Cancer treatment targeting cancer stem cells

Abstract

Compounds, methods, compositions, uses, and kits that allow for the treatment of cancer are disclosed. In some embodiments, the compounds are useful in the treatment of diseases or conditions. The compounds can treat cancer by targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, liver cancer, endometrial cancer, leukemia, or multiple myeloma. Compounds, methods, compositions, uses, and kits useful in regenerative medicine are disclosed. The compounds used in the present disclosure have Formula (0) and (I). # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: November 6, 2020; application number: 202080091217.1 (international application number: PCT / US2020 / 059329); invention name: Cancer treatment targeting cancer stem cells).

[0002] Related applications

[0003] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application USSN 62 / 931,531, filed on November 6, 2019, which is incorporated herein by reference. Background Art

[0004] Cancer is ubiquitous and, despite medical advances, remains the 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. Over the next 20 years, the number of new cases is expected to increase by approximately 70%. The economic impact of cancer is substantial and growing. In 2010, the total annual economic cost of cancer was estimated to be approximately US$1.16 trillion. 2

[0005] Cancer is a general term for a large group of diseases that can affect any part of the body. Other terms used are malignancy and neoplasm. Cancer is caused by the transformation of normal cells into tumor cells in a multistage process, which typically progresses from a precancerous lesion to a malignant tumor. A defining characteristic of cancer is the rapid development of abnormal cells that grow beyond their usual boundaries and can then invade adjacent parts of the body and spread to other organs, a process known as metastasis. Metastasis is the 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 extremely high, with little improvement overall in the ongoing cancer crisis. Almost all modern cancer treatments, including chemotherapy, targeted therapies, and immunotherapy, focus on eliminating tumors without targeting the most dangerous cells within a tumor: 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 the cancer stem cell population, they often lead to the emergence of drug-resistant tumors and continued cancer spread. Summary of the Invention

[0007] The discovery of cancer stem cells provides an opportunity for the convergence of the fields of oncology and stem cell biology. 5,6 By targeting what makes cancer so dangerous—the embryonic or adult stem cell properties of cancer stem cells that underlie their growth, spread, and drug resistance—the development of effective and non-toxic therapies could be achieved through a strategy known as cancer suppressor therapy. Therapies that can both reduce tumor size and destroy cancer stem cells would transform cancer treatment. 7

[0008] This article describes compounds that force cancer stem cells to differentiate and inhibit the same signaling pathways required for metastasis that stem cells use during differentiation and development. 8,9 These properties can be safely targeted because they are present only in stem cells and not in healthy adult tissue.

[0009] Described herein are compounds that modulate nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide mononucleotide (NMN) production, nicotinamide adenine dinucleotide (NAD) production, NAMPT signaling, the NAMPT pathway, and / or cellular metabolism.

[0010] These compounds will be more effective than traditional cancer treatments in reducing tumor growth, prolonging life, and / or preventing metastasis and recurrence. Moreover, because reactivation of embryonic properties is a property shared by many tumors, cancer-suppressing therapies are expected to be effective against many different types of cancer, including leukemias as well as cancers of the colon, stomach, prostate, testicle, and breast.

[0011] Disclosed herein are compounds, methods, compositions, uses, and kits that allow for the treatment of proliferative diseases, benign neoplasms, and cancer.

[0012] In one aspect, the present disclosure provides compounds of formula (0):

[0013]

[0014] 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 certain aspects, the compound of formula (0) has formula (0a), (0b), or (0c):

[0015]

[0016] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein the variables are as described herein.

[0017] In one aspect, the present disclosure provides compounds of 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 certain aspects, the compound of Formula (I) has Formula (Ia):

[0020]

[0021] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein the variables described in Formula (Ia) are as described herein. In certain aspects, the compound of Formula (I) has the following formula:

[0022]

[0023] In another aspect, the present disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (0) or (I) are as described herein.

[0024] In certain embodiments, cancer includes cancer stem cells. In certain embodiments, cancer relates to cancer stem cells or is associated with cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumors, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, prostate cancer, liver cancer or endometrial cancer. In certain embodiments, the cancer is leukemia (e.g., acute myeloid leukemia). In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the subject needs regenerative medicine or therapy.

[0025] In yet another aspect, the present disclosure provides methods and uses comprising contacting a cell with an effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0026] In certain aspects, the present disclosure provides methods and uses comprising killing cells with an effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0027] In certain aspects, the present disclosure provides methods and uses comprising contacting a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, with a cell, tissue, or biological sample to inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic or adult stem cell properties of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0028] In certain aspects, the present disclosure provides a method of inhibiting NAMPT in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0029] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject by inhibiting NAMPT in the subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0030] In certain aspects, the present disclosure provides methods of inhibiting the production of nicotinamide adenine dinucleotide in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0031] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0032] In certain aspects, the present disclosure provides methods of inhibiting the production of nicotinamide mononucleotide in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0033] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0034] In certain aspects, the present disclosure provides a method of reducing inflammatory cell infiltration in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0035] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject by reducing inflammatory cell infiltration in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0036] In certain aspects, the present disclosure provides methods of reducing cell proliferation in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0037] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject by reducing cell proliferation in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0038] In certain aspects, the present disclosure provides a method of reducing the metabolic activity or state of a subject's cells, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0039] In certain aspects, the present disclosure provides a method for treating a disease or condition in a subject by reducing the metabolic activity or state of the subject's cells, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0040] In certain aspects, the present disclosure provides methods of reducing inflammatory activity in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0041] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject by reducing inflammatory activity in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0042] In certain aspects, the present disclosure provides methods of reducing NAMPT signaling in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0043] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject by reducing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0044] In certain aspects, the present disclosure provides methods of inhibiting the NAMPT pathway in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0045] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject by inhibiting the NAMPT pathway in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0046] In certain aspects, the present disclosure provides a method of inhibiting the NAMPT pathway in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0047] In certain aspects, the present disclosure provides a method of reducing NAMPT signaling in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0048] In certain aspects, the present disclosure provides a method of reducing inflammatory activity in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0049] In certain aspects, the present disclosure provides a method of reducing the cellular metabolic activity or state of a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0050] In certain aspects, the present disclosure provides a method of reducing cell proliferation in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0051] In certain aspects, the present disclosure provides a method of reducing inflammatory cell infiltration of a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0052] In certain aspects, the present disclosure provides a method of inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0053] In certain aspects, the present disclosure provides a method of inhibiting the production of nicotinamide mononucleotide in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0054] In certain aspects, the present disclosure provides a method of inhibiting NAMPT in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0055] In some embodiments, contacting is performed in vitro or ex vivo.

[0056] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0057] In some aspects, the present disclosure provides a composition comprising a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the composition further comprises an additional pharmaceutical agent.

[0058] In certain aspects, the present disclosure provides a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a composition disclosed herein, and an additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent is administered before, simultaneously with, or after the compound disclosed herein (e.g., a compound of Formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a composition disclosed herein.

[0059] In other aspects, the present disclosure provides a kit comprising a compound disclosed herein (e.g., a compound of Formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or a composition as described herein; and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0060] The details of certain embodiments of the invention are set forth in the detailed description, as described below. Other features, objects and advantages of the invention will be apparent from the definitions, examples and claims.

[0061] definition

[0062] For convenience, certain terms employed herein, in the specification, examples, and appended claims, are collected here.

[0063] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0064] The phrase "in some embodiments" is used interchangeably with the phrase "in certain embodiments."

[0065] The following definitions are of more general terms used in this application:

[0066] The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0067] Except in the examples, or where otherwise indicated, all numbers used herein expressing amounts of ingredients or reaction conditions are to be understood as modified in all instances by the term "about." "About" and "approximately" generally mean an acceptable degree of error for the amount measured, given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0068] 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 the elements on the inside cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition Cambridge University Press, Cambridge, 1987.

[0069] The compounds described herein may include one or more asymmetric centers and may therefore 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 enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, as well as alternatively, mixtures of various isomers.

[0070] In the formula, is a single bond, wherein the stereochemistry of the moiety directly attached thereto is unspecified, does not exist or is a single bond, and Is a single bond or a double bond.

[0071] Unless otherwise provided, the formulae described herein include compounds that do not include isotopically enriched atoms as well as compounds that include isotopically enriched atoms. Compounds that include isotopically enriched atoms are useful as analytical tools and / or probes, for example, in biological assays.

[0072] Term " aliphatic " includes saturation and unsaturation, non-aromatic, straight chain (that is, non-branched), side chain, non-cyclic and cyclic (that is, carbocycle) hydrocarbon.In some embodiments, aliphatic group is optionally replaced by one or more functional groups (for example, halo, such as fluorine).As will be understood by those of ordinary skill in the art, " aliphatic " is intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moiety in this article.

[0073] When a range of values ​​("range") is listed, it is intended to encompass every value and subrange within the range. Unless otherwise provided, a range includes the values ​​at both ends of the range. For example, "an integer 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.

[0074] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1–20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1–12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1–10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1–9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1–8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1–7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1–6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1–5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1–4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1–3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1–2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2–6 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), octyl (C10), octyl (C11), octyl (C12), octyl (C13), octyl (C14), octyl (C15), octyl (C16), octyl (C17), octyl (C18), octyl (C19), octyl (C21), octyl (C22), octyl (C23), octyl (C24), octyl (C25), octyl (C26), octyl (C27), octyl (C28), octyl (C29), octyl (C30), octyl (C31), octyl (C32), octyl (C33), octyl (C34), octyl (C35), octyl (C36), octyl (C37), octyl (C38), octyl (C39), octyl (C41), octyl (C42), octyl (C43), octyl (C44), octyl (C45), octyl (C46), octyl (C47), octyl (C48), octyl (C49), octyl (C51), 12 ) etc. Unless otherwise specified, each instance of alkyl is independently optionally substituted, e.g., unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is unsubstituted C 1–12 Alkyl (e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1–12 Alkyl (such as substituted C 1-6 Alkyl, for example, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn). The point of attachment of an alkyl group can be a single bond (for example, in -CH3), a double bond (for example, in =CH2), or a triple bond (for example, in ≡CH). The moieties =CH2 and ≡CH are also alkyl groups.

[0075] In some embodiments, the alkyl group is substituted with one or more halogens. A "perhaloalkyl" is a substituted alkyl group as defined herein in which all hydrogen atoms are independently replaced with halogens (e.g., fluorine, bromine, chlorine, or iodine). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C 1–8 In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C 1–6 In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C 1–4 In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C 1–3 In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C 1–2In some embodiments, all hydrogen atoms are replaced by fluorine. In some embodiments, all hydrogen atoms are replaced by chlorine. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0076] "Alkenyl" refers to a straight or branched chain hydrocarbon group ("C 2–20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2–10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2–9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2–8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2–7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2–6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2–5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2–4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2–3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2–6 Examples of the alkenyl group include the aforementioned C 2–4 In some embodiments, alkenyl is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-9, C 2-10, C 3-11, C 3-12, C 3-13, C 3-14, C 3-15, C 3-16, C 3-17, C 3-18, C 3-19, C 4-20, C 4-32, C 4-33, C 4-44, C 4-50, C 4-6, C 4-7, C 4-8, C 4-9, C 4-10, C 4-11, C 4-12, C 4-13, C 4-14, C 4-15, C 4-16, C 4-17, C 4-18, C 4-19, C 4-20, C 4-21, C 4-22, 2–10 In certain embodiments, alkenyl is a substituted C 2–10 In alkenyl, a C=C double bond whose stereochemistry is not specified (e.g., -CH=CHCH3, ) can be in the (E)- or (Z)-configuration.

[0077] "Alkynyl" refers to a straight or branched chain hydrocarbon group ("C 2-20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2–10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2–9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2–8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2–7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2–6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2–5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2–4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2–3 In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2–4 Examples of alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2–6 Examples of alkenyl groups include the above-mentioned C 2–4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkynyl”) or substituted with one or more substituents (a “substituted alkynyl”). In certain embodiments, alkynyl is an unsubstituted C 2–10 In certain embodiments, the alkynyl group is a substituted C 2–10 Alkynyl.

[0078] "Carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 13 ring carbon atoms ("C 3–13 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3–8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3–7In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3–6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5–10 Carbocyclyl”). Exemplary C 3–6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3–8 Carbocyclic groups include the aforementioned C 3–6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3–10 Carbocyclic groups include the aforementioned C 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As shown in the foregoing examples, in certain embodiments, a carbocyclyl is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"). A carbocyclyl can be saturated, and a saturated carbocyclyl is referred to as a "cycloalkyl". In some embodiments, a carbocyclyl is a monocyclic saturated carbocyclyl ("Cycloalkyl") having 3 to 10 ring carbon atoms. 3–10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3–8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3–6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5–6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5–10 Cycloalkyl”). C 5–6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3–6 Examples of the cycloalkyl group include the aforementioned C 5–6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3–8 Examples of the cycloalkyl group include the aforementioned C 3–6Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl is an unsubstituted C 3–10 In certain embodiments, the cycloalkyl group is a substituted C 3–10 Cycloalkyl. Carbocyclyl can be partially unsaturated. Carbocyclyl can include zero, one or more (e.g., two, three or four, where valence permits) C=C double bonds in all rings of a non-aromatic or heteroaromatic carbocyclic system. Carbocyclyls that include one or more (e.g., two or three, where valence permits) C=C double bonds in a carbocyclic ring are referred to as "cycloalkenyls." Carbocyclyls that include one or more (e.g., two or three, where valence permits) C≡C triple bonds in a carbocyclic ring are referred to as "cycloalkynyls." Carbocyclyls include aryls. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in this case, the number of carbons continues to represent the number of carbons in the carbocyclic ring system. Unless otherwise stated, each instance of a carbocyclyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C 3–10 In certain embodiments, a carbocyclyl group is a substituted C 3–10 Carbocyclyl. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 3 to 7 members, and monocyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 5 to 13 members, and bicyclic.

[0079] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3–10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3–8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3–6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5–6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5–10 Cycloalkyl”). C 5–6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3–6 Examples of the cycloalkyl group include the aforementioned C 5–6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3–8Examples of the cycloalkyl group include the aforementioned C 3–6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl is an unsubstituted C 3–10 In certain embodiments, the cycloalkyl group is a substituted C 3–10 Cycloalkyl. In certain embodiments, a carbocyclyl group includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valence permits.

[0080] "Carbocyclylalkyl", "X to X membered carbocyclyl-C x-x "alkyl" or "X to X membered carbocyclyl-C x-x -alkyl", where each instance of X is an integer, is a subset of "alkyl" and refers to an alkyl group substituted with a carbocyclyl group, where the point of attachment is on the alkyl portion. For example, a 3- to 13-membered carbocyclyl-C 1–12 -alkyl refers to a C substituted by a 3- to 13-membered carbocyclic group (e.g., cyclopropyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl). 1–12 Alkyl (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0081] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"). A heterocyclyl group may be saturated or partially unsaturated. A heterocyclyl group may include zero, one or more (e.g., two, three, or four, where valence permits) double bonds in all rings of a non-aromatic or heteroaromatic heterocyclyl ring system. Partially unsaturated heterocyclyl groups include heteroaryls. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each instance of a heterocyclyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl group. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl group. In certain embodiments, a heterocyclyl group is substituted or unsubstituted, 3 to 7 members, and monocyclic. In certain embodiments, a heterocyclyl group is substituted or unsubstituted, 5 to 13 members, and bicyclic. In certain embodiments, the heterocyclyl group is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl group, wherein one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence permits.

[0082] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, a 5-6 membered heterocyclyl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0083] Exemplary 3-membered heterocyclic groups containing one heteroatom include aziridinyl, oxiranyl, or thiothianyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxolanyl, oxasulfanyl, disulfanyl, and oxazolidin-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 thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azocanyl, oxepanyl and thiecanyl. Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone and the like. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepine, yl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl and the like.

[0084] "heterocyclylalkyl", "X to X membered heterocyclyl-C x-x "alkyl" or "X to X membered heterocyclyl-C x-x -alkyl", where each instance of X is an integer, is a subset of "alkyl" and refers to an alkyl group substituted with a heterocyclyl group, where the point of attachment is on the alkyl portion. For example, a 3- to 13-membered heterocyclyl-C 1-12 -alkyl refers to a C substituted by a 3- to 13-membered heterocyclic group (e.g., oxiranyl, oxetane, oxadiazolinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl) 1-12 Alkyl (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0085] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, either monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons in common in the ring array) ("C 6–14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl"; e.g., anthracenyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each instance of an aryl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6–14 In certain embodiments, aryl is a substituted C 6–14 Aryl.

[0086] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0087] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons in common in the ring array) having ring carbon atoms 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 heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryls, in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment 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). In certain embodiments, heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0088] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0089] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0090] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include aza Oxalic acid thia Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0091] "Partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation and is not intended to include aromatic groups (e.g., aryl or heteroaryl) as defined herein. Likewise, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains all single bonds.

[0092] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, 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” carbocyclyl, heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted”, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). In general, the term "substituted", whether or not preceded by "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by an available substituent, such as a substituent that produces a stable compound after substitution, such as a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination or other reactions. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable 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, a substituent on a polycyclic ring can be at any substitutable position of any monocyclic ring of the polycyclic ring. It is envisioned that the term "substituted" includes substitution with all available substituents of an organic compound, and the substituent includes any substituent described herein that causes the formation of a stable compound. The present disclosure contemplates any and all such combinations to obtain stable compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein that satisfies the valence of the heteroatoms and causes the formation of a stable moiety.

