially the same amounts of the pharmaceutical agent described herein.

[0669] In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of administration is three times a day, twice a day, once a day, every other day, every three days, once a week, every two weeks, every three weeks, or every four weeks, or for longer periods. In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the duration between the first and last dose of the multiple dose is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifespan of the subject, tissue, or cell. In some embodiments, the duration between the first and last dose of the multiple dose is three months, six months, or one year. In some embodiments, the duration between the first and last dose of the multiple dose is the lifespan of the subject, tissue, or cell.

[0670] Any composition described herein may be administered in a therapeutically effective amount. In some embodiments, the methods and uses involve 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 specific site in a subject. In some embodiments, the methods and uses involve 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 tumor site in a subject.

[0671] The dosage can be adjusted appropriately to achieve the desired local level of the compound.

[0672] The terms “dose” and “dosage” are used interchangeably herein. In some embodiments, the amount of the compound administered to the subject is about 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g (inclusive) of the compound disclosed herein. In some embodiments, the dose described herein independently comprises 1 mg to 3 mg (inclusive) of the compound disclosed herein. In some embodiments, the dose described herein independently comprises 3 mg to 10 mg (inclusive) of the compound disclosed herein. In some embodiments, the dose described herein independently comprises 10 mg to 30 mg (inclusive) of the compound disclosed herein. In some embodiments, the dosage described herein independently includes 30 mg to 100 mg (inclusive) of the compounds disclosed herein.

[0673] In some embodiments, an initial dose of any of the compositions described herein is administered to the subject, followed by one or more additional doses of any of the compositions described herein. In some embodiments, the initial dose may contain a different amount of any of the compounds described herein compared to one or more additional doses. In some embodiments, the initial dose is a higher dose (e.g., containing more of any of the compounds described herein) compared to one or more additional doses.

[0674] The dosage ranges described herein provide guidance for administering the provided compositions to adults. For example, the dosage for children or adolescents may be determined by a medical practitioner or person skilled in the art, and may be lower than or the same as the dosage for adults. In some embodiments, the dosages described herein are for an adult weighing 70 kg.

[0675] For example, the efficacy of cancer treatment can be measured by determining the growth, replication, proliferation, metastasis, and / or gene expression profiles of one or more cancer cells. Therefore, the effective dose is the dose that clinicians consider toxicologically tolerable but effective.

[0676] Not bound by any particular theory, it is believed that the compounds disclosed herein induce the differentiation of embryonic cells and / or cells exhibiting embryonic cell characteristics. In some embodiments, the methods and uses disclosed herein involve administering an effective amount of any of the compositions described herein to a subject requiring regenerative medicine or regenerative therapy. In some embodiments, the subject requires the restoration or improvement of one or more biological functions of dysfunctional or damaged cells, tissues, and / or organs. In some embodiments, the subject requires tissue engineering and organ regeneration. In some embodiments, the compositions described herein regenerate or differentiate potentially damaged cells, tissues, and / or organs. In some embodiments, the subject has experienced brain injury (e.g., damage or impairment of brain tissue or cells) and / or central nervous system injury (e.g., damage or impairment of central nervous system tissues or cells) and requires repair of said tissues or cells. In some embodiments, the subject has experienced cardiac injury (e.g., damage or impairment of cardiac tissue or cells) and requires repair of said tissues or cells.

[0677] In some embodiments, any of the compositions described herein may be administered via oral administration, intravenous administration (e.g., systemic intravenous injection), parenteral administration, subcutaneous administration, intramuscular administration, mucosal administration, transdermal administration, intradermal administration, intravaginal administration, intraperitoneal administration, local administration, nasal administration, buccal administration, sublingual administration; administration via the intratracheal region supplied by blood and / or lymph, and / or direct administration to the affected site.

[0678] This disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (0):

[0679]

[0680] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0681] L A -N(R) 2 (L) 1 R 1 ) or -C(=O)NR 1 R 2 ;

[0682] L 1 It is a single bond or -C (=O)-;

[0683] When L 1 When it is a single bond, R 1 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0684] When L 1 When R is -C(=O)-, 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic groups, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic groups, substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl groups, or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl groups.

[0685] R 2 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0686] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0687] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0688] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic groups or heteroaryl groups;

[0689] q is 0 or 1;

[0690] Each instance of Y is independently N or CR 4 ;

[0691] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a-N(R) a )2 or -CN;

[0692] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacyclic butyl, -C≡C- or

[0693] when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in the meta or para position relative to each other;

[0694] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0695] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0696] L B -N(R) 6 )L 2 -or-L 2 N(R 6 )-;

[0697] L 2 -C(=O)-、 Or -S(=O)2-;

[0698] Each R 6 Independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0699] s is 0 or 1;

[0700] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0701] R 8Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0702] In some respects, this disclosure further provides a method for treating cancer, said method comprising administering to a subject a therapeutically effective amount of a compound of formula (0′):

[0703]

[0704] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0705] L 1 It is a single bond or -C (=O)-;

[0706] When L 1 When it is a single bond, R 1 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0707] When L 1 When R is -C(=O)-, 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic groups, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic groups, substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl groups, or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl groups.

[0708] R 2 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0709] R 3It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0710] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0711] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic groups or heteroaryl groups;

[0712] q is 0 or 1;

[0713] Each instance of Y is independently N or CR 4 ;

[0714] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0715] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacyclic butyl, -C≡C- or

[0716] when When the group is phenyl, pyridyl, pyridinyl, pyrimidinyl, or pyrazinyl, bond b and bond c are in the meta or para position relative to each other;

[0717] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0718] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0719] L 2 -C(=O)-、 Or -S(=O)2-;

[0720] Each R 6 Independently hydrogen, substituted or unsubstituted C1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0721] s is 0 or 1;

[0722] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0723] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0724] This disclosure also provides a method for treating cancer, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a subject:

[0725]

[0726] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0727] L 1 It is a single bond or -C (=O)-;

[0728] When L 1 When it is a single bond, R 1 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0729] When L 1 When R is -C(=O)-, 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic groups, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic groups, substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl groups, or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl groups.

[0730] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups;

[0731] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0732] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0733] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic groups or heteroaryl groups;

[0734] Each instance of Y is independently N or CR 4 ;

[0735] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0736] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, aziridine, -C≡C- or

[0737] Keys b and c are either interpositional or opposite to each other;

[0738] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0739] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0740] L 2 It is -C(=O)- or -S(=O)2-;

[0741] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0742] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0743] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0744] In some implementation methods of treatment and prevention:

[0745] L 1 It is a single bond or -C (=O)-;

[0746] When L 1 When it is a single bond, R 1 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0747] When L 1 When R is -C(=O)-, 1 For C that is replaced or not replaced 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic groups, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic groups, substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl groups, or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl groups.

[0748] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups;

[0749] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0750] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0751] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic groups or heteroaryl groups;

[0752] Each instance of Y is independently N or CR 4 ;

[0753] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0754] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl;

[0755] Keys b and c are either interpositional or opposite to each other;

[0756] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0757] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0758] L 2It is -C(=O)- or -S(=O)2-;

[0759] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0760] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0761] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0762] In some respects, this disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I):

[0763]

[0764] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0765] L 1 It is a single bond or -C (=O)-;

[0766] When L 1 When it is a single bond, R 1 C is hydrogen, substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alynyl, 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.

[0767] When L 1 When R is -C(=O)-, 1 For C that is replaced or not replaced 1-6Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic carbocyclic groups, substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic groups, substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl groups, or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl groups.

