Cancer therapy targeting cancer stem cells

Abstract

Disclosed are compounds, methods, compositions, uses and kits that allow for the treatment of cancer. In some embodiments, the compounds are used to treat a disease or condition. The compounds can treat cancer by targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumors, 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 for regenerative medicine. The compounds used in the present disclosure have formulas (0) and (I).

Description

[0001] Related applications

[0002] This application claims priority under Title 35, Section 119(e) of the United States Code, U.S. Provisional Application USSN 62 / 931,531, filed November 6, 2019, which is incorporated herein by reference. Background Technology

[0003] Cancer is ubiquitous, and despite medical advancements, it remains a leading cause of death worldwide. In 2017, an estimated 1.7 million new cases of cancer were diagnosed, and 600,000 people died from the disease. 1 Cancer is the second leading cause of death worldwide, accounting for nearly one in six deaths. The number of new cases is projected to increase by approximately 70% over the next 20 years. The economic impact of cancer is enormous and is increasing. It was estimated that the total annual economic cost of cancer in 2010 was approximately US$1.16 trillion. 2

[0004] Cancer is a general term for a large class of diseases that can affect any part of the body. Other terms used are malignant tumors and growths. Cancer is caused by normal cells transforming into tumor cells in a multi-stage process, typically progressing from precancerous lesions to malignant tumors. A defining characteristic of cancer is the rapid production of abnormal cells that grow beyond their normal boundaries and can then invade adjacent parts of the body and spread to other organs; this latter process is called metastasis. Metastasis is a leading cause of cancer death. The most common causes of cancer death are lung cancer, liver cancer, colorectal cancer, stomach cancer, and breast cancer.

[0005] Despite some progress in treating subsets of cancer types, the average cancer mortality rate remains very high, with little overall improvement in the ongoing cancer crisis. Almost all modern cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on eliminating the tumor rather than targeting the most dangerous cells within it: cancer stem cells. Cancer stem cells are responsible for the spread of cancer cells throughout the body, tumor growth, cancer resistance to chemotherapy, and tumor recurrence after treatment or surgical removal. 3，4 Because current treatments do not target cancer stem cell populations, they often lead to the development of drug-resistant tumors and continued cancer spread. Summary of the Invention

[0006] The discovery of cancer stem cells has provided an opportunity for the convergence of oncology and stem cell biology. 5，6The development of effective and non-toxic therapies that target the very characteristics of cancer stem cells—either embryonic or adult stem cells—that form the basis of cancer growth, spread, and drug resistance, can be achieved through strategies known as cancer suppression therapies. Therapies that can both reduce tumor size and destroy cancer stem cells will revolutionize cancer treatment. 7

[0007] This article describes compounds that induce cancer stem cells to differentiate and inhibit metastasis through signaling pathways that are identical to those used by stem cells during differentiation and development. 8，9 These properties can be safely targeted because they exist only in stem cells, not in healthy adult tissues.

[0008] This article describes compounds that regulate the production of nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), NAMPT signaling, the NAMPT pathway, and / or cellular metabolism.

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

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

[0011] In one respect, this disclosure provides compounds of formula (0):

[0012]

[0013] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0) are as described herein. In some respects, compounds of formula (0) have formula (0a), (0b), or (0c):

[0014]

[0015] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug, wherein the variable is as described herein.

[0016] In one respect, this disclosure provides compounds of formula (I):

[0017]

[0018] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (I) are as described herein. In some respects, compounds of formula (I) have formula (Ia):

[0019]

[0020] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (Ia) are as described herein. In some respects, compounds of formula (I) have the following formula:

[0021]

[0022] In another aspect, this disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0) or (I) are as described herein.

[0023] In some implementations, the cancer includes cancer stem cells. In some implementations, the cancer involves or is related to cancer stem cells. In some implementations, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, prostate cancer, liver cancer, or endometrial cancer. In some implementations, the cancer is leukemia (e.g., acute myeloid leukemia). In some implementations, the cancer is lymphoma. In some implementations, the cancer is multiple myeloma. In some implementations, the subject requires regenerative medicine or a therapy.

[0024] In another aspect, this disclosure provides methods and uses that include contacting cells with an effective amount of the compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0025] In some respects, this disclosure provides methods and uses that include killing cells with an effective amount of the compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0026] In some respects, this 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof with cells, tissues, or biological samples 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.

[0027] In some respects, this disclosure provides a method for inhibiting NAMPT in a subject, comprising administering to the subject a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0028] In some respects, this disclosure provides a method of treating a disease or condition of a subject by inhibiting NAMPT in the subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0029] In some respects, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0030] In some respects, this disclosure provides a method for treating a disease or condition of a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0031] In some respects, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0032] In some respects, this disclosure provides a method for treating a disease or condition of a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0033] In some respects, this disclosure provides a method for 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.

[0034] In some respects, this disclosure provides a method for treating a subject’s disease or condition by reducing inflammatory cell infiltration, 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.

[0035] In some respects, this disclosure provides a method for 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.

[0036] In some respects, this disclosure provides a method for treating a disease or condition of a subject by reducing the cell proliferation of 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.

[0037] In some respects, this disclosure provides methods for reducing the cellular metabolic activity or state of a subject, the methods 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.

[0038] In some respects, this disclosure provides a method for treating a disease or condition of a subject by reducing the subject's cellular metabolic activity or state, said 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.

[0039] In some respects, this disclosure provides methods for reducing inflammatory activity in a subject, the methods 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.

[0040] In some respects, this disclosure provides a method for treating a disease or condition of a subject by reducing inflammatory activity, said 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.

[0041] In some respects, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0042] In some respects, this disclosure provides a method for treating a disease or condition of a subject by reducing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0043] In some respects, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0044] In some respects, this disclosure provides a method for treating a disease or condition of a subject by inhibiting the NAMPT pathway, said 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.

[0045] In some respects, this disclosure provides methods for inhibiting the NAMPT pathway in cells, tissues, or biological samples, the methods comprising contacting the cells, tissues, or biological samples 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.

[0046] In some respects, this disclosure provides methods for reducing NAMPT signaling in cells, tissues, or biological samples, the methods comprising contacting the cells, tissues, or biological samples 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.

[0047] In some respects, this disclosure provides methods for reducing the inflammatory activity of cells, tissues, or biological samples, the methods comprising contacting the cells, tissues, or biological samples 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.

[0048] In some respects, this disclosure provides methods for reducing the cellular metabolic activity or state of cells, tissues, or biological samples, said methods comprising contacting the cells, tissues, or biological samples 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.

[0049] In some respects, this disclosure provides methods for reducing cell proliferation in cells, tissues, or biological samples, the methods comprising contacting the cells, tissues, or biological samples 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.

[0050] In some respects, this disclosure provides methods for reducing inflammatory cell infiltration in cells, tissues, or biological samples, the methods comprising contacting the cells, tissues, or biological samples 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.