[0093] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(Raa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counterion;

[0094] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc Replacement;

[0095] R aa Each instance of is independently selected from C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0096] R bb Each instance of 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 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counterion;

[0097] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0098] R dd Each instance of is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(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 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently replaced by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S; where X - is the counterion;

[0099] R ee Each instance of is independently selected from C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0100] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution; and

[0101] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0102] In certain embodiments, carbon atom substituents are independently halogen, substituted (eg, substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa 、-SR aa 、-N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2, -OC(=O)R aa 、-OCO2R aa 、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa or -NR bb C(=O)N(R bb ) 2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (eg, substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -ORaa 、-SR aa 、-N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2, -OC(=O)R aa 、-OCO2R aa 、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa or -NR bb C(=O)N(R bb )2, where R aa is hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or trityl); each R bb are independently hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa 、-SR aa 、-N(R bb )2, -CN, -SCN or -NO2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1-6 Alkyl, -OR aa 、-SR aa 、-N(R bb )2, -CN, -SCN or -NO2, where R aa is hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or trityl); and each R bb are independently hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 Alkyl or nitrogen protecting group.

[0103] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., include one formal negative charge). Anionic counterions can also be multivalent (i.e., include more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halides (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-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-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 (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaic acid, sebacate, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0104] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0105] Where valence permits, the nitrogen atoms may be substituted or unsubstituted and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)(OR cc )2、-P(=O)(R aa )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to the N atom cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As defined above.

[0106] In certain embodiments, nitrogen atom substituents are independently substituted (eg, with one or more halogens) or unsubstituted C 1-6Alkyl, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb ) 2 or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2 or a nitrogen protecting group, wherein R aa is hydrogen, substituted (eg, by one or more halogens) or unsubstituted C 1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl or nitrogen protecting group.

[0107] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups include -OH, -OR aa ,–N(R cc )2, –C(=O)R aa 、–C(=O)N(R cc 2. –CO2R aa ,–SO2R aa 、–C(=NR cc )R aa 、–C(=NR cc )OR aa 、–C(=NR cc )N(R cc )2、–SO2N(R cc )2. –SO2R cc ,–SO2OR cc ,–SOR aa 、–C(=S)N(R cc )2, –C(=O)SR cc , –C(=S)SR cc 、C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd substituted with a group, and wherein R aa 、R bb 、R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition. , Those protecting groups are described in detail in John Wiley & Sons, 1999, which is incorporated herein by reference.

[0108] Amide nitrogen protecting groups (e.g., –C(=O)R aa ) include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0109] Carbamate nitrogen protecting groups (e.g., –C(=O)OR aa) including methyl carbamate, ethyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc ), 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-dicyclohexylcarboxamido)ethylcarbamate, tert-butyl carbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc) , allylcarbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamylcarbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolinylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-dithianyl)]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-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-Dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, tert-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furylmethylcarbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinoyl 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 carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.

[0110] Sulfonamide nitrogen protecting group (e.g. -S(=O)2R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylmethylsulfonamide.

[0111] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-toluenesulfonylaminoacyl derivatives, N'-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenamine (PhF), N-2,7 -Dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, 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 chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphoramide (Dpp), dimethylthiophosphoramide (Mpt), diphenylthiophosphoramide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups together with the nitrogen atom to which the nitrogen protecting group is attached are N,N'-isopropylidenediamine.

[0112] In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, trityl, acetyl, or Ts.

[0113] In certain embodiments, oxygen atom substituents are independently substituted (eg, with 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 groups. In certain embodiments, nitrogen atom substituents are independently substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2 or oxygen protecting group, wherein R aa is hydrogen, substituted (eg, by one or more halogens) or unsubstituted C 1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the oxygen atom substituents are independently substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 Alkyl or oxygen protecting groups.

[0114] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxy protecting group"). Oxygen protecting groups include -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-S(=O)R aa 、-SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - 、-P(OR cc )2、-P(OR cc )3 + X -、-P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - 、R aa 、R bb and R cc As defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0115] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1 Benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylhydrogenseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 3-methyl-2-pyridylmethyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenyl Methyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tritylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methyl Oxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid dithioacetal), pivalate, adamantanoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzoate), methyl alkyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl alkyl carbonate, 2,2,2-trichloroethyl alkyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Ps ec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl alkyl carbonate, vinyl alkyl carbonate, allyl alkyl carbonate, p-nitrophenyl alkyl carbonate, benzyl alkyl carbonate, p-methoxybenzyl alkyl carbonate, 3,4-dimethoxybenzyl alkyl carbonate, o-nitrobenzyl alkyl carbonate, p-nitrobenzyl alkyl carbonate, S-benzyl alkyl 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-( Methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphoramide, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinothioate, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, methanesulfonate (mesylate), phenylmethylsulfonate and toluenesulfonate (Ts).

[0116] In certain embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0117] In certain embodiments, the sulfur atom substituents are independently substituted (eg, with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb ) 2 or a sulfur protecting group. In certain embodiments, the sulfur atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2 or a sulfur protecting group, wherein R aa is hydrogen, substituted (eg, by one or more halogens) or unsubstituted C 1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (eg, substituted with one or more halogens) or unsubstituted C 1-6 In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl or sulfur protecting group.

[0118] In certain embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). In some embodiments, each sulfur protecting group is selected from the group consisting of: -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. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or trityl.

[0119] Other exemplary substituents include hydrogen, halogen, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl), C 1-6 Alkoxy, partially or fully halogenated C 1-6 Alkyl groups (e.g., –CF3, –CHF2, –CH2F), –CN, –NO2, –OR a (e.g., –OMe, –OEt), –SR a ,–N(R a )2 (e.g., -NH2, -NMe2), -NR a (C=O)OR a (e.g., –NH(C=O)OMe, –NH(C=O)OEt, –NH(C=O)O t Bu)、COOR a (e.g., -COOH, -COOMe, -COOEt) and -COR a Other examples include aryl and heteroaryl groups.

[0120] Other exemplary substituents include hydrogen, halogen, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl), C 1-6 Alkoxy, partially or fully halogenated C 1-6 Alkyl groups (e.g., –CF3, –CHF2, –CH2F), –CN, –NO2, –OR aa(e.g., –OMe, –OEt), –SR aa ,–N(R aa )2 (e.g., -NH2, -NMe2), -NR aa (C=O)OR aa (e.g., –NH(C=O)OMe, –NH(C=O)OEt, –NH(C=O)O t Bu),–COOR aa (e.g., -COOH, -COOMe, -COOEt) and -COR aa Other examples include aryl and heteroaryl groups.

[0121] The "molecular weight" of -R (where -R is any monovalent moiety) is calculated by subtracting the atomic weight of the hydrogen atoms from the molecular weight of the molecule RH. The "molecular weight" of -L- (where -L- is any divalent moiety) is calculated by subtracting the combined atomic weight of the two hydrogen atoms from the molecular weight of the molecule HLH.

[0122] In certain embodiments, the molecular weight of the substituent is less than 200, less than 150, less than 100, less than 50 or less than 25g / mol. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulphur, nitrogen and / or silicon atoms. In certain embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine and / or iodine atoms. In certain embodiments, the substituent is composed of carbon, hydrogen and / or fluorine atoms. In certain embodiments, the substituent does not include one or more, two or more or three or more hydrogen bond donors. In certain embodiments, the substituent does not include one or more, two or more or three or more hydrogen bond acceptors.

[0123] Appending the suffix "alkene" to a group indicates that the group is a multivalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In certain embodiments, appending the suffix "alkene" to a group indicates that the group is a divalent moiety.

[0124] The term "hydroxy" refers to the group -OH.

[0125] The term "thiol" or "thio" refers to the group -SH.

[0126] The term "amine" or "amino" refers to the group -NH- or -NH2.

[0127] The term "acyl" refers to a group having the following general formula: -C(=O)R X1 、–C(=O)OR X1 、–C(=O)–O–C(=O)R X1 、–C(=O)SR X1 、–C(=O)N(R X1)2, –C(=S)R X1 、–C(=S)N(R X1 )2、and –C(=S)S(R X1 ),–C(=NR X1 )R X1 、–C(=NR X1 )OR X1 、–C(=NR X1 )SR X1 and –C(=NR X1 )N(R X1 )2, where R X1 is hydrogen; halogen; substituted or unsubstituted hydroxy; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl; 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 branched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphaticthiooxy, heteroaliphaticthiooxy, alkylthiooxy, heteroalkylthiooxy, arylthiooxy, heteroarylthiooxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 The groups together form a 5 to 6 membered heterocyclic ring. 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 substituent described herein that results in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkylsulfoxy, heteroalkylsulfoxy, arylsulfoxy, heteroarylsulfoxy, acyloxy, etc., each of which may or may not be further substituted).

[0128] The term "salt" refers to an ionic compound produced by the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) such that the salt is electrically neutral (having no net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed of an amino group 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 by using other methods known in the art (such as ion exchange methods). Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0129] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1–4 Alkyl)4 - Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0130] The term "solvent" refers to a substance that dissolves one or more solutes to produce a solution. A solvent can serve as a medium for any reaction or transformation described herein. A solvent can dissolve one or more reactants or reagents in a reaction mixture. A solvent can promote mixing of one or more reagents or reactants in a reaction mixture. A solvent can also serve to increase or decrease the rate of a reaction relative to a reaction in a different solvent. Solvents can be polar or nonpolar, protic or aprotic. Common solvents that can be used in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethanol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexane oxane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 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.

[0131] The term "solvate" refers to a form of a compound or salt thereof that is associated with a solvent, typically by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0132] The term "hydrate" refers to a compound associated with water. Generally, the number of water molecules contained in a hydrate of a compound has a definite ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·x H2O, where R is a compound and x is a number greater than 0. A given compound can form more than one hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, such as a hemihydrate (R·0.5H2O)) and a polyhydrate (x is a number greater than 1, such as a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0133] The term "crystalline" or "crystalline form" refers to a solid form that exhibits substantially three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more well-defined peaks.

[0134] The term "amorphous" or "amorphous form" refers to a solid form ("solid form") that is substantially lacking a three-dimensional order. In certain embodiments, the amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, using CuKα radiation, the X-ray powder diffraction (XRPD) pattern of the amorphous form includes a broad scattering band with a peak value at, for example, 20 ° to 70 ° (including end values) of 2θ. In certain embodiments, the XRPD pattern of the amorphous form also includes one or more peaks attributed to the crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to the crystalline structure observed at 2θ of 20 ° to 70 ° (including end values) is no more than 300 times, no more than 100 times, no more than 30 times, no more than 10 times, or no more than 3 times the maximum intensity of the broad scattering band. In certain embodiments, the XRPD pattern of the amorphous form does not include a peak attributed to the crystalline structure.

[0135] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to one crystalline form being dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0136] The term "co-crystal" refers to a crystal structure comprising at least two different components (e.g., a compound of formula (0) or (I) and an acid), wherein each component is independently an atom, ion, or molecule. In certain embodiments, none of the components are solvents. In certain embodiments, at least one component is a solvent. A co-crystal of a compound of formula (0) or (I) and an acid is different from a salt formed by a compound of formula (0) or (I) and an acid. In a salt, the compound disclosed herein is complexed with the acid in such a way that proton transfer (e.g., complete proton transfer) from the acid to the compound disclosed herein occurs readily at room temperature. However, in a co-crystal, the compound disclosed herein is complexed with the acid in such a way that proton transfer from the acid to the compound disclosed herein does not occur readily at room temperature. In certain embodiments, in a co-crystal, there is no proton transfer from the acid to the compound disclosed herein. In certain embodiments, in a co-crystal, there is a partial proton transfer from the acid to the compound disclosed herein. Co-crystals can be used to improve the properties of a compound of formula (0) or (I) (e.g., solubility, stability, and ease of formulation).

[0137] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., a reaction that provides a tautomeric pair) can be catalyzed by either acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different enamine) tautomerizations.

[0138] It should also be understood that compounds with the same molecular formula but different bonding properties or sequences of their atoms or the arrangement of their atoms in space are referred to as "isomers". "Rotational isomers" or "rotamers" are isomers produced by restricted rotation around a single bond. Compounds disclosed herein include all rotational isomers of the isomers. Compounds disclosed herein include all rotational isomers, including but not limited to the rotational isomers. In some embodiments, compounds disclosed herein include all rotational isomers. In certain embodiments, the disclosure provides compounds or their rotational isomers. Isomers with different arrangements of their atoms in space are referred to as "stereoisomers". In certain embodiments, if a phenyl group includes two substituents each bonded to adjacent carbons, the compound may be referred to as an ortho isomer. In certain embodiments, if a phenyl group includes two substituents each bonded to a carbon separated by a ring carbon, the compound may be referred to as a meta isomer. In certain embodiments, if the phenyl group contains two substituents, each bonded to a carbon separated by two ring carbons, the compound can be referred to as a para-isomer.

[0139] Stereoisomers that are not mirror images of one another are termed "diastereomers," while stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, then a pair of enantiomers is possible. 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 the way that the molecules rotate the plane of polarized light and are designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0140] As used herein, the term "agent" refers to a molecule, group of molecules, complex, or substance administered to an organism for diagnostic, therapeutic, preventive medical, or veterinary purposes. In certain embodiments, an agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent). In certain embodiments, the compositions disclosed herein comprise an agent, such as a first therapeutic agent (e.g., at least one (including, for example, at least two, at least three). In some embodiments, the composition may further comprise a second therapeutic agent, a targeting moiety, a diagnostic moiety as described herein.

[0141] As used herein, the term "therapeutic agent" includes agents that are capable of providing a local or systemic biological, physiological, or therapeutic effect in a biological system to which it is applied. For example, therapeutic agents can be used to control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell attachment, and enhance bone growth, among other effects. 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 when administered but are converted to a biologically active agent by metabolism or some other mechanism after administration to a subject.

[0142] An agent (e.g., a therapeutic agent) can include a variety of different 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 specified in the Code of Federal Regulations (CFR); targeting agents; isotopically labeled compounds; agents suitable for bioprocessing; carbohydrates; saccharins; monosaccharides; oligosaccharides; polysaccharides; biomacromolecules (e.g., peptides, proteins, and peptide analogs and derivatives); peptide mimetics; antibodies and antigen-binding fragments thereof; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucins; lipoproteins; synthetic polypeptides or proteins; small molecules linked to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunizing agents; extracts made from biological material such as bacterial, plant, fungal, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combination thereof.

[0143] In some embodiments, the agent is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, for example, by solvolysis, reduction, oxidation, or under physiological conditions to provide a pharmaceutically active compound in vivo. The prodrug may include a derivative of the pharmaceutically active compound, for example, by reacting an acid or anhydride or mixed anhydride portion of the prodrug moiety with a hydroxyl portion of the pharmaceutically active compound to form an ester, or forming an amide prepared by reacting 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 comprise 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.

[0144] In some embodiments, the agent (e.g., 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 a "natural product-like" compound. Rather, a typical feature of a small molecule is that it contains several carbon-carbon bonds and has a molecular weight of less than 5000 daltons (5kDa), preferably less than 3kDa, more preferably less than 2kDa, and most preferably less than 10kDa. In some cases, the molecular weight of the preferred small molecule is equal to or less than 700 daltons.

[0145] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those found in Harrison's Principles of Internal Medicine, 13th ed., TR Harrison et al., eds. McGraw-Hill NY, NY; Physicians' Desk Reference, 50th ed., 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th ed., Goodman and Gilman, 1990; U.S. Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Gilman's The Pharmacological Basis of Therapeutics; and the latest edition of The Merck Index, the entire contents of which are incorporated herein by reference.

[0146] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more of the agents listed in paragraph

[0148] of U.S. Patent No. 9,381,253, which is incorporated herein by reference.

[0147] In other embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more therapeutic agents listed in International Publication No. WO 2013 / 169739, published on November 4, 2013, including, for example, antihypertensive drugs and / or collagen modifying agents ("AHCMs") disclosed in paragraphs 40-49, 283, 286-295; microenvironmental modulators disclosed in paragraphs 113-121 of WO 2013 / 169739, which is incorporated herein by reference. In some embodiments, the composition comprising an AHCM and / or a microenvironment modulator causes one or more of the following in a subject: reduced physiologic stress (e.g., growth-induced physiologic stress in a tumor); reduced tumor fibrosis; reduced interstitial hypertension or interstitial fluid pressure (IFP); increased interstitial tumor transport; increased tumor or vascular perfusion; increased vessel diameter and / or dilation of compressed or collapsed vessels; reduced or depleted one or more of: cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); reduced extracellular matrix components (such as fibers (e.g., collagen, and / or polysaccharides (e.g., glycosaminoglycans such as hyaluronic acid or hyaluronic acid); reducing the level or production of collagen or procollagen; reducing the level or production of hyaluronic acid; increasing tumor oxygenation; reducing tumor hypoxia; reducing tumor acidosis; enabling immune cell infiltration; reducing immunosuppression; increasing anti-tumor immunity; reducing the production of cancer stem cells (also referred to herein as tumor-initiating cells); or enhancing the efficacy (e.g., penetration or spread) of a therapy, such as a cancer therapy (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy), in a tumor or tumor vasculature.