[0768] R 2 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups;

[0769] R 3 It is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0770] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0771] Or R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic groups or heteroaryl groups;

[0772] Each instance of Y is independently N or CR 4 ;

[0773] R 4 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0774] It is phenyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl;

[0775] Keys b and c are either interpositional or opposite to each other;

[0776] R 5 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN;

[0777] Where valence is permissible, n can be 0, 1, 2, 3, or 4, where when n is 1, 2, 3, or 4, there is no R. 5 The case of bonding with a nitrogen atom;

[0778] L 2 It is -C(=O)- or -S(=O)2-;

[0779] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3 to 13 member monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6 to 11 member monocyclic or bicyclic aryl group, substituted or unsubstituted 5 to 11 member monocyclic or bicyclic heteroaryl group or nitrogen protecting group.

[0780] R 7 It is a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; and

[0781] R 8 Each instance is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(R) a )2 or -CN.

[0782] In some embodiments of the treatment and prevention methods and uses section, L 1 R 1 R 2 R 3 R a R 4 Y Keys b and c, R 5 , n, L 2 R 6 R 7 and R 8 As described in the compound section.

[0783] In some embodiments of the treatment and prevention methods and uses section, when L 1 When it is a single bond, R 1 For hydrogen. In some embodiments described in the section on treatment and prevention methods and uses, when L 1 When R is -C(=O)-, 1 To replace C 1-6 Alkyl groups. In some embodiments described in the section on treatment and prevention methods and uses, when L... 1 When R is -C(=O)-, 1 For the unreplaced C 1-6 Alkyl groups (e.g., Me or Et).

[0784] In some embodiments of the treatment and prevention methods and uses section, R 3 It is hydrogen.

[0785] In some embodiments of the treatment and prevention methods and uses section, R 2 and R 3 They connect with their inserted atoms to form substituted or unsubstituted 6-membered monocyclic heterocyclic groups or heteroaryl groups. In some embodiments of the treatment and prevention methods and uses section, R 2 and R 3 They connect with their inserted atoms to form an unsubstituted 6-membered monocyclic heterocyclic group. In some embodiments described in the section on treatment and prevention methods and uses, for

[0786] In certain embodiments of the treatment and prevention methods and uses section, the compound of formula (I) has the formula... Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0787] In certain embodiments of the treatment and prevention methods and uses section, the compound of formula (I) has the formula... Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0788] Another method

[0789] This disclosure also provides a method for contacting cells with an effective amount of the disclosed compound. This disclosure further provides uses for contacting cells with an effective amount of the disclosed compound.

[0790] In some embodiments, any compound described herein is contacted with cells in vivo, such as in an organism. In some embodiments, any compound described herein is contacted with cells in vitro, such as in a cell culture. In some embodiments, any compound described herein is contacted with cells ex vivo, meaning the cells are removed from the organism prior to contact. It will be apparent to those skilled in the art that the term "cell" can be used to refer to a single cell as well as a cell population. In some embodiments, a cell population is contacted with any compound described herein to regenerate or differentiate one or more cells within the cell population. In some embodiments, a cell population is contacted with any compound described herein for personalized medicine, such as for diagnostic and / or therapeutic purposes.

[0791] Generally, any cell known in the art can be used in the methods and uses described herein. In some embodiments, the cell is a cell line. In some embodiments, the cell is obtained from an organism, such as a subject. In some embodiments, the cell is a cancer cell (e.g., a cancer stem cell). In some embodiments, the cell is a stem cell. In some embodiments, the cell is an embryonic stem cell. In some embodiments, the cell is an induced pluripotent stem cell. In some embodiments, the cell is a neural cell, such as a neural stem cell. In some embodiments, the cell is an adult stem cell, such as a gastric stem cell or an intestinal stem cell.

[0792] In some embodiments, the methods and uses further include inhibiting cell growth. In other embodiments, the methods and uses include 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 some embodiments, the cells are cancer stem cells. In some embodiments, the cells are embryonic stem cells. In some embodiments, this disclosure provides methods and uses for inhibiting cell growth and / or killing cells with an effective amount of the compounds of this disclosure. In some aspects, inhibiting cell growth and / or killing cells can be used to treat proliferative diseases including cancer.

[0793] In some embodiments, the methods and uses further include measuring or evaluating 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 the cells have been exposed to any of the compositions described herein. In some embodiments, the level of one or more embryonic characteristics of the cells after exposure to any of the compositions described herein is compared to the level of one or more embryonic characteristics in a reference sample or before exposure to the composition. In some embodiments, exposure to 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 cells are sensitive to treatment with the compositions described herein. In some embodiments, if the level of one or more embryonic characteristics is reduced after exposure to any of the compositions described herein, the cells are determined to be sensitive to treatment with the composition. In some embodiments, if the level of one or more embryonic characteristics is reduced after exposure to any of the compositions described herein, the composition is determined to be a candidate for treatment of cell-related diseases or disorders.

[0794] 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 population of cells, such as tissues or organs. In some embodiments, the regenerated population of cells (such as tissues or organs) can be applied to or implanted 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., autologous transplantation). In some embodiments, the subject is a different subject from whom the cells were obtained, but belongs to the same species (e.g., allogeneic transplantation). In some embodiments, the subject is a different subject from whom the cells were obtained and belongs to a different species (e.g., xenotransplantation).

[0795] Example

[0796] To provide a fuller understanding of this disclosure, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, methods, and uses provided herein, and are not to be construed as limiting their scope in any way.

[0797] Example 1. Dynamics and cell viability of AGS cells

[0798] Approximately 50,000 AGS cells were seeded into each well of a 96-well plate with a medium containing NanoLuc luciferase and the MT cell viability substrate provided in the PROMEGA RealTime Glo MT Cell Viability Assay Kit. Four hours after seeding, cells were treated alone with DMSO (without drug treatment) or diluted concentrations of the disclosed compound to achieve final concentrations of 20, 10, 5, and 2.5 μM. Luminescent units (RLU) were measured every 16–20 hours using a SynergyHTX plate reader with an integration time of 30 ms (see [link to SynergyHTX plate reader]). Figure 1 ).

[0799] Example 2. Human Microarray Research

[0800] AGS human gastric adenocarcinoma cells were treated for two days with either compound I-1 or DMSO alone (as a negative control). Two days later, RNA was isolated in duplicate from cells treated with compound I-1 and those treated with DMSO, and microarray analysis was performed using an AFFYMETRIX CLARIOM S microarray. Data are expressed as fold changes relative to cells treated with compound I-1; negative values ​​indicate higher levels of genes in cells treated with compound I-1 than in those treated with DMSO, while positive values ​​indicate higher levels of genes in those treated with DMSO than in those treated with compound I-1. Values ​​from replicates were averaged. Data for genes whose expression changed more than 3-fold upward or downward in response to compound I-1 are included.

[0801] Table 1 shows a list of genes upregulated after treatment of the AGS human gastric cancer cell line with compound I-1 (as shown below). Negative numbers indicate fold-up regulation after treatment. Positive numbers indicate fold-down regulation after treatment. Overall, these data represent the reactivation of tumor suppressor genes and the decrease in the expression of tumor-promoting genes. For example, DUSP10, NR1D1, and Per1 all showed tumor suppressor activity in preventing runaway cell proliferation, and treatment with compound I-1 significantly increased the expression of these three genes. Furthermore, Chac1, PCK2, and SLC7A11 all showed tumor-promoting activity and were associated with more dangerous and lethal forms of cancer; these three genes were the three most strongly suppressive genes detected in this analysis. Other examples in the data support this model, but the overall model is that compound I-1 increases the expression of tumor suppressor genes and decreases the expression of tumor-promoting genes.

[0802]

[0803] Table 1.

[0804]

[0805]

[0806] Table 2 shows a list of genes downregulated after treatment of the AGS human gastric cancer cell line with compound I-1.

[0807] Table 2.