[0051] In some respects, this disclosure provides a method for inhibiting the production of nicotinamide adenine dinucleotide in cells, tissues, or biological samples, the method comprising contacting the cells, tissues, or biological samples 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.

[0052] In some respects, this disclosure provides a method for inhibiting the production of nicotinamide mononucleotide in cells, tissues, or biological samples, the method comprising contacting the cells, tissues, or biological samples 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.

[0053] In some respects, this disclosure provides a method for inhibiting NAMPT in cells, tissues, or biological samples, the method comprising contacting the cells, tissues, or biological samples 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.

[0054] In some implementations, the contact is performed outside the body or outside the body.

[0055] In some respects, this disclosure provides methods for treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0056] In some aspects, this disclosure provides compositions comprising compounds disclosed herein (e.g., compounds of formula (0) or (I)) or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof; and optionally pharmaceutically acceptable excipients. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises additional pharmaceutical agents.

[0057] In some aspects, this disclosure provides methods for treating a disease or condition in a subject with such need, 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, or a composition disclosed herein, and additional agents. In some embodiments, the additional agents are administered 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, or a composition disclosed herein.

[0058] In other respects, this disclosure provides a kit containing a compound disclosed herein (e.g., a compound of formula (0) or (I)) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or a composition as described herein; and instructions for use of said compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0059] Details of certain embodiments of the present invention are set forth in the detailed description below. Other features, objectives, and advantages of the invention will become apparent from the definitions, embodiments, and claims.

[0060] definition

[0061] For convenience, certain terms used herein in the specification, embodiments and appended claims are included.

[0062] Unless the context otherwise requires, singular terms should include plural terms and plural terms should include singular terms.

[0063] The phrase "in some implementations" and the phrase "in certain implementations" are used interchangeably.

[0064] The following definitions are the more general terms used in this application:

[0065] Unless the context clearly indicates otherwise, the singular terms “a,” “an,” and “the” include plural referents. Similarly, the word “or” is intended to include “and,” unless the context clearly indicates otherwise.

[0066] Except as illustrated in the examples or otherwise stated, all figures used herein to represent amounts of components or reaction conditions should be understood to be modified by the term “about” in all cases. Given the nature or precision of the measurement, “about” and “approximately” generally mean an acceptable degree of error for the measured quantity. Exemplary degrees of error are within 20% (%) of a given value or range, typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1%.

[0067] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the periodic table of elements on the inner cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0068] The compounds described herein may include one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (Ell. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also covers compounds as single isomers substantially free of other isomers, as well as mixtures of various isomers, alternatively.

[0069] In the formula, It is a single bond, where the stereochemistry of the portion directly bonded to it is not specified. It either does not exist or is a single key, and or It is either a single bond or a double bond.

[0070] Unless otherwise specified, the formulas described herein include compounds excluding isotopically enriched atoms as well as compounds including isotopically enriched atoms. Compounds including isotopically enriched atoms can be used as analytical tools and / or probes, for example, in biological assays.

[0071] The term "aliphatic" includes saturated and unsaturated, non-aromatic, straight-chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, the aliphatic group is optionally substituted with one or more functional groups (e.g., halogenated groups, such as fluorine). As will be understood by those skilled in the art, "aliphatic" herein is intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0072] When listing a range of values ​​(“range”), it is intended to encompass every value within that range and its subranges. Unless otherwise provided, a range includes the values ​​at both ends of the range. For example, “integers between 1 and 4” means 1, 2, 3, and 4. For example, “C…” 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0073] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C9). 12 ), etc. Unless otherwise stated, each instance of an alkyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C 1-12 Alkyl groups (e.g., -CH3(Me), unsubstituted ethyl groups (Et), unsubstituted propyl groups (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl groups (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C 1-12 Alkyl groups (such as substituted C1-6 alkyl groups, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)). The linkage of an alkyl group can be a single bond (e.g., in -CH3), a double bond (e.g., in =CH2), or a triple bond (e.g., in ≡CH). Parts =CH2 and ≡CH are also alkyl groups.

[0074] In some embodiments, the alkyl group is substituted with one or more halogens. A “holohaloalkyl” is a substituted alkyl group as defined herein, wherein all hydrogen atoms are independently substituted with a halogen (e.g., fluorine, bromine, chlorine, or iodine). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms (“C…”). 1-8 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C6”). 1-6 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms (“C10”). 1-4 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C10"). 1-3 (Halogenated alkyl group). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C10”). 1-2(Perhaloalkyl). In some embodiments, all hydrogen atoms are replaced by fluorine. In some embodiments, all hydrogen atoms are replaced by chlorine. Examples of perhaloalkyl include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[0075] "Alkenyl" refers to a straight-chain or branched hydrocarbon group ("C") having 2 to 20 carbon atoms and one or more (e.g., two, three, or four carbon-carbon double bonds where valence allows) and no triple bonds. 2-20 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-10 Alkenyl group. In some embodiments, the alkenyl group is a substituted C-group. 2-10 Alkenyl. In alkenyl groups, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3, ...). It can be in (E)- or (Z)- configuration.

[0076] "Alkyne" refers to a straight-chain or branched hydrocarbon group ("C") having 2 to 20 carbon atoms and one or more (e.g., two, three, or four carbon-carbon triple bonds, where valence allows) and optionally one or more double bonds. 2-20 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of the alkynyl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-10 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-10 Alkyne group.

[0077] "Carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 13 ring carbon atoms ("C"). 3-13 The carbocyclic group has 3 to 8 cyclic carbon atoms (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”). The carbocyclic group may be saturated, and saturated carbocyclic groups are referred to as “cycloalkyl”. In some embodiments, the carbocyclic group is a monocyclic saturated carbocyclic group (“C”) having 3 to 10 ring carbon atoms. 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C14 groups. 3-6Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C12. 3-10 Cycloalkyl. The carbocyclic group may be partially unsaturated. The carbocyclic group may include zero, one or more (e.g., two, three, or four, depending on the valence) C=C double bonds in all rings of a non-aromatic or heteroaromatic carbocyclic system. A carbocyclic group that includes one or more (e.g., two or three, depending on the valence) C=C double bonds in the carbocyclic group is called a “cycloalkenyl”. A carbocyclic group that includes one or more (e.g., two or three, depending on the valence) C≡C triple bonds in the carbocyclic group is called a “cycloynyl”. Carbocyclic groups include aryl groups. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaromatic groups, wherein the bonding point is on the carbocyclic ring, and in this case, the number of carbons continues to indicate the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently and optionally substituted, e.g., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is substituted or unsubstituted, 3 to 7 members and monocyclic. In some embodiments, the carbocyclic group is substituted or unsubstituted, 5 to 13 members and bicyclic.