[0148] Agents, such as therapeutic agents, include the classes and specific examples disclosed herein. It is not intended that the classes be limited by the specific examples. One of ordinary skill in the art will also recognize many other compounds that fall into the classes and can be used according to the present disclosure.

[0149] Examples of therapeutic agents include, but are not limited to, antimicrobials, analgesics, anti-inflammatory agents, anti-irritants, coagulants, diuretics, sympathomimetics, anorexia, antacids and other gastrointestinal agents; antiparasitics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid regulators, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetics, dopaminergics, antiemetics, muscle relaxants, sympathomimetics, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast agents, radiopharmaceuticals, antiallergics, tranquilizers, vasodilators, antivirals and antitumor drugs or cell growth inhibitors or other agents with anticancer effects, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins and micronutrients and macronutrients. Other examples include anti-infectives, such as antibiotics and antivirals; analgesics and analgesic combinations; anorexia medications; antiallergics; antiarthritics; antiasthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory drugs; antimigraine preparations; antinausea drugs; antinicotnausea drugs; antineoplastic drugs; antiparkinsonian drugs; antipruritic drugs; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations , including calcium channel blockers and beta-blockers, such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators, including general coronary, peripheral, and cerebral; central nervous system stimulants; cough and cold remedies, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetics; psychostimulants; sedatives; and tranquilizers; as well as naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0150] The terms "composition" and "formulation" are used interchangeably.

[0151] A "subject" intended for administration is a human (i.e., a male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young, middle-aged, or elderly person)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a 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 stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal.

[0152] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0153] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or have 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 prior to the onset of symptoms (e.g., based on a history of symptoms). Treatment may also be continued after symptoms have resolved, e.g., to delay and / or prevent recurrence of the disease or disorder.

[0154] The terms "prevent," "preventing," or "prevention" refer to prophylactic treatment of a subject who does not currently have a disease or has not had a disease in the past but is at risk of developing the disease or who has had a disease in the past and does not currently have a disease but is at risk of regression of the disease. In certain embodiments, the subject has a higher risk of developing the disease or a higher risk of regression of the disease compared to the average healthy member of a population of subjects.

[0155] The term "NAMPT" or "nicotinamide phosphoribosyltransferase" refers to a key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from the natural precursor nicotinamide. NAMPT catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways for salvaging NAD. NAMPT specifically produces nicotinamide mononucleotide (NMN) as a product of the NAMPT enzymatic reaction. NAMPT is present both extracellularly and intracellularly. Thus, in some embodiments, NAMPT is intracellular NAMPT. In certain embodiments, NAMPT is extracellular NAMPT. NAMPT can be present in intracellular compartments and can be present in the nucleus and cytosol. NAMPT is expressed throughout the body, including but not limited to the heart, brain, placenta, lungs, liver, skeletal muscle, kidneys, and pancreas. NAMPT may also be referred to as pre-B cell colony-enhancing factor (PBEF) and visfatin. The protein is also known as NAmPRTase. NAMPT can lead to changes in downstream signaling molecules such as sirtuins, PARP, and NADase. 15NAMPT plays a role in a variety of diseases and conditions, see for example: (i) WO 97 / 48696 on the involvement of NAMPT in the treatment of cancer, (ii) WO 97 / 48397 on the involvement of NAMPT in immunosuppression, (iii) WO 2003 / 80054 on the involvement of NAMPT in the treatment of diseases involving angiogenesis, (iv) WO 2008 / 025857 on the involvement of NAMPT in the treatment of rheumatoid arthritis and septic shock, and (v) WO 2009 / 109610 on the involvement of NAMPT in the prevention and treatment of ischemia.

[0156] The terms "modulate," "modulating," "modulation," or "modulator" refer to the ability of a compound to decrease / increase, slow down / accelerate, stop / start, inhibit / stimulate, or prevent / cause the activity of a specific biological target (e.g., NAMPT) in a cell relative to the vehicle.

[0157] As used herein, the term "activation", "activator", "stimulation" or "stimulant", in the context of an enzyme, for example, in the context of NAMPT, refers to an increase in enzyme activity. In some embodiments, the term refers to an increase in enzyme activity (for example, NAMPT activity) level to a level that is statistically significantly higher than an initial level, which initial level, for example, can be a baseline level of enzyme activity. In some embodiments, the term refers to an increase in enzyme activity (for example, NAMPT activity) level to a level that is 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.1%, greater than 99.5%, greater than 99.9%, greater than 99.99% or greater than 99.999% of the initial level, which initial level, for example, can be a baseline level of enzyme activity.

[0158] The terms "inhibition," "inhibiting," "inhibit," or "inhibitor" refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a specific biological target (e.g., NAMPT) in a cell relative to the vehicle.

[0159] As used herein, the term "inhibit (inhibit)" or "inhibition (inhibition)", in the context of an enzyme, for example, in the context of NAMPT, refers to a reduction in enzyme activity. In some embodiments, the term refers to that enzyme activity (such as NAMPT activity) levels are reduced to a level statistically significantly lower than an initial level, and the initial level, for example, can be the baseline level of enzyme activity. In some embodiments, the term refers to that enzyme activity (such as NAMPT activity) levels are reduced to 75% less than the initial level, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001% or less than 0.0001%, and the initial level, for example, can be the baseline level of enzyme activity.

[0160] The terms "condition," "disease," and "disorder" are used interchangeably.

[0161] "Proliferative disease" refers to a disease caused by abnormal growth or spread due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, England, 1990). Proliferative diseases may be associated with: 1) pathological proliferation of normally quiescent cells; pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

[0162] The terms "inflammatory disease" and "inflammatory condition" are used interchangeably herein to refer to a disease or condition that is caused by, results from, or leads to inflammation. Inflammatory diseases and conditions include those diseases, disorders, or conditions characterized by signs of pain (pain due to the production of noxious substances and nerve irritation), fever (heat due to vasodilation), redness (redness due to vasodilation and increased blood flow), swelling (massage due to excessive influx or restricted outflow of fluid), and / or loss of function (malfunction, which can be partial or complete, temporary or permanent). Inflammation has many forms and includes but is not limited to acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrotic, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, occlusive, substantial, plastic, productive, proliferative, pseudomembranous, purulent (purulent), sclerotic, serous formation, serous, simple type, specific, subacute, purulent (suppurative), toxic, traumatic and / or ulcerative inflammation. The term "inflammatory disease" can also refer to an inflammatory reaction that is dysregulated and causes an overreaction of macrophages, granulocytes and / or T lymphocytes, thereby resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic inflammatory conditions and can be caused by infectious or non-infectious causes.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed Connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphointerstitial pneumonia, giant cell interstitial pneumonia, intercellular pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome Acute renal disease (ARDS), encephalitis, immediate hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis Inflammatory diseases of the eye include, but are not limited to, postoperative inflammation.

[0163] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, adenitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, diverticulitis, diabetes (e.g., type I diabetes, type II diabetes), skin conditions (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barré syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity reactions, headaches (e.g., migraines, tension headaches), intestinal obstruction (e.g., postoperative intestinal obstruction and intestinal obstruction during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (bladder pain syndrome), gastrointestinal disorders (e.g., selected from Peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diverticulitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, Pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain diseases (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, squamous cell tumor, sarcoidosis, spondyloarthropathies, Sjögren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis. In certain embodiments, the inflammatory condition is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis, and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation caused by infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (eg, conditions resulting from asthma, arthritis, and inflammatory bowel disease). These compounds may also be used to treat inflammation associated with trauma and non-inflammatory myalgias.The compounds disclosed herein may also be used to treat inflammation associated with cancer.

[0164] An "autoimmune disease" is a condition caused by an inappropriate immune response against substances and tissues normally present in the body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This may be limited to certain organs (for example, autoimmune thyroiditis) or involve specific tissues in different locations (for example, Goodpasture's disease, which may affect the basement membranes of the lungs and kidneys). Treatment for autoimmune diseases often involves immunosuppression, such as drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Rett's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0165] In certain embodiments, inflammatory disorders and / or immune disorders are gastrointestinal disorders. In some embodiments, gastrointestinal disorders are selected from gastrointestinal disorders (e.g., selected from peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, divertic colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (irritable bowel syndrome)). In certain embodiments, gastrointestinal disorders are inflammatory bowel disease (IBD).

[0166] In certain embodiments, the inflammatory condition and / or immune condition is a skin condition. In some embodiments, the skin condition is pruritus (itch), psoriasis, eczema, burns, or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritus.

[0167] The terms "vegetation" and "tumor" are used interchangeably herein and refer to abnormal tissue masses, wherein the growth of the mass exceeds normal tissue and is not coordinated with the growth of normal tissue. 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 neoplasms" are usually well differentiated, characterized in that they grow slower than malignant neoplasms and are still confined to the site of origin. In addition, benign neoplasms do not have the ability to infiltrate, invade or metastasize to distant sites. Exemplary benign neoplasms include but are not limited to lipomas, chondromas, adenomas, soft droops, senile hemangiomas, seborrheic keratosis, nevus and sebaceous hyperplasia. In some cases, some "benign" tumors may cause malignant neoplasms later, which may be due to other genetic changes in the tumor neoplastic cell subpopulation, and these tumors are referred to as "malignant pre-vegetation". Exemplary malignant pre-vegetation is a teratoma. In contrast, " malignant neoplasm " is usually poorly differentiated (dysplasia), and has characteristic rapid growth, with the progressive infiltration, invasion and destruction of surrounding tissue. In addition, malignant neoplasm usually has the ability to be transferred to distant sites. The term "metastasis (metastasis)", "metastatic (metastatic)" or "metastasize (metastasize)" refers to the diffusion or migration of cancerous cells from primary or original tumor to another organ or tissue, and usually can be identified by "secondary tumors" or "secondary cell clusters" of the tissue type with primary or original tumor rather than "secondary tumors" or "secondary cell clusters" of the organ or tissue where secondary (metastasis) tumor is located. For example, the prostate cancer that has migrated to bone is referred to as metastatic prostate cancer, and includes the cancerous prostate cancer cells grown in bone tissue.

[0168] 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 body tissues. See, for example, Stedman's Medical Dictionary, 25th ed.; Hensyl, ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial cell sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchogenic carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngeal carcinoma Tubuloma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's gland carcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; 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), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemias 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 lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (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, nodal marginal zone B-cell lymphoma, splenic 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, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixtures of one or more leukemias / lymphomas as described above; and multiple myeloma (MM)), heavy chain diseases (e.g., α chain diseases disease, gamma chain disease, μ chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., Wilms' tumor, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM), also known as Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or type 2, schwannoma); neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); 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 neoplasms (IPMNs), islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small bowel cancer; sweat gland cancer; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer;and vulvar cancer (e.g., Paget's disease of the vulva).

[0169] Cancer cells can exhibit properties similar to embryonic stem cells and / or adult stem cells. As used herein, cancer stem cells (CSCs) are cancer cells with one or more embryonic characteristics / properties or adult stem cell characteristics / properties. CSCs are generally considered to be problematic cancer cells because they can metastasize and form tumors in other parts of the human body. As used herein, "embryonic characteristics," "embryonic properties," etc. refer to genes and / or miRNA expression and / or biological properties similar to embryonic cells. Undifferentiated cancer cells with embryonic properties have the ability to metastasize, are resistant to chemotherapy and radiotherapy, and have the ability to regrow tumors after most tumors are removed or reduced after surgery and / or other cancer treatments. As used herein, "adult stem cell characteristics," "adult stem cell properties," etc. refer to genes and / or miRNA expression and / or biological properties similar to adult stem cells. Cancer cells with adult stem cell properties can have the ability to metastasize, split, differentiate, exhibit plasticity, exhibit high-speed cell renewal, can be resistant to chemotherapy and radiotherapy, and can have the ability to regrow tumors after most tumors are removed or reduced after surgery and / or other cancer treatments.

[0170] In some embodiments, cancer stem cells are characterized by expression of genes and / or miRNAs associated with an embryonic state. In some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes or miRNAs associated with an embryonic state.

[0171] In some embodiments, 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, hyperproliferative activity, pluripotency, multipotency, expression of embryonic markers, lack of differentiation markers, resistance to chemotherapy, motility, and the ability to generate different cell lineages.

[0172] In some embodiments, cancer stem cells are characterized by expression of genes and / or miRNAs associated with an adult stem cell state. In some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes or miRNAs associated with an adult stem cell state.

[0173] In some embodiments, cancer stem cells are characterized by one or more adult stem cell characteristics. Examples of adult stem cell characteristics include, but are not limited to, one or more of the following characteristics (depending on the cell type): cell self-renewal properties, proliferation and / or hyperproliferation activity, pluripotency, plasticity, multipotency, resistance to chemotherapy, and the ability to generate different cell lineages (differentiation metastasis).

[0174] As used herein, the term "regenerative medicine" or "regenerative therapy" refers to promoting the regenerative capacity 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 conversion of cells such as stem cells into dividing progenitor cells and differentiated tissue-specific cells. Regenerative capacity can additionally or alternatively indicate the ability of cells, tissues and / or organs to replicate, proliferate, restore function and / or regenerate.

[0175] An "effective amount" of a composition described herein is an amount sufficient to elicit a desired biological response. The effective amount of a composition described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount of a composition or pharmaceutical composition described herein in a single dose. In certain embodiments, the effective amount is the combined amount of a composition or pharmaceutical composition described herein in multiple doses.

[0176] A "therapeutically effective amount" of a composition described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or sufficient to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves overall therapy; reduces or avoids symptoms, signs, or causes of a condition; and / or enhances the therapeutic efficacy of another therapeutic agent.

[0177] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition or one or more symptoms associated with a condition or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0178] The term "gene" refers to a nucleic acid fragment that provides a template for producing a gene product. In certain embodiments, the nucleic acid fragment includes regulatory sequences before and after the coding sequence. A "native gene" refers to a gene found in nature that has its own regulatory sequences. A "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 sequences and coding sequences derived from different sources, or regulatory sequences and coding sequences derived from the same source but arranged in a manner different from nature. An "endogenous gene" refers to a natural gene in its natural location in the genome of an organism. An "exogenous" gene refers to a gene that is not typically found in a host organism, but is introduced into a host organism through gene transfer. An exogenous gene can include a natural gene or a chimeric gene that is inserted into a non-natural organism. A "transgenic gene" is a gene that is introduced into a genome through a transformation procedure.

[0179] The terms "nucleic acid" or "nucleic acid sequence," "nucleic acid molecule," "nucleic acid fragment," or "polynucleotide" are used interchangeably. A polynucleotide molecule is a biological polymer composed of nucleotide monomers covalently bonded in a chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA is composed of two polynucleotide chains, each of which is helical. In nature, RNA typically occurs as a single strand that folds back on itself. Exemplary types of RNA include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin (shRNA), microRNA (miRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0180] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (such as Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0181] The phrases "compounds of the present disclosure," "compounds as disclosed herein," and the like refer to any compound disclosed herein, such as in the specification and claims, including compounds of (i) Formula (0), (ii) Formula (I), (iii) all subclasses, and (iv) all compound species, including compounds as provided in the Additional Compounds section and the Examples section, including Tables E1, E2, and E3, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Specified compounds are not included in the phrases "compounds of the present disclosure," "compounds as disclosed herein," and the like.

[0182] The present disclosure is not intended to be limited in any way by the foregoing list of exemplary substituents.Additional terms may be defined in other sections of this disclosure. DETAILED DESCRIPTION

[0183] Before describing the disclosed systems, compounds, compositions, methods, uses, and kits in greater detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, devices, or configurations and as such may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein.

[0184] The compounds disclosed herein, their compositions, and drug kits can be used for the treatment of cancer and proliferative diseases or for regenerative medicine. The compounds can differentiate embryonic cancer stem cells, kill differentiated cancer stem cells, disrupt their proliferation, and / or inhibit their ability to form new tumors. The compounds can inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce the embryonic or adult stem cell characteristics of one or more cells, reduce cell viability, and / or prevent cell proliferation. Embryonic characteristics, including embryonic gene expression patterns, are reactivated in many different types of cancer. In addition, the compounds can differentiate into somatic cancer stem cells, kill differentiated adult cancer stem cells, disrupt their proliferation, and / or inhibit their ability to form new tumors. Adult stem cells are also associated with many different types of cancer. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, leukemia, or liver cancer. For example, embryonic-like properties have been found in cancer stem cells from solid tumors such as colorectal, gastric, ovarian, lung, breast, pancreatic, and prostate cancers. 10 Embryonic properties have also been found in cancer stem cells from hematopoietic cancers such as leukemias and lymphomas. 14

[0185] Without wishing to be bound by a particular theory, it is believed that the compounds and compositions disclosed herein modulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin and pre-B cell colony enhancing factor 1 (PBEF). NAMPT is an enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. 15 Nicotinamide adenine dinucleotide is an essential cofactor for cellular metabolism. Nicotinamide mononucleotide (NMN) is the product of the NAMPT enzymatic reaction. NAMPT has been implicated in a variety of diseases and conditions, and therefore, modulation (i.e., inhibition) of NAMPT can treat a wide range of indications. 15,16,17 In addition, NAMPT is also involved in signal transduction and acts as an adipokine 18 and immunomodulatory cytokines 19 Elevated NAMPT levels have been described in (i) metabolic / inflammatory conditions, including obesity, type 2 diabetes, metabolic syndrome, atherogenic inflammatory diseases, and cardiovascular and cerebrovascular disorders, (ii) non-metabolic chronic inflammatory diseases, including osteoarthritis and acute lung injury, (iii) infections, such as sepsis or intrauterine infection, and (iv) autoimmune inflammatory diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. 15 Thus, the compounds of the present disclosure, and compositions and kits thereof, can be used to treat or prevent a variety of diseases and conditions.