[0808]

[0809]

[0810]

[0811] Example 3. Dynamics and cell viability of AGS cells

[0812] The ability of compound I-1 to inhibit the growth of 12 additional cell lines derived from various types of human cancer was tested. In addition to effective inhibition of gastric adenocarcinoma and gastrointestinal stromal tumor growth (gastric adenocarcinoma data shown in Example 1, and gastrointestinal stromal tumor data shown in Table 3), compound I-1 also showed the most effective activity against non-Hodgkin's lymphoma, small cell lung cancer, pancreatic cancer, gastrointestinal stromal tumors, and ovarian adenocarcinoma cells. Exemplary results are shown in Table 3. Results are expressed as IC50. 50 The values ​​are listed; the IC50 value is the lowest concentration of compound I-1 that causes a 50% inhibition of cancer cell growth.

[0813] Table 3.

[0814] cell lines Cancer types <![CDATA[IC 50 (μM)]]> IGROV-1 Ovarian adenocarcinoma 4.54 NCI-H69 Small cell lung cancer 1.50 RL Non-Hodgkin's lymphoma 0.13 MCF-7 Breast cancer 6.00 Colo205 Duke D colorectal adenocarcinoma >10 DLD-1 Duke's type C colorectal adenocarcinoma >10 MiaPaca-2 pancreatic cancer 3.38 PC-3 Prostate cancer 5.52 A549 Lung adenocarcinoma >10 CFPAC-1 pancreatic cancer 8.24 UACC-62 Melanoma >10 A498 Kidney cancer >10 GIST T1 Gastrointestinal stromal tumors 0.98

[0815] The general method used in Examples 4 to 10 and 11

[0816] Unless otherwise provided, Examples 4 through 10 and 11 are performed according to the general methods described in this subsection.

[0817] RT-qPCR

[0818] Approximately 2.5 x 10 5 AGS cells were treated with either DMSO (drug-free) or DMSO solution containing 10 μM compound I-1 for 4 days. Cells were lysed, and RNA was extracted using Zymo's Quick RNA-Microprep according to the manufacturer's instructions. 100 ng of RNA was reverse transcribed using MuLV reverse transcriptase (New England Biolabs, USA). qPCR was performed using 2 μL of cDNA and Luna Universal qPCR Master Mix from NEB on a Stratagene Mx 3005P.

[0819] Hepatotoxicity assay

[0820] On the day following perfusion, fresh primary CD-1 mouse hepatocytes were obtained from XenoTech in 96-well plates. After recovery at 37°C for 24 hours using OptiCulture hepatocyte medium, the medium was changed daily to contain only DMSO (without drug treatment) or 10 μM compound I-1 for 4 days. Cell viability was measured using the PROMEGA CellTiter Glo 2.0 kit according to the manufacturer's instructions. luminescence was measured using a SynergyHTX plate reader with an integration time of 1 second.

[0821] Dynamic cell vitality

[0822] Approximately 50,000 AGS cells were seeded into each well of a 96-well plate with culture medium containing NanoLuc luciferase and the MT cell viability substrate provided in the PROMEGA RealTime Glo MT Cell Viability Assay Kit. Four hours post-seeding, cells were treated alone with DMSO (without drug treatment) or diluted concentrations of compound I-1 to achieve final concentrations of 20, 10, 5, and 2.5 μM. Luminescent units (RLUs) were measured every 16–20 hours using a SynergyHTX plate reader with an integration time of 30 ms.

[0823] Absorption, distribution, metabolism, and excretion (ADME) profile analysis

[0824] Plasma stability. Plasma stability was determined using the QuintaraBio stability assay with samples provided in DMSO solution. Briefly, the compound was incubated in duplicate at 37°C in the presence of mouse plasma to a final concentration of 1 μM. At four different time points, 300 μL of quenching solution containing the internal standard (50% acetonitrile, 50% methanol, and 0.05% formic acid, warmed at 37°C) was added to each well. The plate was sealed, vortexed, and centrifuged at 4000 rpm for 15 min at 4°C. The supernatant was transferred to a fresh plate for LC / MS / MS analysis. All samples were analyzed on LC / MS / MS using an ABSciex API 4000 instrument connected to a Shimadzu LC-20AD LC pump system. The degree of metabolism was calculated as the disappearance of the test compound compared to a 0 min control reaction incubation. The initial rate of compound concentration was calculated and used to determine the t-test concentration. 1 / 2 value.

[0825] Microsomal stability. Microsomal stability was determined using the QuintaraBio stability assay with samples in DMSO solution. Briefly, the assay was performed at 37 °C in a 96-well microtiter plate. A reaction mixture (25 μL) containing 1 μM test compound, 0.5 mg / mL liver microsomal protein, and 1 mM NADPH and / or 1 mM uridine 5'-bisphosphate-α-D-glucuronic acid (UDPGA) (containing propyl methylglycinate) was incubated in 100 mM potassium phosphate pH 7.4 buffer containing 3 mM MgCl2. At each time point (0.25, 0.5, 1, 2, 4, 6, 8, and 24 min), 150 μL of quenching solution containing the internal standard (100% acetonitrile and 0.1% formic acid) was transferred to each well. The plate was sealed and centrifuged at 4000 rpm for 15 min at 4 °C. The supernatant was transferred to a fresh plate for LC / MS / MS analysis. All samples were analyzed on LC / MS / MS using an AB Sciex API 4000 instrument connected to a Shimadzu LC-20AD LC pump system. The degree of metabolism was calculated as the disappearance of the test compound compared to a 0-minute incubation time. The initial rate of compound concentration was calculated and used to determine the t0. 1 / 2 The value is then used to calculate the inherent clearance rate CLint = (0.693)(1 / t). 1 / 2 (min))(g liver / kg body weight)(mL incubation / mg microsomal protein)(45mg microsomal protein / g liver weight).

[0826] Kinetic solubility. Solubility was determined using the QuintaraBio solubility assay with the sample in DMSO solution. Briefly, 10 mM compound I-1 was diluted with an appropriate amount of buffer (PBS, pH 7.4), mixed by shaking for 1.5 hours, and then filtered under vacuum. The sample was subsequently analyzed by reversed-phase HPLC with UV detection. Quantification was performed by referring to a three-point standard curve constructed by serial dilutions of the drug dissolved in 100% DMSO.

[0827] Pharmacokinetic profile

[0828] The pharmacokinetic profile of compound I-1 was determined in male CD1 mice (n=3) after oral administration of 100 mg / kg using a freshly prepared formulation. Approximately 0.025 mL of blood was collected from the dorsal metatarsal vein at 15 min, 30 min, and 1, 2, 4, 6, 8, and 24 hours post-administration. Plasma concentrations of the drug were analyzed by LC / MS / MS.

[0829] Maximum tolerated dose study

[0830] Using freshly prepared formulations, the maximum tolerated dose distribution of compound I-1 was determined in female BALB / c nude mice after oral administration of the mediator control (n=3) or compound I-1 (n=9). 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 consecutive days of clinical observation.

[0831] Example 4.

[0832] AGS gastric cancer cells were treated with either DMSO (without drug treatment) or compound I-1 at 10 μM for 4 days. RNA was isolated and oct4 RNA levels were measured by RT-qPCR. Exemplary results are shown in... Figure 2 middle.

[0833] Example 5.

[0834] AGS gastric cancer cells were treated with either DMSO alone (without drug treatment) or 10 μM 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 middle.

[0835] Example 6.

[0836] Normal, healthy mouse hepatocytes were treated for 4 days with either DMSO (drug-free) or 10 μM compound I-1 alone. Cell health was measured using the CELLTITER GLO reagent, which provides a luminescent reading as a measure of total ATP concentration. Exemplary results are shown in... Figure 4 middle.

[0837] Example 7.