[0078] In some implementations, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 10 ring carbon atoms. 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8Examples of cycloalkyl groups include the aforementioned C14 groups. 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C12. 3-10 Cycloalkyl groups. In some embodiments, the carbocyclic group includes 0, 1, or 2 C=C double bonds in the carbocyclic system, where the valence allows.

[0079] "Carbocycloalkyl", "X to X-membered carbocyclo-C" x-x Alkyl" or "X to X-membered carbocyclic -C" x-x "-alkyl", where each example of X is an integer, a subgroup of "alkyl" and refers to an alkyl group substituted with a carbocyclic group, where the linkage is on the alkyl moiety. For example, 3 to 13-membered carbocyclic groups -C 1-12 -alkyl refers to a C-aryl group substituted with a 3 to 13-membered carbocyclic group (e.g., cyclopropyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl). 1-12 Alkyl groups (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0080] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 13-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclic groups"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"). Heterocyclic groups can be saturated or partially unsaturated. Heterocyclic groups can include zero, one or more (e.g., two, three, or four, where the valence allows) double bonds in all rings of a non-aromatic or heteroaromatic heterocyclic system. Partially unsaturated heterocyclic groups include heteroaryl groups. Heterocyclic bicyclic systems can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or includes ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise indicated, each instance of a heterocyclic group is independently and optionally substituted, for example, unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is substituted or unsubstituted, 3 to 7-membered, and monocyclic. In some embodiments, the heterocyclic group is substituted or unsubstituted, 5 to 13-membered, and bicyclic. In some embodiments, the heterocyclic group is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, wherein, where the valence allows, one, two, or three atoms in the heterocyclic system are independently oxygen, nitrogen, or sulfur.

[0081] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0082] Exemplary 3-membered heterocyclic groups containing one heteroatom include aziridinyl, ethylene oxide, or cyclothioethane. Exemplary 4-membered heterocyclic groups containing one heteroatom include azirrobutyl, oxetyl, and thiobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxolanecycloyl, oxetyl, dithioalkyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include triazine alkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with aryl rings (also referred to herein as 6,6-bicyclic heterocycles) include tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthidyl, decahydro-1,8-naphthidyl, octahydropyrrolo[3,2-b]pyrrole, dihydroindolyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diaza The group includes 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolithyl, 5,6-dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-dihydrofurano[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, and 1,2,3,4-tetrahydro-1,6-naphthidyl.

[0083] "Heterocyclic alkyl", "X to X-membered heterocyclic -C" x-x Alkyl group or X to X-membered heterocyclic group -C x-x "-alkyl", where each example of X is an integer, a subgroup of "alkyl" and refers to an alkyl group substituted with a heterocyclic group, where the connecting point is on the alkyl moiety. For example, 3 to 13-membered heterocyclic groups -C 1-12 -alkyl refers to a C-aryl group substituted with a 3 to 13-membered heterocyclic group (e.g., ethylene oxide, oxetane, oxadiazolinyl, piperidinyl, tetrahydropyranyl, piperazineyl, morpholinyl). 1-12 Alkyl groups (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0084] "Aryl" refers to a group ("C") having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons common to the ring array) that provides 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each instance of an aryl is independently and optionally substituted, for example, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0085] "Aryl" is a subset of "alkyl" and refers to an alkyl group that has been substituted with an aryl group, wherein the connecting point is on the alkyl part.

[0086] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons common to the ring array) with a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the linkage is on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl, where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the linkage can be on either ring, for example, a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0087] "Heteroarylene" is a subset of "alkyl" and refers to alkyl groups substituted with heteroaryl groups, where the connecting point is on the alkyl moiety.

[0088] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently and optionally substituted, for example, unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0089] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrole, furanyl, and phenylthio. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azazolyl. basic, oxygen thia Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazole, benzotriazolyl, benzobenzylthio, isobenzobenzylthio, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Examples of 6,6-bicyclic heteroaryl groups include naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Examples of tricyclic heteroaryl groups include phenanthridinel, dibenzofuranyl, carbazoleyl, acridinel, phenothiazinyl, phenotoxazinyl, and phenothiazinyl.

[0090] "Partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, and not to include aromatic groups (e.g., aryl or heteroaryl) as defined herein. Similarly, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains only single bonds.

[0091] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclic, heteroalkyl, heteroalkenyl, heteroynyl, 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, heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroynyl, "substituted" or "unsubstituted", "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted," whether preceded by "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a usable substituent, such that the substitution, for example, yields a stable compound, which is a compound that does not spontaneously undergo transformation, such as through rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has a substituent at one or more substituted positions on the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. Unless otherwise provided, a substituent on a polycyclic ring can be at any substituted position on any monocyclic ring of the polycyclic ring. The term "substituted" is contemplated to include substitution with all available substituents of an organic compound, and said substituents include any substituents described herein that cause the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain a stable compound. For the purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or satisfy the valence of the heteroatom and cause the formation of a stable moiety with any suitable substituent as described herein.

[0092] Exemplary carbon substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(Raa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc 2. -P(OR) cc )2、-P(R cc )3 + X - -P(OR) cc )3 + X - -P(R) cc 4. -P(OR) cc 4. -OP(R) cc )2、-OP(R cc )3 + X - -OP(OR) cc 2. -OP(OR) cc )3 + X - -OP(R) cc 4. -OP(OR) cc )4、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0093] Or two hydrogen atom on a carbon atom are surrounded by =O, =S, =NN(R) groups. bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc Substitute;

[0094] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0095] R bb Each instance is independently selected from hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)(R aa )2、-P(=O)(OR cc)2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0096] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0097] Each instance of Rdd is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)Ree -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10Aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groups dd Substituents can be linked to form =O or =S; where X - It is a counter ion;

[0098] R ee Each instance is independently selected from C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbon cyclo group, C 6-10 aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0099] R ff Each instance is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff Groups are linked to form 3-10 membered heterocyclic groups or 5-10 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0100] Each instance of Rgg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2+ X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6Alkyl)3、-OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl, -P(=O)(OC) 1-6 Alkyl)2、-P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbon cyclo group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two geminal Rs gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0101] In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb )2, -CN, -SCN, -NO2, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-OC(=O)R aa -OCO2R aa -OC(=O)N(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(R bb 2. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SRaa -N(R) bb )2, -CN, -SCN, -NO2, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-OC(=O)R aa -OCO2R aa -OC(=O)N(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(R bb )2, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl group, oxygen-protecting group attached to an oxygen atom, or sulfur-protecting group attached to a sulfur atom (e.g., acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl); each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen-protecting group. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb 2. -CN, -SCN, or -NO2. In some embodiments, the carbon substituent is independently a halogen, substituted (e.g., partially substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb )2, -CN, -SCN or -NO2, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl group, oxygen-protecting group attached to an oxygen atom, or sulfur-protecting group attached to a sulfur atom (e.g., acetamoxymethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl); and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group.

