Cancer treatment targeting cancer stem cells

Abstract

Disclosed are compounds, methods, compositions, uses, and kits that can treat cancer. In some embodiments, the compounds are used to treat a disease or disorder. 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. Disclosed are compounds, methods, compositions, uses, and kits that can be used in regenerative medicine. The compounds utilized in this disclosure are of formula (0) and (I).

Description

Technical Field

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 931,531, filed on November 6, 2019, which is incorporated herein by reference.

Background Art

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

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

[0004] Progress has been made in the treatment of subsets of cancer types, but the average cancer mortality rate remains extremely high, and little overall improvement is seen in the ongoing cancer crisis. Almost all current cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on tumor reduction and do not target cancer stem cells, which are the most dangerous cells within tumors. Cancer stem cells are responsible for the spread of cancer cells throughout the body, tumor growth, cancer resistance to chemotherapy, and tumor recurrence after treatment or surgical removal. 3、4 Since current treatment methods do not target cancer stem cell populations, they often lead to an increase in resistant tumors and the continuous spread of cancer.

Summary of the Invention

[0005] The discovery of cancer stem cells provides an opportunity to integrate the fields of oncology and stem cell biology. 5、6 The development of effective and non-toxic therapies can be achieved through a strategy called cancer containment therapy, which targets the embryonic or adult stem cell characteristics of cancer stem cells that form the basis of the factors that make cancer very dangerous, namely cancer growth, spread, and resistance. Therapies that can reduce tumors and destroy cancer stem cells will change cancer treatment. 7

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

[0007] Described herein are compounds that regulate nicotinamide phosphoribosyltransferase (NAMPT), the production of nicotinamide mononucleotide (NMN), the production of nicotinamide adenine dinucleotide (NAD), NAMPT signaling, the NAMPT pathway, and / or cell metabolism.

[0008] These compounds are more effective than conventional cancer therapies in reducing tumor growth, extending lifespan, and / or preventing metastasis and recurrence. Also, since the reactivation of embryonic characteristics is a property common to many types of tumors, cancer containment therapy is expected to be effective against many different types of cancer, including leukemia and cancers of the colon, stomach, prostate, testis, and breast.

[0009] Compounds, methods, compositions, uses, and kits for treating proliferative diseases, benign neoplasms, and cancer are disclosed herein.

[0010] In one aspect, the present disclosure provides a compound of formula (0):

Chemical formula

Chemical formula

[0011] In one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

[0012] In another aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof (the variables described in formula (0) or (I) are as described herein).

[0013] In certain embodiments, the cancer comprises cancer stem cells. In certain embodiments, the cancer is associated with or related to cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, 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 is in need of regenerative medicine or therapy.

[0014] 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0015] In certain embodiments, the present disclosure provides methods and uses that include 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0016] In certain embodiments, the present disclosure provides methods and uses that include contacting a compound disclosed herein (e.g., a compound of formula (0) or (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-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 the embryonic or adult stem cell properties of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0017] In certain embodiments, the present disclosure provides a method of inhibiting NAMPT in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0018] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting NAMPT 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0019] 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 (e.g., 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.

[0020] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0021] In certain embodiments, the present disclosure provides a method of inhibiting the production of nicotinamide mononucleotide in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0022] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0023] In certain embodiments, the present disclosure provides a method of reducing inflammatory cell infiltration in a subject, the method 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.

[0024] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0025] In certain embodiments, the present disclosure provides a method of reducing cell proliferation in a subject, the method 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.

[0026] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0027] In certain embodiments, the present disclosure provides a method of reducing cellular metabolic activity or status in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0028] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by reducing cellular metabolic activity or status 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0029] In certain embodiments, the present disclosure provides a method of reducing inflammatory activity in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0030] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0031] In certain embodiments, the present disclosure provides a method of reducing NAMPT signaling in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0032] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0033] In certain embodiments, the present disclosure provides a method of inhibiting the NAMPT pathway in a subject, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0034] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0035] In certain embodiments, the present disclosure provides a method of inhibiting the NAMPT pathway in a cell, tissue, or biological sample, the method 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.

[0036] In certain embodiments, the present disclosure provides a method of reducing NAMPT signaling in a cell, tissue, or biological sample, the method 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.

[0037] In certain embodiments, the present disclosure provides a method of reducing inflammatory activity in a cell, tissue, or biological sample, the method 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.

[0038] In certain embodiments, the present disclosure provides a method of reducing cell metabolic activity or status in a cell, tissue, or biological sample, the method 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.

[0039] In certain embodiments, the present disclosure provides a method for reducing cell proliferation in a cell, tissue, or biological sample, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0040] In certain embodiments, the present disclosure provides a method for reducing inflammatory cell infiltration in a cell, tissue, or biological sample, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0041] In certain embodiments, the present disclosure provides a method for inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0042] In certain embodiments, the present disclosure provides a method for inhibiting the production of nicotinamide mononucleotide in a cell, tissue, or biological sample, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0043] In certain embodiments, the present disclosure provides a method of inhibiting NAMPT in a cell, tissue, or biological sample, the method 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0044] In some embodiments, the contacting is in vitro or ex vivo.

[0045] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0046] In some embodiments, 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, co-crystal, 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.

[0047] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, 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, co-crystal, 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 to the subject before, simultaneously with, or after a compound disclosed herein (e.g., 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, or a composition disclosed herein.

[0048] In a further aspect, 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or a composition described herein; and instructions for use of the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0049] Details of certain embodiments of the invention are set forth in the following description of the mode(s) for carrying out the invention. Other features, objects, and advantages of the invention will be apparent from the definition, examples, and claims.

[0050] Definitions For convenience, certain terms used herein, in the examples, and in the appended claims are collected here.

[0051] Unless the context requires otherwise, singular terms shall include pluralities and plural terms shall include the singular.

[0052] The phrases "in some embodiments" and "in certain embodiments" are used interchangeably.

[0053] The following definitions apply to the more general terms used throughout this application.

[0054] Unless the context clearly indicates otherwise, singular terms such as "a," "an," and "the" include plural referents. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0055] Except where otherwise indicated in the examples or elsewhere, all numbers expressing amounts of ingredients or reaction conditions used herein are to be understood as being modified in all instances by the term "about." "About" and "approximately" generally mean the degree of error tolerated in the measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%, 4%, 3%, 2%, or 1%.

[0056] The definitions of specific functional groups and chemical terms are further described below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. (front and back covers), and specific functional groups are generally defined as described in that reference. Also, for general principles of organic chemistry and for specific functional moieties and reactivities, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7 thEdition, 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, 3 rd It is described in the 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0057] The compounds described herein can contain one or more chiral centers and, therefore, can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can exist in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0058] In the formula, [Chemical formula] is a single bond where the stereochemistry of the directly connected part is not specified, [Chemical formula] is absent or is a single bond, [Chemical formula] or [Chemical formula] is a single bond or a double bond.

[0059] Unless otherwise specified, the formulas shown in this specification include compounds that do not contain atoms enriched in isotopes, and also include compounds that contain atoms enriched in isotopes. Compounds containing atoms enriched in isotopes can be useful, for example, as analytical tools and / or as probes for biological assays.

[0060] The term "aliphatic" includes both saturated and unsaturated, non-aromatic, straight-chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, the aliphatic group is optionally substituted with one or more functional groups (e.g., halo such as fluorine). As will be understood by those skilled in the art, "aliphatic" is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0061] When a range of values (a "range") is recited, this is intended to encompass each value and sub-range within the range. The range includes the values at both ends of the range unless otherwise indicated. For example, "integers between 1 and 4" means 1, 2, 3, and 4. For example, "C 1-6"Alkyl" means C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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 and is intended to include.

[0062] "Alkyl" means a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3"alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C 1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanil (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), etc. Unless otherwise specified, each instance of the alkyl group is independently optionally substituted, for example, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., a halogen such as F) ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-12 alkyl (e.g., -CH 3 (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 substituted C1-12 Alkyl (e.g., substituted C 1-6 alkyl, e.g., -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or benzyl (Bn)). The bonding point of the alkyl can be a single bond (e.g., like -CH 3 ), a double bond (e.g., like =CH 2 ), or a triple bond (e.g.,

Chemical formula

Chemical formula

[0063] In some embodiments, the alkyl group is substituted with one or more halogens. "Perhaloalkyl" is a substituted alkyl group as defined herein in which all hydrogen atoms are independently substituted by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C 1-8 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C 1-6 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C 1-4 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C 1-3 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C 1-2"perhaloalkyl"). In some embodiments, all hydrogen atoms are replaced with fluoro. In some embodiments, all hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include -CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CCl 3 , -CFCl 2 , -CF 2 Cl, and the like.

[0064] "Alkenyl" means a radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., 2, 3, or 4 as permitted by valency) carbon-carbon double bonds and no triple bonds ("C 2-20 alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C 2"(alkenyl)". One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), etc. C 2-6 Examples of alkenyl groups include, in addition to the aforementioned C 2-4 alkenyl groups, pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrieneyl (C 8 ), etc. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH 3 ,

Chemical formula

[0065] "Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., 2, 3, or 4 as valence permits) carbon-carbon triple bonds, and optionally one or more double bonds ("C 2-20means "alkynyl". In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2-10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C 2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), etc. C 2-6 Examples of alkenyl groups include, in addition to the aforementioned C 2-4 alkynyl groups, pentynyl (C 5 ), hexynyl (C 6 ), etc. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8) and the like. Unless otherwise specified, each instance of the alkynyl group is independently optionally substituted, for example, unsubstituted (``unsubstituted alkynyl'') or substituted with one or more substituents (``substituted alkynyl''). In certain embodiments, the alkynyl group is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2-10 alkynyl.

[0066] "Carbocyclic" or "carbocyclic ring" means a radical of a non-aromatic cyclic hydrocarbon group having 3 to 13 ring carbon atoms (``C 3-13 carbocyclic'') and having no heteroatoms within the non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms (``C 3-8 carbocyclic''). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms (``C 3-7 carbocyclic''). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms (``C 3-6 carbocyclic''). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms (``C 5-10 carbocyclic''). Exemplary C 3-6 carbocyclic groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Exemplary C 3-8 carbocyclic groups include, in addition to the aforementioned C 3-6 carbocyclic groups, cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7) Cycloheptatrienyl (C 7 ) Cyclooctyl (C 8 ) Cyclooctenyl (C 8 ) Bicyclo[2.2.1]heptanyl (C 7 ) Bicyclo[2.2.2]octanyl (C 8 ) and the like. Exemplary C 3-10 carbocyclic groups include, in addition to the aforementioned C 3-8 carbocyclic groups, cyclononyl (C 9 ) Cyclononenyl (C 9 ) Cyclodecyl (C 10 ) Cyclodecenyl (C 10 ) Octahydro-1H-indenyl (C 9 ) Decahydronaphthalenyl (C 10 ) Spiro[4.5]decanyl (C 10 ) and the like. As shown by the foregoing examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or includes a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclic")). The carbocyclic may be saturated, and a saturated carbocyclic is referred to as "cycloalkyl". In some embodiments, the carbocyclic is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). C 3-6Examples of cycloalkyl groups include, in addition to the aforementioned C 5-6 alkyl groups, cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3-8 cycloalkyl groups include, in addition to the aforementioned C 3-6 cycloalkyl groups, cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3-10 cycloalkyl. The carbocyclic ring may be partially unsaturated. The carbocyclic ring may contain zero, one, or more (e.g., two, three, or four, as valence permits) C=C double bonds in all rings of a carbocyclic ring system that is not aromatic or heteroaromatic. A carbocyclic ring containing one or more (e.g., two or three, as valence permits) C=C double bonds in the carbocyclic ring is referred to as a "cycloalkenyl". A carbocyclic ring containing one or more (e.g., two or three, as valence permits)

Chemical Formula

[0067] In some embodiments, "carbocyclic" refers to a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). C 5-6 Examples of the C 5 cycloalkyl group include cyclopentyl (C 5 ). and cyclohexyl (C 3-6 ). Examples of the C 5-6 cycloalkyl group include, in addition to the aforementioned C 3 alkyl group, cyclopropyl (C 4 ) and cyclobutyl (C 3-8 ). Examples of the C 3-6 cycloalkyl group include, in addition to the aforementioned C 7 cycloalkyl group, cycloheptyl (C 8 ) and cyclooctyl (C 3-10It is cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3-10 It is cycloalkyl. In certain embodiments, the carbocyclic ring contains 0, 1, or 2 C═C double bonds in the carbocyclic ring system as permitted by the valence.

[0068] "Carbocyclic alkyl", "X- to X-membered carbocyclic-C x-x alkyl", or "X- to X-membered carbocyclic-C x-x -alkyl" (each instance of X is an integer) is a subset of "alkyl" and means an alkyl group substituted by a carbocyclic group, with the point of attachment being on the alkyl moiety. For example, a 3- to 13-membered carbocyclic-C 1-12 -alkyl group means a C 1-12 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) substituted by a 3- to 13-membered carbocyclic group (e.g., cyclopropyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl).

[0069] "Heterocyclyl" or "heterocyclic" means a radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclyl"). In the case of a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as the valence permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or any of a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")). The heterocyclic group can be saturated or partially unsaturated. Heterocyclyl can contain zero, one, or more (e.g., 2, 3, or 4 as long as the valence permits) double bonds in all rings of a heterocyclic ring system that is neither aromatic nor heteroaromatic. Partially unsaturated heterocyclyl groups include heteroaryl. The bicyclic heterocyclyl ring system can contain one or more heteroatoms in one or both rings. Also, "heterocyclyl" includes a ring system in which the heterocyclyl ring defined above is fused with one or more carbocyclic groups having a point of attachment on either the carbocyclic ring or the heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups having a point of attachment on the heterocyclyl ring. In such cases, the ring member count continues to indicate the ring member count within the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. In certain embodiments, heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence permits.

[0070] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0071] Exemplary 3-membered heterocyclyl groups containing one heteroatom include aziridinyl, oxiranyl, or thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl. C 6Exemplary 5-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 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.

[0072] "Heterocyclylalkyl", "X-X membered heterocyclyl-C x-x alkyl", or "X-X membered heterocyclyl-C x-x -alkyl" (each instance of X is an integer) is a subset of "alkyl" and means an alkyl group substituted by a heterocyclyl group, with the point of attachment being on the alkyl moiety. For example, a 3-13 membered heterocyclyl-C 1-12 -alkyl group is a C 1-12Means an alkyl group (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0073] "Aryl" means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n + 2 aromatic ring system (e.g., a ring system having 6, 10, or 14 π electrons shared in a cyclic arrangement) with 6 to 14 ring carbon atoms and 0 heteroatoms provided by an aromatic ring system, a radical of which ( 6-14 "C 6 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ( 10 "C 14 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ( 6-14 "C 6-14 aryl", e.g., naphthyl (e.g., 1-naphthyl and 2-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms (

[0074] "Anthracyl"). Also, "aryl" includes ring systems in which the aryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups having a radical or a point of attachment on the aryl ring. In such cases, the number of carbon atoms continues to indicate the number of carbon atoms within the aryl ring system. Unless otherwise specified, each instance of the aryl group is independently optionally substituted, e.g., unsubstituted (

[0075] "unsubstituted aryl") or substituted with one or more substituents (

[0075] "substituted aryl"). In certain embodiments, the aryl group is unsubstituted C

[0075] aryl. In certain embodiments, the aryl group is substituted C

[0075] aryl.

[0075] "Aralkyl" is a subset of "alkyl" and means an alkyl group substituted by an aryl group, with the point of attachment on the alkyl moiety.

[0075] "Heteroaryl" means a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., a ring system having 6 or 10 π electrons shared in a cyclic array) provided by an aromatic ring system and having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom being independently selected from nitrogen, oxygen, and sulfur) ("5- to 10-membered heteroaryl"). In the case of a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. A heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocyclic or heterocyclic groups having a point of attachment on the heteroaryl ring, and in such cases, the ring member count continues to indicate the ring member count within the heteroaryl ring system. Also, "heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups having a point of attachment on either the aryl ring or the heteroaryl ring, and in such cases, the ring member count continues to indicate the ring member count within the fused (aryl / heteroaryl) ring system. The point of attachment of a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) is on either ring, and can be, for example, on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). In certain embodiments, heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl in which 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 in which 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0076] "Heteroalkyl" is a subset of "alkyl" and means an alkyl group substituted by a heteroaryl group, with the point of attachment on the alkyl moiety.

[0077] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms provided by an aromatic ring system and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms provided by an aromatic ring system and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms provided by an aromatic ring system and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0078] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0079] "Partially unsaturated" means a group containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Similarly, "saturated" means a group that contains no double or triple bonds, i.e., contains all single bonds.