[0186] Compound

[0187] In certain aspects, the present disclosure provides compounds of formula (0) or (I).Additional compounds are also provided herein.

[0188] In certain embodiments, the compounds of the present disclosure are compounds (e.g., compounds of formula (0) or (I), or compounds as described in the Additional Compounds section below) or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. In certain embodiments, the compounds of the present disclosure are compounds (e.g., compounds of formula (0) or (I), or compounds as described in the Additional Compounds section below) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In certain embodiments, the compounds of the present disclosure are compounds (e.g., compounds of formula (0) or (I), or compounds as described in the Additional Compounds section below) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

[0189] The compounds of the present disclosure may have high water solubility. Compared to certain similar known compounds, the compounds of the present disclosure may have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000%) water solubility.

[0190] The compounds of the present disclosure may have high microsomal stability. Compared to certain similar known compounds, the compounds of the present disclosure may have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000%) microsomal stability.

[0191] The compounds of the present disclosure can treat cancer. Compared to certain similar known compounds, the compounds of the present disclosure can have better (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%) ability to treat cancer, as evidenced by a reduction in cancer symptoms and / or a decrease in tumor size.

[0192] Compounds of formula (0) and (I)

[0193] In certain embodiments, provided herein are compounds of formula (0):

[0194]

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

[0196] R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl;

[0197] R 2 is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl, substituted or unsubstituted 3 to 13 membered heterocyclyl-C 1-12 -alkyl, substituted or unsubstituted 3 to 13 membered carbocyclic group-C 1-12 -alkyl, or nitrogen protecting group;

[0198] When R 2 When it is an unsubstituted methyl group, R 1 Not an unsubstituted ethyl group;

[0199] R 3 is hydrogen, halogen, substituted or unsubstituted C1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0200] R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 an alkyl group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom;

[0201] R 4 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0202] R 5 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0203] R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group;

[0204] R 8 Each example is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;

[0205] R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2, or R 9 Two examples of are linked to form a 3- to 13-membered heterocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring;

[0206] n is an integer from 0 to 4, inclusive;

[0207] m is an integer from 0 to 3, inclusive;

[0208] p is an integer from 0 to 3, inclusive; and

[0209] q is an integer selected from 0 and 1.

[0210] In certain embodiments, the compound of formula (0) has formula (0a):

[0211]

[0212] In certain embodiments, the compound of formula (0) has formula (0b):

[0213]

[0214] In certain embodiments, the compound of formula (0) has formula (0c):

[0215]

[0216] In certain embodiments, provided herein are compounds of Formula (I):

[0217]

[0218] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein:

[0219] R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl;

[0220] R 2 is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl, substituted or unsubstituted 3 to 13 membered heterocyclyl-C 1-12 -alkyl, substituted or unsubstituted 3 to 13 membered carbocyclic group-C 1-12 -alkyl, or nitrogen protecting group;

[0221] When R 2 When it is an unsubstituted methyl group, R 1 Not an unsubstituted ethyl group;

[0222] R 3 is hydrogen, halogen, substituted or unsubstituted C1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0223] R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 an alkyl group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom;

[0224] R 4 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0225] R 5 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0226] R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group;

[0227] R 8 Each example is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;

[0228] R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2;

[0229] n is an integer from 0 to 4, inclusive;

[0230] m is an integer from 0 to 3, inclusive; and

[0231] p is an integer from 0 to 3, inclusive.

[0232] In certain embodiments, the compound of Formula (I) has Formula (Iz):

[0233]

[0234] In certain embodiments, the compound of Formula (I) has Formula (Ia):

[0235]

[0236] In certain embodiments, the compound of Formula (I) has Formula (Ib):

[0237]

[0238] In certain embodiments, the compound of Formula (I) has Formula (Ic):

[0239]

[0240] In certain embodiments, R 1 is substituted or unsubstituted C 1-12 In certain embodiments, R 1 is replaced by C 1-12 In certain embodiments, R 1 is unsubstituted C 1-12 In certain embodiments, R 1 is substituted or unsubstituted C 1-6 In certain embodiments, R 1 is unsubstituted C 1-6 In certain embodiments, R 1 is unsubstituted C1 alkyl. In certain embodiments, R 1 is unsubstituted C2 alkyl. In certain embodiments, R 1 is unsubstituted C3 alkyl. In certain embodiments, R 1 is unsubstituted C4 alkyl. In certain embodiments, R 1 is unsubstituted C5 alkyl. In certain embodiments, R 1 is unsubstituted C6 alkyl. In certain embodiments, R 1 is replaced by C 1-6 In certain embodiments, R 1 is a substituted C1 alkyl. In certain embodiments, R 1is a substituted C2 alkyl. In certain embodiments, R 1 is a substituted C3 alkyl. In certain embodiments, R 1 is a substituted C4 alkyl. In certain embodiments, R 1 is a substituted C5 alkyl. In certain embodiments, R 1 is a substituted C6 alkyl. In certain embodiments, R 1 It is fluorinated C 1-6 In certain embodiments, R 1 In certain embodiments, R 1 In some embodiments, R 1 In certain embodiments, R 1 is substituted or unsubstituted C 1-12 In certain embodiments, R 1 is unsubstituted C 1-12 In certain embodiments, R 1 is replaced by C 1-12 In certain embodiments, R 1 is substituted or unsubstituted C 1-6 In certain embodiments, R 1 is unsubstituted C 1-6 In certain embodiments, R 1 is unsubstituted C1 heteroalkyl. In certain embodiments, R 1 is unsubstituted C2 heteroalkyl. In certain embodiments, R 1 is unsubstituted C3 heteroalkyl. In certain embodiments, R 1 is unsubstituted C4 heteroalkyl. In certain embodiments, R 1 is unsubstituted C5 heteroalkyl. In certain embodiments, R 1 is unsubstituted C6 heteroalkyl. In certain embodiments, R 1 is replaced by C 1-6 In certain embodiments, R 1 is a substituted C1 heteroalkyl. In certain embodiments, R 1 is a substituted C2 heteroalkyl. 1 is a substituted C3 heteroalkyl. 1 is a substituted C4 heteroalkyl. 1 is a substituted C5 heteroalkyl. 1 is a substituted C6 heteroalkyl.1 is methoxy, ethoxy or propoxy. In certain embodiments, R 1 Substituted by: halo, -CN, -NR a 2. -CO2R aa 、-C(=O)R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa , or -NR bb C(=O)N(R bb )2. In certain embodiments, R 1 Replaced by: -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa , or -NR bb C(=O)N(R bb )2.

[0241] In some embodiments, R bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl.

[0242] In certain embodiments, R 1 The substituents on the group are –CN, –F, –Cl, –N(R a )(C=O)OR a , or –COOR a In certain embodiments, R 1 The substituents on the group are –CN, –F, –Cl, -NR a 2. –N(R a )(C=O)OR a 、–COOR a , or –(C=O)R a In certain embodiments, R 1 The substituents on the group are -CN, -F, -Cl, -NH2, -NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)Ot Bu, or -C(=O)CH3.

[0243] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 In certain embodiments, R 2 is substituted or unsubstituted C 1-12 In certain embodiments, R 2 is unsubstituted C 1-12 In certain embodiments, R 2 is replaced by C 1-12 In certain embodiments, R 2 In certain embodiments, R 2 is Et, Pr or Bu. In certain embodiments, R 2 It is a nitrogen protecting group.

[0244] In certain embodiments, R 2 is substituted or unsubstituted C 1-12 In certain embodiments, R 2 is unsubstituted C 1-12 In certain embodiments, R 2 is replaced by C 1-12 In certain embodiments, R 2 is substituted or unsubstituted C 1-6 In certain embodiments, R 2 is unsubstituted C 1-6 In certain embodiments, R 2 is unsubstituted C1 alkyl. In certain embodiments, R 2 is unsubstituted C2 alkyl. In certain embodiments, R 2 is unsubstituted C3 alkyl. In certain embodiments, R 2 is unsubstituted C4 alkyl. In certain embodiments, R 2 is unsubstituted C5 alkyl. In certain embodiments, R 2 is unsubstituted C6 alkyl. In certain embodiments, R 2 is replaced by C 1-6 In certain embodiments, R 2 is a substituted C1 alkyl. In certain embodiments, R 2 is a substituted C2 alkyl. In certain embodiments, R 2 is a substituted C3 alkyl. In certain embodiments, R 2 is a substituted C4 alkyl. In certain embodiments, R 2is a substituted C5 alkyl. In certain embodiments, R 2 is a substituted C6 alkyl. In certain embodiments, R 2 It is halogenated C 1-12 In certain embodiments, R 2 is a substituted C6 alkyl. In certain embodiments, R 2 It is fluorinated C 1-6 In certain embodiments, R 2 In certain embodiments, R 2 In some embodiments, R 2 In certain embodiments, R 2 is substituted or unsubstituted C 1-12 In certain embodiments, R 2 is replaced by C 1-12 In certain embodiments, R 2 is unsubstituted C 1-12 In certain embodiments, R 2 is substituted or unsubstituted C 1-6 In certain embodiments, R 2 is unsubstituted C 1-6 In certain embodiments, R 2 is unsubstituted C1 heteroalkyl. In certain embodiments, R 2 is unsubstituted C2 heteroalkyl. In certain embodiments, R 2 is unsubstituted C3 heteroalkyl. In certain embodiments, R 2 is unsubstituted C4 heteroalkyl. In certain embodiments, R 2 is unsubstituted C5 heteroalkyl. In certain embodiments, R 2 is unsubstituted C6 heteroalkyl. In certain embodiments, R 2 is replaced by C 1-6 In certain embodiments, R 2 is a substituted C1 heteroalkyl. In certain embodiments, R 2 is a substituted C2 heteroalkyl. 2 is a substituted C3 heteroalkyl. 2 is a substituted C4 heteroalkyl. 2 is a substituted C5 heteroalkyl. 2 is a substituted C6 heteroalkyl. 2is methoxy, ethoxy or propoxy.

[0245] In certain embodiments, R 2 is a substituted or unsubstituted 3- to 13-membered heterocyclic-C 1-12 In certain embodiments, R 2 is an unsubstituted 3- to 13-membered heterocyclyl-C 1-12 In certain embodiments, R 2 is a substituted 3- to 13-membered heterocyclyl-C 1-12 In certain embodiments, R 2 is a substituted or unsubstituted 3- to 13-membered heterocyclic-C 1-6 In certain embodiments, R 2 is an unsubstituted 3- to 6-membered heterocyclyl-C 1-6 In certain embodiments, R 2 is an unsubstituted 3 to 6 membered heterocyclyl-C1 alkyl. In certain embodiments, R 2 is an unsubstituted 3 to 6 membered heterocyclyl-C2 alkyl. In certain embodiments, R 2 is an unsubstituted 3 to 6 membered heterocyclyl-C3 alkyl. In certain embodiments, R 2 is an unsubstituted 3 to 6 membered heterocyclyl-C4 alkyl. 2 is an unsubstituted 3 to 6 membered heterocyclyl-C5 alkyl. 2 is an unsubstituted 3 to 6 membered heterocyclyl-C6 alkyl. 2 is a substituted 3- to 6-membered heterocyclic-C 1-6 In certain embodiments, R 2 is a substituted 3 to 6 membered heterocyclyl-C1 alkyl. In certain embodiments, R 2 is a substituted C2 alkyl. In certain embodiments, R 2 is a substituted 3 to 6 membered heterocyclyl-C3 alkyl. In certain embodiments, R 2 is a substituted 3 to 6 membered heterocyclyl-C4 alkyl. 2 is a substituted 3 to 6 membered heterocyclyl-C5 alkyl. 2 is a substituted 3 to 6 membered heterocyclyl-C6 alkyl. 2 is a halogenated 3- to 6-membered heterocyclic-C 1-12 In certain embodiments, R 2 It is a substituted 3- to 6-membered heterocyclyl-C6 alkyl group.

[0246] In certain embodiments, R2 is a substituted or unsubstituted 3 to 13 membered carbocyclyl-C 1-12 In certain embodiments, R 2 is an unsubstituted 3- to 13-membered carbocyclyl-C 1-12 In certain embodiments, R 2 is a substituted 3- to 13-membered carbocyclyl-C 1-12 In certain embodiments, R 2 is a substituted or unsubstituted 3 to 13 membered carbocyclyl-C 1-6 In certain embodiments, R 2 is an unsubstituted 3- to 6-membered carbocyclyl-C 1-6 In certain embodiments, R 2 is an unsubstituted 3 to 6 membered carbocyclyl-C1 alkyl. 2 is an unsubstituted 3 to 6 membered carbocyclyl-C2 alkyl. 2 is an unsubstituted 3 to 6 membered carbocyclyl-C3 alkyl. 2 is an unsubstituted 3 to 6 membered carbocyclyl-C4 alkyl. 2 is an unsubstituted 3 to 6 membered carbocyclyl-C5 alkyl. 2 is an unsubstituted 3 to 6 membered carbocyclyl-C6 alkyl. 2 is a substituted 3- to 6-membered carbocyclyl-C 1-6 In certain embodiments, R 2 is a substituted 3 to 6 membered carbocyclyl-C1 alkyl. 2 is a substituted C2 alkyl. In certain embodiments, R 2 is a substituted 3 to 6 membered carbocyclyl-C3 alkyl. 2 is a substituted 3 to 6 membered carbocyclyl-C4 alkyl. 2 is a substituted 3 to 6 membered carbocyclyl-C5 alkyl. 2 is a substituted 3 to 6 membered carbocyclyl-C6 alkyl. 2 is a halogenated 3- to 6-membered carbocyclyl-C 1-12 In certain embodiments, R 2 It is a substituted 3- to 6-membered carbocyclyl-C6 alkyl group.

[0247] In certain embodiments, R 2 is a substituted C6 heteroalkyl. 2 is methoxy, ethoxy or propoxy.

[0248] In certain embodiments, R 2 Substituted by: halo, -CN, -NR a 2. -CO2R aa 、-C(=O)R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa , or -NR bb C(=O)N(R bb )2. In certain embodiments, R 2 Replaced by: -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa , or -NR bb C(=O)N(R bb )2.

[0249] In some embodiments, R bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl.

[0250] In certain embodiments, R 2 The substituents on the group are –CN, –F, –Cl, –N(R a )(C=O)OR a , or COOR a .

[0251] In certain embodiments, R 2 The substituents on the group are –CN, –F, –Cl, –N(R a )(C=O)OR a , or –COOR a In certain embodiments, R 2 The substituents on the group are –CN, –F, –Cl, -NR a 2. –N(R a )(C=O)OR a、–COOR a , or –(C=O)R a In certain embodiments, R 1 The substituents on the group are -CN, -F, -Cl, -NH2, -NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)O t Bu, or -C(=O)CH3.

[0252] In certain embodiments, when R 2 When it is an unsubstituted methyl group, R 1 is not unsubstituted ethyl. In some embodiments, when R 2 When it is methyl, R 1 Not ethyl.

[0253] In certain embodiments, when R 2 When it is an unsubstituted methyl group, R 1 is not unsubstituted n-propyl. In some embodiments, when R 2 When it is methyl, R 1 Not propyl.

[0254] In certain embodiments, when R 2 When it is an unsubstituted methyl group, R 1 is not unsubstituted ethoxy. In some embodiments, when R 2 When it is methyl, R 1 Not ethoxy.

[0255] In certain embodiments, R 1 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, methoxy or ethoxy; and R 2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted 3- to 6-membered carbocyclyl-C1alkyl, substituted or unsubstituted 3- to 6-membered carbocyclyl-C2alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl-C1alkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl-C2alkyl.

[0256] In certain embodiments, R 2 is replaced by C 1-6 In some embodiments, R 2 In certain embodiments, R 2 In some embodiments, R 2 It is 2,2-difluoroethyl.

[0257] In some embodiments, R 2 is a substituted or unsubstituted 3 to 6-membered carbocyclic group-C 1-6 In some embodiments, R 2 is a substituted or unsubstituted 3 to 6 membered carbocyclyl-C1 alkyl. 2 It is cyclopropylmethyl.

[0258] In some embodiments, R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2. In some embodiments, R 3 is hydrogen, chloro, bromo, iodo, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2. In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2.