[0102] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one form of negative charge). Anionic counterions can also be polyvalent (i.e., comprising more than one form of negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F). - Cl - ,Br - I - NO3 - ClO4 - OH - H2PO4 - HCO3 - HSO4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - PF4 - PF6 - AsF6 - SbF6 - B[3,5-(CF3)2C6H3]4] - B(C6F5)4 - BPh4 - Al(OC(CF3)3)4 - and carborane anions (e.g., CB) 11 H 12 -or (HCB) 11 Me5Br6)-). Exemplary multivalent counterions include CO32-. 2- HPO4 2- PO4 3- B4O7 2- SO4 2- S2O3 2- Carboxylate anions (such as tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0103] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0104] Where valence permits, the nitrogen atom can be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include hydrogen, -OH, and -OR. aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)(OR) cc )2、-P(=O)(R aa )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, or two R groups bonded to a N atom cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As defined above.

[0105] In some embodiments, the nitrogen substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C atom. 1-6 Alkyl, -C(=O)R aa -CO2Raa -C(=O)N(R) bb )2 or nitrogen protecting group. In some embodiments, the nitrogen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or nitrogen protecting group, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the nitrogen substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C atom. 1-6 Alkyl or nitrogen protecting group.

[0106] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). Nitrogen protecting groups include -OH, -OR... aa -N(R) cc )2、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups.dd Base substitution, and where R aa R bb R cc and R dd As defined herein, nitrogen protecting groups are those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0107] Amide nitrogen protecting group (e.g., -C(=O)R) aa This includes formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0108] Carbamate nitrogen protecting groups (e.g., -C(=O)OR) aaThis includes methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiopheneyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), and 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc). ), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-diphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylcarbamate)ethylcarbamate, tert-butyl carbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc). Allyl carbamate (Alloc), 1-Isopropylallyl carbamate (Ipaoc), Cinnamyl carbamate (Coc), 4-Nitrocinnamyl carbamate (Noc), 8-Quinolinyl carbamate, N-Hydroxypiperidinyl carbamate, Alkyl dithiocarbamate, Benzyl carbamate (Cbz), p-Methoxybenzyl carbamate (Moz), p-Nitrobenzyl carbamate, p-Bromobenzyl carbamate, p-Chlorobenzyl carbamate, 2,4-Dichlorobenzyl carbamate, 4-Methylsulfinylbenzyl carbamate (Msz), 9-Anthrylmethyl carbamate, Diphenylmethyl carbamate, 2-Methylthioethyl carbamate, 2-Methylsulfonylethyl carbamate Carbamates, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-dithiaalkyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonoethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonemethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3...5-Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylethylene carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl Carbamates, isobornyl carbamate, isobutyl carbamate, isonicoyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamates, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0109] sulfonamide nitrogen protecting group (e.g., -S(=O)2R) aa This includes p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylsomn-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethylsulfonamide.

[0110] 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-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazopentanyl adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluoreneamine (PhF), N-2,7 -Dichloro-9-fluorenylmethyleneamine, N-ferrocene-methylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitrosamines, N-nitrosamines, amine N-oxides, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkyl aminophosphate, dibenzyl aminophosphate, diphenyl aminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys). In some embodiments, two examples of the nitrogen protecting group together with the nitrogen atom to which the nitrogen protecting group is attached are N,N'-isopropylidene diamine.

[0111] In some embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0112] In some embodiments, the oxygen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C atom. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group. In some embodiments, the nitrogen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group, where R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the oxygen atom substituent is independently a substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

[0113] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X --P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - R aa R bb and R cc As defined herein. Oxygen protecting groups are those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0114] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, and 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-methyl 4-Oxypiperidinyl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylbridged benzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2- Trimethylsilylethyl, 2-(phenylhydroselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxide, diphenylmethyl, p,p'-Dinitrodiphenylmethyl, 5-Dibenzocycloheptanyl, Triphenylmethyl, α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4”-Tris(4,5-dichlorobenzoyliminophenyl)methyl, 4,4',4”-Tris(acetylpropionyloxy)oxy 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)oxanthracene, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithio-2-yl, benzisothiazolyl S,S-dioxide Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethylhexylsilyl, Tert-butyldimethylsilyl (TBDMS), Tert-butyldiphenylsilyl (TBDPS), Triphenylmethylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), Tert-butylmethoxyphenylsilyl (TBMPS), Formate, Benzoyl Formate, Acetate, Chloroacetate, Dichloroacetate, Trichloroacetate, Trichloroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, 3-Phenylacetate, 4-Oxyvalerate (Aleuprolate), 4,4-(Ethylene dithio)valerate (acetylpropionyl dithioacetal), neovalerate, adamantinate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC) 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl Dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid ester, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid ester, 2,4-bis(1,1- Dimethylpropylphenoxyacetic acid ester, dichlorophenylacetic acid ester, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthylcarbamate, nitrate ester, alkyl N,N,N',N'-tetramethylphosphonidamide, N-phenylcarbamate, borate ester, dimethylphosphonothio, 2,4-dinitrophenylsulfenic acid ester, sulfate ester, methanesulfonate (methanesulfonate), benzyl methylsulfonate, and toluenesulfonate (Ts).

[0115] In some embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, neopentanoyl, or benzoyl.

[0116] In some embodiments, the sulfur atom substituent is either independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or sulfur protecting group. In some embodiments, the sulfur atom substituent is an independently substituted (e.g., substituted by one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa -CO2Raa -C(=O)N(R) bb )2 or sulfur protecting group, wherein R aa It is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl groups, or oxygen protecting groups when attached to oxygen atoms; and each R bb Independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, the sulfur substituent is an independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or sulfur protecting group.

[0117] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). In some embodiments, each sulfur protecting group is selected from the group consisting of: -R aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X - -P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where R aa R bb and R ccAs defined herein, a sulfur protecting group is those well known in the art and included in detail in Protecting Groups in Organic Synthesis, TW Greene and P. GMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In some embodiments, the sulfur protecting group is acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfinyl, 2-pyridine-sulfinyl, or triphenylmethyl.

[0118] Other exemplary substituents include hydrogen, halogen, and C. 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl), C 1-6 Alkoxy, partially or fully halogenated C 1-6 Alkyl groups (e.g., -CF3, -CHF2, -CH2F), -CN, -NO2, -OR a (e.g., -OMe, -OEt), -SR a -N(R) a -2 (e.g., -NH2, -NMe2), -NR a (C=O)OR a (For example, -NH(C=O)OMe, -NH(C=O)OEt, -NH(C=O)O t Bu), COOR a (e.g., -COOH, -COOMe, -COOEt) and -COR a Other examples include aryl and heteroaryl groups.