[0080] In some embodiments, the aliphatic, alkyl, alkenyl, alkynyl, carbocyclic, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted", "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). Generally, the term "substituted" means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom), whether or not preceded by the term "optionally", is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound (e.g., a compound that is not spontaneously converted by rearrangement, cyclization, elimination, or other reactions) when substituted. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when a plurality of positions in any given structure are substituted, the substituents at each position are the same or different. Unless otherwise specified, a substituent on a polycyclic ring may be at any substitutable position of any monocyclic ring in the polycyclic ring. The term "substituted" includes substitution by any of the substituents described herein that results in the formation of a stable compound and includes any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any such combinations to reach stable compounds. For the purposes of the present disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0081] Exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R 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 SO 2 R aa , -NR bb SO 2 R aa, -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa ) 3 , -OSi(R aa ) 3 , -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P(=O)(N(R bb ) 2 ) 2 , -OP(=O)(N(R bb ) 2 ) 2 , -NR bb P(=O)(R aa ) 2 , -NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(N(R bb ) 2 ) 2 , -P(R cc ) 2 , -P(OR cc ) 2 , -P(R cc ) 3 + X - , -P(ORcc ) 3 + X - 、 -P(R cc ) 4 、 -P(OR cc ) 4 、 -OP(R cc ) 2 、 -OP(R cc ) 3 + X - 、 -OP(OR cc ) 2 、 -OP(OR cc ) 3 + X - 、 -OP(R cc ) 4 、 -OP(OR cc ) 4 、 -B(R aa ) 2 、 -B(OR cc ) 2 、 -BR aa (OR cc )、 C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 alkyl, hetero C 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclic, 3 - 14 membered heterocyclic, C 6-14 aryl, and 5 - 14 membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and X - is a counterion), or, two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb ) 2 、 =NNR bb C(=O)R aa 、 =NNR bb C(=O)OR aa 、 =NNRbb S(=O) 2 R aa 、 =NR bb 、 or =NOR cc is replaced by, R aa in each case is independently, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclic, 3 - to 14 - membered heterocyclic, C 6-14 aryl, and 5 - to 14 - membered heteroaryl, or two R aa groups are linked to form a 3 - to 14 - membered heterocyclic or 5 - to 14 - membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups), R bb in each case is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O)(N(R cc ) 2 ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 alkyl, hetero C 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclic, 3 - to 14 - membered heterocyclic, C 6-14 aryl, and 5 - to 14 - membered heteroaryl, or two R bb groups are linked to form a 3 - to 14 - membered heterocyclic or 5 - to 14 - membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and X - is a counterion), R cc in each case is independently hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 alkyl, hetero C 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclic, 3 - to 14 - membered heterocyclic, C 6-14 aryl, and 5 - to 14 - membered heteroaryl, or two R ccThe groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups), R dd in each case is independently halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R 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(=NRff )N(R ff ) 2 、 -NR ff C(=NR ff )N(R ff ) 2 、 -NR ff SO 2 R ee 、 -SO 2 N(R ff ) 2 、 -SO 2 R ee 、 -SO 2 OR ee 、 -OSO 2 R ee 、 -S(=O)R ee 、 -Si(R ee ) 3 、 -OSi(R ee ) 3 、 -C(=S)N(R ff ) 2 、 -C(=O)SR ee 、 -C(=S)SR ee 、 -SC(=S)SR ee 、 -P(=O)(OR ee ) 2 、 -P(=O)(R ee ) 2 、 -OP(=O)(R ee ) 2 、 -OP(=O)(OR ee ) 2 、C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic, 3 - 10 membered heterocyclic, C 6-10 aryl, 5 - 10 membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R ddThe substituent may be linked to form =O or =S, and X - is a counterion) and is selected from R ee in each case is independently C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups) and is selected from R ff in each case is independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups), and R gg in each case is independently halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 (C 1-6 alkyl) + X - , -NH 3 + 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), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6Alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 -C(=S)N(C 1-6 alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -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 1-6Perhaloalkyl, 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, C 6-10 Aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg Substituents may be linked to form =O or =S (wherein X - is a counterion).

[0082] 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, -NO 2 , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)R aa , -OCO 2 R aa , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , or -NR bb C(=O)N(R bb ) 2 is. 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, -NO 2 , -C(=O)R aa , -CO2 R aa 、 -C(=O)N(R bb ) 2 、 -OC(=O)R aa 、 -OCO 2 R aa 、 -OC(=O)N(R bb ) 2 、 -NR bb C(=O)R aa 、 -NR bb CO 2 R aa 、 or -NR bb C(=O)N(R bb ) 2 and in the formula, R aa is hydrogen, substituted (for example, substituted with one or more halogens) or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a sulfur protecting group (for example, acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when bonded to a sulfur atom, and each R bb is independently hydrogen, substituted (for example, substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, the carbon atom substituents are independently halogen, substituted (for example, substituted with one or more halogens) or unsubstituted C 1-6 alkyl, -OR aa 、 -SR aa 、 -N(R bb ) 2 、 -CN, -SCN, or -NO 2 . In certain embodiments, the carbon atom substituents are independently halogen, substituted (for example, substituted with one or more halogen moieties) or unsubstituted C 1-6 alkyl, -OR aa 、 -SR aa 、 -N(R bb ) 2 、 -CN, -SCN, or -NO 2 and in the formula, R aa is hydrogen, substituted (for example, substituted with one or more halogens) or unsubstituted C 1-6Alkyl, an oxygen protecting group when bonded to an oxygen atom, or a sulfur protecting group when bonded to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl), and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.

[0083] As used herein, "counterion" or "anionic counterion" refers to a negatively charged group that associates with a positively charged group to maintain electrical neutrality. The anionic counterion may be monovalent (i.e., including one formal negative charge). Also, the anionic counterion may be polyvalent (i.e., including multiple formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3- 、 ClO 4 - , OH - , H 2 PO 4 - , HCO 3 - , HSO 4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid ion, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid ion, etc.), BF 4 - , PF 4 - , PF 6 - , AsF 6 - , SbF6 - , B[3,5-(CF 3 ) 2 C 6 H 3 4 - , B(C 6 F 5 ) 4 - , BPh 4 - , Al(OC(CF 3 ) 3 ) 4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me 5 Br 6 ) - ) are included. Exemplary counterions that can be polyvalent include CO 3 2- , HPO 4 2- , PO 4 3- , B 4 O 7 2- , SO 4 2- , S 2 O 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate ion, etc.), and carborane.

[0084] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0085] The nitrogen atom may be substituted or unsubstituted as long as the valence permits, and primary, secondary, tertiary, and quaternary nitrogen atoms are included. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR​​aa , -N(R cc ), 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ), 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ), 2 , -SO 2 N(R cc ), 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ), 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc ), 2 , -P(=O)(R aa ), 2 , -P(=O)(N(R cc ), 2 ), 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 alkyl, hetero C 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, and two Rs attached to the N atom ccThe groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd are as defined above.

[0086] 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 , -CO 2 R 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 , -CO 2 R aa , -C(=O)N(R bb ) 2 , or a nitrogen protecting group, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.

[0087] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Examples of nitrogen protecting groups include -OH, -OR aa , -N(R cc ), 2 , -C(=O)R aa , -C(=O)N(R cc ), 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ), 2 , -SO 2 N(R cc ), 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ), 2 , -C(=O)SR cc , -C(=S)SR cc , C 1-10 alkyl (e.g., aralkyl, heteroalkyl), C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd are as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rdThis includes those described in detail in the 1999 edition, John Wiley & Sons (this document is incorporated herein by reference).

[0088] Examples of amide nitrogen protecting groups (e.g., -C(=O)R aa ) include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyl-oxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0089] Examples of carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acetyloxybenzylcarbamate, p-(dihydroxyboronyl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p’-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,Examples include 6 - trimethylbenzyl carbamate.,

[0090] Sulfonamide nitrogen - protecting groups (e.g., -S(=O) 2 R aa ) include p - toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6 - trimethyl - 4 - methoxybenzenesulfonamide (Mtr), 2,4,6 - trimethoxybenzenesulfonamide (Mtb), 2,6 - dimethyl - 4 - methoxybenzenesulfonamide (Pme), 2,3,5,6 - tetramethyl - 4 - methoxybenzenesulfonamide (Mte), 4 - methoxybenzenesulfonamide (Mbs), 2,4,6 - trimethylbenzenesulfonamide (Mts), 2,6 - dimethoxy - 4 - methylbenzenesulfonamide (iMds), 2,2,5,7,8 - pentamethylchroman - 6 - sulfonamide (Pmc), methanesulfonamide (Ms), β - trimethylsilylethanesulfonamide (SES), 9 - anthracenesulfonamide, 4-(4’,8’ - dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0091] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberlylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of the nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, are N,N'-isopropylidenediamine.,

[0092] In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0093] In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , or an oxygen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , or an oxygen protecting group, wherein R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or, when attached to an oxygen atom, an oxygen protecting group, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl or an oxygen protecting group.

[0094] In certain embodiments, the substituent present on the oxygen atom is a nitrogen protecting group (also referred to herein as a “hydroxyl protecting group”). Examples of oxygen protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R 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(Rbb ) 2 ) 2 include, wherein X - , R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (which is incorporated herein by reference).

[0095] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyl oxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberil, Triphenylmethyl, α-Naphthyldiphenylmethyl, p-Methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxyphenyl)diphenylmethyl, 4,4',4”-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4”-Tris(levulinoyloxyphenyl)methyl, 4,4',4”-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-yl)bis(4’,4”-dimethoxyphenyl)methyl, 1,1-Bis(4-methoxyphenyl)-1’-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl, 1,3-Benzodisulfuran-2-yl, Benzisothiazolyl S,S-dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethyltexylsilyl, t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), t-Butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylformate, Acetate, Chloroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, 3-Phenylpropionate, 4-Oxopentanoate (levulinate), 4,4-(Ethylenedithio)pentanoate (levulinoyldithioacetal), Pivaloate, Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (mesitoate), Alkylmethyl carbonate, 9-Fluorenylmethyl carbonate (Fmoc), Alkylethyl carbonate, Alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts) are included.,

[0096] In certain embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0097] In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , or a sulfur protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , or a sulfur protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom, and each R bb is independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl or a sulfur protecting group.

[0098] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). In some embodiments, each sulfur protecting group is -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(Rbb ) 2 , -S(=O)R aa , -SO 2 R 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 (In the formula, R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0099] Additional 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 (e.g., -CF 3 , -CHF 2 , -CH 2 F), -CN, -NO2 -OR a (e.g., -OMe, -OEt), -SR a -N(R a ) 2 (e.g., -NH 2 , -NMe 2 ) -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 are included. Further examples include aryl and heteroaryl.

[0100] Additional 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 (e.g., -CF 3 , -CHF 2 , -CH 2 F), -CN, -NO 2 , -OR aa (e.g., -OMe, -OEt), -SR aa , -N(R aa ) 2 (e.g., -NH 2 , -NMe 2 ) -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 are included. Further examples include aryl and heteroaryl.

[0101] -R (where R is any monovalent moiety) "molecular weight" is calculated by subtracting the atomic weight of a hydrogen atom from the molecular weight of molecule R-H. -L- (where -L- is any divalent moiety) "molecular weight" is calculated by subtracting the combined atomic weight of two hydrogen atoms from the molecular weight of molecule H-L-H.

[0102] In certain embodiments, the molecular weight of the substituent is less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, less than 50 g / mol, or less than 25 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, and / or fluorine atoms. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond donors. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond acceptors.

[0103] When the suffix "ene" is attached to a group, it indicates that the group is a polyvalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In certain embodiments, when the suffix "ene" is attached to a group, it indicates that the group is a divalent moiety.

[0104] The term "hydroxy" or "hydroxyl" means an -OH group.

[0105] The term "thiol" or "thio" means an -SH group.

[0106] The term "amine" or "amino" means an -NH- group or -NH 2 means.

[0107] The term "acyl" has the general formula -C(=O)R X1 -C(=O)OR X1 -C(=O)-O-C(=O)RX1 、 -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 means a group having, wherein R X1 is hydrogen, halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, 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 groups together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehyde (-CHO), carboxylic acid (-CO 2H) Examples include ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Examples of acyl substituents include, but are not limited to, substituents that result in the formation of stable moieties (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted) described herein.

[0108] The term "salt" means an ionic compound resulting from the neutralization reaction of an acid and a base. Since salts are composed of one or more cations (positively charged ions) and one or more anions (negative ions), salts are electrically neutral (having no net charge). The salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed by inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl) 4Salts are included. Representative salts of alkali metals or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acid ions).

[0109] The term "pharmaceutically acceptable salt" means a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). The pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl) 4- Salts are included. Representative salts of alkali metals or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkylsulfonic acids, and arylsulfonic acid ions).

[0110] The term "solvent" means a substance that dissolves one or more solutes to yield a solution. The solvent can function as a medium for any reaction or transformation described herein. The solvent can dissolve one or more reactants or reagents into the reaction mixture. The solvent can facilitate the mixing of one or more reagents or reactants in the reaction mixture. Also, the solvent can function to increase or decrease the reaction rate compared to reactions in different solvents. The solvent can be polar or nonpolar, protic or aprotic. Common solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.

[0111] The term "solvate" usually means a compound or its salt form that associates with a solvent through solvolysis reactions. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can also be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both the solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0112] The term "hydrate" means a compound that associates with water. Typically, the number of water molecules contained in a hydrate of a compound takes a certain ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH 2 2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, for example, monohydrate (x is 1), low hydrate (x is greater than 0 and less than 1, for example, hemihydrate (R·0.5H 2 2O)), as well as polyhydrates (x is greater than 1, for example, dihydrate (R·2H 2 2O) and hexahydrate (R·6H 2 2O)) are included therein.

[0113] The term "crystalline" or "crystalline form" means a solid form that substantially exhibits three-dimensional order. In certain embodiments, the 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 a crystalline form includes one or more sharply defined peaks.

[0114] The term "amorphous" or "amorphous form" means a form of a solid ("solid form") that lacks substantial three-dimensional order. In certain embodiments, the amorphous form of the solid is a solid form that is not substantially crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form includes a broad diffused band having peaks at 2θ between, for example, 20° and 70° (including both end values) using CuKα radiation. In certain embodiments, the XRPD pattern of the amorphous form further includes one or more peaks due to a crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks due to the crystalline structure observed at 2θ between 20° and 70° (including both end values) is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broad diffused band. In certain embodiments, the XRPD pattern of the amorphous form does not include peaks due to a crystalline structure.

[0115] The term "polymorph" means a crystalline form of a compound (or a salt, hydrate, or solvate thereof). 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, stabilities, and solubilities. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may be favored. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0116] The term "cocrystal" means a crystal structure that includes at least two different components (e.g., a compound of formula (0) or (I) and an acid), where each component is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound of formula (0) or (I) and an acid is different from a salt formed from the compound of formula (0) or (I) and the acid. In a salt, the compounds disclosed herein are complexed with an acid in a manner such that proton transfer (e.g., complete proton transfer) from the acid to the compounds disclosed herein occurs readily at room temperature. However, in a cocrystal, the compounds disclosed herein are complexed with an acid in a manner such that proton transfer from the acid to the compounds disclosed herein does not occur readily at room temperature. In certain embodiments, in a cocrystal, no proton transfer occurs from the acid to the compounds disclosed herein. In certain embodiments, in a cocrystal, partial proton transfer occurs from the acid to the compounds disclosed herein. Cocrystals can be useful in improving the properties (e.g., solubility, stability, and ease of formulation) of a compound of formula (0) or (I).

[0117] The term "tautomer" or "tautomerism" means two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, from a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. Tautomerization (i.e., the reaction that gives rise to tautomeric pairs) can be catalyzed by an acid or a base. Exemplary tautomerizations include the tautomerization from keto to enol, from amide to imide, from lactam to lactim, from enamine to imine, and from enamine to (a different enamine).

[0118] It should also be understood that compounds having the same molecular formula but different in the nature of atoms or bond order, or the spatial arrangement of atoms are called "isomers". "Rotational isomers or rotamers" are isomers resulting from restricted rotation about a single bond. The compounds disclosed herein include all rotational isomers of the isomers shown. The compounds disclosed herein include all rotational isomers including but not limited to the rotational isomers shown. In some embodiments, the compounds disclosed herein include all rotational isomers. In certain embodiments, the present disclosure provides a compound, or a rotational isomer thereof. Isomers with different spatial arrangements of atoms are called "stereoisomers". In certain embodiments, when a phenyl group contains two substituents each bonded to adjacent carbons, this compound can be called an ortho isomer. In certain embodiments, when a phenyl group contains two substituents each bonded to carbons separated by one ring carbon, this compound can be called a meta isomer. In certain embodiments, when a phenyl group contains two substituents each bonded to carbons separated by two ring carbons, this compound can be called a para isomer.

[0119] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". For example, when a compound has an asymmetric center, for example, is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the Cahn and Prelog R- and S-rank rules, or by the way the molecule rotates the plane of polarization, and are called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0120] As used herein, the term "agent" means a molecule, group of molecules, complex, or substance that is administered to an organism for purposes of diagnosis, therapy, prophylactic medicine, or veterinary medicine. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent). In certain embodiments, the compositions disclosed herein comprise an agent(s), e.g., a first therapeutic agent (e.g., comprising at least one (e.g., including at least two, at least three)). In some embodiments, the composition can further comprise a second therapeutic agent, a targeting moiety, a diagnostic moiety as described herein.

[0121] As used herein, the term "therapeutic agent" includes an agent capable of producing a local or systemic biological, physiological, or therapeutic effect in a biological system to which it is applied. For example, a therapeutic agent can act, among other functions, to control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and enhance bone growth. Other suitable therapeutic agents can include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active upon administration but are converted to a biologically active agent in the subject by metabolism or some other mechanism.

[0122] Agents (e.g., therapeutic agents) can include a wide variety of different compounds, including chemical compounds and mixtures of chemical compounds (e.g., organic or inorganic small molecules), such as compounds like drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration in accordance with the provisions of the Code of Federal Regulations (CFR)); targeted agents; isotope-labeled chemical compounds; agents useful in bioprocessing; carbohydrates; saccharin; monosaccharides; oligosaccharides; polysaccharides; biopolymers (e.g., peptides, proteins, and peptide analogs and derivatives); peptidomimetics; antibodies and their antigen-binding fragments; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucoproteins; lipoproteins; synthetic polypeptides or proteins; small molecules bound to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunological agents; extracts made from biological materials such as bacteria, plants, fungi, animal cells, etc.; animal tissues; natural or synthetic compositions; and any combination thereof.

[0123] In some embodiments, the agent takes the form of a prodrug. The term "prodrug" means a compound that, for example, by solvolysis, reduction, oxidation, or under physiological conditions, becomes active and provides a pharmaceutically active compound, for example, in vivo. Prodrugs include derivatives of pharmaceutically active compounds. For example, esters can be formed by the reaction of an acid, or acid anhydride, or mixed anhydride moiety of the prodrug portion with a hydroxyl moiety of the pharmaceutically active compound, or amides can be prepared by an acid, or acid anhydride, or mixed anhydride moiety of the prodrug portion and a substituted or unsubstituted amine of the pharmaceutically active compound. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups can include prodrugs. In some embodiments, the compositions described herein incorporate one therapeutic agent or a prodrug thereof. In some embodiments, the compositions described herein incorporate two or more therapeutic agents or prodrugs.