[0838] AGS gastric cancer cells were treated for 4 days with either DMSO alone (drug-free) or various concentrations of compound I-1 (including 2.5M, 5M, 10M, and 20M). Cell health and replication were measured using the REALTIME-GLO MT cell viability assay, which provides luminescent readings as a measure of cell number and health. Exemplary results are shown in [Figure / Table / Insert Figure ... Figure 5 middle.

[0839] Example 8.

[0840] Selected chemical properties of compound I-1 were measured. Solubility in aqueous solution was measured at pH 1.2 or 7.4. Mouse liver microsomal stability was assessed using the measured half-life (t). 1 / 2 Results are listed in minutes, while plasma stability is listed as the percentage of compound I-1 retained in mouse plasma after 4 hours. Exemplary results are shown in... Figure 6 middle.

[0841] Example 9.

[0842] Mice were administered a single oral PO (100 mg / kg) injection, and the plasma concentration of compound I-1 was measured within 24 hours. Exemplary results are shown in... Figure 7 The half-life is approximately 6 hours.

[0843] Example 10.

[0844] Naked BALB / c mice were treated once daily (orally) with either the mediator control or 50 mg / kg compound I-1, 25 mg / kg compound I-1, or 12.5 mg / kg compound I-1 for 5 days. Three mice were treated with the mediator control, and three mice were treated with compound I-1. Mice were monitored for 10 days, and their body weight was measured to assess overall health. Exemplary results are shown in... Figure 8 middle.

[0845] Example 11. Dynamics and cell viability of AGS cells

[0846] The ability of compound I-1 to inhibit the growth of 11 additional cell lines derived from various types of human cancer was tested. Exemplary results are shown in Table 4. Results are expressed in IC50 values. 50 The values ​​are listed; the IC50 value is the lowest concentration of compound I-1 that causes a 50% inhibition of cancer cell growth.

[0847] Table 4.

[0848]

[0849]

[0850] Example 12. Preparation of Exemplary Compounds

[0851] 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 through commercial suppliers.

[0852] The following LC-MS methods (analytics) were used to prepare 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.

[0853] Method 1 (LC-MS) 2 min low 3 97 BEH: LC / MS system: Acquity UPLC combined with SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm x 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid in acetonitrile solution; gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 3% A, 97% B, flow rate 0.9 ml / min; 1.9 min 3% A, 97% B, flow rate 0.9 ml / min; 2.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1000 AMU.

[0854] Method 2 (LC-MS): 2 min high 3 97 BEH: LC / MS system: Acquity UPLC combined with SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm x 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 10 mM ammonium bicarbonate aqueous solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 3% A, 97% B, flow rate 0.9 ml / min; 1.9 min 3% A, 97% B, flow rate 0.9 ml / min; 2.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0855] Method 5 (LC-MS): 12 min_low_3_97_BEH: LC / MS system: Acquity UPLC combined with SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm x 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid in acetonitrile solution; gradient: 0.0 min 97% A, 3% B, flow rate 0.9 mL / min; 1.5 min 97% A, 3% B, flow rate 0.9 mL / min; 11.5 min 3% A, 97% B, flow rate 0.9 mL / min; 12.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0856] Method 6 (LC-MS): 12 min high 3 97 BEH: LC / MS system: Acquity UPLC combined with SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm x 2.1 mm inner diameter, 1.7 μm packing diameter); mobile phase A: 10 mM ammonium bicarbonate aqueous solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97% A, 3% B, flow rate 0.9 ml / min; 1.5 min 97% A, 3% B, flow rate 0.9 ml / min; 11.5 min 3% A, 97% B, flow rate 0.9 ml / min; 12.0 min 97% A, 3% B, flow rate 0.05 ml / min; column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scan positive and negative electrospray (ES+ / ES-); scan range: 100 to 1500 AMU.

[0857] Synthesis of 4-(1-acetylindololin-5-yl)-N-(pyridin-3-ylmethyl)benzamide (compound I-42)

[0858] Preparation of tert-butyl 5-bromoindoline-1-carboxylate

[0859]

[0860] Step A: A solution of di-tert-butyl dicarbonate (11.2 g, 51.3 mmol) in DCM (20 mL) was added to a mixture of 5-bromoindoline (10.0 g, 50.8 mmol) in DCM (80 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated under vacuum to give a yellow oily tert-butyl 5-bromoindoline-1-carboxylate (18.0 g, quantitative yield). LC-MS (ESI): m / z (M) + =297.12 / 299.33.

[0861] Preparation of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate

[0862]

[0863] Step B: To a mixture of tert-butyl 5-bromoindoline-1-carboxylate (18.0 g, 50.8 mmol) in dioxane / H₂O (135 mL), (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) were added. 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 silica gel rapid column chromatography (PE / EA₄:1, v / v) to give a yellow solid of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylate (11.2 g, 62%). LC-MS (ESI): m / z (M-56) + =298.14.

[0864] Preparation of 4-(1-(tert-butoxycarbonyl)indoline-5-yl)benzoic acid

[0865]

[0866] Step C: LiOH (1N, 30 mL) was added to a mixture of tert-butyl 5-(4-(methoxycarbonyl)phenyl)indoline-1-carboxylic acid (5.0 g, 14.2 mmol) in MeOH / THF 1:1 (60 mL). The reaction mixture was stirred at 70 °C for 3 hours. It was then concentrated under vacuum and acidified with an aqueous HCl solution (1N). After filtration, the solid was dried to give a white solid of 4-(1-(tert-butoxycarbonyl)indoline-5-yl)benzoic acid (5.6 g, quantitative yield). LC-MS (ESI): m / z (M-56) + =284.09.

[0867] Preparation of tert-butyl 5-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)indoline-1-carboxylic acid

[0868]

[0869] Process D To a mixture of 4-(1-(tert-butoxycarbonyl)indoline-5-yl)benzoic acid (3.0 g, 8.8 mmol) in DMF, pyridin-3-ylmethylamine (1.1 g, 10.6 mmol), HATU (5.0 g, 13.2 mmol), and DIPEA (3.4 g, 26.4 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. It was then diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (DCM / MeOH 9:1, v / v) to give solid tert-butyl 5-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)indoline-1-carboxylate (3.2 g, 85%). LC-MS (ESI): m / z (M+1) + =430.28.

[0870] Preparation of 4-(indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide

[0871]

[0872] Step E: A dioxane solution of HCl (4N, 20 mL) was added 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). The reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure to give a red solid (2.4 g). The residue (100 mg) was purified by preparative HPLC (C18, 40-100% MeCN in H2O with 0.1% formic acid) to give a white solid of 4-(indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (27 mg, 35%).

[0873] Preparation of 4-(1-acetylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-42)

[0874]

[0875] Following procedure D, the reaction began with 4-(indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (200 mg, 0.5 mmol) and HOAc (36 mg, 0.6 mmol). In this case, the reagents were added at 0 °C, and the reaction mixture was heated to room temperature. A white solid (1-acetylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (47 mg, 25%) was isolated. LC-MS (ESI): m / z (M+H) + =372.21. 1 H NMR (400MHz, DMSO-d6) δ9.12(t,J=5.9Hz,1H),8.57(d,J=1.8Hz,1H),8.46(dd,J=4.7, 1.5Hz,1H),8.15-8.06(m,J=8.4Hz,1H),7.98-7.92(m,J=8.4Hz,2H),7.78-7.71(m,J= 9.0,5.1Hz,3H),7.63(s,1H),7.57-7.52(m,J=8.4Hz,1H),7.39-7.34(m,J=7.8,4.8Hz ,1H),4.51(d,J=5.9Hz,2H),4.14(t,J=8.5Hz,2H),3.21(t,J=8.5Hz,2H),2.18(s,3H).