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

[0120] The molecular weight of -R (where -R is any monovalent part) is calculated by subtracting the atomic weight of hydrogen atoms from the molecular weight of the molecule RH. The molecular weight of -L- (where -L- is any divalent part) is calculated by subtracting the combined atomic weight of two hydrogen atoms from the molecular weight of the molecule HLH.

[0121] In some embodiments, the molecular weight of the substituent is less than 200, less than 150, less than 100, less than 50, or less than 25 g / mol. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the substituent is composed of carbon, hydrogen, and / or fluorine atoms. In some embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond donors. In some embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond acceptors.

[0122] Adding the suffix "ene" to a group indicates that the group is a polyvalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In some embodiments, adding the suffix "ene" to a group indicates that the group is a divalent moiety.

[0123] The term "hydroxyl group" refers to the -OH group.

[0124] The term "thiol" or "thio" refers to the -SH group.

[0125] The term "amine" or "amino" refers to the group -NH- or -NH2.

[0126] The term "acyl" refers to a group having the following general formula: -C(=O)R X1 -C(=O)OR X1 -C(=O)-OC(=O)R X1 -C(=O)SR X1 -C(=O)N(R) X1 )2、-C(=S)R X1 -C(=S)N(R) X1 )2, and -C(=S)S(R X1 -C (=NR) X1 )R X1 -C(=NR) X1 OR X1 -C(=NR) X1 )SR X1 and -C(=NR) X1 )N(R X1)2, where R X1 Hydrogen; halogen; substituted or unsubstituted hydroxyl group; substituted or unsubstituted thiol; substituted or unsubstituted amino group; substituted or unsubstituted acyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched... Branched alkenyl group; substituted or unsubstituted alkynyl group; substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, aliphatic oxy group, heteroaliphatic oxy group, alkoxy group, heteroalkoxy group, aryloxy group, heteroaryloxy group, aliphatic sulfoxy group, heteroaliphatic sulfoxy group, alkyl sulfoxy group, heteroalkyl sulfoxy group, aryl sulfoxy group, heteroaryl sulfoxy group, mono- or dialiphatic amino group, mono- or dialkylamino group, mono- or diheteroalkylamino group, mono- or diarylamino group, or mono- or diheteroarylamino group; or two R groups. X1 The groups together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any substituents described herein that lead to the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkyl sulfoxy, heteroalkyl sulfoxy, aryl sulfoxy, heteroaryl sulfoxy, acyloxy, etc., each of which may or may not be further substituted).

[0127] The term "salt" refers to an ionic compound produced by the neutralization reaction of an acid and a base. A salt consists of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (has no net charge). Salts of the compounds disclosed herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0128] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 - Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0129] The term "solvent" refers to a substance that dissolves one or more solutes to produce a solution. Solvents can be used as the medium for any reaction or transformation described herein. Solvents can dissolve one or more reactants or reagents in the reaction mixture. Solvents can promote the mixing of one or more reagents or reactants in the reaction mixture. Solvents can also be used to increase or decrease the reaction rate relative to reactions in different solvents. Solvents can be polar or nonpolar, protons or aprotons. Common solvents that can be used in the methods described herein include, but are not limited to, acetone, acetonitrile, benzyl nitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethanol, ethylene glycol, dimethyl ether, heptane, n-hexane, and hexane. Alkane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, ethyl 2-methoxyethyl acetate, methanol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidone, dimethyl sulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.

[0130] The term "solvent" refers to a compound or its salt that typically associates with a solvent via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, as well as stoichiometric and non-stoichiometric solvates. In some cases, solvates will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvent" includes both the solution phase and the separable solvate. Representative solvates include hydrates, ethanolides, and methanolides.

[0131] The term "hydrate" refers to a compound that associates with water. Typically, the number of water molecules in a hydrate of a compound is in a definite ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0132] The term "crystal" or "crystalline form" refers to a solid form that exhibits essentially a three-dimensional order. In some embodiments, the crystalline form of a solid is a solid form that is not substantially amorphous. In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form includes one or more well-defined peaks.

[0133] The term "amorphous" or "amorphous form" refers to a solid form ("solid form") that substantially lacks three-dimensional order. In some embodiments, the amorphous form of a solid is a solid form that is substantially non-crystalline. In some embodiments, using CuKα radiation, the X-ray powder diffraction (XRPD) pattern of the amorphous form includes a broad scattering band with peaks at 2θ, for example, from 20° to 70° (inclusive). In some embodiments, the XRPD pattern of the amorphous form also includes one or more peaks attributed to a crystal structure. In some embodiments, the maximum intensity of any one of the one or more peaks attributed to a crystal structure observed at 2θ from 20° to 70° (inclusive) is no more than 300 times, no more than 100 times, no more than 30 times, no more than 10 times, or no more than 3 times the maximum intensity of the broad scattering band. In some embodiments, the XRPD pattern of the amorphous form does not include peaks attributed to a crystal structure.

[0134] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0135] The term "cocrystal" refers to a crystal structure comprising at least two distinct components (e.g., a compound of formula (0) or (I) and an acid), wherein each component is independently an atom, ion, or molecule. In some embodiments, none of the components are solvents. In some embodiments, at least one component is a solvent. A cocrystal of a compound of formula (0) or (I) with an acid differs from a salt formed by a compound of formula (0) or (I) with an acid. In a salt, the disclosed compound is complexed with the acid in a manner that facilitates proton transfer (e.g., complete proton transfer) from the acid to the disclosed compound at room temperature. However, in a cocrystal, the disclosed compound is complexed with the acid in a manner that facilitates proton transfer from the acid to the disclosed compound at room temperature. In some embodiments, no proton transfer from the acid to the disclosed compound is present in the cocrystal. In some embodiments, partial proton transfer from the acid to the disclosed compound is present in the cocrystal. Cocrystals can be used to improve the properties (e.g., solubility, stability, and ease of formulation) of compounds of formula (0) or (I).

[0136] The term "tautomer" or "tautomerizing" refers to two or more interconvertible compounds resulting from at least one formal migration of hydrogen atoms and at least one change in valence (e.g., single to double, triple to single, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone-to-enol, amide-to-imide, lactam-to-lactamimide, enamine-to-imide, and enamine-to-(different enamines) tautomerization.

[0137] It should also be understood that compounds having the same molecular formula but differing in the bonding properties or order of their atoms or in the spatial arrangement of their atoms are called "isomers". A "rotational isomer" or "rotamer" is an isomer produced by restricted rotation around a single bond. The compounds disclosed herein include all rotational isomers of said isomers. The compounds disclosed herein encompass all rotational isomers, including but not limited to said rotational isomers. In some embodiments, the compounds disclosed herein include all rotational isomers. In some embodiments, this disclosure provides a compound or its rotational isomers. Isomers whose atoms have different spatial arrangements are called "stereoisomers". In some embodiments, if the phenyl group contains two substituents, each bonded to an adjacent carbon, the compound may be called an ortho isomer. In some embodiments, if the phenyl group contains two substituents, each bonded to a carbon separated by a ring carbon, the compound may be called a meta isomer. In some embodiments, if the phenyl group contains two substituents, each bonded to a carbon separated by two ring carbons, the compound may be referred to as the para-isomer.