[0124] In some embodiments, the agent (e.g., a therapeutic agent) is a small molecule. As used herein, the term "small molecule" can mean a compound that is "natural product-like". However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, small molecules are typically characterized by containing several carbon-carbon bonds and having a molecular weight of less than 5000 daltons (5 kDa), preferably less than 3 kDa, even more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases, it is preferred that the molecular weight of the small molecule is 700 daltons or less.

[0125] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those described in Harrison’s Principles of Internal Medicine, 13th Edition, Eds. T.R. Harrison et al., McGraw-Hill N.Y., NY; Physicians’ Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics; and the latest edition of The Merck Index, and the entire contents of all of these documents are incorporated herein by reference.

[0126] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more of the agents listed in paragraph

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

[0127] In other embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more of the therapeutic agents listed in International Publication No. WO2013 / 169739, published November 14, 2013, which is incorporated herein by reference, and which includes antihypertensive agents and / or collagen modifying agents (“AHCM”) (e.g., disclosed in paragraphs 40-49, 283, 286-295), microenvironment modulators (e.g., disclosed in paragraphs 113-121 of WO2013 / 169739). In some embodiments, a composition comprising an AHCM and / or a microenvironment modulator causes, in a subject, one or more of the following: reduction of solid stress (e.g., solid stress of a growth-inducing tumor); reduction of tumor fibrosis; reduction of interstitial hypertension or interstitial fluid pressure (IFP); increase of interstitial tumor transport; increase of tumor or vascular perfusion; increase of blood vessel diameter and / or dilation of compressed or collapsed blood vessels; reduction or depletion of one or more of cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); reduction of the level or production of extracellular matrix components, e.g., fibers (e.g., collagen, procollagen) and / or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid); reduction of the level or production of collagen or procollagen; reduction of the level or production of hyaluronic acid; increase of tumor oxygenation; reduction of tumor hypoxia; reduction of tumor acidosis; enabling of immune cell infiltration; reduction of immunosuppression; increase of anti-tumor immunity; reduction of the production of cancer stem cells (also referred to herein as tumor-initiating cells); or enhancement of the effectiveness (e.g., penetration or diffusion) of a therapy, e.g., cancer therapy (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy) in a tumor or tumor vasculature.

[0128] Agents, e.g., therapeutic agents, include the categories and specific examples disclosed herein. This category is not intended to be limited by the specific examples. One of ordinary skill in the art will recognize many other compounds that fall within the scope of this category and are useful in accordance with this disclosure.

[0129] Examples of therapeutic agents include, but are not limited to, antimicrobials, analgesics, anti - inflammatory agents, counter - irritants, coagulation modifiers, diuretics, sympathomimetics, anorectics, antacids and other gastrointestinal agents, anthelmintics, antidepressants, antihypertensives, anticholinergics, stimulants, anti - hormonal agents, central and respiratory stimulants, drug antagonists, lipid regulators, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergics, antiemetics, muscle relaxants, parasympathomimetics, anticonvulsants, antihistamines, beta - blockers, cathartics, antiarrhythmics, contrast agents, radiopharmaceuticals, anti - allergics, tranquilizers, vasodilators, antiviral agents, antineoplastic agents or cytostatic agents or other agents having anticancer properties, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Still other examples include anti - infective agents, such as antibiotics and antiviral agents; analgesics and combinations of analgesics; anorectics; anthelmintics; anti - arthritis agents; anti - asthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti - inflammatory agents; anti - migraine formulations; antiemetics; anti - nicot nausea agents; antineoplastic agents; anti - Parkinson's disease agents; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular formulations (including calcium channel blockers and beta - blockers (e.g., pindolol and anti - arrhythmics)); antihypertensives; diuretics; vasodilators (including general coronary, peripheral, and cerebral blood vessels); central nervous system stimulants; cough and cold formulations (including expectorants); hormones, such as estradiol and other steroids (including corticosteroids); hypnotics; immunosuppressants; muscle relaxants; parasympathetic blockers; psychostimulants; sedatives; and psychotropics; as well as proteins, polysaccharides, glycoproteins, or lipoproteins of natural origin or genetically engineered.

[0130] "Composition" and "formulation" are used interchangeably.

[0131] The "subject" for which administration is contemplated means a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey)), a commercially important mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal.

[0132] The terms "administer", "administering", or "administration" mean introducing the compounds or compositions thereof described herein into or onto a subject by implantation, absorption, ingestion, injection, inhalation, or other means.

[0133] The terms "treat", "treating", and "treatment" mean effecting recovery from, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have occurred or been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject before the onset of symptoms (e.g., based on the subject's treatment history). Further, treatment can continue after symptoms have resolved to delay and / or prevent recurrence of the disease or disorder.

[0134] The terms "prevent", "preventing", or "prevention" mean prophylactic treatment of a subject who does not currently have and has never had a disease but is at risk of developing the disease, or a subject who has had the disease in the past but does not currently have it and is at risk of the disease returning. In certain embodiments, the subject is at higher risk of developing the disease or the disease returning than the average healthy member of the subject population.

[0135] The term "NAMPT" or "nicotinamide phosphoribosyltransferase" refers to an important 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 generates nicotinamide mononucleotide (NMN) as the product of the NAMPT enzyme reaction. NAMPT is found both extracellularly and intracellularly. Thus, in some embodiments, NAMPT is intracellular NAMPT. In certain embodiments, NAMPT is extracellular NAMPT. NAMPT can be found in intracellular compartments and is found in both the nucleus and the cytosol. NAMPT is expressed throughout the body including, but not limited to, the heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. NAMPT can also be referred to as pre-B cell colony enhancing factor (PBEF) and visfatin. The protein is also known as NAmPRTase. NAMPT can result in changes in downstream signaling molecules such as sirtuins, PARP, and NADase 15 . NAMPT plays a role in a variety of diseases and disorders, see for example, (i) WO97 / 48696 regarding the involvement of NAMPT in the treatment of cancer, (ii) WO97 / 48397 regarding the involvement of NAMPT in immunosuppression, (iii) WO2003 / 80054 regarding the involvement of NAMPT for the treatment of diseases associated with angiogenesis, (iv) WO2008 / 025857 regarding the involvement of NAMPT for the treatment of rheumatoid arthritis and septic shock, and (v) WO2009 / 109610 regarding the involvement of NAMPT for the prevention and treatment of ischemia.

[0136] The term "modulate", "modulating", "modulation" or "modulator" means the ability of a compound to reduce / increase, delay / accelerate, stop / start, inhibit / stimulate, or prevent / cause the activity of a specific biological target (e.g., NAMPT) in a cell as compared to a vehicle.

[0137] As used herein, the terms "activate", "activator", "stimulate", or "stimulator" in the context of an enzyme, e.g., in the context of NAMPT, mean an increase in the activity of the enzyme. In some embodiments, the term means an increase in the enzyme activity, e.g., the level of NAMPT activity, to a level that is statistically significantly higher than the starting level, which may be the baseline level of the enzyme activity. In some embodiments, the term means an increase in the enzyme activity, e.g., the level of NAMPT activity, to a level that is more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 85%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.1%, more than 99.5%, more than 99.9%, more than 99.99%, or more than 99.999% of the starting level, which may be the baseline level of the enzyme activity.

[0138] The terms "inhibit", "inhibition", "inhibiting", or "inhibitor" mean the ability to reduce, delay, arrest, or prevent the activity of a specific biological target (e.g., NAMPT) in a cell as compared to a vehicle.

[0139] As used herein, the terms "inhibit" or "inhibition" in the context of an enzyme, e.g., in the context of NAMPT, mean a reduction in the activity of the enzyme. In some embodiments, the term means a reduction in the enzyme activity, e.g., the level of NAMPT activity, to a level that is statistically significantly lower than the starting level, which may be the baseline level of the enzyme activity. In some embodiments, the term means a reduction in the enzyme activity, e.g., the level of NAMPT activity, to a level that is less than 75%, 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% of the starting level, which may be the baseline level of the enzyme activity.

[0140] The terms "condition", "disease", and "disorder" are used interchangeably.

[0141] "Proliferative disease" means a disease caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be 1) the pathological proliferation of cells that are normally quiescent; 2) the pathological movement of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) associated with pathological angiogenesis such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasm"), benign neoplasm, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

[0142] The terms "inflammatory disease" and "inflammatory condition" are used interchangeably herein and mean a disease or condition caused by, resulting from, or leading to inflammation. Inflammatory diseases and inflammatory conditions include those diseases, disorders or conditions characterized by signs of pain (pain from the production of noxious substances and stimulation of nerves), heat (heat from vasodilation), redness (erythema from vasodilation and increased blood flow), swelling (tumor from excessive influx or restricted outflow of body fluids), and / or loss of function (loss of function that can be partial or complete, primary or permanent). Inflammation takes many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrotic, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obstructive, parenchymal, plastic, productive, proliferative, pseudomembranous, purulent, sclerotic, serofibrinous, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term "inflammatory disease" may also mean an uncontrolled inflammatory response that causes an exaggerated reaction by macrophages, granulocytes, and / or T lymphocytes leading to abnormal tissue damage and / or cell death. Inflammatory diseases can be either 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, Sjogren'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, beryllium poisoning, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related vasculitic forms (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed hypersensitivity (e.g., poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity, asthma, hay fever, allergies, acute anaphylaxis, 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, ethmoiditis, epididymitis, fasciitis, cellulitis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enteritis. Ocular inflammatory diseases include, but are not limited to, postoperative inflammation.

[0143] Additional exemplary inflammatory conditions include acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu 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, 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 (itching)), endometriosis, Guillain - Barré syndrome, infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headache (e.g., migraine, tension headache), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., peptic ulcer, Crohn's disease, 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, pouchitis, Behçet's syndrome, indeterminate colitis) and irritable bowel syndrome (IBS)), lupus, multiple sclerosis, localized scleroderma, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, primary biliary cirrhosis, brain disorders associated with neuroinflammation (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, Crohn's disease, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthropathy, Sjögren's syndrome, thyroiditis, transplant rejection, tendinitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injury), vasculitis, vitiligo, and inflammation associated with Wegener's granulomatosis, among others.In certain embodiments, the inflammatory disorder 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 resulting from an infection, for example). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., a condition resulting from asthma, arthritis, and inflammatory bowel disease). The compounds may also be useful in the treatment of inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in the treatment of inflammation associated with cancer.

[0144] "Autoimmune disease" means a disease resulting from an inappropriate immune response of the subject's body against substances and tissues that are normally present in the body. That is, the immune system misinterprets some parts of the body as pathogens and attacks its own cells. This can be limited to a particular organ (e.g., in the case of autoimmune thyroiditis) or can involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membranes of both the lungs and the kidneys). Treatment of autoimmune diseases typically involves immunosuppression, e.g., treatment that reduces the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture 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, Sjogren syndrome, Crohn's disease, Reiter syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and myocarditis.

[0145] In certain embodiments, the inflammatory disorder and / or immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from gastrointestinal disorders (e.g., peptic ulcer, Crohn's disease, 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, pouchitis, Behcet's syndrome, indeterminate colitis) and irritable bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD).

[0146] In certain embodiments, the inflammatory condition and / or immune disorder is a skin condition. In some embodiments, the skin condition is itching, psoriasis, eczema, burns or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is itching.

[0147] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is uncoordinated with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. "Benign neoplasms" are generally well-differentiated, characteristically grow more slowly than malignant neoplasms, and remain localized to the site of origin. In addition, benign neoplasms do not have the ability to invade, penetrate, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile angiomas, seborrheic keratoses, nevi, and sebaceous hyperplasia. In some cases, a particular "benign" tumor may later give rise to a malignant neoplasm. This can result from additional genetic changes in a subpopulation of the neoplastic cells of the tumor, and such tumors are referred to as "premalignant neoplasms". An exemplary premalignant neoplasm is a dysplasia. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic), characteristically grow rapidly, and are associated with progressive invasion, infiltration, and destruction of the surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites. The terms "metastasis", "metastatic", or "metastasize" mean that cancer cells spread or move from the primary tumor or original tumor to another organ or tissue, and are typically distinguishable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary tumor or original tumor, rather than the organ or tissue where the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to the bone is considered metastatic prostate cancer and includes cancerous prostate cells that grow within the bone tissue.

[0148] The term "cancer" means a class of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammaglobulinemia; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., adenocarcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; epithelioma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., adenocarcinoma of the stomach); gastrointestinal stromal tumor (GIST); lung cell cancer; head and neck cancer (e.g., squamous cell carcinoma of the head and neck, oral cancer (e.g., squamous cell carcinoma of the oral cavity), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL), and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large B-cell lymphoma (DLBCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixtures of one or more of the foregoing leukemias / lymphomas; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma (also known as Wilms tumor), renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); rhabdomyosarcoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (AMM) (also known as myelofibrosis), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL) eosinophilia syndrome (HES)); neuroblastoma; neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine carcinoma (e.g., gastroenteropancreatic endocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian fetal cancer, ovarian embryonal cancer, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; tumor associated syndrome; intraepithelial neoplasm; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small intestine cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, testicular fetal cancer); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid cancer (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).;

[0149] Cancer cells can exhibit characteristics similar to those of embryonic stem cells and / or adult stem cells. As used herein, cancer stem cells (CSCs) are cancer cells that have one or more embryonic features / characteristics or adult stem cell features / characteristics. CSCs are generally considered to be the problematic cancer cells because they have the ability to metastasize to other sites in the body and form tumors. As used herein, "embryonic features", "embryonic characteristics", etc. mean gene and / or miRNA expression and / or similar biological characteristics as embryonic cells. Undifferentiated cancer cells with embryonic characteristics have the ability to metastasize, are resistant to chemotherapy and radiation therapy, and have the ability to regrow tumors after surgery and / or additional cancer therapeutic treatments have removed or reduced most of the tumor. As used herein, "adult stem cell features", "adult stem cell characteristics", etc. mean gene and / or miRNA expression and / or similar biological characteristics as adult stem cells. Cancer cells with adult stem cells can have the ability to metastasize, divide, and differentiate, exhibit plasticity, show a high rate of cell turnover, can be resistant to chemotherapy and radiation therapy, and can have the ability to regrow tumors after most of the tumor has been removed or reduced after surgery and / or additional cancer therapeutic treatments.

[0150] In some embodiments, cancer stem cells are characterized by the expression of genes and / or miRNAs associated with an embryonic state. In some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes or miRNAs associated with an embryonic state.

[0151] In some embodiments, cancer stem cells are characterized by one or more embryonic features. Examples of embryonic features include, but are not limited to, cell self-renewal properties, hyperproliferative activity, multipotency, pluripotency, expression of embryonic markers, absence of differentiation markers, resistance to chemotherapy, motility, and the ability to give rise to different cell lineages.

[0152] In some embodiments, cancer stem cells are characterized by the 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.

[0153] In some embodiments, cancer stem cells are characterized by one or more adult stem cell features. Examples of adult stem cell features include, but are not limited to, one or many of the following features (depending on the cell type): cell self-renewal properties, proliferative and / or hyperproliferative activity, bipotency, plasticity, multipotency, resistance to chemotherapy, and the ability to give rise to different cell lineages (transdifferentiation).

[0154] As used herein, the terms "regenerative medicine" or "regenerative therapy" mean promoting the regenerative capacity of cells, tissues, and / or organs. Regenerative medicine encompasses the manipulation of cells and / or tissues for replacing, manipulating, or regenerating cells, tissues, and / or organs, and / or repairing or improving one or more biological functions of cells, tissues, and / or organs that are dysfunctional or abnormal, as well as tissue manipulation and organ regeneration. As used herein, "regenerative capacity" means converting cells such as stem cells into dividing progenitor cells or differentiated tissue-specific cells. Regenerative capacity can additionally or alternatively mean the ability of cells, tissues, and / or organs to replicate, proliferate, recover function, and / or regenerate.

[0155] "Effective amount" of the compositions described herein means an amount sufficient to induce a desired biological response. The effective amount of the compositions described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the mode of administration, and the age and health status of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount in a single administration of the composition or pharmaceutical composition described herein. In certain embodiments, the effective amount is the total amount in multiple administrations of the composition or pharmaceutical composition described herein.

[0156] "Therapeutically effective amount" of the compositions described herein means an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with that condition. The therapeutically effective amount of a composition means the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves the overall therapy, reduces or avoids symptoms, signs, or conditions, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0157] The "preventive effective amount" of a compound described herein is an amount sufficient to prevent a condition or one or more symptoms associated with that condition, or to prevent its recurrence. The preventive effective amount of a compound means the amount of a therapeutic agent that provides a preventive benefit in the prevention of a condition, either alone or in combination with other agents. The term "preventive effective amount" can include an amount that improves the overall prevention method or enhances the preventive effectiveness of another preventive agent.

[0158] The term "gene" means a nucleic acid fragment that provides a template that can be used for the production of a gene product. In certain embodiments, the nucleic acid fragment includes regulatory sequences located before and after the coding sequence. A "native gene" means a gene found in nature with its own regulatory sequences. A "chimeric gene" or "chimeric construct" means any gene or construct that is not a native gene and includes regulatory and coding sequences that are not found together in nature. Thus, a chimeric gene or chimeric construct can include regulatory and coding sequences from different sources, or regulatory and coding sequences from the same source but arranged in a manner different from that found in nature. An "endogenous gene" means a native gene in its natural position within the genome of an organism. A "foreign" gene means a gene that is not normally found within a host organism but is introduced into the host organism by genetic transfer. A foreign gene can include a native gene inserted into a non-native organism, or a chimeric gene. A "transgene" is a gene that has been introduced into the genome by a transformation procedure.

[0159] The terms "nucleic acid", or "nucleic acid sequence", "nucleic acid molecule", "nucleic acid fragment", or "polynucleotide" are used interchangeably. A polynucleotide molecule is a biopolymer composed of nucleotide monomers covalently linked within the chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two strands of polynucleotides, and each strand takes a helical form. RNA is more frequently found in nature as a single strand folded upon itself. Exemplary RNA types include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin (shRNA), microRNA (miRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0160] The term "biological sample" means any sample including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal matter, 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 oral swabs), or any substance containing biomolecules derived from an initial biological sample.