[0259] In some embodiments, R 3 is hydrogen. In certain embodiments, R 3 In certain embodiments, R 3 is chloro, bromo or iodo. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 is substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 3 In certain embodiments, R 3 In some embodiments, R 3is propyl or butyl. In certain embodiments, R 3 It is fluorinated C 1-6 In certain embodiments, R 3 Yes–OR a In certain embodiments, R 3 In certain embodiments, R 3 Is -O (substituted or unsubstituted C 1-6 In certain embodiments, R 3 Yes – COOR a In certain embodiments, R 3 Yes-COOR a , where R a is hydrogen or substituted or unsubstituted C 1-6 Alkyl (e.g., -COOMe, -COOEt, -COO(CH2)2CH3, -COO(CH2)3CH3, or -COOC(CH3)3. In certain embodiments, R 3 Yes – COR a In certain embodiments, R 3 Yes – COR a , where R a is hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R 3 Yes – N(R a )2. In certain embodiments, R 3 is -NH2. In certain embodiments, R 3 Yes – NHR a (e.g., –NH(substituted or unsubstituted C 1-6 In certain embodiments, R 3 Yes – N (substituted or unsubstituted C 1-6 In certain embodiments, R 3 Yes –C(=O)N(R a )2. In certain embodiments, R 3 is -C(=O)NH2. In certain embodiments, R 3 Yes –C(=O)NHR a (e.g., –C(=O)NH (substituted or unsubstituted C 1-6 In certain embodiments, R3 Is –C(=O)N(substituted or unsubstituted C 1-6 In some embodiments, R 3 is a halo or –COOR a In some embodiments, R 3 is chloro or –COOMe.

[0260] In certain embodiments, R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 In certain embodiments, R a Each instance of is hydrogen. In certain embodiments, R a Examples of R are other than hydrogen. In certain embodiments, R a At least one example is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R a At least one example is Me. In certain embodiments, R a At least one example is Et, Pr or Bu. In certain embodiments, R a At least one example is a fluorinated C 1-6 Alkyl (eg, fluorinated methyl, eg, -CF3).

[0261] In some embodiments, R 4 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2. In some embodiments, R 4 is hydrogen. In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 4 In certain embodiments, R 4In some embodiments, R 4 is propyl or butyl. In certain embodiments, R 4 It is fluorinated C 1-6 In certain embodiments, R 4 Yes–OR a In certain embodiments, R 4 In certain embodiments, R 4 Is -O (substituted or unsubstituted C 1-6 In certain embodiments, R 4 Yes – COOR a In certain embodiments, R 4 Yes – COOR a , where R a is hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R 4 Yes – COR a In certain embodiments, R 4 Yes – COR a , where R a is hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R 4 Yes – N(R a )2. In certain embodiments, R 4 is -NH2. In certain embodiments, R 4 Yes – NHR a (e.g., –NH(substituted or unsubstituted C 1-6 In certain embodiments, R 4 Yes – N (substituted or unsubstituted C 1-6 In certain embodiments, R 4 Yes –C(=O)N(R a )2. In certain embodiments, R 4 Yes –C(=O)N(R a )2, where R a is hydrogen or substituted or unsubstituted C 1-6 alkyl.

[0262] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0263] In certain embodiments, the R 3 and optionally with R 4The benzene ring is composed of: In some embodiments, the 3 and optionally with R 4 The benzene ring is composed of: In certain embodiments, the 3 and optionally with R 4 The benzene ring is composed of: In certain embodiments, the 3 and optionally with R 4 The benzene ring is composed of: express.

[0264] In certain embodiments, each instance of R5 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a ,–N(R a )2 or -CN. In certain embodiments, R 5 Each instance of is independently -COOR a 、-COR a or –(C=O)N(R a )2. In certain embodiments, R 5 At least one example of is hydrogen. In certain embodiments, R 5 Each instance of is hydrogen. In certain embodiments, R 5 In certain embodiments, at least one example of R is not hydrogen. 5 Examples of R are other than hydrogen. In certain embodiments, R 5 At least one example of is halogen. In certain embodiments, R 5 At least one example is F. In certain embodiments, R 5 At least one example of is Cl. In certain embodiments, R 5 At least one example is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 5 At least one example is Me. In certain embodiments, R 5 At least one example is Et, Pr or Bu. In certain embodiments, R 5 At least one example is a fluorinated C 1-6 In certain embodiments, R 5 At least one example is -OR a In certain embodiments, R 5 At least one example of is -OH. In certain embodiments, R5 At least one example is -O (substituted or unsubstituted C 1-6 In certain embodiments, R 5 At least one example is –N(R a )2. In certain embodiments, R 5 At least one example is -NH2. In certain embodiments, R 5 At least one example is –NHR a (e.g., –NH(substituted or unsubstituted C 1-6 In certain embodiments, R 5 At least one example is -N (substituted or unsubstituted C 1-6 In certain embodiments, R 5 At least one example is -CN. In certain embodiments, R 5 At least one example is halogen, substituted or unsubstituted C 1-6 Alkyl or -OR a .

[0265] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.

[0266] In some embodiments, m is 0 and p is 0. In some embodiments, m is 0 and p is 1. In some embodiments, m is 0, p is 0, and n is 0. In some embodiments, m is 0, p is 0, and n is 1. In some embodiments, m is 0, p is 1, and n is 1.

[0267] In certain embodiments, optionally with R 5 The central pyridine ring is composed of: In certain embodiments, optionally with R 5 The central pyridine ring is composed of: In certain embodiments, optionally with R 5 The central pyridine ring is composed of: In certain embodiments, optionally with R 5 The central pyridine ring is composed of: express.

[0268] In certain embodiments, R 6 is hydrogen, substituted or unsubstituted C 1-6 In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6is substituted or unsubstituted C 1-6 In some embodiments, R 6 is substituted or unsubstituted methyl. In certain embodiments, R 6 is a substituted or unsubstituted ethyl group. In some embodiments, R 6 is a nitrogen protecting group selected from tosyl, tert-butyloxycarbonyl, acetyl or benzoyl.

[0269] In certain embodiments, R 8 Each example is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 In certain embodiments, R 8 Each instance of is hydrogen. In certain embodiments, R 8 An example of is hydrogen. In certain embodiments, R 8 At least one example of is halogen. In certain embodiments, R 8 At least one example is a substituted or unsubstituted C 1-6 In certain embodiments, R 8 At least one example is unsubstituted C 1-6 In certain embodiments, R 8 At least one example of C is substituted with at least one example of halogen (eg, F). 1-6 alkyl.

[0270] In certain embodiments, q is 0. In some embodiments, q is 1.

[0271] In some embodiments, q is 0 and n is 0, 1, or 2. In some embodiments, q is 1 and n is 0, 1, or 2.

[0272] In some embodiments, R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COOR a ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2, or R 9 Two examples of are connected to form a 3- to 13-membered heterocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring. 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a 、–COORa ,–COR a ,–N(R a )2, –CN, or –(C=O)N(R a )2. R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a , or –N(R a )2. In certain embodiments, R 9 At least one example of is hydrogen. In certain embodiments, R 9 Each instance of is hydrogen. In certain embodiments, R 9 In certain embodiments, at least one example of R is not hydrogen. 9 Examples of R are other than hydrogen. In certain embodiments, R 9 At least one example of is halogen. In certain embodiments, R 9 At least one example is F. In certain embodiments, R 9 At least one example of is Cl. In certain embodiments, R 9 At least one example is a substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6 In certain embodiments, R 9 At least one example is Me. In certain embodiments, R 9 At least one example is Et. In certain embodiments, R 9 At least one example is Pr or Bu. In certain embodiments, R 9 At least one example is a fluorinated C 1-6 In certain embodiments, R 9 At least one example is -OR a In certain embodiments, R 9 At least one example of is -OH. In certain embodiments, R 9 At least one example is -O (substituted or unsubstituted C 1-6 In certain embodiments, R 9 At least one example is -OMe. In certain embodiments, R 9 At least one example is –N(R a )2. In certain embodiments, R 9 At least one example is -NH2. In certain embodiments, R 9 At least one example is –NHR a (e.g., –NH(substituted or unsubstituted C1-6 In certain embodiments, R 9 At least one example is –NHR a , where R a is replaced by C 1-6 In certain embodiments, R 9 At least one example is –NHR a , where R a C is substituted by -NH2, -NHMe or -NMe2 1-6 In certain embodiments, R 9 At least one example is –NHR a , where R a is unsubstituted C 1-6 In certain embodiments, R 9 At least one example is -N (substituted or unsubstituted C 1-6 In certain embodiments, R 9 At least one example is -N(Me)2. In certain embodiments, R 9 At least one example is -CN. In certain embodiments, R 9 At least one example is halogen, substituted or unsubstituted C 1-6 Alkyl or -OR a In certain embodiments, R 9 More than one example is C 1-6 Alkyl (e.g., R 9 Two examples of are methyl). In certain embodiments, R 9 More than one example is halogen (e.g., R 9 Two examples of are fluoro). In some embodiments, R 9 An example is C 1-6 Alkyl, and R 9 A second example is halogen. In some embodiments, R 9 An example is methyl, and R 9 A second example is a fluoro group.

[0273] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0274] In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In some embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In some embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: express.

[0275] In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: In certain embodiments, optionally with R 9 The terminal pyridine ring is composed of: express.

[0276] In some embodiments, R 9 Two examples of are connected to form a 3- to 13-membered heterocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring. 9 Two examples of are connected to form a 5-membered heteroaryl ring. In certain embodiments, R 9 Two examples of are connected to form a 5-membered heterocyclyl ring. In some embodiments, R 9 Two examples of are connected to form pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl or imidazolinyl. In certain embodiments, R 9 The two examples are connected to form a 5-membered heteroaryl or heterocyclyl ring, and when combined with R 9 When viewed together with the pyridyl ring to which the group is attached, the group consists of: express.

[0277] In certain embodiments, R 3is a halo or -COOR a , R 2 It is C 1-6 haloalkyl or 3 to 6 membered carbocyclic-C 1-6 Alkyl, and R 1 is substituted or unsubstituted C 1-6 In certain embodiments, R 3 is a halo or -COOR a , R 2 It is C 1-6 haloalkyl or 3 to 6 membered carbocyclic-C 1-6 Alkyl, and R 1 is a substituted or unsubstituted methyl group.

[0278] In some embodiments, the compound of formula (I) has formula (Iz), wherein each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro, and R 3 In certain embodiments, each R 9 is a methyl group, and R 3 In some embodiments, each R 9 In certain embodiments, R 3 It's methyl.

[0279] In some embodiments, the compound of formula (I) has the formula:

[0280]

[0281] Each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino; and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro; and R 3 In certain embodiments, each R 9 is methyl; and R 3 In some embodiments, each R 9In certain embodiments, R 3 It's methyl.

[0282] In some embodiments, the compound of formula (I) has formula (Iz), wherein each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro, and R 3 In certain embodiments, each R 9 is a methyl group, and R 3 In some embodiments, each R 9 In certain embodiments, R 3 It is a chloro group.

[0283] In some embodiments, the compound of formula (I) has the formula:

[0284]

[0285] Each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino; and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro; and R 3 In certain embodiments, each R 9 is methyl; and R 3 In some embodiments, each R 9 In certain embodiments, R 3 It is a chloro group.

[0286] In some embodiments, the compound of formula (0) has formula (0a), (0b), or (0c), wherein each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, or R 9 The two examples are connected to form a ring, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro, and R 3 In certain embodiments, each R 9 is a methyl group, and R 3 In some embodiments, each R 9 In certain embodiments, R 3 It's methyl.

[0287] In some embodiments, the compound of formula (0) has formula (0a), (0b), or (0c), wherein each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, or R 9 The two examples are connected to form a ring, and R 3 is methyl, fluoro or chloro. In certain embodiments, each R 9 are independently selected from methyl, fluoro, chloro, methoxy and amino, and R 3 In some embodiments, each R 9 are independently selected from methyl, fluoro and chloro, and R 3 In certain embodiments, each R 9 is a methyl group, and R 3 In some embodiments, each R 9 In certain embodiments, R 3 It is a chloro group.

[0288] In certain embodiments, in compounds of formula (0), q is 1. In certain embodiments, in compounds of formula (0a), q is 1. In certain embodiments, in compounds of formula (0b), q is 1. In certain embodiments, in compounds of formula (0c), q is 1. In certain embodiments, in compounds of formula (0), (0a), (0b), or (0c), q is 1, and R 3 is methyl, chloro or -COOR a .

[0289] In certain embodiments, in compounds of formula (0), q is 0. In certain embodiments, in compounds of formula (0a), q is 0. In certain embodiments, in compounds of formula (0b), q is 0. In certain embodiments, in compounds of formula (0c), q is 0. In certain embodiments, in compounds of formula (0), (0a), (0b), or (0c), q is 0, and R 3 is methyl, chloro or -COORa .

[0290] In certain embodiments, the compound of formula (0) or (I) has the formula:

[0291]

[0292]

[0293]

[0294] or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0295] In some embodiments, the compound of formula (0) or (I) is a mixture having the formula:

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0314] In certain embodiments, the compound is selected from the group consisting of: I-466, I-467, I-468, I-482, I-483, I-484, I-485, I-486, I-487, I-488, I-489, I-491, I-492, I-495, I-497, I-499, I-500, I-501, I-502, I-503, I-510, I-512, I-517, I-593, I-594, I-595, I-596, I-599, I-600, I-601, I-602, I-603 , I-604, I-605, I-606, I-608, I-609, I-610, I-611, I-619, I-620, I-626, I-629, I-631, I-639, I-652, I-658, I-662, I-663, I-6 77. I-685, I-689, I-690, I-T2106, I-T2107, I-T2120, I-T2161, I-T2162, I-T2163, I-T2164, I-T2165, I-T2166, I-T2167, I-T216 8. I-T2169, I-T2170, I-T2171, I-T2172, I-T2174, I-T2175, I-T2176, I-T2177, I-T2178, I-T2179, I-T2180, I-T2181, I-T2182, I-T2183, I-T2184, I-T2185, I-T2186, I-T2187, I-T2188, I-T2206, I-T2211, I-T2212, I-T2213, I-T2217, I-T2218, I-T2219, I-T I-T2254, I-T2255, I-T2256, I-T2257 and I-T2258, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0315] In certain embodiments, the compound is selected from the group consisting of: I-674, I-676, I-679, I-681, I-683, I-684, I-687, I-T2101, I-T2102, I-T2109, I-T2135, I-T2136, I-T2139, I-T2157, I-T2158, I-T2159, I-T2160, I-T2173, I-T2189, I-T2190, I-T2191, I-T2192, I-T2193, I-T2194, I-T2195, I-T2196, I-T2197, I-T2198, I-T2199, I-T I-T2237, I-T2238, I-T2239 and I-T2240, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0316] In certain embodiments, the compound is selected from the group consisting of: 1-403, 1-404, 1-412, 1-453, 1-468, 1-495, 1-594, 1-5 95. I-596, I-599, I-600, I-601, I-602, I-603, I-604, I-606, I-609, I-610, I-611 , I-619, I-620, I-626, I-652, I-662, I-677, I-679, I-681, I-683, I-685, I-689, I-690, I-696 and I-697, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0317] In certain embodiments, the compound is selected from the group consisting of:

[0318]

[0319] or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0320] In certain aspects, the compound of formula (0) or (I) does not have the formula:

[0321] In certain embodiments, the compound of formula (0) or (I) is not a compound disclosed in International PCT Application No. PCT / US2019 / 030664, filed May 3, 2019, which is incorporated herein by reference. In certain aspects, the compound of formula (0) or (I) does not have the following formula:

[0322] or is not a compound disclosed in International PCT Application No. PCT / US2019 / 030664, filed May 3, 2019, which is incorporated herein by reference.

[0323] Other compounds

[0324] Also provided herein are compounds selected from the group consisting of:

[0325] or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0326] Also provided herein are compounds selected from the group consisting of:

[0327] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0328] Also provided herein are compounds selected from the group consisting of:

[0329] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0330] In some embodiments, the compound is selected from the group consisting of 1-481, 1-597, 1-624, 1-630, and 1-675, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0331] In certain embodiments, the compound is selected from the group consisting of 1-331, 1-496, 1-511, 1-450, and 1-527, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0332] In certain embodiments, the compound is selected from the group consisting of 1-331, 1-402, 1-597, 1-624, and 1-630, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0333] Also provided herein are compounds selected from the group consisting of:

[0334] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

[0335] Compositions and kits

[0336] The present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present disclosure (e.g., a compound of Formula (0) or (I), any compound described herein, or any compound appearing in the section entitled "Additional Compounds") and an excipient (e.g., a pharmaceutically acceptable excipient). In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the excipient is a pharmaceutically acceptable excipient.

[0337] The present disclosure also provides compositions further comprising an additional pharmaceutical agent.

[0338] The compositions described herein can be prepared by any method known in the art. Generally, such preparation methods include associating the compounds of the present disclosure described herein with an excipient and may include one or more agents or auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dose units. In certain embodiments, the agent is a pharmaceutical agent.

[0339] In certain embodiments, the compounds of the present disclosure are in the form of pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs.

[0340] The composition can be prepared, packaged, and / or sold as a single unit dose and / or as a plurality of single unit doses in bulk. A "unit dose" is a discrete amount of a composition comprising a predetermined amount of a dose. The amount of a dose is generally equal to the dose of the dose to be administered to a subject and / or a suitable fraction of such a dose, such as half or one-third of such a dose.

[0341] The relative amounts of the compounds of the present disclosure, excipients, agents, and / or any additional ingredients in the compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and will also vary depending on the route of administration of the composition. The composition may contain 0.1% to 100% (w / w) of the agent.

[0342] Excipients and auxiliary ingredients used to make the provided compositions include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients and auxiliary ingredients such as cocoa butter, polyethylene glycol lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavorings, and fragrances may also be present in the compositions.