[0138] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, it may have a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or by rotating the molecule in a plane of polarized light and specifying it as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0139] As used herein, the term "agent" refers to a molecule, molecular group, complex, or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. In some embodiments, an agent is a pharmaceutical agent (e.g., a therapeutic agent, diagnostic agent, or preventative agent). In some embodiments, the compositions disclosed herein comprise an agent, such as a first therapeutic agent (e.g., at least one, including, for example, at least two or at least three). In some embodiments, the composition may also comprise a second therapeutic agent, a targeting portion, or a diagnostic portion as described herein.

[0140] As used herein, the term "therapeutic agent" includes agents capable of providing local or systemic biological, physiological, or therapeutic effects in the biological system to which they are applied. For example, therapeutic agents can be used to control tumor growth, control infection or inflammation, act as analgesics, promote anti-cell adhesion, and enhance bone growth. Other suitable therapeutic agents may include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active at the time of administration but are converted into biologically active agents through metabolism or some other mechanism after administration to a subject.

[0141] Agents (e.g., therapeutic agents) can include a wide variety of compounds, including chemical compounds and mixtures of chemical compounds (e.g., small organic or inorganic molecules), such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use as defined in the Code of Federal Regulations (CFR)); targeting agents; isotopically labeled compounds; agents suitable for bioprocessing; carbohydrates; saccharin; monosaccharides; oligosaccharides; polysaccharides; biological macromolecules (e.g., peptides, proteins, and peptide analogs and derivatives); peptide mimics; antibodies and their antigen-binding fragments; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucins; lipoproteins; synthetic polypeptides or proteins; small molecules linked to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunizing agents; extracts made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combination thereof.

[0142] In some embodiments, the agent is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, for example, through solvent decomposition, reduction, oxidation, or under physiological conditions, to provide, for example, a pharmaceutically active compound in vivo. A prodrug may include a derivative of a pharmaceutically active compound, for example, an ester formed by reacting an acid or anhydride or mixed anhydride portion of the prodrug moiety with a hydroxyl portion of the pharmaceutically active compound, or an amide prepared by reacting an acid or anhydride or mixed anhydride portion of the prodrug moiety with a substituted or unsubstituted amine of the pharmaceutically active compound. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups may contain prodrugs. In some embodiments, the compositions described herein incorporate a therapeutic agent or a prodrug thereof. In some embodiments, the compositions described herein incorporate more than one therapeutic agent or prodrug.

[0143] In some embodiments, the agent (e.g., a therapeutic agent) is a small molecule. As used herein, the term "small molecule" can refer to a "natural product-like" compound. However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, a small molecule is typically characterized by containing several carbon-carbon bonds and having a molecular weight of less than 5000 Daltons (5 kDa), preferably less than 3 kDa, more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases, it is preferred that the molecular weight of the small molecule is equal to or less than 700 Daltons.

[0144] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those found in the following literature: Harrison's Principles of Internal Medicine, 13th edition, TR. Harrison et al., McGraw-Hill NY, NY; Physicians' Desk Reference, 50th edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Gilman's The Pharmacological Basis of Therapeutics; and the latest edition of the Merck Index, the entire contents of which are incorporated herein by reference.

[0145] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more agents listed in paragraph

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

[0146] In other embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more therapeutic agents listed in International Publication No. WO 2013 / 169739, published on 4 November 2013, including, for example, antihypertensive drugs and / or collagen modifiers (“AHCM”) disclosed in paragraphs 40-49, 283, 286-295; and, for example, microenvironment modifiers disclosed in paragraphs 113-121 of WO 2013 / 169739, which is incorporated herein by reference. In some embodiments, compositions comprising AHCM and / or microenvironment modifiers induce one or more of the following in subjects: reduced solid stress (e.g., growth-induced solid stress in tumors); reduced tumor fibrosis; reduced interstitial hypertension or interstitial fluid pressure (IFP); increased interstitial tumor transport; increased tumor or vascular perfusion; increased vessel diameter and / or dilation of compressed or collapsed vessels; reduced or depleted one or more of the following: cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); reduced extracellular matrix components (such as fibers (e.g., collagen, ...). The levels or production of procollagen and / or polysaccharides (such as glycosaminoglycans like hyaluronic acid or hyaluronic acid) may be reduced; the levels or production of collagen or procollagen may be decreased; the levels or production of hyaluronic acid may be decreased; tumor oxygenation may be increased; tumor hypoxia may be reduced; tumor acidosis may be reduced; immune cell infiltration may be increased; immunosuppression may be reduced; antitumor immunity may be increased; the production of cancer stem cells (also referred to herein as tumor-initiating cells) may be decreased; or the efficacy of therapies may be enhanced (e.g., penetration or spread), such as cancer therapies in the tumor or tumor vascular system (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy).

[0147] Agents, such as therapeutic agents, include the categories and specific examples disclosed herein. The categories are not intended to be limited by specific examples. Those skilled in the art will also recognize many other compounds that belong to the categories and can be used according to this disclosure.

[0148] Examples of therapeutic agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, anti-irritants, coagulation modifiers, diuretics, sympathomimetic agents, anorexia nervosa, antacids, and other gastrointestinal agents; antiparasitic agents, antidepressants, antihypertensive agents, anticholinergic agents, stimulants, antihormonal agents, central and respiratory stimulants, drug antagonists, lipid modulators, uric acid excretion agents, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, sympathomimetic agents, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast agents, radiopharmaceuticals, antiallergics, sedatives, vasodilators, antiviral agents, and antitumor agents or cell growth inhibitors or other agents with anticancer effects, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Other examples include anti-infectives, such as antibiotics and antiviral agents; analgesics and combinations of analgesics; anorexia; antihistamines; anti-arthritis drugs; anti-asthma drugs; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory drugs; anti-migraine preparations; anti-nausea drugs; anti-nicotine nicotine drugs; antitumor drugs; anti-Parkinson's disease drugs; antipruritics; antipsychotics; antipyretics and antispasmodics; anticholinergics; sympathomimetic drugs; xanthine derivatives; and cardiovascular preparations. This includes calcium channel blockers and beta-blockers, such as indole and antiarrhythmic drugs; antihypertensive drugs; diuretics; vasodilators, including those for the coronary, peripheral, and cerebral systems; central nervous system stimulants; cough and cold medicines, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic drugs; psychostimulants; sedatives; and tranquilizers; as well as naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0149] The terms “composition” and “formulation” are used interchangeably.