[0161] The terms "compounds of the present disclosure", "compounds disclosed herein", etc. mean any compound disclosed herein, such as in the specification and claims, including (i) Formula (0), (ii) Formula (I), (iii) all subgenera, and (iv) all compound species, including the compounds provided in the additional compounds section and in the examples including Tables E1, E2, and E3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. Provisoed compounds are not included in the terms "compounds of the present disclosure", "compounds disclosed herein", etc.

[0162] The present disclosure is not intended to be limited in any way by the above exemplary lists of substituents. Additional terms may be defined in other sections of the present disclosure.

Mode for Carrying Out the Invention

[0163] Before describing the systems, compounds, compositions, methods, uses, and kits of the present disclosure in more detail, it is to be understood that the aspects described herein are not limited to a particular embodiment, method, apparatus, system, or configuration and, accordingly, may of course vary. It is also to be understood that the terms used herein are for the purpose of describing particular aspects only and are not intended to be limiting unless specifically defined herein.

[0164] The compounds of the present disclosure, as well as their compositions and kits, are useful for the treatment of cancer and proliferative diseases, or are used for regenerative medicine. The compounds can differentiate embryonic-like cancer stem cells, kill differentiated cancer stem cells, interfere with their proliferation, and / or inhibit the 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-like characteristics, including embryonic gene expression patterns, are reactivated in various different types of cancer as a whole. Also, the compounds can differentiate adult-like cancer stem cells, kill differentiated adult cancer stem cells, interfere with their proliferation, and / or inhibit the ability to form new tumors. Adult stem cells are also associated with various 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 characteristics have been found in cancer stem cells from solid tumors (e.g., colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer). 10 Also, embryonic-like characteristics have been found in cancer stem cells from hematopoietic cancers (e.g., leukemia and lymphoma). 14

[0165] While not wishing to be bound by any particular theory, the compounds and compositions disclosed herein are thought to 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 cell metabolism. Nicotinamide mononucleotide (NMN) is a product of the NAMPT enzyme reaction. NAMPT has been implicated in various diseases and disorders, and thus, modulation (i.e., inhibition) of NAMPT may treat a wide range of indications 15,16,17Furthermore, NAMPT is also involved in signal transduction and exhibits activity as an adipokine 18 and an immunomodulatory cytokine. 19 Elevated levels of NAMPT have been described in (i) metabolic / inflammatory conditions including obesity, type 2 diabetes, metabolic syndrome, atherosclerotic inflammatory diseases, and cardiovascular disorders, (ii) non-metabolic chronic inflammatory diseases including osteoarthritis and acute lung injury, (iii) infectious diseases such as sepsis or intrauterine infections, and (iv) autoimmune inflammatory diseases including psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. 15 Accordingly, the compounds of the present disclosure, as well as their compositions and kits, are useful for treating or preventing a variety of diseases and disorders.

[0166] Compound In certain embodiments, the present disclosure provides compounds of formula (0) or (I). Additional compounds are also provided herein.

[0167] In certain embodiments, the compounds of the present disclosure are a compound (e.g., a compound of formula (0) or (I), or a compound described in the Additional Compounds section below), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the compounds of the present disclosure are a compound (e.g., a compound of formula (0) or (I), or a compound described in the Additional Compounds section below), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, the compounds of the present disclosure are a compound (e.g., a compound of formula (0) or (I), or a compound described in the Additional Compounds section below), or a pharmaceutically acceptable salt thereof.

[0168] The compounds of the present disclosure can have high water solubility. The compounds of the present disclosure can have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) water solubility compared to certain similar known compounds.

[0169] The compounds of the present disclosure can have high microsomal stability. The compounds of the present disclosure can have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) microsomal stability compared to certain similar known compounds.

[0170] The compounds of the present disclosure can treat cancer. The compounds of the present disclosure can be 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% better) at treating cancer compared to certain similar known compounds, which can be evidenced by a reduction in cancer symptoms and / or tumor size.

[0171] Compounds of formula (0) and (I) In certain embodiments, as used herein, compounds of formula (0):

Chemical formula

[0172] In certain embodiments, the compound of formula (0) is of formula (0a):

Chemical formula

[0173] In certain embodiments, the compound of formula (0) is of formula (0b):

Chemical formula

[0174] In certain embodiments, the compound of formula (0) is of formula (0c):

Chemical formula

[0175] In certain embodiments, herein, the compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof is provided (wherein, R 1 is substituted or unsubstituted C 1-12 alkyl or 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 carbocyclyl-C 1-12 -alkyl, or a nitrogen protecting group, R 2 when it is unsubstituted methyl, R 1 is not unsubstituted ethyl, 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 is, R a in each case is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, R 4 in each case 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 ) 2and, R 5 in each case, independently, 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 and, R 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, R 8 in each case, independently, is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl, R 9 in each case, independently, 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 and, n is an integer from 0 to 4 (including both end values), m is an integer from 0 to 3 (including both end values), p is an integer from 0 to 3 (including both end values).

[0176] In certain embodiments, the compound of formula (I) is of formula (Iz):

Chemical formula

[0177] In certain embodiments, the compound of formula (I) is of formula (Ia):

Chemical formula

[0178] In certain embodiments, the compound of formula (I) is of formula (Ib): [Chemical formula] wherein.

[0179] In certain embodiments, the compound of formula (I) is of formula (Ic): [Chemical formula] wherein.

[0180] In certain embodiments, R 1 is substituted or unsubstituted C 1-12 alkyl. In certain embodiments, R 1 is substituted C 1-12 alkyl. In certain embodiments, R 1 is unsubstituted C 1-12 alkyl. In certain embodiments, R 1 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1 alkyl. In certain embodiments, R 1 is unsubstituted C 2 alkyl. In certain embodiments, R 1 is unsubstituted C 3 alkyl. In certain embodiments, R 1 is unsubstituted C 4 alkyl. In certain embodiments, R 1 is unsubstituted C 5 alkyl. In certain embodiments, R 1 is unsubstituted C 6 alkyl. In certain embodiments, R 1 is substituted C 1-6 alkyl. In certain embodiments, R 1 is substituted C 1is alkyl. In certain embodiments, R 1 is substituted C 2 alkyl. In certain embodiments, R 1 is substituted C 3 alkyl. In certain embodiments, R 1 is substituted C 4 alkyl. In certain embodiments, R 1 is substituted C 5 alkyl. In certain embodiments, R 1 is substituted C 6 alkyl. In certain embodiments, R 1 is fluorinated C 1-6 alkyl (e.g., -CF 3 , -CHF 2 , -CH 2 F). In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In certain embodiments, R 1 is substituted or unsubstituted C 1-12 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 1-12 heteroalkyl. In certain embodiments, R 1 is substituted C 1-12 heteroalkyl. In certain embodiments, R 1 is substituted or unsubstituted C 1-6 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 1-6 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 1 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 2 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 3 heteroalkyl. In certain embodiments, R1 is unsubstituted C 4 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 5 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 6 heteroalkyl. In certain embodiments, R 1 is substituted C 1-6 heteroalkyl. In certain embodiments, R 1 is substituted C 1 heteroalkyl. In certain embodiments, R 1 is substituted C 2 heteroalkyl. In certain embodiments, R 1 is substituted C 3 heteroalkyl. In certain embodiments, R 1 is substituted C 4 heteroalkyl. In certain embodiments, R 1 is substituted C 5 heteroalkyl. In certain embodiments, R 1 is substituted C 6 heteroalkyl. In some embodiments, R 1 is methoxy, ethoxy, or propoxy. In certain embodiments, R 1 is halo, -CN, -NR a 2 , -CO 2 R aa , -C(=O)R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , or -NR bb C(=O)N(R bb ) 2is replaced. In certain embodiments, R 1 is -CO 2 R aa ,-OC(=O)R aa ,-OCO 2 R aa ,-C(=O)N(R bb ) 2 ,-OC(=O)N(R bb ) 2 ,-NR bb C(=O)R aa ,-NR bb CO 2 R aa ,or -NR bb C(=O)N(R bb ) 2 is replaced.

[0181] In some embodiments, R bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or pentyl.

[0182] In certain embodiments, the substituent on the R 1 group is -CN, -F, -Cl, -N(R a )(C=O)OR a ,or -COOR a In certain embodiments, the substituent on the R 1 group is -CN, -F, -Cl, -NR a 2 ,-N(R a )(C=O)OR a ,-COOR a ,or -(C=O)R a In certain embodiments, the substituent on the R 1 group is -CN, -F, -Cl, -NH 2 ,-NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)O t Bu, or -C(=O)CH 3 is.

[0183] In certain embodiments, R 2is hydrogen. In certain embodiments, R 2 is not hydrogen. In certain embodiments, R 2 is substituted or unsubstituted C 1-12 alkyl. In certain embodiments, R 2 is unsubstituted C 1-12 alkyl. In certain embodiments, R 2 is substituted C 1-12 alkyl. In certain embodiments, R 2 is Me. In certain embodiments, R 2 is Et, Pr, or Bu. In certain embodiments, R 2 is a nitrogen protecting group.

[0184] In certain embodiments, R 2 is substituted or unsubstituted C 1-12 alkyl. In certain embodiments, R 2 is unsubstituted C 1-12 alkyl. In certain embodiments, R 2 is substituted C 1-12 alkyl. In certain embodiments, R 2 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted C 1 alkyl. In certain embodiments, R 2 is unsubstituted C 2 alkyl. In certain embodiments, R 2 is unsubstituted C 3 alkyl. In certain embodiments, R 2 is unsubstituted C 4 alkyl. In certain embodiments, R 2 is unsubstituted C 5 alkyl. In certain embodiments, R 2 is unsubstituted C 6is alkyl. In certain embodiments, R 2 is substituted C 1-6 alkyl. In certain embodiments, R 2 is substituted C 1 alkyl. In certain embodiments, R 2 is substituted C 2 alkyl. In certain embodiments, R 2 is substituted C 3 alkyl. In certain embodiments, R 2 is substituted C 4 alkyl. In certain embodiments, R 2 is substituted C 5 alkyl. In certain embodiments, R 2 is substituted C 6 alkyl. In certain embodiments, R 2 is halogenated C 1-12 alkyl. In certain embodiments, R 2 is substituted C 6 alkyl. In certain embodiments, R 2 is fluorinated C 1-6 alkyl (e.g., -CF 3 , -CHF 2 , -CH 2 F). In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In certain embodiments, R 2 is substituted or unsubstituted C 1-12 heteroalkyl. In certain embodiments, R 2 is substituted C 1-12 heteroalkyl. In certain embodiments, R 2 is unsubstituted C 1-12 heteroalkyl. In certain embodiments, R 2 is substituted or unsubstituted C 1-6 heteroalkyl. In certain embodiments, R 2 is unsubstituted C1-6 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 1 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 2 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 3 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 4 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 5 is heteroalkyl. In certain embodiments, R 2 is unsubstituted C 6 is heteroalkyl. In certain embodiments, R 2 is substituted C 1-6 is heteroalkyl. In certain embodiments, R 2 is substituted C 1 is heteroalkyl. In certain embodiments, R 2 is substituted C 2 is heteroalkyl. In certain embodiments, R 2 is substituted C 3 is heteroalkyl. In certain embodiments, R 2 is substituted C 4 is heteroalkyl. In certain embodiments, R 2 is substituted C 5 is heteroalkyl. In certain embodiments, R 2 is substituted C 6 is heteroalkyl. In some embodiments, R 2 is methoxy, ethoxy, or propoxy.

[0185] In certain embodiments, R 2 is substituted or unsubstituted 3- to 13-membered heterocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 13-membered heterocyclyl-C 1-12is alkyl. In certain embodiments, R 2 is substituted 3- to 13-membered heterocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is substituted or unsubstituted 3- to 13-membered heterocyclyl-C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 1 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 2 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 3 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 4 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 5 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered heterocyclyl-C 6 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 1-6 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 1 alkyl. In certain embodiments, R 2 is substituted C 2 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 3 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 4 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 5is alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 6 alkyl. In certain embodiments, R 2 is halogenated 3- to 6-membered heterocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered heterocyclyl-C 6 alkyl.

[0186] In certain embodiments, R 2 is substituted or unsubstituted 3- to 13-membered carbocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 13-membered carbocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is substituted 3- to 13-membered carbocyclyl-C 1-12 alkyl. In certain embodiments, R 2 is substituted or unsubstituted 3- to 13-membered carbocyclyl-C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 1 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 2 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 3 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 4 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 5 alkyl. In certain embodiments, R 2 is unsubstituted 3- to 6-membered carbocyclyl-C 6is alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 1-6 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 1 alkyl. In certain embodiments, R 2 is substituted C 2 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 3 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 4 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 5 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 6 alkyl. In certain embodiments, R 2 is halogenated 3- to 6-membered carbocyclic-C 1-12 alkyl. In certain embodiments, R 2 is substituted 3- to 6-membered carbocyclic-C 6 alkyl.

[0187] In certain embodiments, R 2 is substituted C 6 heteroalkyl. In some embodiments, R 2 is methoxy, ethoxy, or propoxy.

[0188] In certain embodiments, R 2 is halo, -CN, -NR a 2 , -CO 2 R aa , -C(=O)R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(Rbb ) 2 、 -NR bb C(=O)R aa 、 -NR bb CO 2 R aa 、 or -NR bb C(=O)N(R bb ) 2 is substituted. In certain embodiments, R 2 is -CO 2 R aa 、 -OC(=O)R aa 、 -OCO 2 R aa 、 -C(=O)N(R bb ) 2 、 -OC(=O)N(R bb ) 2 、 -NR bb C(=O)R aa 、 -NR bb CO 2 R aa 、 or -NR bb C(=O)N(R bb ) 2 is substituted.

[0189] In some embodiments, R bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert - butyl, or pentyl.

[0190] In certain embodiments, the substituent on the R 2 group is -CN, -F, -Cl, -N(R a )(C=O)OR a 、 or COOR a 。

[0191] In certain embodiments, the substituent on the R 2 group is -CN, -F, -Cl, -N(R a )(C=O)OR a 、 or -COOR a 。 In certain embodiments, the substituent on the R 2 group is -CN, -F, -Cl, -NR a 2 、 -N(Ra )(C=O)OR a 、 -COOR a 、 or -(C=O)R a is. In certain embodiments, R 1 The substituent on the group is -CN, -F, -Cl, -NH 2 , -NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)O t Bu, or -C(=O)CH 3 .

[0192] In certain embodiments, when R 2 is unsubstituted methyl, R 1 is not unsubstituted ethyl, and in some embodiments, when R 2 is methyl, R 1 is not ethyl.

[0193] In certain embodiments, when R 2 is unsubstituted methyl, R 1 is not unsubstituted n-propyl, and in some embodiments, when R 2 is methyl, R 1 is not n-propyl.

[0194] In certain embodiments, when R 2 is unsubstituted methyl, R 1 is not unsubstituted ethoxy, and in some embodiments, when R 2 is methyl, R 1 is not ethoxy.

[0195] 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 carbocyclic-C 1Alkyl, substituted or unsubstituted 3- to 6-membered carbocyclyl-C 2 Alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl-C 1 Alkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl-C 2 is alkyl.

[0196] In certain embodiments, R 2 is substituted C 1-6 alkyl. In some embodiments, R 2 is haloalkyl. In certain embodiments, R 2 is difluoroethyl. In some embodiments, R 2 is 2,2-difluoroethyl.

[0197] In some embodiments, R 2 is substituted or unsubstituted 3- to 6-membered carbocyclyl-C 1-6 alkyl. In some embodiments, R 2 is substituted or unsubstituted 3- to 6-membered carbocyclyl-C 1 alkyl. In some embodiments, R 2 is cyclopropylmethyl.

[0198] 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(Ra ) 2 is. 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 .

[0199] In some embodiments, R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is chloro, bromo, or iodo. In certain embodiments, R 3 is chloro. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is -CN. In certain embodiments, R 3 is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl or butyl. In certain embodiments, R 3 is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF 3 ). In certain embodiments, R 3 is -OR a . In certain embodiments, R 3 is -OH. In certain embodiments, R 3 is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 3 is -COOR ais. In certain embodiments, R 3 is -COOR a and R a is hydrogen or substituted or unsubstituted C 1-6 alkyl (e.g., -COOMe, -COOEt, -COO(CH 2 ) 2 CH 3 , -COO(CH 2 ) 3 CH 3 , or -COOC(CH 3 ) 3 In certain embodiments, R 3 is -COR a In certain embodiments, R 3 is -COR a and R a is hydrogen or substituted or unsubstituted C 1-6 alkyl (e.g., -COMe, -COEt, -CO(CH 2 ) 2 CH 3 , -CO(CH 2 ) 3 CH 3 , or -COC(CH 3 ) 3 ) In certain embodiments, R 3 is -N(R a ) 2 In certain embodiments, R 3 is -NH 2 In certain embodiments, R 3 is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R 3 is -N(substituted or unsubstituted C 1-6 alkyl) 2 , e.g., -N(Me) 2 ) In certain embodiments, R 3 is -C(=O)N(R a ) 2 In certain embodiments, R 3 is -C(=O)NH2 is. In certain embodiments, R 3 is -C(=O)NHR a (e.g., -C(=O)NH(substituted or unsubstituted C 1-6 alkyl), e.g., -C(=O)NHMe). In certain embodiments, R 3 is -C(=O)N(substituted or unsubstituted C 1-6 alkyl) 2 , e.g., -C(=O)N(Me) 2 ). In some embodiments, R 3 is halo or -COOR a . In some embodiments, R 3 is chloro or -COOMe.

[0200] In certain embodiments, each instance of R a is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, each instance of R a is hydrogen. In certain embodiments, there is no instance where R a is hydrogen. In certain embodiments, at least one instance of R a is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, at least one instance of R a is Me. In certain embodiments, at least one instance of R a is Et, Pr, or Bu. In certain embodiments, at least one instance of R a is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF 3 ).