[0343] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dibasic calcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0344] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinyl pyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, 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.

[0345] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, gum tragacanth, 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, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate ( 20), polyoxyethylene sorbitan ( 60), polyoxyethylene sorbitan monooleate ( 80), Sorbitan monopalmitate ( 40), Sorbitan monostearate ( 60), Sorbitan tristearate ( 65), monoolein, sorbitan monooleate ( 80), polyoxyethylene esters (such as 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 (such as polyoxyethylene lauryl ether ( 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, F-68, poloxamer P-188, cetyltrimethylammonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and / or mixtures thereof.

[0346] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, carrageenan extract, panwar gum, ghatti gum, mucilage from isapol shells, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl pyrrolidone), magnesium aluminum silicate, and larch arabinogalactan), alginate, polyoxyethylene, polyethylene glycol, inorganic calcium salt, silicic acid, polymethacrylate, wax, water, alcohol and / or mixtures thereof.

[0347] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0348] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0349] 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, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0350] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0351] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0352] 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.

[0353] Other preservatives include tocopherol, tocopheryl acetate, deferoxamine mesylate, cetyltrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Plus, Methylparaben, 115. II. and

[0354] Exemplary buffers include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glucuronate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0355] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0356] Exemplary natural oils include almond, apricot, avocado, babassu, bergamot, black currant seed, borage, juniper, chamomile, canola, caraway, palm wax, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, citronellol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, macadamia, lavender, lavender, lemon, litsea cubeba, macadamia, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, citrus, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia, tamarisk, sea buckthorn, sesame, shea butter, silicone, soy, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0357] In certain embodiments, the composition further comprises an agent and can be used to deliver the agent (e.g., to a subject, tissue, biological sample, or cell). In certain embodiments, the composition is a pharmaceutical composition that can be used to treat a disease in a subject in need thereof. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer). In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is gastrointestinal stromal tumor (GIST). In certain embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In certain embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is pancreatic cancer (e.g., pancreatic cancer or pancreatic adenocarcinoma). In certain embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In certain embodiments, the cancer is testicular cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In certain embodiments, the cancer is lymphoma, such as non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma). In certain embodiments, cancer is B cell lymphoma (e.g., Burkitt B cell lymphoma, large B cell lymphoma). In certain embodiments, cancer is T cell lymphoma. In certain embodiments, cancer is Burkitt lymphoma (e.g., Burkitt B cell lymphoma). In certain embodiments, cancer is large cell immunoblastic lymphoma. In certain embodiments, cancer is leukemia. In certain embodiments, cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) (also referred to as acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, acute myeloid leukemia and acute non-lymphocytic leukemia), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML) (also referred to as chronic myeloid leukemia). In certain embodiments, cancer is AML. In some embodiments, cancer is a subtype of AML selected from the group consisting of undifferentiated acute myeloblastic leukemia (M0), minimal mature acute myeloblastic leukemia (M1), mature acute myeloblastic leukemia (M2), acute promyelocytic leukemia (APL) (M3), acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with eosinophilia (M4 eos), acute monocytic leukemia (M5), acute erythroid leukemia (M6), and acute megakaryoblastic leukemia (M7). In certain embodiments, cancer is acute monocytic leukemia or acute lymphocytic leukemia (e.g., B cell acute lymphoblastic leukemia). In certain embodiments, cancer is acute lymphoblastic leukemia (e.g., B cell acute lymphoblastic leukemia or T cell acute lymphoblastic leukemia). In certain embodiments, cancer is multiple myeloma (e.g., B cell myeloma).

[0358] As described herein, the composition can be administered in combination with one or more other agents. In certain embodiments, the agent is an organic molecule. In certain embodiments, the agent is an inorganic molecule. In certain embodiments, the agent is a targeting agent. In certain embodiments, the agent is an isotope-labeled compound. In certain embodiments, the agent is an agent that can be used for bioprocessing. In certain embodiments, the agent is a medicament (e.g., a therapeutic and / or preventive agent). The medicament includes a therapeutic agent. The medicament also includes a preventive agent. The medicament includes 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 the U.S. Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules connected to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunizing agents, and cells.

[0359] In certain embodiments, the compounds of the present disclosure described herein are provided in an effective amount in a composition. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is an amount that effectively treats cancer in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively inhibits the signaling pathways required for metastasis in a subject or cell.

[0360] In certain embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%. In certain embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT within a range (including the end values) between one percentage described in this paragraph and another percentage described in this paragraph.

[0361] In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.5%, at least 99.9%, at least 99.99%, or at least 99.999% of an initial level, which may, for example, be a baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, no more than 98%, or no more than 99.9%. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT within a range between one percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0362] In certain embodiments, an effective amount is an amount that effectively inhibits the signaling of NAMPT by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or at least about 98%. In certain embodiments, an effective amount is an amount that effectively inhibits the signaling of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95% or no more than 98%. In certain embodiments, an effective amount is an amount that effectively inhibits the signaling of NAMPT in the range (including end values) between one percentage described in this paragraph and another percentage described in this paragraph.

[0363] In certain embodiments, an effective amount is an amount effective to increase the signaling of NAMPT by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.5%, at least 99.9%, at least 99.99% or at least 99.999% of an initial level, which may, for example, be a baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to increase the signaling of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, no more than 98% or no more than 99.9%. In certain embodiments, an effective amount is an amount effective to increase signaling of NAMPT within a range between one percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0364] In certain embodiments, the cell is in vitro. In certain embodiments, the cell is ex vivo. In certain embodiments, the cell is in vivo.

[0365] The composition 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 the agent, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances. In certain embodiments for parenteral administration, the composition described herein is mixed with a solubilizer such as Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and mixtures thereof.

[0366] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations 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 vehicles and solvents that can be employed are water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are typically used as solvents or suspending media. For this purpose, any mild fixed oil can be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectable preparations.

[0367] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0368] In order to prolong the effects of the compounds of the present invention, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenteral drug form can be achieved by dissolving or suspending the compound in an oil vehicle.

[0369] Compositions for rectal or vaginal administration are typically suppositories that can be prepared by mixing the compositions described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compounds of the present disclosure.

[0370] 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 the present disclosure are mixed with at least one pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) dissolution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0371] Solid compositions of similar types can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar 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 can optionally contain opacifiers and can have compositions in which they release the disclosed compounds only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of operable encapsulated compositions include polymeric substances and waxes. Solid compositions of similar types can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0372] The compounds of the present invention can be in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with 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 the present invention can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can contain other substances other than inert diluents according to conventional practice, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can include a buffer. They can optionally include an opacifier and can have a composition in which they release the compounds of the present invention only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of usable encapsulating agents include polymeric substances and waxes.

[0373] Dosage forms for topical and / or transdermal administration of the compositions described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Typically, the disclosed compounds are mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any desired preservatives and / or buffers as may be required.

[0374] Suitable devices for delivering intradermal compositions as herein described include short needle devices. Intradermal compositions can be applied by limiting the device of the length of the needle effectively penetrating into the skin. Alternatively or additionally, conventional syringes can be used in the classic Mantoux method of intradermal administration. It is suitable to deliver liquid formulations to the jet injection device of the dermis by a liquid jet injector and / or by puncturing the stratum corneum and producing a jet that arrives at the dermis. It is suitable to use compressed gas to accelerate the ballistic powder / particle delivery device that the polymer present in powder form passes through the outer layer of the skin and arrives at the dermis.

[0375] Preparations suitable for topical administration include liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments and / or pastes, and / or solutions and / or suspensions. Topically administrable preparations may, for example, comprise from about 1% to about 100% (w / w) of a compound of the disclosure, although the concentration of the compound of the disclosure may be as high as the solubility limit of the compound of the disclosure in the solvent. Preparations for topical administration may further comprise one or more additional ingredients as described herein.

[0376] Compositions as described herein can be suitable for preparation, packaging and / or sale of formulations for pulmonary administration via the buccal cavity. Such formulations can include dry particles comprising compounds of the present disclosure. Such compositions are conveniently present in the form of dry powders for administration, which are administered using a device comprising a dry powder reservoir that can direct the propellant to flow to disperse the powder and / or using a self-propelling solvent / powder dispersion container such as a device comprising a low-boiling-point propellant dissolved and / or suspended in a sealed container. Dry powder compositions can include a solid fine powder diluent such as sugar and conveniently provided in unit dosage form.

[0377] Low-boiling-point propellants typically include liquid propellants having a boiling point below 65°F at atmospheric pressure. Typically, the propellant may comprise 50% to 99.9% (w / w) of the composition, and the disclosed compound may comprise 0.1% to 100% (w / w) of the composition. The propellant may further comprise additional ingredients, such as liquid nonionic and / or solid anionic surfactants and / or solid diluents.

[0378] The compositions described herein formulated for pulmonary delivery can provide the compounds of the present invention in the form of droplets of solutions and / or suspensions. Such formulations can be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions comprising the compounds of the present invention and can be conveniently administered using any spray and / or atomizing device. Such formulations may further comprise one or more additional ingredients, including flavorings such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methyl hydroxybenzoate.

[0379] The formulations described herein that 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 comprising a compound of the present disclosure. Such formulations are administered by rapid inhalation through the nasal passages from a container containing the powder held close to the nose.

[0380] Formulations for nasal administration may, for example, contain as little as 0.1% (w / w) to as much as 100% (w / w) of a compound of the present disclosure, and may contain one or more additional ingredients as described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in the form of formulations for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges prepared using conventional methods, and may, for example, contain 0.1% to 20% (w / w) of the agent, the remainder comprising an orally soluble and / or degradable composition and, optionally, one or more additional ingredients as described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension containing a compound of the present disclosure.

[0381] The compositions described herein can be prepared, packaged, and / or sold in the form of formulations for ophthalmic administration. Such formulations may be present, for example, in the form of eye drops, including, for example, 0.1%-100% (w / w) solutions and / or suspensions of the disclosed compounds in aqueous or oily liquid carriers or excipients. Such drops may also contain a buffer, salts, and / or one or more additional ingredients described herein. Other ophthalmically administrable formulations that may be used include those containing the disclosed compounds in microcrystalline form and / or in the form of liposomal formulations. Ear drops and / or eye drops are also encompassed within the scope of the present disclosure.

[0382] Although the descriptions of the compositions provided herein relate primarily to compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well known, and the ordinary veterinary pharmacologist can design and / or perform such modifications through ordinary experimentation.

[0383] The compositions provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dosage of the compositions described herein will be determined by a physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject or organism will depend on a variety of factors, including the cancer being treated and the severity of the cancer; the activity of the specific disclosed compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific disclosed compound employed; the duration of treatment; drugs used in combination or concurrently with the specific disclosed compound employed; and similar factors well known in the medical field.

[0384] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specifically, the intended route is oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via blood and / or lymphatic supply, and / or direct administration to the affected site. In general, the most suitable route of administration will depend on a variety of factors, including the properties of the disclosed compounds (e.g., their stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, compositions as described herein are suitable for topical administration to the eyes of the subject.

[0385] In some embodiments, administration of any of the compositions described herein occurs at least one hour prior to treatment with another cancer therapy.

[0386] The composition can be administered in combination with another agent that improves their activity (e.g., efficacy and / or efficacy), improves bioavailability, improves safety, reduces drug resistance, reduces and / or alters metabolism, inhibits excretion, and / or alters distribution in a subject or cell in treating a disease or condition (e.g., cancer) in a subject in need thereof and / or in inhibiting a signaling pathway in a subject or cell. It will also be understood that the therapy employed may achieve the desired effect for the same condition, and / or it may achieve different effects. In certain embodiments, the compositions described herein (including the compounds of the present disclosure as described herein) and agents exhibit synergistic effects that are not present in compositions comprising one, but not both, of the compounds or agents of the present disclosure.

[0387] The composition can be used simultaneously with one or more other agents, before or after one or more other agents, which are different from the composition and can be used as, for example, a combination therapy. Each other medicament can be used under the dosage and / or schedule determined for this medicament. Other medicaments can also be used in a single dose or separately with different doses, together with each other and / or with the compounds of the present disclosure or the compositions described herein. The specific combination adopted in the scheme will take into account the compatibility of the compounds of the present disclosure described herein with the other medicament and / or the desired treatment and / or preventive effect to be achieved. In general, it is expected that the other medicaments of the combination will be used at a level not exceeding that of their individual use. In some embodiments, the level of the combination will be lower than those used alone.

[0388] Other agents include antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives and analgesics. In certain embodiments, other agents are antiproliferative agents. In certain embodiments, other agents are anticancer agents. In certain embodiments, other agents are chemotherapeutic agents. In certain embodiments, other agents are differentiating agents (e.g., retinoids, all-trans retinoic acid (ATRA), vitamin D, peroxisome proliferator-activated receptor γ (PPARγ) inhibitors). In certain embodiments, other agents are antiviral agents. In certain embodiments, other agents are binding agents or inhibitors of protein kinases. In certain embodiments, the additional agent is 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 regulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions of the present disclosure described herein can be administered in combination with anti-cancer therapies, including surgery, radiotherapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In some embodiments, one or more additional agents, such as one or more additional cancer therapies, are administered to the subject simultaneously, before, or after. In some embodiments, one or more additional cancer therapies include immunotherapy. In general, immunotherapy (also known as biological therapy) is a type of cancer treatment that strengthens the subject's natural defenses to treat cancer. In certain embodiments, immunotherapy utilizes a compound biologically produced by the subject. In certain embodiments, immunotherapy utilizes a compound not biologically produced by the subject. In certain embodiments, immunotherapy utilizes cells from the subject. In certain embodiments, immunotherapy utilizes cells not from the subject. In certain embodiments, immunotherapy utilizes a compound biologically produced by an organism that is not the subject. In certain embodiments, immunotherapy utilizes cells biologically produced by an organism that is not the subject. In certain embodiments, immunotherapy includes at least one chemical modification of a compound or cell from the subject. In certain embodiments, immunotherapy includes at least one chemical modification of a compound or cell not from the subject.

[0389] In some embodiments, the additional agent is selected from the group consisting of niacin, ibrutinib, idelalisib, lenalidomide, a BCL-2 inhibitor, venetoclax, a FLT3 inhibitor, an IDH 1 / 2 inhibitor, glasdegib, azacytidine, cyclophosphamide, decitabine, enasidenib, erastin, gilterinib, idasanutlin, ivosidenib, ixazomib, midostaurin, navitoclax, onvasertib, cyclosporin A, A), PARP inhibitors, pacritinib, phorbol 12-myristate 13-acetate (PMA), ruxolitinib, S055746, selinexor,KPT-330), trametinib, tretinoin, etoposide, P7C3, napabucasin, olaparib, AraC, daunorubicin, 1-methyl-3-nitro-1-nitroguanidine (MNNG), melphalan, verapamil, etoposide, cisplatin, anti-PD-1, tumor necrosis factor-α apoptosis-inducing ligand (TRAIL), EX527, sirtinol, cambinol, vorinostat, valproic acid, butyric acid, JPH203, L-asparaginase, bortezomib, rituximab, PGP-4008, β-lapachone, β-methyleneadenosine 5′-diphosphate (APCP), gemcitabine, Lu-DOTATATE, 5-fluorouracil (5-FU), pemetrexed, and onvastatin. nsertib), cedazuridine, galinpepimut-S, cedazuridine / decitabine, cytarabine / daunorubicin, uproleselan, gedatolisib, devimistat, glagib, edanuline, ganetespib, tipifarnib, midostaurin, pevonedistat, ivenitinib, crenostat crenolanib, quizartinib, pracinostat, guadecitabine, DFP10917, vosaroxin, rexlemestrocel-L-mesoblast, treosulfan, sapacitabine, ensiditinib, volasertib, and temozolomide.

[0390] In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, APG 2575, BCL201, BGB-11417, LP-108, or S65487.

[0391] In some embodiments, the additional agent is a Toll-like receptor 4 (TLR4) inhibitor. In some embodiments, the Toll-like receptor 4 inhibitor is TAK-242, E5564, OM-174, GSK1795091, GLA-SE, NI-0101, AV-411, AS04, amitriptyline, cyclobenzaprine, ketotifen, imipramine, mianserin, ibudilast, pinocembrin, resatorvid, naloxone, naltrexone, LPS-RS, propentofylline, tapentadol, palmitoylethanolamide,

[0392] In some embodiments, the additional agent is a sirtuin inhibitor. In some embodiments, the sirtuin inhibitor is nicotinamide, a nicotinamide derivative, a benzamide, a 3'-phenylethoxy-2-anilinobenzamide analog, AK7, a 1,4-dihydropyridine, a cambinol, EX-527, AGK2, 3'-(3-fluoro-phenylethoxy)-2-iminobenzamide, SirReal2, UBCS0137, ELT-11c, or a thioacylated lysine-containing compound.

[0393] In some embodiments, the additional agent is selected from ibrutinib or idelalisib.

[0394] In some embodiments, the additional agent is lenalidomide.

[0395] In some embodiments, the additional agent is selected from the group consisting of venetoclax, a FLT3 inhibitor, an IDH1 / 2 inhibitor, geragib, azacytidine, cyclophosphamide, decitabine, ensitutinib, alastin, gilteritinib, edanoline, iventinib, ixazomib, midostaurin, navitoclax, anvansetib, paclitinib, PMA, ruxolitinib, S055746, selinexor (KPT-330), trametinib, tretinoin, etoposide, and nababufloxacin.