[0150] The intended "subject" refers to a human (i.e., a male or female of any age, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly person)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog) or a bird. The non-human animal can be male or female at any developmental stage. The non-human animal can be a transgenic or genetically engineered animal.

[0151] The terms “administer,” “administering,” or “administration” refer to the implantation, absorption, ingestion, injection, inhalation, or other introduction of the compound or its composition described herein into or onto a subject.

[0152] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., based on a history of symptoms). Treatment may also continue after symptom relief, for example, to delay and / or prevent recurrence of the disease or disorder.

[0153] The terms "prevent," "preventing," or "prevention" refer to preventive treatment for subjects who currently do not have or have not had any disease but are at risk of developing it, or who have had a disease in the past but are currently not at risk of remission. In some implementations, subjects have a higher risk of developing a disease or a higher risk of disease remission compared to the average healthy member of the subject population.

[0154] The term "NAMPT" or "nicotinamide phosphoribosyltransferase" refers to the key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from the natural precursor nicotinamide. NAMPT catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of the two pathways for rescuing NAD. NAMPT is specifically formulated to produce nicotinamide mononucleotide (NMN) as a product of the NAMPT enzymatic reaction. NAMPT exists both extracellularly and intracellularly. Therefore, in some embodiments, NAMPT is intracellular NAMPT. In some embodiments, NAMPT is extracellular NAMPT. NAMPT can be present in intracellular compartments and can be present in the nucleus and cytosol. NAMPT is expressed systemically, including but not limited to the heart, brain, placenta, lungs, liver, skeletal muscle, kidneys, and pancreas. NAMPT may also be referred to as pre-B cell colony-enhancing factor (PBEF) and adipokines. The protein is also known as NAMPRTase. NAMPT can cause changes in downstream signaling molecules such as sirtuins, PARP, and NADase. 15NAMPT plays a role in a variety of diseases and conditions, see, for example: (i) WO 97 / 48696 on the role of NAMPT in the treatment of cancer, (ii) WO 97 / 48397 on the role of NAMPT in immunosuppression, (iii) WO 2003 / 80054 on the role of NAMPT in the treatment of diseases involving angiogenesis, (iv) WO 2008 / 025857 on the role of NAMPT in the treatment of rheumatoid arthritis and septic shock, and (v) WO 2009 / 109610 on the role of NAMPT in the prevention and treatment of ischemia.

[0155] The terms “modulate,” “modulating,” “modulation,” or “modulator” refer to the ability of a compound to reduce / increase, slow down / accelerate, stop / start, inhibit / stimulate, or prevent / cause the activity of a specific biological target (e.g., NAMPT) in a cell relative to a medium.

[0156] As used herein, the terms “activation,” “activator,” “stimulator,” or “stimulant,” in the context of an enzyme, such as NAMPT, refer to an increase in enzyme activity. In some embodiments, the term refers to an increase in enzyme activity (e.g., NAMPT activity) to a level that is statistically significantly higher than an initial level, which may be, for example, the baseline level of enzyme activity. In some embodiments, the term refers to an increase in enzyme activity (e.g., NAMPT activity) to a level that is 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.5%, 99.9%, 99.99%, or 99.999% greater than an initial level, which may be, for example, the baseline level of enzyme activity.

[0157] The terms “inhibition,” “inhibiting,” “inhibit,” or “inhibitor” refer to the ability of a compound to reduce, slow down, stop, or prevent the activity of a specific biological target (e.g., NAMPT) in a cell relative to a medium.

[0158] As used herein, the term "inhibit" or "inhibition," in the context of an enzyme, such as NAMPT, refers to a reduction in enzyme activity. In some embodiments, the term refers to a reduction in enzyme activity (e.g., NAMPT activity) to a level that is statistically significantly lower than an initial level, which may be, for example, a baseline level of enzyme activity. In some embodiments, the term refers to a reduction in enzyme activity (e.g., NAMPT activity) to a level that is 75%, 50%, 40%, 30%, 25%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001%, or 0.0001% lower than an initial level, which may be, for example, a baseline level of enzyme activity.

[0159] The terms “symptoms,” “disease,” and “symptoms” are used interchangeably.

[0160] "Proliferative disorders" are diseases caused by abnormal growth or spread due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastases. Exemplary proliferative disorders include cancer (i.e., "malignant growths"), benign growths, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

[0161] The terms “inflammatory disease” and “inflammatory symptom” are used interchangeably in this document and refer to a disease or symptom caused by, resulting from, or leading to inflammation. Inflammatory diseases and symptoms include those diseases, conditions, or symptoms characterized by signs of pain (pain caused by the production of harmful substances and nerve stimulation), fever (heat caused by vasodilation), redness (redness caused by vasodilation and increased blood flow), swelling (a lump caused by excessive inflow or restricted outflow of fluid), and / or loss of function (a dysfunction that may be partial or complete, temporary or permanent). Inflammation takes many forms, including but not limited to acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrotic, focal, granulomatous, proliferative, hypertrophic, interstitial, metastatic, necrotic, obliterative, solid, plastic, productive, proliferative, pseudomembranous, purulent, sclerotic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term "inflammatory disease" can also refer to a dysregulated inflammatory response that causes an excessive reaction of macrophages, granulocytes, and / or T lymphocytes, resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic inflammatory symptoms and can be caused by infectious or non-infectious factors.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, bullous pemphigoid, diabetes mellitus (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodbastien's disease, and mixed diseases. Combined connective tissue diseases, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nausea anemia, inflammatory dermatitis, common interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphointerstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatitis, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, adult respiratory distress syndrome. ARDS, encephalitis, immediate-type hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allogeneic transplant rejection, host-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis Iritis, laryngitis, jaundice, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. Ocular inflammatory diseases include, but are not limited to, postoperative inflammation.

[0162] Other exemplary inflammatory symptoms include, but are not limited to, inflammation associated with: acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Goran's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Ritter's arthritis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, and chronic prostatitis. Diabetic analgesia, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, diverticulitis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin conditions (e.g., psoriasis, eczema, burns, dermatitis, pruritus), endometriosis, Guillain-Barré syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity reactions, headache (e.g., migraine, tension headache), intestinal obstruction (e.g., postoperative intestinal obstruction and intestinal obstruction during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (bladder pain syndrome), gastrointestinal disorders (e.g., selected from...). Peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, metastatic colitis, Behçet's syndrome, indeterminate colitis), and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, scleroderma, myasthenia gravis, myocardial ischemia, nephrotic syndrome, and more. Common pemphigus, nausea-zoster anemia, peptic ulcer, polymyositis, primary biliary cirrhosis, neuroinflammatory diseases associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, squamous cell carcinoma, sarcoidosis, spondyloarthritis, Sjögren's syndrome, thyroiditis, transplant rejection, tendinitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injuries), vasculitis, vitiligo, and Wegener's granulomatosis. In some embodiments, the inflammatory condition is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis, and prostatitis. In some embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation caused by infection). In some implementations, the inflammatory symptoms are chronic inflammatory symptoms (e.g., symptoms caused by asthma, arthritis, and inflammatory bowel disease). These compounds can also be used to treat trauma-related inflammatory and non-inflammatory myalgia.The compounds disclosed in this article can also be used to treat cancer-related inflammation.