[0201] 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 is. In some embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is chloro. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 is -CN. In certain embodiments, R 4 is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl or butyl. In certain embodiments, R 4 is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF 3 ). In certain embodiments, R 4 is -OR a . In certain embodiments, R 4 is -OH. In certain embodiments, R 4 is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 4 is -COOR a . In certain embodiments, R 4 is -COOR a , and R a is hydrogen or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 4 is -COR a . In certain embodiments, R 4 is -CORa and R a is hydrogen or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 4 is -N(R a ) 2 . In certain embodiments, R 4 is -NH 2 . In certain embodiments, R 4 is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl)). In certain embodiments, R 4 is -N(substituted or unsubstituted C 1-6 alkyl) 2 , e.g., -N(Me) 2 ). In certain embodiments, R 4 is -C(=O)N(R a ) 2 . In certain embodiments, R 4 is -C(=O)N(R a ) 2 , and R a is hydrogen or substituted or unsubstituted C 1-6 alkyl.

[0202] In certain embodiments, p is 0. In some embodiments, p is 1. In certain embodiments, p is 2. In some embodiments, p is 3.

[0203] In certain embodiments, the phenyl ring having R 3 and optionally having R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0204] is independently hydrogen, halogen, substituted or unsubstituted C 5 alkyl, -OR 1-6 , -N(R a ), or -CN. In a certain specific embodiment, each instance of R a is independently -COOR 2 , -COR 5 , or -(C=O)N(R a ). In a certain specific embodiment, at least one instance of R a is hydrogen. In a certain specific embodiment, each instance of R a is hydrogen. In a certain specific embodiment, at least one instance of R 2 is not hydrogen. In a certain specific embodiment, there is no instance where R 5 is hydrogen. In a certain specific embodiment, at least one instance of R 5 is halogen. In a certain specific embodiment, at least one instance of R 5 is F. In a certain specific embodiment, at least one instance of R 5 is Cl. In a certain specific embodiment, at least one instance of R 5 is substituted or unsubstituted C 5 alkyl (for example, unsubstituted C 5 alkyl, unsubstituted C 5 alkyl, unsubstituted C 1-6 alkyl (for example, unsubstituted C 1-6is (alkyl). In certain embodiments, R 5 in at least one instance is Me. In certain embodiments, R 5 in at least one instance is Et, Pr, or Bu. In certain embodiments, R 5 in at least one instance is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF 3 ). In certain embodiments, R 5 in at least one instance is -OR a . In certain embodiments, R 5 in at least one instance is -OH. In certain embodiments, R 5 in at least one instance is -O(substituted or unsubstituted C 1-6 alkyl) (e.g., -OMe). In certain embodiments, R 5 in at least one instance is -N(R a ) 2 . In certain embodiments, R 5 in at least one instance is -NH 2 . In certain embodiments, R 5 in at least one instance is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R 5 in at least one instance is -N(substituted or unsubstituted C 1-6 alkyl) 2 , e.g., -N(Me) 2 . In certain embodiments, R 5 in at least one instance is -CN. In certain embodiments, R 5 in at least one instance is halogen, substituted or unsubstituted C 1-6 alkyl, or -OR a .

[0205] In certain embodiments, m is 0. In some embodiments, m is 1. In certain embodiments, m is 2. In some embodiments, m is 3.

[0206] 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.

[0207] In certain embodiments, the central pyridinyl ring optionally having R 5 is represented by

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0208] In certain embodiments, R 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, R 6 is hydrogen. In certain embodiments, R6 is a substituted or unsubstituted C 1-6 alkyl. In some embodiments, R 6 is a substituted or unsubstituted methyl. In certain embodiments, R 6 is a substituted or unsubstituted ethyl. In some embodiments, R 6 is a nitrogen protecting group selected from tosyl, tert-butyloxycarbonyl, acetyl, or benzoyl.

[0209] In certain embodiments, each instance of R 8 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, each instance of R 8 is hydrogen. In certain embodiments, one instance of R 8 is hydrogen. In certain embodiments, at least one instance of R 8 is halogen. In certain embodiments, at least one instance of R 8 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 8 is unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl). In certain embodiments, at least one instance of R 8 is C 1-6 alkyl substituted with at least one instance of halogen (e.g., F).

[0210] In certain embodiments, q is 0. In some embodiments, q is 1.

[0211] 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.

[0212] In some embodiments, each instance of R 9 is independently 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 wherein, or two instances of R 9 are linked to form a 3- to 13-membered heterocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl ring, or 5- to 14-membered heteroaryl ring. In certain embodiments, each instance of R 9 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 . Each instance of R 9 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -OR a , or -N(R a ) 2 . In certain embodiments, at least one instance of R 9 is hydrogen. In certain embodiments, each instance of R 9 is hydrogen. In certain embodiments, at least one instance of R 9 is not hydrogen. In certain embodiments, there is no instance where R 9 is hydrogen. In certain embodiments, at least one instance of R 9 is halogen. In certain embodiments, at least one instance of R 9 is F. In certain embodiments, at least one instance of R 9 is Cl. In certain embodiments, at least one instance of R 9 is substituted or unsubstituted C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl). In certain embodiments, R 9At least one instance of is Me. In certain embodiments, R 9 At least one instance of is Et. In certain embodiments, R 9 At least one instance of is Pr or Bu. In certain embodiments, R 9 At least one instance of is fluorinated C 1-6 alkyl (e.g., fluorinated methyl, e.g., -CF 3 ). In certain embodiments, R 9 At least one instance of is -OR a . In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of is -O(substituted or unsubstituted C 1-6 alkyl). In certain embodiments, R 9 At least one instance of is -OMe. In certain embodiments, R 9 At least one instance of is -N(R a ) 2 . In certain embodiments, R 9 At least one instance of is -NH 2 . In certain embodiments, R 9 At least one instance of is -NHR a (e.g., -NH(substituted or unsubstituted C 1-6 alkyl), e.g., -NHMe). In certain embodiments, R 9 At least one instance of is -NHR a , and R a is substituted C 1-6 alkyl. In certain embodiments, R 9 At least one instance of is -NHR a , and R a is C 2 alkyl substituted with -NH 2 , -NHMe, or -NMe 1-6 alkyl. In certain embodiments, R 9 At least one instance of is -NHRa and R a is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 9 is -N(substituted or unsubstituted C 1-6 alkyl) 2 In certain embodiments, at least one instance of R 9 is -N(Me) 2 In certain embodiments, at least one instance of R 9 is -CN. In certain embodiments, at least one instance of R 9 is halogen, substituted or unsubstituted C 1-6 alkyl, or -OR a In certain embodiments, multiple instances of R 9 are C 1-6 alkyl (e.g., two instances of R 9 are methyl). In certain embodiments, multiple instances of R 9 are halogen (e.g., two instances of R 9 are fluoro). In some embodiments, the first instance of R 9 is C 1-6 alkyl and the second instance of R 9 is halogen. In some embodiments, the first instance of R 9 is methyl and the second instance of R 9 is fluoro.

[0213] In certain embodiments, n is 0. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4.

[0214] In certain embodiments, the terminal pyridinyl ring optionally having R 9 is

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0215] In certain embodiments, optionally R 9 having a terminal pyridinyl ring is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0216] In some embodiments, two instances of R 9 are linked to form a 3- to 13-membered heterocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl ring, or 5- to 14-membered heteroaryl ring. In certain embodiments, two instances of R 9 are linked to form a 5-membered heteroaryl ring. In certain embodiments, two instances of R 9 are linked to form a 5-membered heterocyclyl ring. In some embodiments, two instances of R 9 are linked to form pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl, or imidazolinyl. In certain embodiments, two instances of R 9 are linked to form a 5-membered heteroaryl or heterocyclyl ring, and when viewed together with the pyridinyl ring to which the R 9 group is attached, the group is

Chemical formula

[0217] In certain embodiments, R 3 is halo or -COOR a and R 2 is C 1-6Haloalkyl or 3- to 6-membered carbocyclic-C 1-6 alkyl, and R 1 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is halo or -COOR a and R 2 is C 1-6 haloalkyl or 3- to 6-membered carbocyclic-C 1-6 alkyl, and R 1 is substituted or unsubstituted methyl.

[0218] In some embodiments, the compound of formula (I) is of formula (Iz) (wherein each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, and R 3 is methyl, fluoro, or chloro). In certain embodiments, each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, and R 3 is methyl. In some embodiments, each R 9 is independently selected from methyl, fluoro, and chloro, and R 3 is methyl. In certain embodiments, each R 9 is methyl and R 3 is methyl. In some embodiments, each R 9 is methyl. In certain embodiments, R 3 is methyl.

[0219] In some embodiments, the compound of formula (I) is of the formula:

Chemical formula

[0220] In some embodiments, the compound of formula (I) is of formula (Iz) (wherein each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, R 3 is methyl, fluoro, or chloro). In certain embodiments, each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, R 3 is chloro. In some embodiments, each R 9 is independently selected from methyl, fluoro, and chloro, R 3 is chloro. In certain embodiments, each R 9 is methyl, R 3 is chloro. In some embodiments, each R 9 is methyl. In certain embodiments, R 3 is chloro.

[0221] In some embodiments, the compound of formula (I) is of the formula:

Chemical formula

[0222] In some embodiments, the compound of formula (0) is of formula (0a), (0b), or (0c) (wherein each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, or two instances of R 9 are linked to form a ring, and R 3 is methyl, fluoro, or chloro). In certain embodiments, each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, and R 3 is methyl. In some embodiments, each R 9 is independently selected from methyl, fluoro, and chloro, and R 3 is methyl. In certain embodiments, each R 9 is methyl, and R 3 is methyl. In some embodiments, each R 9 is methyl. In certain embodiments, R 3 is methyl.

[0223] In some embodiments, the compound of formula (0) is of formula (0a), (0b), or (0c) (wherein each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, or two instances of R 9 are linked to form a ring, and R 3is methyl, fluoro, or chloro). In certain embodiments, each R 9 is independently selected from methyl, fluoro, chloro, methoxy, and amino, and R 3 is chloro. In some embodiments, each R 9 is independently selected from methyl, fluoro, and chloro, and R 3 is chloro. In certain embodiments, each R 9 is methyl, and R 3 is chloro. In some embodiments, each R 9 is methyl. In certain embodiments, R 3 is chloro.

[0224] In certain embodiments, q is 1 in the compound of formula (0). In certain embodiments, q is 1 in the compound of formula (0a). In certain embodiments, q is 1 in the compound of formula (0b). In certain embodiments, q is 1 in the compound of formula (0c). In some embodiments, in the compounds of formula (0), (0a), (0b), or (0c), q is 1, and R 3 is methyl, chloro or -COOR a .

[0225] In certain embodiments, q is 0 in the compound of formula (0). In certain embodiments, q is 0 in the compound of formula (0a). In certain embodiments, q is 0 in the compound of formula (0b). In certain embodiments, q is 0 in the compound of formula (0c). In some embodiments, in the compounds of formula (0), (0a), (0b), or (0c), q is 0, and R 3 is methyl, chloro or -COOR a .

[0226] In certain embodiments, the compound of formula (0) or (I) is of the formula:

Chemical formula

[0227] In some embodiments, the compound of formula (0) or (I) is of the formula: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] The compound, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0228] 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-677, 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-T2168, 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-T2223, I-T2224, I-T2225, I-T2241, I-T2242, I-T2243, I-T2244, I-T2245, I-T2246, I-T2247, I-T2248, I-T2249, I-T2250, I-T2251, I-T2252, I-T2253, 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.

[0229] 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-T2200, I-T2208, I-T2209, I-T2210, I-T2214, I-T2215, I-T2216, I-T2220, I-T2221, I-T2222, I-T2226, I-T2227, I-T2228, I-T2229, I-T2230, I-T2231, I-T2232, I-T2233, I-T2234, I-T2235, I-T2236, 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.

[0230] In certain embodiments, the compound is selected from the group consisting of I-403, I-404, I-412, I-453, I-468, I-495, I-594, I-595, 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.

[0231] In certain embodiments, the compound is

Chemical Structure

Chemical Structure

Chem.

[0232] In certain embodiments, the compound of formula (0) or (I) is of the formula:

Chem.

Chem.

[0233] Additional compounds Also provided herein is

Chem.

[0234] Also provided herein is

Chem.

[0235] Also, in this specification,

Chemical Formula

[0236] In some embodiments, the compound is selected from the group consisting of I-481, I-597, I-624, I-630, and I-675, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0237] In certain embodiments, the compound is selected from the group consisting of I-331, I-496, I-511, I-450, and I-527, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0238] In certain embodiments, the compound is selected from the group consisting of I-331, I-402, I-597, I-624, and I-630, or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0239] Also, in this specification,

Chemical Formula

[0240] Compositions and Kits The present disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure (e.g., a compound of formula (0) or (I), any compound described herein, or any compound appearing within 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.

[0241] The present disclosure also provides a composition further comprising an additional pharmaceutical agent.

[0242] The compositions described herein can be prepared by any method known in the art. Generally, such methods of preparation include associating a compound of the present disclosure described herein with an excipient, and may include one or more agents or auxiliary components, and, if necessary and / or desired, shaping and / or packaging the product into desired single-dose or multi-dose units. In certain embodiments, the agent is a pharmaceutical agent.

[0243] 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.

[0244] Compositions can be prepared, packaged, and / or sold in large quantities as a single unit dose and / or as multiple single unit doses. A “unit dose” is an individual quantity of a composition containing a predetermined amount of an agent. The amount of the agent is generally equal to the dosage of the agent that is considered to be administered to a subject and / or a convenient fraction of such dosage (e.g., half or one third of such dosage).

[0245] The relative amounts of the compounds, excipients, agents, and / or any additional components of the present disclosure in the compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is administered. The composition can contain from 0.1% to 100% (w / w) of the agent.

[0246] Excipients and auxiliary components used in the manufacture of the provided compositions include diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Also, excipients and auxiliary components such as cocoa butter, PEGylated lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and fragrances may be present in the composition.

[0247] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, corn starch, powdered sugar, and mixtures thereof.

[0248] Exemplary granulating agents and / or dispersants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, crosslinked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked carboxymethyl cellulose (croscarmellose) sodium, methyl cellulose, pregelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, carboxymethyl cellulose calcium, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0249] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, xanthan, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate,Sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, doxart sodium, and / or mixtures thereof may be mentioned.

[0250] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, tragacanth extract, panwa gum, ghatti gum, isapol husk mucilage, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, waxes, water, alcohol, and / or mixtures thereof.

[0251] Non-limiting examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative can be an antioxidant. In other embodiments, the preservative can be a chelating agent.

[0252] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0253] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0254] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0255] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0256] 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.

[0257] Other preservatives include tocopherol, tocopherol acetate, detroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip® , methylparaben, Germall® 115, Germaben® II, Neolone® , Kathon® , and Euxyl® .

[0258] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydrogen phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0259] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0260] Exemplary oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, borrage oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, marula oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange raffia oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, peony oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, celery oil, seabuckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and malt oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0261] In certain embodiments, the composition further comprises an agent that is useful for delivering the agent (e.g., to a subject, tissue, biological sample, or cell). In certain embodiments, the composition is a pharmaceutical composition useful for treating a disease in a subject in need of treatment for the disease. 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 a gastrointestinal stromal tumor. In certain embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In certain embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is pancreatic cancer (e.g., pancreatic carcinoma or pancreatic adenocarcinoma). In certain embodiments, the cancer is prostate cancer (e.g., prostatic adenocarcinoma). In certain embodiments, the cancer is testicular cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In certain embodiments, the cancer is a lymphoma, e.g., non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma). In certain embodiments, the cancer is B-cell lymphoma (e.g., Burkitt B-cell lymphoma, large cell type B-cell lymphoma). In certain embodiments, the cancer is T-cell lymphoma. In certain embodiments, the cancer is Burkitt lymphoma (e.g., Burkitt's B-cell lymphoma). In certain embodiments, the cancer is large cell immunoblastic lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) (also known as acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, acute myelocytic leukemia, and acute non-lymphocytic leukemia), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) (also known as chronic myeloid leukemia).In certain embodiments, the cancer is AML. In some embodiments, the cancer is a subtype of AML selected from undifferentiated acute myeloblastic leukemia (M0), acute myeloblastic leukemia with minimal maturation (M1), acute myeloblastic leukemia with maturation (M2), acute promyelocytic leukemia (APL) (M3), acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with eosinophilia (M4 eos), acute monocytic leukemia (M5), acute erythroleukemia (M6), and acute megakaryoblastic leukemia (M7). In certain embodiments, the cancer is acute monocytic leukemia or acute lymphocytic leukemia (e.g., B-cell acute lymphocytic leukemia). In certain embodiments, the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia). In certain embodiments, the cancer is multiple myeloma (e.g., B-cell myeloma).

[0262] The compositions described herein can be administered in combination with one or more additional agents. In certain embodiments, the agent is an organic molecule. In certain embodiments, the agent is an inorganic molecule. In certain embodiments, the agent is a targeted agent. In certain embodiments, the agent is an isotope-labeled chemical compound. In certain embodiments, the agent is an agent useful for bioprocessing. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutically and / or prophylactically active agent). Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Examples of pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the US Food and Drug Administration for human or veterinary use in accordance with the provisions of the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules conjugated to proteins, glycoproteins, steroids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunological agents, and cells.

[0263] In certain embodiments, the compounds of the disclosure described herein are provided in an effective amount in a composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an amount effective for the treatment of cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting a signaling pathway required for metastasis in a subject or cell.

[0264] In certain embodiments, the effective amount is an amount effective to inhibit 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, the effective amount is an amount effective to inhibit the activity of NAMPT by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In certain embodiments, the effective amount is an amount effective to inhibit the activity of NAMPT within a range (including both endpoints) between a percentage described in this paragraph and another percentage described in this paragraph.

[0265] 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 a starting level which may be a baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, 98% or less, or 99.9% or less. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by an amount within a range (including both end values) between a percentage described in this paragraph and another percentage described in this paragraph.