[0396] In some embodiments, the additional agent is P7C3.

[0397] In some embodiments, the FLT3 inhibitor is selected from the group consisting of sorafenib, sunitinib, lestaurtinib, tandutinib, ponatinib, midostaurin, gilteritinib, quizartinib, crenolanib, cabozantinib, ibrutinib and KW-2449. In some embodiments, the FLT3 inhibitor is sorafenib, sunitinib, ponatinib, cabozantinib, ibrutinib, midostaurin or gilteritinib. In some embodiments, the FLT3 inhibitor is midostaurin or gilteritinib.

[0398] In some embodiments, the IDH 1 / 2 inhibitor is selected from the group consisting of ivitinib and ensiditinib.

[0399] In some embodiments, the PARP inhibitor is selected from the group consisting of: olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, CEP-8983, E7016, iniparib, and 3-aminobenzamide. In some embodiments, the PARP inhibitor is selected from the group consisting of: olaparib, rucaparib, niraparib, and talazoparib. In some embodiments, the PARP inhibitor is selected from the group consisting of: veliparib, pamiparib, CEP 9722, CEP-8983, E7016, iniparib, and 3-aminobenzamide.

[0400] In certain embodiments, the additional agent is an HDAC inhibitor.

[0401] In certain embodiments, the additional agent is hydrochloric acid.

[0402] In some embodiments, the additional agent is afatinib, afatinib dimaleate, alectinib, atezolizumab, bevacizumab, brigatinib, capmatinib, capmatinib hydrochloride, carboplatin, carboplatin-paclitaxel, ceritinib, crizotinib, dabrafenib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin, doxorubicin hydrochloride, durvalumab, entrectinib, erlotini, erlotinib hydrochloride, everolimus, Etoposide phosphate, etoposide, gefitinib, gemcitabine, gemcitabine hydrochloride, gemcitabine-cisplatin, ipilimumab, lorlatinib, lurbinectedin, methotrexate, methotrexate sodium, necitumumab, nivolumab, osimertinib mesylate, osimertinib, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, pralsetinib, pemetrexed, pemetrexed disodium, ramucirumab, selpercatinib, topotecan, topotecan hydrochloride, trametinib, vinorelbine, or vinorelbine tartrate.

[0403] In some embodiments, the additional agent is selected from the group consisting of a topoisomerase II inhibitor (e.g., etoposide, doxorubicin), a topoisomerase I inhibitor (e.g., irinotecan, CPT-11, camptostar, topotecan), a tubulin-interacting agent (e.g., paclitaxel, docetaxel, epothilones), a thymidylate synthase inhibitor (e.g., 5-fluorouracil or 5-FU), an alkylating agent (e.g., temozolomide, cyclophosphamide), a farnesyl protein transferase inhibitor (e.g., lonafarnib, L778,123, BMS214662), a signal transduction inhibitor (e.g., gefitinib), an EGFR antibody (e.g., cetuximab), cytarabine, an aromatase inhibitor (e.g., exemestance, anastrozole, letrozole).

[0404] In some embodiments, the additional agent is cytarabine.

[0405] In some embodiments, the additional agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 1,4,6-androstane-3,17-dione, or 4-androstane-3,6,17-trione.

[0406] In certain embodiments, the additional agent is an anticancer agent or an antineoplastic agent. In some embodiments, the additional agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlormethine, hexamethylmelamine, zevalin, trisenox, xeloda, aminoglutethimide, 6-thioguanine, pentostatine, mithramycin, ifosfamide, pipobroman, triethylenemelamine, methyltestosterone, amsacrine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, dromostanolone propionate, propionate, triethylenethiophosphoramine, streptozocin, 6-mercaptopurine, deoxycoformycin, mitomycin-C, 17a-ethinylestradiol, diethylstilbestrol, testolactone, megestrolacetate, methylprednisolone, chlorotrianisene, hydroxyprogesterone sterone), medroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, reloxafme, droloxafme, porfimer, thiotepa, altretamine, lerozole, fulvestrant, exemestane, a 5-HT3 receptor inhibitor (e.g., dolansetron, granisetron, ondansetron), or dexamethasone.

[0407] In some embodiments, the additional agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlormethine, hexamethylmelamine, zevalin, arsenic trioxide, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mithramycin, ifosfamide, pipobroman, triethylene melamine, methyltestosterone, phenacidine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, drostanolone propionate, triethylenethiophosphamide, streptozotocin, 6- Mercaptopurine, deoxycodimidine, mitomycin C, 17a-ethinyl estradiol, diethylstilbestrol, testolactone, megestrol acetate, methylprednisolone, chlorethoxyquin, hydroxyprogesterone, medroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, lelothifen, drolothifen, porfimer, thiotepa, altretamine, letrozole, fulvestrant, exemestane, or dexamethasone, and 5-HT3 receptor inhibitors (e.g., dolansetron, granisetron, ondansetron).

[0408] In some embodiments, the additional agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlormethine, hexamethylmelamine, zevalin, arsenic trioxide, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mithramycin, ifosfamide, pipobroman, triethylene melamine, methyltestosterone, phenacidine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, drostanolone propionate, triethylenethiophosphamide, streptozotocin, 6- Mercaptopurine, deoxycodimidine, mitomycin C, 17a-ethinyl estradiol, diethylstilbestrol, testolactone, megestrol acetate, methylprednisolone, chlorethoxyquin, hydroxyprogesterone, medroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, lelothifen, drolothifen, porfimer, thiotepa, altretamine, letrozole, fulvestrant, exemestane, or 5-HT3 receptor inhibitors (e.g., dolansetron, granisetron, ondansetron), and dexamethasone.

[0409] In some embodiments, the additional agent is cytarabine. In some embodiments, the additional agent is doxorubicin. In some embodiments, the additional agent is cyclophosphamide. In some embodiments, the additional agent is FX-11. In certain embodiments, the additional agent is uracil mustard. In some embodiments, the additional agent is chlormethine. In some embodiments, the additional agent is hexamethylmelamine. In some embodiments, the additional agent is zevalin. In some embodiments, the additional agent is arsenic trioxide. In some embodiments, the additional agent is Xeloda. In some embodiments, the additional agent is aminoglutethimide. In some embodiments, the additional agent is 6-thioguanine. In some embodiments, the additional agent is pentostatin. In some embodiments, the additional agent is mithramycin. In some embodiments, the additional agent is ifosfamide. In some embodiments, the additional agent is pipobroman. In some embodiments, the additional agent is triethylenemelamine. In some embodiments, the additional agent is methyltestosterone. In some embodiments, the additional agent is amifenecridine. In some embodiments, the additional agent is mitotane. In some embodiments, the additional agent is levamisole. In some embodiments, the additional agent is triamcinolone. In some embodiments, the additional agent is testosterone. In some embodiments, the additional agent is fluoxymesterone. In some embodiments, the additional agent is drostanolone propionate. In some embodiments, the additional agent is triethylenethiophosphamide. In some embodiments, the additional agent is streptozotocin. In some embodiments, the additional agent is 6-mercaptopurine. In some embodiments, the additional agent is deoxycodimidine. In some embodiments, the additional agent is mitomycin C. In some embodiments, the additional agent is 17a-ethinyl estradiol. In some embodiments, the additional agent is diethylstilbestrol. In some embodiments, the additional agent is testolactone. In some embodiments, the additional agent is megestrol acetate. In some embodiments, the additional agent is methylprednisolone. In some embodiments, the additional agent is chlorethoxyquin. In some embodiments, the additional agent is hydroxyprogesterone. In some embodiments, the additional agent is medroxyprogesterone acetate. In some embodiments, the additional agent is toremifene. In some embodiments, the additional agent is navelbene. In some embodiments, the additional agent is anastrozole. In some embodiments, the additional agent is letrozole. In some embodiments, the additional agent is lerothixene. In some embodiments, the additional agent is drolothixene. In some embodiments, the additional agent is a porphim. In some embodiments, the additional agent is thiotepa. In some embodiments, the additional agent is altretinoin. In some embodiments, the additional agent is letrozole.In some embodiments, the additional agent is fulvestrant. In some embodiments, the additional agent is exemestane. In some embodiments, the additional agent is a 5-HT3 receptor inhibitor. In some embodiments, the additional agent is dolansetron. In some embodiments, the additional agent is granisetron. In some embodiments, the additional agent is ondansetron. In some embodiments, the additional agent is dexamethasone.

[0410] In some embodiments, the additional agent is used to treat small cell lung cancer. In some embodiments, the additional agent is everolimus, atezolizumab, doxorubicin, doxorubicin hydrochloride, durvalumab, etoposide phosphate, etoposide, topotecan, topotecan hydrochloride, pembrolizumab, rubitidin, methotrexate, methotrexate sodium, or nivolumab.

[0411] In some embodiments, the additional agent is ibrutinib. In some embodiments, the additional agent is idelalisib. In some embodiments, the additional agent is lenalidomide. In some embodiments, the additional agent is venetoclax. In some embodiments, the additional agent is a FLT3 inhibitor. In some embodiments, the additional agent is an IDH 1 / 2 inhibitor. In some embodiments, the additional agent is gradizib. In some embodiments, the additional agent is azacytidine. In some embodiments, the additional agent is cyclophosphamide. In some embodiments, the additional agent is decitabine. In some embodiments, the additional agent is ensitatinib. In some embodiments, the additional agent is alastinib. In some embodiments, the additional agent is gilteritinib. In some embodiments, the additional agent is edanuline. In some embodiments, the additional agent is ivertinib. In some embodiments, the additional agent is ixazomib. In some embodiments, the additional agent is midostaurin. In some embodiments, the additional agent is navitoclax. In some embodiments, the additional agent is avansetib. In some embodiments, the additional agent is cyclosporine A. In some embodiments, the additional agent is paclitinib. In some embodiments, the additional agent is phorbol 12-myristate 13-acetate (PMA). In some embodiments, the additional agent is ruxolitinib. In some embodiments, the additional agent is S055746. In some embodiments, the additional agent is selinexor (KPT-330). In some embodiments, the additional agent is trametinib. In some embodiments, the additional agent is tretinoin. In some embodiments, the additional agent is etoposide. In some embodiments, the additional agent is P7C3. In some embodiments, the additional agent is nababufloxacin. In some embodiments, the additional agent is olaparib. In certain embodiments, the additional agent is AraC. In some embodiments, the additional agent is daunorubicin. In some embodiments, the additional agent is 1-methyl-3-nitro-1-nitroguanidine (MNNG). In some embodiments, the additional agent is melphalan. In some embodiments, the additional agent is verapamil. In some embodiments, the additional agent is etoposide. In some embodiments, the additional agent is cisplatin. In certain embodiments, the additional agent is anti-PD1. In some embodiments, the additional agent is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In some embodiments, the additional agent is EX527. In some embodiments, the additional agent is sirtinol. In some embodiments, the additional agent is cambinol. In some embodiments, the additional agent is vorinostat. In some embodiments, the additional agent is valproic acid. In some embodiments, the additional agent is butyric acid.In some embodiments, the additional agent is JPH203. In some embodiments, the additional agent is L-asparaginase. In some embodiments, the additional agent is bortezomib. In some embodiments, the additional agent is rituximab. In some embodiments, the additional agent is cyclosporine A. In some embodiments, the additional agent is PGP-4008. In some embodiments, the additional agent is β-lapachone. In some embodiments, the additional agent is β-methyleneadenosine 5′-diphosphate (APCP). In some embodiments, the additional agent is gemcitabine. In some embodiments, the additional agent is Lu-DOTATATE. In some embodiments, the additional agent is fluorouracil (5-FU). In some embodiments, the additional agent is pemetrexed. In some embodiments, the additional agent is temozolomide. In some embodiments, the additional agent is avanafil. In some embodiments, the additional agent is cedaridine. In some embodiments, the additional agent is galinpepimut-S. In some embodiments, the additional agent is cedaruridine / decitabine. In some embodiments, the additional agent is cytarabine / daunorubicin. In some embodiments, the additional agent is uproleselan. In some embodiments, the additional agent is gadalesi. In some embodiments, the additional agent is desidastat. In some embodiments, the additional agent is galaxilib. In some embodiments, the additional agent is edanuline. In some embodiments, the additional agent is ganetespib. In some embodiments, the additional agent is tipifarnib. In some embodiments, the additional agent is midostaurin. In some embodiments, the additional agent is pedinostat. In some embodiments, the additional agent is ivertinib. In some embodiments, the additional agent is crenolanib. In some embodiments, the additional agent is quizartinib. In some embodiments, the additional agent is pralinostat. In some embodiments, the additional agent is guadecitabine. In some embodiments, the additional agent is DFP 10917. In some embodiments, the additional agent is vorxalonfloxacin. In some embodiments, the additional agent is rexlemestrocel-L-mesoblast. In some embodiments, the additional agent is suosulfan. In some embodiments, the additional agent is sabacitabine. In some embodiments, the additional agent is ensiditinib. In some embodiments, the additional agent is volacetidine.

[0412] In some embodiments, immunotherapy can 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 increasing the ability and activity of the immune system to kill cancer cells. Non-limiting examples of immunotherapy include: monoclonal antibodies, checkpoint inhibitors, non-specific immunotherapy, oncolytic virus therapy, T cell therapy, and cancer vaccines.

[0413] In certain embodiments, immunotherapy utilizes monoclonal antibodies. In some embodiments, monoclonal antibodies target (bind to) and / or block abnormal proteins on cancer cells.

[0414] In certain embodiments, immunotherapy comprises an immunotherapy strategy for leukemia. In some embodiments, immunotherapy comprises vaccination with leukemia-associated antigens. In certain embodiments, immunotherapy comprises adoptive transfer of allogeneic natural killer cells.

[0415] In certain embodiments, immunotherapy utilizes checkpoint inhibitors. In certain embodiments, immune checkpoint inhibitors are monoclonal antibodies. Immune checkpoints are regulators of immune activation that maintain immune homeostasis and prevent autoimmunity. In cancer cells, the immune checkpoint mechanism is typically activated to suppress the nascent anti-cancer immune response. 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, ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0416] In certain embodiments, the immunotherapy is a nonspecific immunotherapy (eg, interferon or interleukin). In certain embodiments, the immunotherapy is an oncolytic virus therapy.

[0417] In certain embodiments, the immunotherapy is T cell therapy. In some embodiments, the T cell therapy is chimeric antigen receptor (CAR) T cell therapy.

[0418] In certain embodiments, the immunotherapy is an anti-cancer vaccine.

[0419] Anticancer agents include biotherapeutic anticancer agents and chemotherapeutic agents. Exemplary biotherapeutic anticancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon alpha, interferon gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, 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 (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., Such as carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (such as busulfan and threosulfan), triazenes (such as dacarbazine, temozolomide), platinum-containing compounds (such as cisplatin, carboplatin, oxaliplatin), vinca alkaloids (such as vincristine, vinblastine, vindesine and vinorelbine), taxanes (such as paclitaxel or paclitaxel equivalents) docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate-bound paclitaxel (PG-paclitaxel, polyglutamic acid paclitaxel) poliglumex), CT-2103, XYOTAX), tumor-activated prodrugs (TAPs) ANG1005 (Angiopep-2 conjugated to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, such as 2′-paclitaxel methyl 2-glucopyranosyl succinate;oxadiazine, dapoxet ... C), cytarabine and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB1089, CB 1093 and KH 1060), prenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium salt), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, levorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca; 2+ ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN TM , AZD2171), dasatinib ( BMS-354825), erlotinib Gefitinib Imatinib ( CGP57148B, STI-571), lapatinib CEP-701, Neratinib (HKI-272), Nilotinib Semaxinib (SU5416), sunitinib ( SU11248), toceranib ( )、Vandetanib( ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab Bevacizumab Rituximab Cetuximab Panitumumab Ranibizumab Nilotinib Sorafenib Everolimus Alemtuzumab Gemtuzumab ozogamicin temsirolimus ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (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, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus), AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Novartis), XL765 (Sanofi

[0015] The following are examples of the drugs listed in Table 1: Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methylfolate, methylmitomycin, melphalan, isovinblastine, vinblastine cyclooxygenase, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and altretamine.

[0420] In some embodiments, the compound or composition is substantially soluble in water (e.g., hydrophilic). In some embodiments, the compound or composition is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the compound or composition is substantially insoluble in water and requires greater than about 10,000 parts of water to dissolve 1 part of the compound of the present disclosure.

[0421] In some embodiments, the percentage of the composition comprising the compounds of the present disclosure is from about 1% to about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of the composition comprising the compounds of the present 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 the present disclosure is from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 25%, or from about 5% to about 20%. In some embodiments, the percentage of the composition comprising the compounds of the present disclosure is from about 5% to 90%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is from about 5% to about 75%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is from about 5% to about 50%. In some embodiments, the percentage of the composition comprising a compound of the present disclosure is from about 10% to about 25%.

[0422] In some embodiments, the total amount of Compounds of the Disclosure present in the composition is greater than about 1% (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) of the total size or weight of the composition. In some embodiments, the total amount of Compounds of the Disclosure present in the composition is greater than about 10% (e.g., about 12%, about 15%, about 20%, about 25%, about 30%, or more) of the total size or weight of the composition.