[0876] Synthesis of 4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-43)

[0877] 3.4.1 Preparation of 4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-43)

[0878]

[0879] Following standard procedure D, starting with 4-(indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (1.5 g, 5.0 mmol) and propionic acid (340 mg, 6.0 mmol), a white solid, 4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (690 mg, 36%), was isolated. LC-MS (ESI): m / z (M+H) + =386.23. 1H NMR(400MHz, DMSO-d6)δ9.17-9.09(m,J=5.9Hz,1H),8.57(d,J=1.7Hz,1H),8.47(d d,J=4.7,1.5Hz,1H),8.22-8.11(m,1H),7.99-7.92(m,2H),7.80-7.71(m,5.2Hz,3 H),7.63(s,1H),7.58-7.53(m,1H),7.40-7.31(m,1H),4.52(d,J=5.8Hz,2H),4.12 (t,J=8.5Hz,2H),3.21(t,J=8.4Hz,2H),2.50-2.44(m,2H),1.08(t,J=7.3Hz,3H).

[0880] Synthesis of 4'-propamido-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (Compound I-44)

[0881]

[0882] Pd(PPh3)4 (1.33 g, 1.15 mmol) was added in a single batch to a solution of methyl 4-iodobenzoate (3.0 g, 11.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (3.03 g, 13.8 mmol), and K2CO3 (3.2 g, 23.0 mmol) in dioxane / H2O (25 / 5 mL). 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 rapid chromatography to give methyl 4'-amino-[1,1'-biphenyl]-4-carboxylate (2.5 g, quantitative yield) as a white solid. LC-MS (ESI): m / z (M+H) + =220.19.

[0883] Following standard procedure D, starting with methyl 4'-amino-[1,1'-biphenyl]-4-carboxylate (2.4 g, 10.6 mmol) and propionic acid (1.18 g, 15.9 mmol), a white solid, methyl 4'-propamido-[1,1'-biphenyl]-4-carboxylate (2.1 g, 70%), was isolated. LC-MS (ESI): m / z (M+H) = 284.14.

[0884] To a solution of methyl 4'-propamido-[1,1'-biphenyl]-4-carboxylic acid (200 mg, 0.7 mmol) in MeOH / THF (2 / 2 mL), 3.5 mL of NaOH (3.5 mmol) was added. The mixture was stirred at room temperature for 12 hours. Acidification was performed with 4N HCl and extraction with EA was carried out. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by rapid chromatography to give 4'-propamido-[1,1'-biphenyl]-4-carboxylic acid (150 mg, 79%) as a white solid. LC-MS (ESI): m / z (M+H) = 270.09.

[0885] Compound I-44 was prepared according to general procedure D, starting with 4'-propamido-[1,1'-biphenyl]-4-carboxylic acid (150 mg, 0.56 mmol) and pyridin-3-ylmethylamine (91 mg, 0.84 mmol). Preparative HPLC purification yielded a white solid, 4'-propamido-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (32 mg, 16%). LC-MS (ESI): m / z (M+H) + =360.25. 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.13(t,J=5.9Hz,1H),8.57(d,J=1.5Hz,1H),8.47(dd,J=4.7,1.4Hz,1H),7.96(d, J=8.4Hz,2H),7.81-7.65(m,7H),7.40-7.33(m,1H),4.52(d,J=5.8Hz,2H),2.35(q,J=7.5Hz,2H),1.10(t,J=7.5Hz,3H).

[0886] Synthesis of 4'-(N-methylpropionamido)-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (Compound I-45)

[0887]

[0888] MeI (0.22 mL, 3.54 mmol) was added in a single addition to a solution of methyl 4'-propamido-[1,1'-biphenyl]-4-carboxylate (500 mg, 1.77 mmol) and Cs₂CO₃ (1.36 g, 3.54 mmol) in MeCN (10 mL). The mixture was stirred at 80 °C for 10 hours. It was then extracted with EA, the combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by rapid chromatography to give methyl 4'-(N-methylpropamido)-[1,1'-biphenyl]-4-carboxylate (475 mg, 90%) as a white solid. LC-MS (ESI): m / z (M+H) + =298.14.

[0889] To a solution of methyl 4'-(N-methylpropamido)-[1,1'-biphenyl]-4-carboxylic acid (200 mg, 0.68 mmol) in MeOH / THF (2 / 2 mL), 3.4 mL of NaOH (3.4 mmol) was added in a single addition. The mixture was stirred at room temperature for 12 hours. It was then acidified with 4N HCl and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by rapid chromatography to give 4'-(N-methylpropamido)-[1,1'-biphenyl]-4-carboxylic acid (140 mg, 73%) as a white solid. LC-MS (ESI): m / z (M+H) + =284.14.

[0890] Following standard procedure D, starting with 4'-(N-methylpropamido)-[1,1'-biphenyl]-4-carboxylic acid (140 mg, 0.50 mmol) and pyridin-3-ylmethylamine (82 mg, 0.75 mmol), a white solid 4'-(N-methylpropamido)-N-(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4-carboxamide (30 mg, 16%) was isolated. LC-MS (ESI): m / z (M+H) + =374.30. 1 H NMR (400MHz, DMSO-d6) δ9.17(t,1H),8.58(s,1H),8.47(d,J=3.7Hz,1H),8.00(d,J=8.3Hz,2H),7.90-7.66(m,5H),7. 44(d,J=8.3Hz,2H),7.40-7.31(m,1H),4.53(d,J=5.8Hz,2H),3.20(s,3H),2.32-1.89(m,2H),0.95(t,J=7.3Hz,3H).

[0891] Synthesis of 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-46)

[0892]

[0893] NBS (2.67 g, 15.0 mmol) was added in a single addition to a solution of 1,2,3,4-tetrahydroquinoline (2.0 g, 15.0 mmol) in DMF (20 mL). The mixture was stirred at 0 °C for 1 hour. It was then extracted with EA, and the combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by rapid chromatography to give a yellow oily 6-bromo-1,2,3,4-tetrahydroquinoline (3.1 g, 97%). LC-MS (ESI): m / z (M+H) = 212.08 / 214.08.

[0894] At 0 °C, AcCl (1.72 g, 21.9 mmol) was added in a single addition to a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (13.1 g, 14.6 mmol) and DIPEA (6.5 mL, 36.5 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 4 hours and then quenched with water. It was extracted with EA, the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a pale yellow oily 1-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)ethyl-1-one (3.33 g, 90%). LC-MS (ESI): m / z (M+H) + =254.06 / 256.06.

[0895] Pd(PPh3)4 (466 mg, 0.4 mmol) was added to a solution of 1-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)ethyl-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). The mixture was stirred at 100 °C for 10 hours. It was then extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by rapid chromatography to give methyl 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)benzoate (1.25 g, 100%) as a white solid. LC-MS (ESI): m / z (M+H) + =310.13.

[0896] Step F: NaOH (2.1 mL, 8.1 mmol) was added to a solution of methyl 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)benzoate (500 mg, 1.62 mmol) in MeOH (10 mL). The mixture was stirred at 50 °C for 12 hours, acidified with HCl (4N), and then extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by rapid chromatography to give 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)benzoic acid (445 mg, 93%) as a white solid. LC-MS (ESI): m / z (M+H) + =296.15.

[0897] Following standard procedure D, starting with 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)benzoic acid (150 mg, 0.51 mmol) and pyridin-3-ylmethylamine (66 mg, 0.61 mmol), a white solid, 4-(1-acetyl-1,2,3,4-tetrahydroquinoline-6-yl)-N-(pyridin-3-ylmethyl)benzamide (53 mg, 27%), was isolated. LC-MS (ESI): m / z (M+H) + =386.25. 1 HNMR (400MHz, DMSO-d6) δ9.17(t,J=5.9Hz,1H),8.51(d,J=5.5Hz,2H),8.00(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.66-7.48(m ,3H),7.32(d,J=5.5Hz,2H),4.52(d,J=5.8Hz,2H),3.71(t,J=6.3Hz,2H),2.80(t,J=6.5Hz,2H),2.21(s,3H),1.94-1.87(m,2H).