[0266] In certain embodiments, an effective amount is an amount effective to inhibit NAMPT signaling 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 effective to inhibit NAMPT signaling by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In certain embodiments, an effective amount is an amount effective to inhibit NAMPT signaling by an amount within a range (including both end values) between a percentage described in this paragraph and another percentage described in this paragraph.

[0267] In certain embodiments, the effective amount is an amount effective to increase NAMPT signaling 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 a starting level, which may be a baseline level of enzyme activity. In certain embodiments, the effective amount is an amount effective to increase NAMPT signaling by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, 98% or less, or 99.9% or less. In certain embodiments, the effective amount is an amount effective to increase NAMPT signaling by an amount within a range (including both endpoints) between a percentage described in this paragraph and another percentage described in this paragraph.

[0268] In certain embodiments, the cells are in vitro. In certain embodiments, the cells are ex vivo. In certain embodiments, the cells are in vivo.

[0269] The composition can be formulated into liquid dosage forms for oral and parenteral administration, which include pharmaceutically acceptable emulsifiers, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the drug, the liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. Oral compositions can include, in addition to the inert diluent, adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In certain embodiments of parenteral administration, the compositions described herein are mixed with solubilizing agents such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0270] Injectable preparations, such as aqueous or oleaginous sterile injectable suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent (such as in solution in 1,3 - butanediol). Acceptable vehicles and solvents that can be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally been used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable solutions.

[0271] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0272] To prolong the effect of the compounds of the present disclosure, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. In that case, the absorption rate of the compound depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, to delay the absorption of a parenterally administered drug form, it can be accomplished by dissolving or suspending the compound in an oily vehicle.

[0273] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, with the compositions described herein. Such excipients or carriers are solid at ambient temperature but liquid at body temperature, so they melt within the rectal or vaginal cavity and release the compounds of the present disclosure.

[0274] 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 combined with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) dissolution retardants, such as paraffin, (f) absorption promoters, such as quaternary ammonium compounds, (g) wetting agents, such as cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite clay, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can include buffering agents.

[0275] Solid compositions of the same type can be used as fillers within soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and also high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. These dosage forms can optionally include opacifying agents and can also be compositions that release the compounds of the present disclosure in a delayed manner, either limitedly or preferentially, in certain parts of the intestinal tract. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of the same type can be used as fillers within soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and also high molecular weight polyethylene glycol.

[0276] The compounds of the present disclosure can take a microencapsulated form having one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In the case of such solid dosage forms, the compounds of the present disclosure can be mixed with at least one inert diluent, for example, sucrose, lactose, or starch. Such dosage forms may, as is customary, contain additional substances other than the inert diluent, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can contain buffering agents. These dosage forms can optionally contain opacifying agents and can also optionally be compositions that release the compounds of the present disclosure in a delayed manner, limitedly or preferentially, in a particular part of the intestinal tract. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0277] Dosage forms for topical and / or transdermal administration of the compositions described herein can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the compounds of the present disclosure are mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffering agents as required.

[0278] Suitable devices for use in delivering the intradermal compositions described herein include short needle devices. The intradermal compositions can be delivered by a device that limits the effective penetration length of the needle into the dermis. Alternatively or additionally, a conventional syringe may be used for intradermal administration by the classical Mantoux method. Jet injection devices are suitable for delivering liquid formulations to the dermis via a liquid jet syringe and / or via a needle that provides a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder / particle delivery devices that use compressed gas to accelerate a polymer in powder form through the outer layer of the skin to the dermis are suitable.

[0279] Formulations suitable for topical administration include liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes, and / or solutions, and / or suspensions. Topically administrable formulations can contain, for example, from about 1% to about 100% (w / w) of a compound of the present disclosure, although the concentration of the compound of the present disclosure can be on the order of the solubility limit of the compound of the present disclosure in the solvent. Formulations for topical administration can further contain one or more of the additional components described herein.

[0280] The compositions described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the oral vestibule. Such formulations can contain dry particles containing a compound of the present disclosure. Such compositions can conveniently be in the form of a dry powder and administered using a device having a dry powder reservoir that can direct a stream of propellant to disperse the powder and / or using an auto-propelled solvent / powder dispensing container (e.g., a device containing a drug dissolved and / or suspended in a low-boiling propellant in a sealed container). The dry powder composition can contain a solid fine powder diluent such as sugar and is conveniently provided in unit dosage form.

[0281] Low-boiling propellants generally include liquid propellants having a boiling point of less than 65°F at atmospheric pressure. Generally, the propellant constitutes 50 to 99.9% (w / w) of the composition, and the compounds of the present disclosure can constitute 0.1 to 100% (w / w) of the composition. The propellant can further include additional components such as liquid nonionic and / or solid anionic surfactants and / or solid diluents.

[0282] The compositions described herein formulated for pulmonary delivery can deliver the compounds of the present disclosure in the form of droplets of a liquid and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcohol solutions and / or suspensions (optionally sterilized) containing the compounds of the present disclosure and can be conveniently administered using any spray and / or atomization device. Such formulations can further include one or more additional components including flavoring agents (e.g., sodium saccharin), volatile oils, buffering agents, surfactants, and / or preservatives (e.g., methyl hydroxybenzoate).

[0283] The formulations described herein as useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the compounds of the present disclosure. Such a formulation is administered by rapid inhalation through the nasal cavity from a powder container held near the nostrils.

[0284] Formulations for nasal administration can, for example, contain from about 0.1% (w / w) to 100% (w / w) of the compounds of the present disclosure and can contain one or more of the additional ingredients described herein. The pharmaceutical compositions described herein can be prepared, packaged, and / or sold as formulations for buccal administration. Such formulations can, for example, take the form of tablets and / or lozenges prepared using conventional methods, contain, for example, 0.1 to 20% (w / w) of the drug, and the remainder can contain a composition that is orally soluble and / or decomposable and, optionally, one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may contain powders and / or aerosolized and / or micronized solutions and / or suspensions containing the compounds of the present disclosure.

[0285] The compositions described herein can be prepared, packaged, and / or sold as formulations for ophthalmic administration. Such formulations can, for example, take the form of eye drops containing a 0.1 to 100% (w / w) solution and / or suspension of the compounds of the present disclosure in an aqueous or oily liquid carrier or excipient. Such droplets can further contain a buffering agent, salts, and / or one or more of the additional ingredients described herein. Other useful ophthalmically administrable formulations include formulations containing the compounds of the present disclosure in microcrystalline form and / or liposomal preparations. Ear drops and / or eye drops are also contemplated as being within the scope of the present disclosure.

[0286] The description of the compositions provided herein is primarily directed to compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are also widely suitable for administration to all kinds of animals. It is well understood that modifications can be made to compositions suitable for administration to humans to render them suitable for administration to various animals, and a veterinary pharmacologist of ordinary skill can design and / or carry out such modifications using routine experimentation.

[0287] The compositions described herein are typically formulated in dosage unit form for ease of administration and to provide a uniform dosage. However, it should be understood that the total daily usage of the compositions described herein will be decided within the scope of a physician's sound medical judgment. It should be appreciated that the specific therapeutically effective dosage levels for any particular subject or organism will depend upon a variety of factors including the cancer to be treated and its severity, the activity of the specific compounds of the present disclosure being used, the specific composition being used, the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion of the specific compounds of the present disclosure being used, the duration of the treatment, drugs used in combination with or contemporaneously with the specific compounds of the present disclosure being used, as well as other factors well known in the medical arts.

[0288] The compositions provided herein can be administered by any route including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (by powder, ointment, cream, and / or droplet), transmucosal, nasal, buccal, sublingual, by endotracheal instillation, bronchial instillation, and / or inhalation, and / or by oral spray, nasal spray, and / or aerosol. Specifically, the contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and / or lymphatic supply, and / or direct administration to the site of affliction. Generally, the most appropriate route of administration will depend upon a variety of factors including the nature of the compounds of the present disclosure (e.g., stability within the gastrointestinal tract environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compositions described herein are suitable for topical administration to the eyes of a subject.

[0289] In some embodiments, administration of any of the compositions described herein is performed at least 1 hour prior to treatment with another cancer therapy.

[0290] The composition can be administered in combination with additional agents to improve its bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell, in order to improve its activity (e.g., efficacy and / or effectiveness) in treating a disease or disorder (e.g., cancer) in a subject in need thereof and / or inhibiting a signaling pathway in a subject or cell. It will also be understood that the therapies used may achieve the desired effect for the same disease and / or may achieve different effects. In certain embodiments, the compositions described herein that include the compounds and agents of the present disclosure exhibit a synergistic effect not present in compositions that include only one of the compounds or agents of the present disclosure but not both.

[0291] The composition, unlike the composition itself, can be administered simultaneously with, before, or after one or more additional agents that may be useful, for example, as combination therapies. Each additional pharmaceutical agent can be administered at the dosage and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents can be administered together with each other and / or with the compounds of the present disclosure or the compositions described herein, either as a single dose or at different doses separately. The specific combinations used in the regimen take into account the compatibility of the compounds of the present disclosure described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the combined additional pharmaceutical agent(s) will be used at levels that do not exceed those when they are used individually. In some embodiments, the levels used in combination are lower than those used individually.

[0292] Additional pharmaceutical agents include anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergy agents, contraceptives, and analgesics. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is a chemotherapeutic agent. In certain embodiments, the additional pharmaceutical agent is a differentiating agent (e.g., retinoids, all-trans retinoic acid (ATRA), vitamin D, peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibitors). In certain embodiments, the additional pharmaceutical agent is an antiviral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is an epigenetic or transcriptional modulator (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), anti-mitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), inhibitors of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation, selected from the group consisting of. In certain embodiments, the compounds or pharmaceutical compositions of the present disclosure described herein can be administered in combination with anti-cancer therapies (including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy). In some embodiments, the subject is administered one or more additional agents (e.g., one or more additional cancer therapies) simultaneously with, prior to, or after the administration of the compounds or pharmaceutical compositions of the present disclosure. In some embodiments, the one or more additional cancer therapies include immunotherapy. Generally, immunotherapy (also called biological therapy) is a type of cancer treatment that boosts the subject's natural defenses to treat cancer.In certain embodiments, the immunotherapy utilizes a compound biologically produced by the subject. In certain embodiments, the immunotherapy utilizes a compound not biologically produced by the subject. In certain embodiments, the immunotherapy utilizes cells from the subject. In certain embodiments, the immunotherapy utilizes cells not from the subject. In certain embodiments, the immunotherapy utilizes a compound biologically produced by an organism other than the subject. In certain embodiments, the immunotherapy utilizes cells biologically produced by an organism other than the subject. In certain embodiments, the immunotherapy comprises at least one chemical modification to a compound or cell from the subject. In certain embodiments, the immunotherapy comprises at least one chemical modification to a compound or cell not from the subject.

[0293] In some embodiments, the additional pharmaceutical agent is selected from the group consisting of nicotinic acid, ibrutinib, idelalisib, lenalidomide, a BCL-2 inhibitor, venetoclax, an FLT3 inhibitor, an IDH1 / 2 inhibitor, glasdegib, azacitidine, cyclophosphamide, decitabine, enasidenib, elastin, gilteritinib, idasanutlin,ivosidenib, ixazomib, midostaurin, navitoclax, onbasertib, cyclosporin A, a PARP inhibitor, 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-nitrosoguanidinium (MNNG), melphalan, verapamil, etoposide, cisplatin, anti-PD1, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), EX527, silmitasertib, cambinol, vorinostat, valproic acid, butyrate, JPH203, L-asparaginase, bortezomib, rituximab, PGP-4008, β-lapachone, β-methylene adenosine 5′-diphosphate (APCP), gemcitabine, Lu-DOTATATE, fluorouracil (5-FU), pemetrexed, onbasertib, sedaxridine, galinpepimut-S, sedaxridine / decitabine, cytarabine / daunorubicin, uprolceran, gedatolisib, debimistat, glasdegib, idasanutlin, ganetespib, tipifarnib, midostaurin, pevonedistat, ivosidenib, clenolanib, quizartinib, platosetinib, guadecitabine, DFP10917, boscaloxine, rexlemestrocel-L mesoblast, treosulfan, sapacitabine, enasidenib, volasertib, and temozolomide.

[0294] In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, APG2575, BCL201, BGB-11417, LP-108, or S65487.

[0295] In some embodiments, the additional pharmaceutical agent is a toll-like receptor 4 (TLR 4 ) 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, pinobanksin, resatorvid, naloxone, naltrexone, LPS-RS, propentofylline, tapentadol, palmitoylethanolamide.

[0296] In some embodiments, the additional pharmaceutical agent is a sirtuin inhibitor. In some embodiments, the sirtuin inhibitor is nicotinamide, a nicotinamide derivative, benzamide, a 3′-phenethyloxy-2-anilinobenzamide analog, AK7, 1,4-dihydropyridine, cambinol, EX-527, AGK2, 3′-(3-fluoro-phenethyloxy)-2-anilinobenzamide, SirReal2, UBCS0137, ELT-11c, or a thioacyl lysine-containing compound.

[0297] In some embodiments, the additional pharmaceutical agent is a selected ibrutinib or idelalisib.

[0298] In some embodiments, the additional pharmaceutical agent is lenalidomide.

[0299] In some embodiments, the additional pharmaceutical agent is selected from the group consisting of venetoclax, an FLT3 inhibitor, an IDH1 / 2 inhibitor, glasdegib, azacitidine, cyclophosphamide, decitabine, enasidenib, elastin, gilteritinib, idasanutlin, ivosidenib, ixazomib, midostaurin, navitoclax, onbasertib, pacritinib, PMA, luxolitinib, S055746, selinexor (KPT-330), trametinib, tretinoin, etoposide, and napabucasin.

[0300] In some embodiments, the additional pharmaceutical agent is P7C3.

[0301] 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.

[0302] In some embodiments, the IDH1 / 2 inhibitor is selected from the group consisting ofivosidenib and enasidenib.

[0303] In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, 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, CEP9722, CEP-8983, E7016, iniparib, and 3-aminobenzamide.

[0304] In certain embodiments, the additional pharmaceutical agent is an HDAC inhibitor.

[0305] In certain embodiments, the additional pharmaceutical agent is nicotinic acid.

[0306] In some embodiments, the additional pharmaceutical 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, erlotinib, 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.

[0307] In some embodiments, the additional pharmaceutical agent is selected from the group consisting of topoisomerase II inhibitors (e.g., etoposide, doxorubicin), topoisomerase I inhibitors (e.g., irinotecan, CPT - 11, camptothecin, topotecan), tubulin - interacting agents (e.g., paclitaxel, docetaxel, epothilone), thymidylate synthase inhibitors (e.g., 5 - fluorouracil or 5 - FU), alkylating agents (e.g., temozolomide, cyclophosphamide), farnesyl protein transferase inhibitors (e.g., lonafarnib, L778,123, BMS214662), signal transduction inhibitors (e.g., gefitinib), antibodies against EGFR (e.g., cetuximab), cytarabine, aromatase inhibitors (e.g., exemestane, anastrozole, letrozole).

[0308] In some embodiments, the additional pharmaceutical agent is cytarabine.

[0309] In some embodiments, the additional pharmaceutical agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 1,4,6-androstatriene-3,17-dione, or 4-androstene-3,6,17-trione.

[0310] In certain embodiments, the additional pharmaceutical agent is an anti-cancer or anti-neoplastic agent. In some embodiments, the additional pharmaceutical agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlorambucil, hexamethylmelamine, zevalin, trisenox, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mitomycin, ifosfamide, pipobroman, triethylenemelamine, methyltestosterone, amsacrine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, drostanolone propionate, triethylenethiophosphoramide, streptozocin, 6-mercaptopurine, deoxycoformycin, mitomycin-C, 17a-ethinyl estradiol, diethylstilbestrol, testolactone, megestrol acetate, methylprednisolone, chlorotrianisene, hydroxyprogesterone, medroxyprogesterone acetate, tamoxifen, nafoxidine, anastrozole, letrozole, leloxafum, droloxafum, porfimer, thiotepa, altretamine, letrozole, fulvestrant, exemestane, a 5-HT3 receptor inhibitor (e.g., dolasetron, granisetron, ondansetron) or dexamethasone.

[0311] In some embodiments, the additional pharmaceutical agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlorambucil, hexamethylmelamine, zevalin, trisenox, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mitomycin, ifosfamide, pipobroman, triethylenemelamine, methyltestosterone, amsacrine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, drostanolone propionate, triethylenethiophosphoramide, streptozocin, 6-mercaptopurine, deoxycoformycin, mitomycin-C, 17a-ethinylestradiol, diethylstilbestrol, testolactone, megestrol acetate, methylprednisolone, chlorotrianisene, hydroxyprogesterone, medroxyprogesterone acetate, tamoxifen, nafoxidine, anastrozole, letrozole, leloxafum, droloxafum, porfimer, thiotepa, altretamine, letrozole, fulvestrant, exemestane, or dexamethasone and a 5-HT3 receptor inhibitor (e.g., dolasetron, granisetron, ondansetron).

[0312] In some embodiments, the additional pharmaceutical agent is cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlorambucil, hexamethylmelamine, zevalin, trisenox, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mitomycin, ifosfamide, pipobroman, triethylenemelamine, methyltestosterone, amsacrine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, drostanolone propionate, triethylenethiophosphoramide, streptozocin, 6-mercaptopurine, deoxycoformycin, mitomycin-C, 17a-ethinyl estradiol, diethylstilbestrol, testolactone, megestrol acetate, methylprednisolone, chlorotrianisene, hydroxyprogesterone, medroxyprogesterone acetate, tamoxifen, nafoxidine, anastrozole, letrozole, leloxafum, droloxafum, porfimer, thiotepa, altretamine, letrozole, fulvestrant, exemestane, or a 5-HT3 receptor inhibitor (e.g., dolasetron, granisetron, ondansetron) and dexamethasone.