[0423] In some embodiments, the compounds of the present disclosure are incorporated into compositions at a dose or amount that is less than the dose or amount of the compounds in free form to have a desired effect (e.g., a desired therapeutic effect). In certain embodiments, the compositions increase the amount of the compounds of the present disclosure delivered to the tissues or cells where they are needed, and reduce the amount of the compounds of the present disclosure exposed to non-target tissues or cells, compared to the free compound.

[0424] In another aspect, a kit is provided, comprising a compound of the present disclosure; or a pharmaceutical composition described herein; and instructions for using the compound of the present disclosure or the pharmaceutical composition of the present disclosure.

[0425] In some embodiments, the medicine box further comprises another pharmaceutical agent as described herein. In certain embodiments, the medicine box further comprises instructions for the order of use of the compound of the present disclosure or the composition of the present disclosure and the other pharmaceutical agent. In some embodiments, the instructions specify that the compound of the present disclosure or the composition of the present disclosure is applied before the other pharmaceutical agent. In some embodiments, the instructions specify that the compound of the present disclosure or the composition of the present disclosure is applied simultaneously with the other pharmaceutical agent. In some embodiments, the instructions specify that the compound of the present disclosure or the composition of the present disclosure is applied after the other pharmaceutical agent.

[0426] In certain embodiments, the instructions of the medicine box may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the medicine box is prescription information. In certain embodiments, the medicine box and instructions are used to deliver the disclosed compounds. In certain embodiments, the medicine box and instructions are used to deliver compositions. In certain embodiments, the medicine box and instructions are used to treat cancer in subjects in need thereof. In certain embodiments, the medicine box and instructions are used to inhibit signal transduction pathways in subjects or cells.

[0427] Treatment and prevention methods and uses

[0428] Also provided herein are methods and uses of using the compounds or compositions as described herein to treat or prevent any of the diseases as described herein.

[0429] In some embodiments, the present disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound of Formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (0) or (I) are as described herein.

[0430] In certain embodiments, cancer includes cancer stem cells. In certain embodiments, cancer relates to cancer stem cells or is associated with cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumors, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, prostate cancer, liver cancer or endometrial cancer. In certain embodiments, the cancer is leukemia (e.g., acute myeloid leukemia). In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the subject needs regenerative medicine or therapy.

[0431] In yet another aspect, the present disclosure provides methods and uses comprising contacting a cell with an effective amount of a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0432] In certain aspects, the present disclosure provides methods and uses comprising killing cells with an effective amount of a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0433] In certain aspects, the present disclosure provides methods and uses comprising contacting a compound of formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, with a cell, tissue, or biological sample to inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic or adult stem cell properties of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0434] In certain embodiments, the present disclosure provides methods of modulating NAMPT in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0435] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by modulating NAMPT in the subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0436] In certain embodiments, the present disclosure provides methods of inhibiting NAMPT in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0437] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by inhibiting NAMPT in the subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0438] In certain embodiments, the present disclosure provides methods of modulating inflammatory activity in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0439] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by modulating inflammatory activity in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0440] In certain embodiments, the present disclosure provides methods of reducing inflammatory activity in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0441] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing inflammatory activity in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0442] In certain embodiments, the present disclosure provides methods of modulating cellular metabolism in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0443] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by modulating the subject's cellular metabolism, the methods comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0444] In certain embodiments, the present disclosure provides a method of reducing cellular metabolism in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0445] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing cellular metabolism in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0446] In certain embodiments, the present disclosure provides a method of modulating cellular metabolic activity or state in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0447] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by modulating the metabolic activity or state of the subject's cells, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0448] In certain embodiments, the present disclosure provides a method of reducing the metabolic activity or state of a cell in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0449] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing the metabolic activity or state of the subject's cells, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0450] In certain embodiments, the present disclosure provides a method of reducing cell proliferation in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0451] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing cell proliferation in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0452] In certain embodiments, the present disclosure provides a method of reducing inflammatory cell infiltration in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0453] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing inflammatory cell infiltration in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0454] In certain embodiments, the present disclosure provides methods of modulating the production of nicotinamide adenine dinucleotide in a subject, the methods comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0455] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by modulating the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0456] In certain embodiments, the present disclosure provides a method of inhibiting the production of nicotinamide adenine dinucleotide in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0457] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0458] In certain embodiments, the present disclosure provides methods of modulating the production of nicotinamide mononucleotide in a subject, the methods comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0459] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by modulating the subject's production of nicotinamide mononucleotide, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0460] In certain embodiments, the present disclosure provides methods of inhibiting the production of nicotinamide mononucleotide in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0461] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0462] In certain embodiments, the present disclosure provides methods of modulating the NAMPT pathway in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0463] In certain embodiments, the present disclosure provides methods of inhibiting the NAMPT pathway in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0464] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by modulating the subject's NAMPT pathway, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0465] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by inhibiting the NAMPT pathway in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0466] In certain embodiments, the present disclosure provides methods of modulating NAMPT signaling in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0467] In certain embodiments, the present disclosure provides methods of treating a disease or condition in a subject by modulating NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0468] In certain embodiments, the present disclosure provides a method of reducing NAMPT signaling in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0469] In certain embodiments, the present disclosure provides a method of treating a disease or condition in a subject by reducing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0470] In certain embodiments, the present disclosure provides a method for treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a composition disclosed herein. In some embodiments, the disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism and / or NAMPT signaling. In some embodiments, the disease or condition is mediated by NAMPT, NMN, NAD, cellular metabolism and / or NAMPT signaling.

[0471] In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition as described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in the Additional Compounds section, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition as described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound as described in the Additional Compounds section, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Table E1 or Table E2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or condition described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Table E1 or Table E2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling. In some embodiments, the disease or condition is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling.

[0472] In some embodiments, the disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism and / or NAMPT signaling, wherein the disease or condition is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), arthritis, rheumatoid arthritis, acute lung injury, pneumonia, pneumonitis, severe acute respiratory distress syndrome, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopy Dermatitis, UV-induced skin damage, autoimmune diseases, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, infection-related inflammation, vascular inflammation, atherothrombotic diseases, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, atherogenic inflammatory diseases, cardiovascular disease, cerebrovascular disorders, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorders, COVID-19, lung inflammation, coronavirus infection, and tumors.

[0473] In some embodiments, the disease or condition is mediated by NAMPT, NMN, NAD, cellular metabolism and / or NAMPT signaling, wherein the disease or condition is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), arthritis, rheumatoid arthritis, acute lung injury, pneumonia, pneumonitis, severe acute respiratory distress syndrome, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopic dermatitis, inflammation, UV-induced skin damage, autoimmune diseases, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, infection-related inflammation, vascular inflammation, atherothrombotic diseases, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, atherogenic inflammatory diseases, cardiovascular disease, cerebrovascular disorders, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorders, COVID-19, lung inflammation, coronavirus infection, and tumors.

[0474] In some embodiments, the disease or condition is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), arthritis, rheumatoid arthritis, acute lung injury, pneumonia, pneumonitis, severe acute respiratory distress syndrome, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopic dermatitis, UV-induced skin damage, autoimmune diseases, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, infection-related inflammation, vascular inflammation, atherothrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, atherogenic inflammatory diseases, cardiovascular disease, cerebrovascular disorders, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorders, COVID-19, lung inflammation, coronavirus infection, and tumors.

[0475] In some embodiments, the disease or disorder is selected from heart failure, dilated cardiomyopathy, pain, graft-versus-host disease (GCDH), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopic dermatitis, UV-induced skin damage, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, cardiovascular disease, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, neurodegenerative disorder and tumor.

[0476] In some embodiments, the disease or condition is selected from diabetes, rheumatoid arthritis, inflammatory bowel disease, acute respiratory distress syndrome, and ventilator-induced lung injury.

[0477] In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is heart failure. In some embodiments, the disease or condition is dilated cardiomyopathy. In some embodiments, the disease or condition is pain. In certain embodiments, the disease or condition is acute respiratory distress syndrome. In some embodiments, the disease or condition is ventilator-induced lung injury. In some embodiments, the disease or condition is inflammation. In some embodiments, the disease or condition is graft-versus-host disease (GCDH). In some embodiments, the disease or condition is arthritis. In some embodiments, the disease or condition is acute lung injury. In some embodiments, the disease or condition is colitis. In some embodiments, the disease or condition is inflammatory bowel disease (IBD). In some embodiments, the disease or condition is diabetes. In some embodiments, the disease or condition is obesity. In some embodiments, the disease or condition is axonal degeneration. In some embodiments, the disease or condition is a tissue repair disorder. In some embodiments, the disease or condition is asthma. In some embodiments, the disease or condition is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease or condition is osteoarthritis. In some embodiments, the disease or condition is osteoporosis. In some embodiments, the disease or condition is a fibrotic disease. In some embodiments, the disease or condition is a skin disease. In some embodiments, the disease or condition is psoriasis. In some embodiments, the disease or condition is atopic dermatitis. In some embodiments, the disease or condition is UV-induced skin damage. In some embodiments, the disease or condition is an autoimmune disease. In some embodiments, the disease or condition is Alzheimer's disease. In some embodiments, the disease or condition is stroke. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, the disease or condition is restenosis. In some embodiments, the disease or condition is glomerulonephritis. In some embodiments, the disease or condition is cachexia. In some embodiments, the disease or condition is inflammation associated with infection. In some embodiments, the disease or condition is vascular inflammation. In some embodiments, the disease or condition is atherothrombotic disease. In some embodiments, the disease or condition is acquired immunodeficiency syndrome (AIDS). In some embodiments, the disease or condition is adult respiratory distress syndrome. In some embodiments, the disease or condition is ataxia-telangiectasia. In some embodiments, the disease or condition is an atherogenic inflammatory disease. In some embodiments, the disease or condition is cardiovascular disease. In some embodiments, the disease or condition is cerebrovascular disease.In some embodiments, the disease or condition is acute coronary syndrome. In some embodiments, the disease or condition is polycystic ovary syndrome. In some embodiments, the disease or condition is preeclampsia. In some embodiments, the disease or condition is sepsis. In some embodiments, the disease or condition is septic shock. In some embodiments, the disease or condition is intrauterine infection. In some embodiments, the disease or condition is Crohn's disease (CD). In some embodiments, the disease or condition is ulcerative colitis (UC). In some embodiments, the condition is a neurodegenerative disorder. In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is COVID-19. In some embodiments, the disease or condition is lung inflammation. In some embodiments, the disease or condition is a coronavirus infection. In some embodiments, the disease or condition is pneumonia. In some embodiments, the disease or condition is localized pneumonitis. In some embodiments, the disease or condition is severe acute respiratory distress syndrome.

[0478] In some embodiments, the autoimmune disease is systemic lupus erythematosus, multiple sclerosis, ankylosing spondylitis, tissue and organ rejection, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Rett syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy. In some embodiments, the autoimmune disease is systemic lupus erythematosus, multiple sclerosis, ankylosing spondylitis, or tissue and organ rejection.

[0479] In some embodiments, the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease.

[0480] In some embodiments, the arthritis is osteoarthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, fibromyalgia, gout, lupus, ankylosing spondylitis, reactive arthritis, septic arthritis, thumb arthritis, knee arthritis, infectious arthritis, degenerative arthritis, Reiter's arthritis, crystalline arthritis, or inflammatory arthritis. In some embodiments, the arthritis is osteoarthritis, rheumatoid arthritis, or psoriatic arthritis. In some embodiments, the arthritis is osteoarthritis or rheumatoid arthritis.

[0481] In some embodiments, the neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, a tauopathy (including frontotemporal dementia), Huntington's disease, multiple sclerosis, Friedreich's ataxia, Lewy body disease, or spinal muscular atrophy.

[0482] In some embodiments, the intrauterine infection is chorioamnionitis.

[0483] In some embodiments, the diabetes is type 2 diabetes.

[0484] In some embodiments, the cerebrovascular disease is stroke, carotid stenosis, vertebral stenosis and intracranial stenosis, aneurysm or vascular malformation. In some embodiments, the cerebrovascular disease is stroke.

[0485] In some embodiments, the cardiovascular disorder is acute coronary syndrome, heart failure, dilated cardiomyopathy, or cardiomyopathy.

[0486] In certain embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a colorectal tumor, an ovarian tumor, a breast tumor, a stomach tumor, a prostate tumor, a thyroid tumor, a pancreatic tumor, a melanoma, a glioma, a sarcoma, an endometrial tumor, a carcinoma, or a hematologic malignancy.

[0487] Some aspects of the present invention relate to methods, uses, compositions and kits for administering to a subject in need thereof. In some embodiments, the subject is a subject suffering from, suspected of suffering from, or at risk of developing a disease or condition (e.g., a proliferative disease, cancer). As used herein, "subject," "individual," and "patient" can be used interchangeably. In some embodiments, the subject is a mammalian subject, including but not limited to dogs, cats, horses, cows, pigs, sheep, goats, chickens, rodents, or primates. In some embodiments, the subject is a human subject, such as a patient. The human subject can be a pediatric or adult subject.

[0488] As used herein, "treating" includes improving, curing, preventing its worsening, slowing down the rate of progression, preventing the disease from recurring (i.e., preventing recurrence), or preventing or slowing down the rate of metastasis. The effective amount of a compound or composition refers to the amount of the compound or composition that provides a therapeutic effect. For example, in a method or use for treating a subject's cancer, the effective amount of a chemotherapeutic agent is any amount that provides an anticancer effect, such as reducing or preventing cancer cell proliferation or having cytotoxicity to cancer cells.

[0489] The methods and uses disclosed herein relate to administering any of the compounds of the present disclosure or compositions described herein to a subject in an effective amount. In certain embodiments, the subject has a proliferative disease. In other embodiments, the subject requires regenerative medicine. In some aspects, the uses and methods inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic or adult stem cell properties of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0490] The methods and uses disclosed herein involve administering any of the compounds of the present disclosure or compositions described herein in an effective amount 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 neoplasm.

[0491] Methods and uses disclosed herein relate to any one of the compounds disclosed herein or compositions described herein being administered in an effective amount to a subject in need of regenerative medicine or regenerative therapy. In some embodiments, the subject needs to recover or improve one or more biological functions of dysfunctional or damaged cells, tissues and / or organs. In some embodiments, the subject needs tissue engineering and organ regeneration. In some embodiments, the compounds described herein or compositions regenerate or differentiate cells, tissues and / or organs that may be damaged.

[0492] The methods and uses disclosed herein involve administering an effective amount of any of the compounds of the present disclosure or compositions described herein to a subject suffering from cancer or at risk of cancer. In some embodiments, the cancer is characterized by the presence of cancer stem cells. In some embodiments, the cancer comprises stem cells, relates to stem cells, or is associated with stem cells. In some embodiments, the subject has been or is receiving cancer therapy (e.g., chemotherapy, immunotherapy, surgery, radiation). Whether a subject is considered to be "at risk" for a disease or condition such as cancer can be determined by a skilled practitioner.

[0493] In some embodiments, the present disclosure provides methods and uses for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in the additional compound section, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the present disclosure provides methods and uses for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound as described in the additional compound section, or a pharma...

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: R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl; R 2 is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl, substituted or unsubstituted 3 to 13 membered heterocyclyl-C 1-12 -alkyl, substituted or unsubstituted 3 to 13 membered carbocyclic group-C 1-12 - alkyl, or nitrogen protecting group; When R 2 When it is an unsubstituted methyl group, R 1 Not an unsubstituted ethyl group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 An alkyl group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; R 4 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R 5 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group; R 8 Each example is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; R 9 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2, or R 9 Two examples of are connected to form a 3- to 13-membered heterocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring; n is an integer from 0 to 4, inclusive; m is an integer from 0 to 3, inclusive; p is an integer from 0 to 3, inclusive; and q is an integer selected from 0 and 1; provided that the compound does not have the formula:

2. The compound of claim 1, wherein the compound has formula (0a): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

3. The compound of claim 1, wherein the compound has formula (0b): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

4. The compound of claim 1, wherein the compound has formula (0c): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

5. The compound of any one of claims 1 to 4, wherein q is 0.

6. The compound of any one of claims 1 to 4, wherein q is 1.

7. A compound as claimed in any one of claims 1 to 6, wherein R 9 The two examples are connected to form a 5-membered heteroaryl ring or a 5-membered heterocyclyl ring.

8. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof, wherein: R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl; R 2 is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 heteroalkyl, substituted or unsubstituted 3 to 13 membered heterocyclyl-C 1-12 -alkyl, substituted or unsubstituted 3 to 13 membered carbocyclic group-C 1-12 - alkyl, or nitrogen protecting group; When R 2 When it is an unsubstituted methyl group, R 1 Not an unsubstituted ethyl group; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1-6 An alkyl group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; R 4 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R 5 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; R 6 is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group; R 8 Each example is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; R 9 Each example of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR a , –COOR a , –COR a , –N(R a )2, –CN, or –(C=O)N(R a )2; n is an integer from 0 to 4, inclusive; m is an integer from 0 to 3, inclusive; and p is an integer from 0 to 3, inclusive; provided that the compound does not have the formula:

9. The compound of claim 1 or 8, wherein the compound has formula (Iz): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug thereof.

10. The compound of any one of claims 1 and 8 to 9, wherein n is 0.

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