[0898] Synthesis of 4-(1-(2-hydroxyacetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-47)

[0899] Preparation of 4-(1-(2-(benzyloxy)acetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide

[0900]

[0901] Following standard procedure D, starting with 4-(indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (150 mg, 0.45 mmol) and 2-(benzyloxy)acetic acid (60 mg, 0.54 mmol), a white solid of 4-(1-(2-(benzyloxy)acetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (140 mg, 65%) was obtained. LC-MS (ESI): m / z (M-56) + =478.32.

[0902] Preparation of 4-(1-(2-hydroxyacetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-47)

[0903]

[0904] BBr3 (262 mg, 1.05 mmol) was added to a solution of 4-(1-(2-(benzyloxy)acetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (100 mg, 0.209 mmol) in DCM (5 mL). The reaction mixture was stirred at 0 °C under N2 for 2 h. After quenching with aqueous NaHCO3 solution, 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 with 0.1% formic acid) to give 4-(1-(2-hydroxyacetyl)indoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (15 mg, 18%) as a white solid. LC-MS (ESI): m / z (M+H) + =388.61. 1 H NMR (400MHz, DMSO-d6) δ9.14(t,J=5.9Hz,1H),8.57(d,J=1.6Hz,1H),8.47(dd,J =4.7,1.4Hz,1H),8.15(d,J=8.3Hz,1H),7.96(d,J=8.4Hz,2H),7.82-7.70(m,3H ),7.65(s,2H),7.59(d,J=8.4Hz,1H),7.37(dd,J=7.7,4.8Hz,1H),4.94(s,1H), 4.52(d,J=5.8Hz,2H), 4.21(s,2H), 4.06(t,J=8.5Hz,2H), 3.22(t,J=8.3Hz,2H).

[0905] Synthesis of 4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide (Compound I-48)

[0906] Preparation of 1-(5-bromoindololin-1-yl)prop-1-one

[0907]

[0908] Following standard procedure D, the reaction began with 5-bromoindoline (3.0 g, 15.2 mmol) and propionic acid (1.37 g, 18.3 mmol). In this case, the reagents were added at 0 °C, and the reaction mixture was warmed to room temperature. A white solid, 1-(5-bromoindoline-1-yl)prop-1-one (3.0 g, 78%), was isolated. LC-MS (ESI): m / z (M) + =253.01,255.52.

[0909] Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indololin-1-yl)prop-1-one

[0910]

[0911] Step G: B2Pin2 (1.65 g, 6.5 mmol), Pd(dppf)Cl2 (240 mg, 0.3 mmol), and KOAc (1.7 g, 17.7 mmol) were added to a mixture of 1-(5-bromoindololin-1-yl)prop-1-one (1.5 g, 5.9 mmol) in dioxane (15 mL). The reaction mixture was stirred at 80 °C for 20 hours. It was then diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (PE / EA4:1, v / v) to give a yellow solid of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indololin-1-yl)prop-1-one (800 mg, 45%). LC-MS (ESI): m / z (M-56) + =254.20.

[0912] Preparation of 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide

[0913]

[0914] To a mixture of 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (200 mg, 0.783 mmol) in THF (5 mL), pyridin-3-ylmethylamine (92.9 mg, 0.861 mmol) and DIPEA (303.1 mg, 2.349 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. It was quenched with water, washed with brine, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (PE / EA₄:1, v / v) to give 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (140 mg, 55%) as a yellow solid. LC-MS (ESI): m / z (M) + =326.02,328.33.

[0915] Preparation of 4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide (Compound I-48)

[0916]

[0917] Following procedure B, the reaction proceeded from 4-bromo-N-(pyridin-3-ylmethyl)benzenesulfonamide (100 mg, 0.31 mmol) and 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)indololin-1-yl)propion-1-one. In this case, the reaction mixture was stirred in a microwave at 80 °C for 1 h. Purification by preparative HPLC (C18, 40–100% MeCN solution in H₂O with 0.1% formic acid) yielded a white solid, 4-(1-propionylindololin-5-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide (18 mg, 13%). LC-MS (ESI): m / z (M+1) + =422.23. 1 HNMR(400MHz,DMSO-d6)δ8.47-8.40(m,2H),8.31-8.25(m,J=15.9Hz,1H),8.21- 8.13(m,J=8.3Hz,1H),7.83(s,4H),7.68-7.61(m,J=11.3,3.2Hz,2H),7.59-7.54 (m,J=8.4Hz,1H),7.32-7.27(m,J=7.8,4.8Hz,1H),4.15(t,J=8.5Hz,2H),4.07( d, J=3.5Hz, 2H), 3.23 (t, J=8.4Hz, 3H), 2.50-2.46 (m, 2H), 1.09 (t, J=7.3Hz, 3H).

[0918] Synthesis of 4-(1-propionylindoline-5-yl)-N-(pyridin-4-ylmethyl)benzamide (Compound I-49)

[0919] Preparation of methyl 4-(indoline-5-yl)benzoate

[0920]

[0921] Following step E, methyl 4-(indoline-5-yl)benzoate (1.5 g, 95%) was obtained in solid form. LC-MS (ESI): m / z (M-56) + =254.14.

[0922] Preparation of methyl 4-(1-propionylindoline-5-yl)benzoate

[0923]

[0924] Following standard procedure D, the reaction began with methyl 4-(indoline-5-yl)benzoate (4.8 g, 19.0 mmol) and propionic acid (1.7 g, 22.7 mmol). In this case, the reagents were added at 0 °C, and the reaction mixture was warmed to room temperature. methyl 4-(1-propionylindoline-5-yl)benzoate (4.4 g, 75%) was isolated as a solid. LC-MS (ESI): m / z (M+1) + =310.14.

[0925] Preparation of 4-(1-propionylindoline-5-yl)benzoic acid

[0926]

[0927] Following step C, 4-(1-propionylindoline-5-yl)benzoate (1.8 g, 5.8 mmol) was reacted with methyl 4-(1-propionylindoline-5-yl)benzoate to obtain a white solid 4-(1-propionylindoline-5-yl)benzoic acid (intermediate B) (1.3 g, 76%). LC-MS (ESI): m / z (M+1) + =296.09.

[0928] Preparation of 4-(1-propionylindoline-5-yl)-N-(pyridin-4-ylmethyl)benzamide (Compound I-49)

[0929]

[0930] Following standard procedure D, starting with 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and pyridin-4-ylmethylamine (44 mg, 0.41 mmol), a white solid, 4-(1-propionylindolin-5-yl)-N-(pyridin-4-ylmethyl)benzamide (70 mg, 53%), was isolated. LC-MS (ESI): m / z (M+H) + =386.22. 1 H NMR (400MHz, DMSO-d6) δ9.16 (t, J=6.0Hz, 1H), 8.55-8.45 (m, J=4.5, 1.6Hz, 2H) ,8.16(d,J=8.4Hz,1H),8.02-7.93(m,J=8.5Hz,2H),7.81-7.73(m,J=8.5Hz,2H ),7.64(s,1H),7.60-7.54(m,J=8.4Hz,1H),7.32(d,J=5.9Hz,2H),4.52(d,J=5 .9Hz, 2H), 4.13 (t, J = 8.5Hz, 2H), 3.21 (t, J = 8.4Hz, 2H), 1.08 (t, J = 7.3Hz, 3H).