[0313] In some embodiments, the additional pharmaceutical agent is cytarabine. In some embodiments, the additional pharmaceutical agent is doxorubicin. In some embodiments, the additional pharmaceutical agent is cyclophosphamide. In some embodiments, the additional pharmaceutical agent is FX-11. In certain embodiments, the additional pharmaceutical agent is uracil mustard. In some embodiments, the additional pharmaceutical agent is chlorambucil. In some embodiments, the additional pharmaceutical agent is hexamethylmelamine. In some embodiments, the additional pharmaceutical agent is zevalin. In some embodiments, the additional pharmaceutical agent is trisenox. In some embodiments, the additional pharmaceutical agent is xeloda. In some embodiments, the additional pharmaceutical agent is aminoglutethimide. In some embodiments, the additional pharmaceutical agent is 6-thioguanine. In some embodiments, the additional pharmaceutical agent is pentostatin. In some embodiments, the additional pharmaceutical agent is mitomycin. In some embodiments, the additional pharmaceutical agent is ifosfamide. In some embodiments, the additional pharmaceutical agent is pipobroman. In some embodiments, the additional pharmaceutical agent is triethylenemelamine. In some embodiments, the additional pharmaceutical agent is methyltestosterone. In some embodiments, the additional pharmaceutical agent is amsacrine. In some embodiments, the additional pharmaceutical agent is mitotane. In some embodiments, the additional pharmaceutical agent is levamisole. In some embodiments, the additional pharmaceutical agent is triamcinolone. In some embodiments, the additional pharmaceutical agent is testosterone. In some embodiments, the additional pharmaceutical agent is fluoxymesterone. In some embodiments, the additional pharmaceutical agent is drostanolone propionate. In some embodiments, the additional pharmaceutical agent is triethylenethiophosphoramide. In some embodiments, the additional pharmaceutical agent is streptozocin. In some embodiments, the additional pharmaceutical agent is 6-mercaptopurine.In some embodiments, the additional pharmaceutical agent is deoxycholormycin. In some embodiments, the additional pharmaceutical agent is mitomycin-C. In some embodiments, the additional pharmaceutical agent is 17a-ethinyl estradiol. In some embodiments, the additional pharmaceutical agent is diethylstilbestrol. In some embodiments, the additional pharmaceutical agent is testolactone. In some embodiments, the additional pharmaceutical agent is megestrol acetate. In some embodiments, the additional pharmaceutical agent is methylprednisolone. In some embodiments, the additional pharmaceutical agent is chlorotrianisene. In some embodiments, the additional pharmaceutical agent is hydroxyprogesterone. In some embodiments, the additional pharmaceutical agent is medroxyprogesterone acetate. In some embodiments, the additional pharmaceutical agent is tamoxifen. In some embodiments, the additional pharmaceutical agent is nafarelin. In some embodiments, the additional pharmaceutical agent is anastrozole. In some embodiments, the additional pharmaceutical agent is letrozole. In some embodiments, the additional pharmaceutical agent is leuprorelin. In some embodiments, the additional pharmaceutical agent is goserelin. In some embodiments, the additional pharmaceutical agent is porfimer. In some embodiments, the additional pharmaceutical agent is thiotepa. In some embodiments, the additional pharmaceutical agent is altretamine. In some embodiments, the additional pharmaceutical agent is letrozole. In some embodiments, the additional pharmaceutical agent is fulvestrant. In some embodiments, the additional pharmaceutical agent is exemestane. In some embodiments, the additional pharmaceutical agent is a 5-HT3 receptor inhibitor. In some embodiments, the additional pharmaceutical agent is dolasetron. In some embodiments, the additional pharmaceutical agent is granisetron. In some embodiments, the additional pharmaceutical agent is ondansetron. In some embodiments, the additional pharmaceutical agent is dexamethasone.

[0314] In some embodiments, the additional pharmaceutical agent is for treating small cell lung cancer. In some embodiments, the additional pharmaceutical agent is everolimus, atezolizumab, doxorubicin, doxorubicin hydrochloride, durvalumab, etoposide phosphate, etoposide, topotecan, topotecan hydrochloride, pembrolizumab, lurbinectedin, methotrexate, methotrexate sodium, or nivolumab.

[0315] In some embodiments, the additional pharmaceutical agent is ibrutinib. In some embodiments, the additional pharmaceutical agent is idelalisib. In some embodiments, the additional pharmaceutical agent is lenalidomide. In some embodiments, the additional pharmaceutical agent is venetoclax. In some embodiments, the additional pharmaceutical agent is an FLT3 inhibitor. In some embodiments, the additional pharmaceutical agent is an IDH1 / 2 inhibitor. In some embodiments, the additional pharmaceutical agent is glasdegib. In some embodiments, the additional pharmaceutical agent is azacitidine. In some embodiments, the additional pharmaceutical agent is cyclophosphamide. In some embodiments, the additional pharmaceutical agent is decitabine. In some embodiments, the additional pharmaceutical agent is enasidenib. In some embodiments, the additional pharmaceutical agent is elastin. In some embodiments, the additional pharmaceutical agent is gilteritinib. In some embodiments, the additional pharmaceutical agent is idasanutlin. In some embodiments, the additional pharmaceutical agent isivosidenib. In some embodiments, the additional pharmaceutical agent is ixazomib. In some embodiments, the additional pharmaceutical agent is midostaurin. In some embodiments, the additional pharmaceutical agent is navitoclax. In some embodiments, the additional pharmaceutical agent is onbasertib. In some embodiments, the additional pharmaceutical agent is cyclosporine A. In some embodiments, the additional pharmaceutical agent is pacritinib. In some embodiments, the additional pharmaceutical agent is phorbol 12-myristate 13-acetate (PMA). In some embodiments, the additional pharmaceutical agent is ruxolitinib. In some embodiments, the additional pharmaceutical agent is S055746. In some embodiments, the additional pharmaceutical agent is selinexor (KPT-330). In some embodiments, the additional pharmaceutical agent is trametinib. In some embodiments, the additional pharmaceutical agent is tretinoin. In some embodiments, the additional pharmaceutical agent is etoposide. In some embodiments, the additional pharmaceutical agent is P7C3.In some embodiments, the additional pharmaceutical agent is napabucasin. In some embodiments, the additional pharmaceutical agent is olaparib. In some embodiments, the additional pharmaceutical agent is AraC. In some embodiments, the additional pharmaceutical agent is daunorubicin. In some embodiments, the additional pharmaceutical agent is 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG). In some embodiments, the additional pharmaceutical agent is melphalan. In some embodiments, the additional pharmaceutical agent is verapamil. In some embodiments, the additional pharmaceutical agent is etoposide. In some embodiments, the additional pharmaceutical agent is cisplatin. In some embodiments, the additional pharmaceutical agent is anti-PD1. In some embodiments, the additional pharmaceutical agent is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In some embodiments, the additional pharmaceutical agent is EX527. In some embodiments, the additional pharmaceutical agent is silmitasertib. In some embodiments, the additional pharmaceutical agent is silmitasertib. In some embodiments, the additional pharmaceutical agent is vorinostat. In some embodiments, the additional pharmaceutical agent is valproic acid. In some embodiments, the additional pharmaceutical agent is butyrate. In some embodiments, the additional pharmaceutical agent is JPH203. In some embodiments, the additional pharmaceutical agent is L-asparaginase. In some embodiments, the additional pharmaceutical agent is bortezomib. In some embodiments, the additional pharmaceutical agent is rituximab. In some embodiments, the additional pharmaceutical agent is cyclosporine-A. In some embodiments, the additional pharmaceutical agent is PGP-4008. In some embodiments, the additional pharmaceutical agent is β-lapachone. In some embodiments, the additional pharmaceutical agent is β-methylene adenosine 5′-diphosphate (APCP). In some embodiments, the additional pharmaceutical agent is gemcitabine. In some embodiments, the additional pharmaceutical agent is Lu-DOTATATE.In some embodiments, the additional pharmaceutical agent is fluorouracil (5-FU). In some embodiments, the additional pharmaceutical agent is pemetrexed. In some embodiments, the additional pharmaceutical agent is temozolomide. In some embodiments, the additional pharmaceutical agent is onvansertib. In some embodiments, the additional pharmaceutical agent is sedanserin. In some embodiments, the additional pharmaceutical agent is galinpepimut-S. In some embodiments, the additional pharmaceutical agent is sedanserin / decitabine. In some embodiments, the additional pharmaceutical agent is cytarabine / daunorubicin. In some embodiments, the additional pharmaceutical agent is uproleselan. In some embodiments, the additional pharmaceutical agent is gedatolisib. In some embodiments, the additional pharmaceutical agent is debio 10917. In some embodiments, the additional pharmaceutical agent is glasdegib. In some embodiments, the additional pharmaceutical agent is idasanutlin. In some embodiments, the additional pharmaceutical agent is ganetespib. In some embodiments, the additional pharmaceutical agent is tipifarnib. In some embodiments, the additional pharmaceutical agent is midostaurin. In some embodiments, the additional pharmaceutical agent is pebonexstat. In some embodiments, the additional pharmaceutical agent is ivosidenib. In some embodiments, the additional pharmaceutical agent is clenolanib. In some embodiments, the additional pharmaceutical agent is quizartinib. In some embodiments, the additional pharmaceutical agent is plinabulin. In some embodiments, the additional pharmaceutical agent is guadecitabine. In some embodiments, the additional pharmaceutical agent is DFP10917. In some embodiments, the additional pharmaceutical agent is boscaloxine. In some embodiments, the additional pharmaceutical agent is rexlemestrocel-L-mesoblast. In some embodiments, the additional pharmaceutical agent is treosulfan. In some embodiments, the additional pharmaceutical agent is sapacitabine. In some embodiments, the additional pharmaceutical agent is enasidenib.In some embodiments, the additional pharmaceutical agent is volasertib.

[0316] In some embodiments, immunotherapy may involve one or more of the following steps: preventing or inhibiting the growth of cancer cells; preventing the cancer from spreading to other parts of the body; and improving the ability and activity of the immune system to kill cancer cells. Non-limiting examples of immunotherapy include monoclonal antibodies, checkpoint inhibitors, non-specific immunotherapy, oncolytic virus therapy, T cell therapy, and cancer vaccines.

[0317] In certain embodiments, immunotherapy utilizes monoclonal antibodies. In some embodiments, the monoclonal antibodies target (bind to) and / or block abnormal proteins on cancer cells.

[0318] In certain embodiments, immunotherapy includes an immunotherapy strategy for leukemia. In some embodiments, immunotherapy includes vaccination with leukemia-associated antigens. In certain embodiments, immunotherapy includes adoptive transfer of allogeneic natural killer cells.

[0319] In certain embodiments, the immunotherapy utilizes checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitor is a monoclonal antibody. Immune checkpoints are regulators of immune activation by maintaining immune homeostasis and preventing autoimmunity. In the case of cancer cells, the immune checkpoint mechanism is often activated to suppress the anti-cancer immune response during the development stage. In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-L1 (programmed death ligand 1). In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (cytotoxic T lymphocyte-associated protein 4). Examples of immune checkpoint inhibitors include, but are not limited to, ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0320] In certain embodiments, the immunotherapy is non-specific immunotherapy (e.g., interferon or interleukin). In certain embodiments, the immunotherapy is oncolytic virus therapy.

[0321] In certain embodiments, the immunotherapy is T cell therapy. In some embodiments, the T cell therapy is chimeric antigen receptor (CAR) T cell therapy.

[0322] In certain embodiments, the immunotherapy is an anti-cancer vaccine.

[0323] Anticancer agents include biotherapy anticancer agents and chemotherapeutic agents. Exemplary biotherapy anticancer agents include, but are not limited to, interferon, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulants, and / or immunomodulators (e.g., IL-1, 2, 4, 6, or 12), immunocyte growth factors (e.g., GM-CSF), and antibodies (e.g., 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), LHRH agonists (e.g., goserelin and leuprorelin), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents), docosahexaenoic acid-conjugated paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrugs (TAP), ANG1005 (Angiopep-2 conjugated to three paclitaxel molecules), paclitaxel-EC-1 (paclitaxel conjugated to erbB2 recognition peptide EC-1),Paclitaxel albumin-stabilized nanoparticle formulations, and glucose-conjugated paclitaxel, such as, 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllin (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimethoprim, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, thiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB1089, CB1093, and KH1060), prenylation inhibitors (e.g., lovastatin), dopamine-acting neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN (trademark), AZD2171), dasatinib (SPRYCEL (registered trademark), BMS-354825), erlotinib (TARCEVA (registered trademark)), gefitinib (IRESSA (registered trademark)), imatinib (Gleevec (registered trademark), CGP57148B, STI-571), lapatinib (TYKERB (registered trademark), TYVERB (registered trademark)), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA (registered trademark)), semaxinib (semaxinib, SU5416), sunitinib (SUTENT (registered trademark), SU11248), toceranib (PALLADIA (registered trademark)), vandetanib (ZACTIMA (registered trademark), ZD6474), batatinib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN (registered trademark)), bevacizumab (AVASTIN (registered trademark)), rituximab (RITUXAN (registered trademark)), cetuximab (ERBITUX (registered trademark)), panitumumab (VECTIBIX (registered trademark)), ranibizumab (Lucentis (registered trademark)), nilotinib (TASIGNA (registered trademark)), sorafenib (NEXAVAR (registered trademark)), everolimus (AFINITOR (registered trademark)), alemtuzumab (CAMPATH (registered trademark)), gemtuzumab ozogamicin (MYLOTARG (registered trademark)), temsirolimus (TORISEL (registered trademark)), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (TOVOK (trademark)), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF (registered trademark)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tibiozaniib (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 Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, calicheamicin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, calicheamicin, aminopterin, and hexamethylmelamine are included.

[0324] 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 more than about 10,000 parts of water to dissolve one part of the compound of the present disclosure.

[0325] In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 1% to about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of the composition comprising the compound of the present disclosure is less than about 50%, e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 25%, or from about 5% to about 20%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 5% to 90%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 5% to about 75%. In some embodiments, the composition comprising the compound of the present disclosure is from about 5% to about 50%. In some embodiments, the percentage of the composition comprising the compound of the present disclosure is from about 10% to about 25%.

[0326] In some embodiments, the total amount of the compound of the present disclosure present in the composition is greater than about 1% of the total size or weight of the composition (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30%, or more). In some embodiments, the total amount of the compound of the present disclosure present in the composition is greater than about 10% of the total size or weight of the composition (e.g., about 12%, about 15%, about 20%, about 25%, about 30%, or more).

[0327] In some embodiments, the compounds of the present disclosure are incorporated into a composition at a dosage that is less than the dosage or amount of the compound in its free form to achieve the desired effect (e.g., the desired therapeutic effect). In certain embodiments, the composition increases the amount of the compound of the present disclosure delivered to the tissue or cells to which the compound of the present disclosure needs to be delivered, as compared to the free compound, and reduces the amount of the compound of the present disclosure exposed to non-target tissues or cells, as compared to the free compound.

[0328] In another aspect, there is provided a kit comprising a compound of the present disclosure, or a pharmaceutical composition described herein, and instructions for using the compound of the present disclosure or the pharmaceutical composition of the present disclosure.

[0329] In some embodiments, the kit further comprises additional pharmaceutical agents described herein. In certain embodiments, the kit further comprises instructions regarding the order of use of the compound or composition of the present disclosure and the additional pharmaceutical agent. In some embodiments, the instructions specify that the compound or composition of the present disclosure is administered before the additional pharmaceutical agent. In some embodiments, the instructions specify that the compound or composition of the present disclosure is administered simultaneously with the additional pharmaceutical agent. In some embodiments, the instructions specify that the compound or composition of the present disclosure is administered after the additional pharmaceutical agent.

[0330] In certain embodiments, the instructions for the kit may also include information required by a regulatory authority such as the US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit and the instructions result in the delivery of the compound of the present disclosure. In certain embodiments, the kit and the instructions result in the delivery of the composition. In certain embodiments, the kit and the instructions result in the treatment of cancer in a subject in need of cancer treatment. In certain embodiments, the kit and the instructions result in the inhibition of a signaling pathway in a subject or cell.

[0331] Methods of Treatment and Prevention and Uses Also provided herein are methods of using the compounds or compositions described herein for treating or preventing any of the diseases described herein, and uses thereof.

[0332] 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof (wherein the variables described in formula (0) or (I) are as described herein).

[0333] In certain embodiments, the cancer comprises cancer stem cells. In certain embodiments, the cancer is associated with or related to cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, 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 is in need of regenerative medicine or therapy.

[0334] 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, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0335] In certain aspects, the present disclosure provides methods and uses comprising killing a cell with an effective amount of a compound of formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0336] In certain embodiments, the present disclosure provides methods and uses that include contacting 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, with a cell, tissue, or biological sample to 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.

[0337] In certain embodiments, the present disclosure provides a method of modulating NAMPT in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0338] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by modulating NAMPT 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0339] In certain embodiments, the present disclosure provides a method of inhibiting NAMPT in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0340] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting NAMPT 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.

[0341] In certain embodiments, the present disclosure provides a method of modulating inflammatory activity 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.

[0342] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0343] In certain embodiments, the present disclosure provides a method of reducing inflammatory activity 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.

[0344] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0345] In certain embodiments, the present disclosure provides a method of modulating cellular metabolism in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0346] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by modulating cellular metabolism in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0347] In certain embodiments, the present disclosure provides a method of decreasing cellular metabolism in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0348] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by decreasing cellular metabolism in the subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0349] In certain embodiments, the present disclosure provides a method of modulating cellular metabolism activity or status in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0350] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by modulating a cellular metabolic activity or state 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.

[0351] In certain embodiments, the present disclosure provides a method of reducing a 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.

[0352] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by reducing a cellular metabolic activity or state 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.

[0353] In certain embodiments, the present disclosure provides a method of reducing cell proliferation 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.

[0354] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0355] In certain embodiments, the present disclosure provides a method of reducing inflammatory cell infiltration 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.

[0356] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0357] In certain embodiments, the present disclosure provides a method of modulating 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.

[0358] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0359] 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.

[0360] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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.

[0361]

[0360] In certain embodiments, the present disclosure provides a method of modulating the production of nicotinamide mononucleotide 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.

[0362] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by modulating 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.

[0363] In certain embodiments, the present disclosure provides a method of inhibiting the production of nicotinamide mononucleotide 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.