[0931] Synthesis of 4-(1-propionylindoline-5-yl)-N-(pyrimidin-5-ylmethyl)benzamide (Compound I-51)

[0932]

[0933] At 0 °C, NaBH4 (262 mg, 6.9 mmol) was added in a single addition to a solution of pyrimidine-5-carboxaldehyde (500 mg, 4.6 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 4 hours. 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 pyrimidine-5-ylmethanol (456 mg, 89%) as a white solid. LC-MS (ESI): m / z (M+H) = 111.13.

[0934] At 0 °C, SOCl2 (1.33 g, 11.1 mmol) was added in a single addition to a solution of pyrimidin-5-ylmethanol (410 mg, 3.7 mmol) in THF (10 mL). The mixture was stirred at room temperature for 4 hours. It was then quenched with Na2CO3, extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a white solid of 5-(chloromethyl)pyrimidin (456 mg, 95%). LC-MS (ESI): m / z (M+H) = 129.02 / 131.07.

[0935] NH3·H2O (4 mL) was added to a solution of 5-(chloromethyl)pyrimidine (200 mg, 1.56 mmol) in THF. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and purified by rapid chromatography to give a white solid (pyrimidine-5-ylmethylamine (130 mg, 38%). LC-MS (ESI): m / z (M+H) = 110.13.

[0936] Following standard procedure D, starting with 4-(1-propionylindololin-5-yl)benzoic acid (238 mg, 0.8 mmol) and pyrimidin-5-ylmethylamine (130 mg, 1.2 mmol), a white solid 4-(1-propionylindololin-5-yl)-N-(pyrimidin-5-ylmethyl)benzamide (38 mg, 12%) was isolated. LC-MS (ESI): m / z (M+H) = 387.24. 1 H NMR (400MHz, DMSO-d6) δ9.21-9.06(m,2H),8.80(s,2H),8.16(d,J=6.2Hz,1H),7.95(d,J=6.6Hz,2H),7.76(d,J=6.4Hz, 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).

[0937] Synthesis of 4-(1-propionylindoline-5-yl)-N-(pyridazin-4-ylmethyl)benzamide (Compound I-52)

[0938]

[0939] Following standard procedure D, starting with 4-(1-propionylindolin-5-yl)benzoic acid (106 mg, 0.36 mmol) and pyridazin-4-ylmethylamine (50 mg, 0.33 mmol), a white solid 4-(1-propionylindolin-5-yl)-N-(pyridazin-4-ylmethyl)benzamide (59 mg, 42%) was isolated. LC-MS (ESI): m / z (M+H) + =387.22. 1H NMR(400MHz, DMSO-d6)δ9.29-9.24(m,1H),9.22(s,1H),9.16(dd,J=5.3,1.0Hz,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=5.8Hz,2H),4.13(t,J=8.5Hz,2H),3.21(t,J=8.3Hz,2H),2.50-2.44(m,2H),1.08(t,J=7.3Hz,3H).

[0940] Synthesis of 4-(1-propionylindoline-5-yl)-N-(1-(pyridin-3-yl)ethyl)benzamide (Compound I-57)

[0941]

[0942] Following standard procedure D, starting with 4-(1-propionylindolin-5-yl)benzoic acid (100 mg, 0.34 mmol) and 1-(pyridin-3-yl)ethyl-1-amine (38 mg, 0.31 mmol), a white solid, 4-(1-propionylindolin-5-yl)-N-(1-(pyridin-3-yl)ethyl)benzamide (50 mg, 40%) was isolated. LC-MS (ESI): m / z (M+H) + =400.20. 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J=7.8Hz,1H),8.62(d,J=2.0Hz,1H),8.45(dd,J=4.7,1.5Hz ,1H),8.16(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.83-7.78(m,1H),7.75(d,J=8.4Hz,2H) ,7.62(s,1H),7.55(d,J=8.4Hz,1H),7.39-7.34(m,1H),5.26-5.18(m,1H),4.13(t,J=8.5Hz ,2H),3.21(t,J=8.3Hz,2H),2.50-2.44(m,2H),1.53(d,J=7.1Hz,3H),1.08(t,J=7.3Hz,3H).

[0943] Synthesis of 4-(1-propionylindoline-5-yl)-N-(2-(pyridin-3-yl)prop-2-yl)benzamide (Compound I-58)

[0944]

[0945] Following standard procedure D, starting with 4-(1-propionylindolin-5-yl)benzoic acid (80 mg, 0.271 mmol) and 2-(pyridin-3-yl)propyl-2-amine (40 mg, 0.298 mmol), a white solid, 4-(1-propionylindolin-5-yl)-N-(2-(pyridin-3-yl)propyl-2-yl)benzamide (63 mg, 56%), was isolated. LC-MS (ESI): m / z (M+H) + =414.32. 1 H NMR(400MHz, DMSO-d6)δ8.62(d,J=2.2Hz,1H),8.56(s,1H),8.39(dd,J=4.7, 1.4Hz,1H),8.16(d,J=8.3Hz,1H),7.91(d,J=8.4Hz,2H),7.77-7.71(m,3H),7 .62(s,1H),7.55(d,J=8.3Hz,1H),7.33-7.29(m,1H),4.13(t,J=8.5Hz,2H), 3.21(t,J=8.5Hz,2H),2.50-2.46(m,2H),1.71(s,6H),1.08(t,J=7.3Hz,3H).

[0946] Synthesis of N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-59)

[0947] Preparation of (6-methylpyridin-3-yl)methylamine

[0948]

[0949] Step H: Raney nickel (50 mg) was added to a mixture of 6-methylnicotinonitrile (300 mg, 2.54 mmol) in MeOH / NH3 (7 N, 10 mL). The reaction mixture was stirred at room temperature under H2 for 3 h. It was then filtered, and the filtrate was concentrated under vacuum to give a yellow oily 6-methylpyridin-3-yl)methylamine (280 mg, 90%). LC-MS (ESI): m / z (M+1) + =123.30.

[0950] Preparation of N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-59)

[0951]

[0952] Following standard procedure D, starting with 4-(1-propionylindoline-5-yl)benzoic acid (100 mg, 0.34 mmol) and (6-methylpyridin-3-yl)methylamine (50 mg, 0.41 mmol), a white solid N-((6-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (50 mg, 36%) was isolated. LC-MS (ESI): m / z (M+H) + =400.32. 1 H NMR (400MHz, DMSO-d6) δ9.08(t,J=5.8Hz,1H),8.42(d,J=1.9Hz,1H),8.15(d,J=8 .4Hz,1H),7.94(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.65-7.59(m,2H),7.56( d,J=8.4Hz,1H),7.21(d,J=8.0Hz,1H),4.46(d,J=5.8Hz,2H),4.13(t,J=8.4Hz,2 H), 3.21 (t, J = 8.4Hz, 2H), 2.50-2.47 (m, 2H), 2.44 (s, 3H), 1.07 (t, J = 7.3Hz, 3H).

[0953] Synthesis of N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-60)

[0954] Preparation of 2,6-dimethylnicotinonitrile

[0955]

[0956] Step I: CuCN (480 mg, 5.38 mmol) was added to a mixture of 3-bromo-2,6-dimethylpyridine (500 mg, 2.69 mmol) in DMF (5 mL). The reaction mixture was stirred at 150 °C for 12 hours. It was then diluted with DCM and washed with NH4Cl aqueous solution (85%) / NH3·H2O (15%), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (DCM / MeOH 10:1, v / v) to give 2,6-dimethylnicotinonitrile (210 mg, 59%) as a yellow solid. LC-MS (ESI): m / z (M+1) + =133.17.

[0957] Preparation of (2,6-dimethylpyridin-3-yl)methylamine

[0958]

[0959] Following step H, a yellow oily (2,6-dimethylpyridin-3-yl)methylamine (60 mg, 58%) was obtained from 2,6-dimethylnicotinonitrile (100 mg, 0.176 mmol). LC-MS (ESI): m / z (M+1) + =137.20.

[0960] Preparation of N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-60)

[0961]

[0962] Following standard procedure D, starting with 4-(1-propionylindololin-5-yl)benzoic acid (100 mg, 0.34 mmol) and (2,6-dimethylpyridin-3-yl)methylamine (50 mg, 0.41 mmol), a white solid N-((2,6-dimethylpyridin-3-yl)methyl)-4-(1-propionylindololin-5-yl)benzamide (41 mg, 29%) was isolated. LC-MS (ESI): m / z (M+H) + =414.32. 1 HNMR(400MHz,DMSO-d6)δ8.96(t,J=5.5Hz,1H),8.18-8.14(m,1H),7.96(d,J=8 .3Hz,2H),7.75(d,J=8.3Hz,2H),7.62(s,1H),7.55(d,J=8.3Hz,1H),7.49(d,J =7.8Hz,1H),7.04(d,J=7.7Hz,1H),4.44(d,J=5.5Hz,2H),4.13(t,J=8.4Hz,2H ), 3.21 (t, J = 8.4Hz, 2H), 2.50-2.45 (m, 5H), 2.39 (s, 3H), 1.08 (t, J = 7.2Hz, 3H).

[0963] Synthesis of N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-61)

[0964] Preparation of 2-methylnicotinonitrile

[0965]

[0966] Following step I, 2-methylnicotinonitrile (110 mg, 32%) was obtained as a yellow solid from 3-bromo-2-methylpyridine (500 mg, 2.9 mmol). LC-MS (ESI): m / z (M+1)+ =119.20.

[0967] Preparation of (2-methylpyridin-3-yl)methylamine

[0968]

[0969] According to step H: (100 mg, 0.85 mmol) of 2-methylnicotinonitrile yielded a yellow solid (2-methylpyridin-3-yl)methylamine (80 mg, 77%). LC-MS (ESI): m / z (M+1) + =123.71.

[0970] Preparation of N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (Compound I-61)

[0971]

[0972] Following standard procedure D, starting with 4-(1-propionylindoline-5-yl)benzoic acid (145 mg, 0.49 mmol) and (2-methylpyridin-3-yl)methylamine (60 mg, 0.49 mmol), a white solid N-((2-methylpyridin-3-yl)methyl)-4-(1-propionylindoline-5-yl)benzamide (41 mg, 29%) was obtained. LC-MS (ESI): m / z (M+H) + =400.31. 1 HNMR(400MHz,DMSO-d6)δ9.02(t,J=5.6Hz,1H),8.33(d,J=3.9Hz,1H),8.16 (d,J=8.4Hz,1H),7.97(d,J=8.3Hz,2H),7.75(d,J=8.3Hz,2H),7.65-7.52(m ,3H),7.20(dd,J=7.5,4.9Hz,1H),4.49(d,J=5.5Hz,2H),4.13(t,J=8.4Hz, 2H), 3.21 (t, J = 8.3Hz, 3H), 2.53 (s, 3H), 2.48 (t, 2H), 1.08 (t, J = 7.2Hz, 3H).

[0973] Synthesis of N-methyl-4-(1-propionylindoline-5-yl)-N-(pyridin-3-ylmethyl)benzamide (Compound I-62)

[0974] Preparation of N-(pyridin-3-ylmethyl)formamide

[0975]

[0976] A mixture of pyridin-3-ylmethylamine (1.0 g, 9.2 mmol) and ethyl formate (10 mL) was stirred at 60 °C for 4 h. The mixture was then concentrated under reduced pressure to give a colorless oily N-(pyridin-3-ylmethyl)formamide (1.0 g, 79%). LC-MS (ESI): m / z (M+1) + =137.06.

[0977] Preparation of N-methyl-1-(py...

Claims

1. A compound of formula (0): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof, wherein: L A -N(R 2 )(L 1 R 1 ) or -C(=O)NR 1 R 2 ; L 1 is a single bond or -C(=O)-; When L 1 When it 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 carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; When L 1 When it is -C(=O)-, R 1 To replace C 1-6 Alkyl, wherein the substituent contains 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 group; substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group; 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 carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or R 2 and R 3 are linked to 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 ; R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C- or when When it is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, bond b and bond c are in meta or para position relative 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; Where valence permits, n is 0, 1, 2, 3 or 4, wherein when n is 1, 2, 3 or 4, there is no R 5 The connection with nitrogen atom; L B -N(R 6 )L 2 -or-L 2 N(R 6 )-; L 2 is -C(=O)-, or -S(=O)2-; Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, 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; and 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 of claim 1, wherein the compound has the formula (0'): 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)-; When L 1 When it 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 carbocyclyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclyl, or substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl; When L 1 When it is -C(=O)-, R 1 To replace C 1-6 Alkyl, wherein the substituent contains 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 group; substituted or unsubstituted 3 to 13 membered monocyclic or bicyclic heterocyclic group; substituted or unsubstituted 6 to 11 membered monocyclic or bicyclic aryl group; or substituted or unsubstituted 5 to 11 membered monocyclic or bicyclic heteroaryl group; 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 carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or R 2 and R 3 are linked to 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 ; R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C- or when When it is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, bond b and bond c are in meta or para position relative 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; Where valence permits, n is 0, 1, 2, 3 or 4, wherein when n is 1, 2, 3 or 4, there is no R 5 The connection with nitrogen atom; L 2 -C(=O)-, or -S(=O)2-; Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, 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; and 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. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound of formula (0): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof, wherein: L A -N(R 2 )(L 1 R 1 ) or -C(=O)NR 1 R 2 ; L 1 is a single bond or -C(=O)-; When L 1 When it 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; When L 1 When it 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 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 carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or R 2 and R 3 are linked to their intervening atoms to form a substituted or unsubstituted 5-membered or 6-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1; Each instance of Y is independently N or CR 4 ; R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C- or when When it is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, bond b and bond c are in meta or para position relative 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; Where valence permits, n is 0, 1, 2, 3 or 4, wherein when n is 1, 2, 3 or 4, there is no R 5 The connection with nitrogen atom; L B -N(R 6 )L 2 -or-L 2 N(R 6 )-; L 2 -C(=O)-, or -S(=O)2-; Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, 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; and 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. The method of claim 3, wherein the compound of formula (0) has formula (0'): 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)-; When L 1 When it 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; When L 1 When it 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 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 carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or R 2 and R 3 are linked to their intervening atoms to form a substituted or unsubstituted 5-membered or 6-membered monocyclic heterocyclyl or heteroaryl; q is 0 or 1; Each instance of Y is independently N or CR 4 ; R 4 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN; is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, -C≡C- or when When it is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, bond b and bond c are in meta or para position relative 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; Where valence permits, n is 0, 1, 2, 3 or 4, wherein when n is 1, 2, 3 or 4, there is no R 5 The connection with nitrogen atom; L 2 is -C(=O)-, or -S(=O)2-; Each R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic carbocyclic group, substituted or unsubstituted 3- to 13-membered monocyclic or bicyclic heterocyclic group, substituted or unsubstituted 6- to 11-membered monocyclic or bicyclic aryl group, substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heteroaryl group, 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; and R 8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a 、-N(R a )2 or -CN.

5. A method comprising contacting a cell with an effective amount of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof as described in claim 3 or 4.

6. A method comprising killing cells with an effective amount of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof as described in claim 3 or 4.

7. A pharmaceutical composition comprising: A compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof; and optionally Pharmaceutically acceptable excipients.

8. A method for treating cancer, comprising administering the pharmaceutical composition of claim 7 to a subject.

9. A kit comprising: A compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof; or a pharmaceutical composition as claimed in claim 7; as well as Instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug or pharmaceutical composition.

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