[0364] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0365] In certain embodiments, the present disclosure provides a method of modulating the NAMPT pathway in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0366] In certain embodiments, the present disclosure provides a method of inhibiting the NAMPT pathway in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0367] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by modulating 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0368] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0369] In certain embodiments, the present disclosure provides a method of modulating NAMPT signaling in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0370] In certain embodiments, the present disclosure provides a method of treating a disease or disorder 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0371] In certain embodiments, the present disclosure provides a method of decreasing NAMPT signaling in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0372] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject by decreasing 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0373] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition disclosed herein. In some embodiments, the disease or disorder is associated with changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling. In some embodiments, the disease or disorder is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling.

[0374] In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or disorder 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, cocrystal, 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 disorder described herein in a subject in need thereof, comprising administering to the subject a composition comprising 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. In some embodiments, the present disclosure provides methods and uses for treating or preventing a disease or disorder described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in the additional compounds section, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, 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 disorder described herein in a subject in need thereof, comprising administering to the subject a composition comprising a therapeutically effective amount of a compound described in the additional compounds section, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, 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 disorder 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, cocrystal, 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 disorder described herein in a subject in need thereof, the methods and uses comprising administering to the subject a composition comprising 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 disease or disorder is related to changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling. In some embodiments, the disease or disorder is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling.

[0375] In some embodiments, the disease or disorder is related to changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling, and the disease or disorder is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), arthritis, rheumatoid arthritis, acute lung injury, pneumonia, pneumonitis, severe acute distress syndrome, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin damage, autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, infection-related inflammation, vascular inflammation, atherosclerotic thrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherosclerotic inflammatory disease, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertensive nephropathy, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorder, COVID-19, lung inflammation, coronavirus infection, and tumor.

[0376] In some embodiments, the disease or disorder is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling, and the disease or disorder is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute 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 disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin damage, autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, atherosclerotic thrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherosclerotic inflammatory disease, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertensive nephropathy, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorder, COVID-19, lung inflammation, coronavirus infection, and tumor.

[0377] In some embodiments, the disease or disorder is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute 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 disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin damage, autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, atherosclerotic thrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherosclerotic inflammatory disease, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertensive nephropathy, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorder, COVID-19, lung inflammation, coronavirus infection, and tumor.

[0378] 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 disorder, asthma, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin damage, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertension nephropathy, sepsis, septic shock, intrauterine infection, neurodegenerative disorder, and tumor.

[0379] ...

Claims

1. The compound of formula (0): 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, (wherein R １ is a substituted or unsubstituted C １－１２ alkyl or a 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 carbocyclyl-C １－１２ -alkyl, or a nitrogen protecting group, R ２ When R is an unsubstituted methyl, １ R is not an unsubstituted ethyl, 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 and R ａ In each case, independently, is hydrogen, substituted or unsubstituted C １－６ alkyl, an oxygen protecting group when bonded to an oxygen atom, or a nitrogen protecting group when bonded to a nitrogen atom, R ４ In each case, 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 and is R ６ is hydrogen, substituted or unsubstituted C １－６ alkyl, or a nitrogen protecting group, R ８ In each case, independently, is hydrogen, halogen, or substituted or unsubstituted C １－６ alkyl, R ９ Each instance 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 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; Each case of the nitrogen protecting group is independently formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyl-oxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrosinamide, N-acetylmethionine, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamide) ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpcc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acetyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Troc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, 2,4,6-trimethylbenzylcarbamate, 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, phenacylsulfonamide, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberlylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, or 3-nitropyridinesulfenamide (Npys), Each case of the oxygen protecting group is, independently, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyl oxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberil, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiol-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyltexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPMS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkylethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, or tosylate (Ts),, n is an integer from 0 to 4 (including both end values), m is 0, p is an integer from 0 to 3 (including both end values), q is an integer selected from 0 and 1, provided that the compound is not of the formula: [Chemical 2] ).

2. (a) The compound is of formula (0a): [Chemical Formula 3] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof; (b) The compound is of formula (0b): 【Chemical Formula 4】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof; or (c) The compound is of formula (0c): 【Chemical Formula 5】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof (In formulas (0a) to (0c), when present, R1, R2, R3, R9, n, q are as described in Claim 1, The compound according to Claim 1.)

3. (a) q is 0, or (b) q is 1, The compound according to Claim 1 or 2.)

4. R ９ The two cases of which are compounds according to any one of claims 1 to 3 that are linked to form a 5-membered heteroaryl ring or a 5-membered heterocyclic ring.

5. Formula (I): 【Chemical Formula 6】 The compound according to Claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, (In formula (I), R1, R2, R3, R4, R6, R8, R9, n, m, p, q are as defined in Claim 1.)

6. (a) The compound is of formula (Iz): 【Chemical Formula 8】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof; (b) The compound is of formula (Ia): 【Chemical Formula 9】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof; (c) The compound is of formula (Ib): 【Chemical Formula 10】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof; or (d) The compound is of formula (Ic): 【Chemical Formula 11】 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof (In formulas (Ia) to (Ic), when R1, R2, R3, Ra, and n are present, they are as described in claim 1) The compound according to any one of claims 1 to 5

7. (a) n is 0; (b) n is 1; or (c) n is 2 The compound according to any one of claims 1 to 6

8. Each R ９ is (a) Independently, hydrogen, substituted or unsubstituted methyl, chloro, fluoro, methoxy, or -NH ２ is it; (b) independently, substituted or unsubstituted methyl, chloro, fluoro, methoxy, or -NH ２ ; or (c) is methyl The compound according to any one of claims 1 to 7

9. (a) R ３ is hydrogen, substituted or unsubstituted methyl, fluoro, chloro, -CN, or -COOR ａ or; (b) R ３ is hydrogen, substituted or unsubstituted methyl, chloro, bromo, iodo, -CN, or -COOR ａ or; (c) R ３ is hydrogen, substituted or unsubstituted methyl, -CN, or -COOR ａ or; or (d) R ３ is methyl or chloro, The compound according to any one of claims 1 to 8

10. (a) R １ is a substituted or unsubstituted C １－３ alkyl; (b) R １ is a substituted or unsubstituted C １－３ heteroalkyl; or (c) R １ The compound according to any one of claims 1 to 9, wherein R is methyl or ethyl.

11. (a) R ２ is a substituted or unsubstituted C １－６ alkyl or a substituted or unsubstituted C １－６ heteroalkyl; (b) R ２ is a substituted or unsubstituted 3- to 6-membered heterocyclyl-C １－６ -alkyl, or a substituted or unsubstituted 3- to 6-membered carbocyclyl-C １－６ -alkyl; or (c) R ２ is a substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, or substituted or unsubstituted isobutyl; (d) R ２ is a substituted or unsubstituted 3- to 6-membered heterocyclyl-C １ -alkyl, or a substituted or unsubstituted 3- to 6-membered carbocyclyl-C １ -alkyl; or (e) R ２ is a substituted or unsubstituted 3- to 6-membered carbocyclic-C １－６ -alkyl or a substituted or unsubstituted C １－６ alkyl; or (f) R ２ is unsubstituted 3- to 6-membered carbocyclic-C １－２ -alkyl or substituted C １－６ alkyl, The compound according to any one of claims 1 to 10

12. R １ and R ２ are (a) includes a total number of 4 or more carbon atoms; or (b) includes a total number of 4 or more non-hydrogen atoms The compound according to any one of claims 1 to 11

13. The compound is (a) 【Chemical Formula 12-1】 【Chemical 12-2】 [Chemical Formula 12-3] or selected from the group consisting of its pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; (b) 【Chemical Formula 12-4】 【Chemical 12-5】 【Chemical Formula 12-6】 【Chemical 12-7】 【Chemical 12-8】 【Chemical Formula 12-9】 【Chemical 12-10】 ​ 【Chemical 12-12】 【Chemical 12-13】 【Chemical 12-14】 【Chemical Formula 12-15】 【Chemical 12-16】 or selected from the group consisting of its pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; (c) ​ 【Chemical 12-18】 【Chemical 12-19】 【Chemical 12-20】 ​ 【Chemical 12-22】 or selected from the group consisting of its pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; or (d) 【Chemical Formula 13-1】 【Chemical Formula 13-2】 【Chemical 13-3】 【Chemical 13-4】 or selected from the group consisting of its pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative The compound according to any one of claims 1 to 12

14. A compound, (a) 【Chemical Formula 14】 selected from the group consisting of its pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; (b) 【Chemical Formula 15-1】 or selected from the group consisting of its pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; (c) 【Chemical 15-2】 or selected from the group consisting of its pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative; (d) 【Chemical Formula 15-3】 【Chemical Formula 15-4】 or is selected from the group consisting of its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, or isotope-labeled derivatives; or (e) 【Chemical 16】 or is selected from the group consisting of its pharmaceutically acceptable salts, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, or isotope-labeled derivatives, said compound. [

15. ] A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof; and optionally, a pharmaceutically acceptable excipient, optionally further comprising an additional pharmaceutical agent, and optionally, said additional pharmaceutical agent is a chemotherapeutic agent or a differentiating agent, said pharmaceutical composition. [

16. ] A pharmaceutical composition for use in the treatment of a disease or disorder in a subject, comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, optionally, said disease or disorder is heart failure, dilated cardiomyopathy, pain, inflammation, acute distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), pneumonia, pneumonitis, severe acute respiratory syndrome, arthritis, acute lung injury, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin injury, autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, atherosclerotic thrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherosclerotic inflammatory disease, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertensive nephropathy, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorder, COVID-19, lung inflammation, coronavirus infection, or a tumor; and / or optionally, said disease or disorder is (a) inhibiting NAMPT in the subject; (b) inhibiting the NAMPT pathway in the subject; (c) reducing NAMPT signaling in a subject; (d) inhibiting the production of nicotinamide mononucleotide in a subject; (e) inhibiting the production of nicotinamide adenine dinucleotide in a subject; (f) reducing inflammatory activity in a subject; (g) reducing inflammatory cell infiltration in a subject; (h) reducing cell proliferation in a subject; or (i) reducing the cellular metabolic activity or state in a subject is treated by the pharmaceutical composition. **Claim 17** The pharmaceutical composition according to claim 16, further comprising an additional pharmaceutical agent, wherein the additional pharmaceutical agent is the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, or is used for administration before, together with, or after the composition. **Claim 18** A pharmaceutical composition for use in the treatment of cancer in a subject in need thereof, comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, or the pharmaceutical composition according to claim 15, optionally, the cancer comprises cancer stem cells; and / or optionally, the cancer is (a) gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, or prostate cancer; (b) gastric cancer; optionally, the gastric cancer is gastric cancer subtype GS or gastric cancer subtype CIN; (c) colorectal cancer; optionally, the colorectal cancer is colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4; (d) testicular cancer; (e) liver cancer; (f) uterine cancer; optionally, the cancer is endometrial cancer; (g) small cell lung cancer; (h) lymphoma; optionally, the lymphoma is (1) non-Hodgkin lymphoma; (2) B-cell lymphoma; (3) large cell type B-cell lymphoma; (4) Burkitt lymphoma; (5) Burkitt B-cell lymphoma; or (6) large cell type immunoblastic lymphoma; (i) leukemia; optionally, the leukemia is (1) acute myeloid leukemia; optionally, the acute myeloid leukemia is (I) undifferentiated acute myeloblastic leukemia (M0); (II) acute myeloblastic leukemia with minimal maturation (M1); (III) acute myeloblastic leukemia with maturation (M2); (IV) Acute promyelocytic leukemia (APL) (M3); (V) Acute myelomonocytic leukemia (M4); (VI) Acute myelomonocytic leukemia with eosinophilia (M4 eos); (VII) Acute monocytic leukemia (M5); (VIII) Acute erythroid leukemia (M6); or (I) Acute megakaryoblastic leukemia (M7); (2) Acute monocytic leukemia; (3) Acute lymphocytic leukemia; (4) B-cell acute lymphocytic leukemia; (5) Chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia; (6) Acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, or T-cell acute lymphoblastic leukemia; or (j) Multiple myeloma; optionally, the multiple myeloma is B-cell myeloma; (Optional) The subject has or is receiving one or more additional cancer therapies, and / or the subject requires regenerative medicine. (The pharmaceutical composition.) (Claim 19) (A method comprising contacting a cell, tissue, or biological sample with an effective amount of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, (wherein the contacting is in vitro or ex vivo; (Optionally, the cell (a) is characterized by one or more embryonic, pluripotent, or adult stem cell properties; and / or (b) is a cancer stem cell, embryonic stem cell, induced pluripotent stem cell, neural stem cell, differentiated cancer cell, or adult stem cell; and / or (Optionally, the contacting (i) reduces one or more embryonic or adult stem cell properties of the cell; (ii) reduces cell viability and / or prevents cell proliferation; (iii) kills the cell; (iv) inhibits tumor growth; (v) prevents metastasis; (vi) differentiates one or more cells; and / or (vii) regenerates one or more cells. (The method.) (Claim 20) (A method comprising killing a cell with an effective amount of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, (wherein the killing is in vitro or ex vivo; (Optionally, the cell characterized by one or more embryonic or adult stem cell properties; and / or is a cancer stem cell, embryonic stem cell, induced pluripotent stem cell, neural stem cell, adult stem cell, or differentiated cancer cell; optionally, said killing reduces one or more embryonic or adult stem cell properties of said cells said method

21. comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, inhibiting NAMPT in a subject; inhibiting the NAMPT pathway in a subject; decreasing NAMPT signaling in a subject; inhibiting the production of nicotinamide mononucleotide in a subject; inhibiting the production of nicotinamide adenine dinucleotide in a subject; decreasing inflammatory activity in a subject; reducing inflammatory cell infiltration in a subject; reducing cell proliferation in a subject; or reducing the cell metabolic activity or state in a subject A pharmaceutical composition for use therefor.

22. inhibiting NAMPT in a cell, tissue, or biological sample; inhibiting the NAMPT pathway in a cell, tissue, or biological sample; decreasing NAMPT signaling in a cell, tissue, or biological sample; inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample; inhibiting the production of nicotinamide mononucleotide in a cell, tissue, or biological sample; decreasing inflammatory activity in a cell, tissue, or biological sample; reducing inflammatory cell infiltration in a cell, tissue, or biological sample; reducing the cell metabolic activity or state in a cell, tissue, or biological sample; or reducing cell proliferation in a cell, tissue, or biological sample A method comprising contacting the cell, tissue, or biological sample with the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, wherein the contacting is performed in vitro or ex vivo, said method.

23. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof; or the pharmaceutical composition according to claim 15; and Instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative, or pharmaceutical composition A kit comprising.

24. A pharmaceutical composition for use in the treatment of a disease or disorder in a subject, comprising The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, Optionally, the disease or disorder is heart failure, dilated cardiomyopathy, pain, inflammation, acute distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GVHD), pneumonia, pneumonitis, severe acute distress syndrome, arthritis, acute lung injury, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic disease, skin disease, psoriasis, atopic dermatitis, ultraviolet-induced skin injury, autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, atherosclerotic thrombotic disease, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherosclerotic inflammatory disease, cardiovascular disorder, cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, pregnancy-induced hypertension nephropathy, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative disorder, COVID-19, lung inflammation, coronavirus infection, or tumor; and / or Optionally, the disease or disorder is (a) modulating NAMPT in the subject; (b) modulating the NAMPT pathway in a subject; (c) modulating NAMPT signaling in a subject; (d) modulating the production of nicotinamide mononucleotide in a subject; (e) modulating the production of nicotinamide adenine dinucleotide in a subject; (f) modulating inflammatory activity in a subject; or (g) modulating cell metabolic activity or state in a subject for treating, said pharmaceutical composition.

25. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or a pharmaceutical composition according to claim 15, comprising (a) modulating NAMPT in a subject; (b) modulating the NAMPT pathway in a subject; (c) modulating NAMPT signaling in a subject; (d) modulating the production of nicotinamide mononucleotide in a subject; (e) modulating the production of nicotinamide adenine dinucleotide in a subject; (f) modulating inflammatory activity in a subject; or (g) modulating cell metabolic activity or state in a subject for use in a pharmaceutical composition.

26. A pharmaceutical composition for use in contact with a cell, tissue, or biological sample, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or a pharmaceutical composition according to claim 15, optionally, said cell is (a) characterized by one or more embryonic, pluripotent, or adult stem cell properties; and / or (b) a cancer stem cell, embryonic stem cell, induced pluripotent stem cell, neural stem cell, differentiated cancer cell, or adult stem cell; and / or optionally, said contact (i) reducing one or more embryonic or adult stem cell properties of said cell; (ii) reducing cell viability and / or preventing cell proliferation; (iii) killing said cell; (iv) inhibiting tumor growth; (v) preventing metastasis; (vi) differentiating one or more cells; and / or (vii) regenerating one or more cells, said pharmaceutical composition.

27. A pharmaceutical composition for use in killing cells, comprising The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, comprising Optionally, said cell is characterized by (a) one or more embryonic or adult stem cell characteristics; and / or is (b) a cancer stem cell, embryonic stem cell, induced pluripotent stem cell, neural stem cell, adult stem cell, or differentiated cancer cell; Optionally, said killing reduces one or more embryonic or adult stem cell characteristics of said cell. Said pharmaceutical composition.

28. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotope-labeled derivative thereof, or the pharmaceutical composition according to claim 15, comprising inhibiting NAMPT in (a) cells, tissues, or biological samples; inhibiting the NAMPT pathway in (b) cells, tissues, or biological samples; decreasing NAMPT signaling in (c) cells, tissues, or biological samples; inhibiting the production of nicotinamide adenine dinucleotide in (d) cells, tissues, or biological samples; inhibiting the production of nicotinamide mononucleotide in (e) cells, tissues, or biological samples; decreasing inflammatory activity in (f) cells, tissues, or biological samples; reducing inflammatory cell infiltration in (g) cells, tissues, or biological samples; reducing the cell metabolic activity or state in (h) cells, tissues, or biological samples; or reducing cell proliferation in (i) cells, tissues, or biological samples A pharmaceutical composition for use therefor.

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