[0163] Autoimmune diseases are illnesses caused by an inappropriate immune response in a subject's body to normally present substances and tissues. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This may be limited to certain organs (e.g., autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodbach's disease, which may affect the basement membrane of the lungs and kidneys). Treatment for autoimmune diseases typically involves immunosuppression, such as medications that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodbach's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Ritter syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0164] In some embodiments, the inflammatory and / or immune-related conditions are gastrointestinal conditions. In some embodiments, the gastrointestinal condition is selected from gastrointestinal diseases (e.g., peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal diseases (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, metastatic colitis, Behçet's syndrome, indeterminate colitis), and inflammatory bowel syndrome (irritable bowel syndrome)). In some embodiments, the gastrointestinal condition is inflammatory bowel disease (IBD).

[0165] In some embodiments, inflammatory and / or immune symptoms are skin conditions. In some embodiments, skin conditions are pruritus (itching), psoriasis, eczema, burns, or dermatitis. In some embodiments, the skin condition is psoriasis. In some embodiments, the skin condition is pruritus.

[0166] The terms “vesicle” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is not in harmony with the growth of normal tissue. A vegetation or tumor can be “benign” or “malignant”, depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign vegetations” are generally well-differentiated and are characterized by slower growth than malignant vegetations and remain confined to the site of origin. Furthermore, benign vegetations do not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign vegetations include, but are not limited to, lipomas, chondromas, adenomas, acanthomas, senile hemangiomas, seborrheic keratosis, nevi, and sebaceous hyperplasia. In some cases, certain “benign” tumors may later develop into malignant vegetations, possibly due to other genetic changes in a subset of neoplastic cells, and these tumors are referred to as “malignant pre-vesicles.” An exemplary malignant pre-vesicle is a teratoma. In contrast, "malignant growths" are typically poorly differentiated (dysplastic) and characterized by rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue, and are usually identified by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type in which the primary or original tumor is located, rather than by the presence of a "secondary tumor" or "secondary cell mass" of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to bone is called metastatic prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0167] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal human tissues. See, for example, Stedman's Medical Dictionary, 25th edition; edited by Hensyl; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial cell sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct cancer); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); chordoma; craniopharynx Hemangioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g.) Oral squamous cell carcinoma), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell). HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e. Macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixtures of one or more of the above-mentioned leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain diseases). (e.g., gamma chain disease, μ chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastoma; immune cell amyloidosis; renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., generalized mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), amyelometaplasia of unknown etiology (AMM)). Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibroma type 1 or 2, schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (e.g., Paget's penile and scrotal disease); pineal tumor; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), corneal acanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testis carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer;And vulvar cancer (e.g., Paget's vulvary disease).

[0168] Cancer cells can exhibit characteristics similar to embryonic stem cells and / or adult stem cells. As used herein, cancer stem cells (CSCs) are cancer cells that possess one or more embryonic or adult stem cell characteristics. CSCs are generally considered problematic cancer cells due to their ability to metastasize and form tumors in other parts of the body. As used herein, “embryonic characteristics,” “embryonic traits,” etc., refer to gene and / or miRNA expression and / or biological characteristics similar to those of embryonic cells. Undifferentiated cancer cells with embryonic characteristics are metastatic, resistant to chemotherapy and radiotherapy, and capable of regrowth even after most tumors have been removed or shrunk following surgery and / or other cancer treatments. As used herein, “adult stem cell characteristics,” “adult stem cell traits,” etc., refer to gene and / or miRNA expression and / or biological characteristics similar to those of adult stem cells. Cancer cells with adult stem cell traits can metastasize, divide, differentiate, exhibit plasticity, exhibit rapid cell renewal, be resistant to chemotherapy and radiotherapy, and be capable of regrowth even after most tumors have been removed or shrunk following surgery and / or other cancer treatments.

[0169] In some embodiments, cancer stem cells are characterized by the expression of genes and / or miRNAs associated with embryonic state. In some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6 or more) genes or miRNAs associated with embryonic state.

[0170] In some implementations, cancer stem cells are characterized by one or more embryonic characteristics. Examples of embryonic characteristics include, but are not limited to, cell self-renewal properties, excessive proliferative activity, pluripotency, multipotency, expression of embryonic markers, lack of differentiation markers, resistance to chemotherapy, motility, and the ability to generate different cell lineages.

[0171] In some embodiments, cancer stem cells are characterized by the expression of genes and / or miRNAs associated with the 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 the adult stem cell state.

[0172] In some implementations, cancer stem cells are characterized by one or more adult stem cell characteristics. Examples of adult stem cell characteristics include, but are not limited to, one or more of the following characteristics (depending on cell type): cell self-renewal properties, proliferative and / or hyperproliferative activity, pluripotency, plasticity, multipotency, resistance to chemotherapy, and the ability to generate different cell lineages (differentiation and metastasis).

[0173] As used herein, the terms “regenerative medicine” or “regenerative therapy” refer to the ability to promote the regeneration of cells, tissues, and / or organs. Regenerative medicine includes cell and / or tissue engineering to replace, engineer, or regenerate cells, tissues, and / or organs; and / or restore or improve one or more biological functions of dysfunctional or damaged cells, tissues, and / or organs; as well as tissue engineering and organ regeneration. As used herein, “regenerative capacity” refers to the ability of cells, such as stem cells, to transform into dividing progenitor cells and differentiated tissue-specific cells. Regenerative capacity may additionally or alternatively refer to the ability of cells, tissues, and / or organs to replicate, proliferate, restore function, and / or regenerate.

[0174] The term "effective amount" for the compositions described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of the compositions described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the route of administration, and the age and health status of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic effective amount. In some embodiments, the effective amount is the amount of the composition or pharmaceutical composition described herein in a single dose. In some embodiments, the effective amount is the combined amount of the composition or pharmaceutical composition described herein in multiple doses.

[0175] The "therapeuticly effective amount" of the compositions described herein is an amount sufficient to provide therapeutic benefit in the treatment of a condition or sufficient to delay or minimize one or more symptoms associated with the condition. Therapeuticly effective amount of a composition refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a condition. The term "therapeuticly effective amount" can include amounts that improve overall therapy; reduce or avoid symptoms, signs, or causes of a condition; and / or enhance the therapeutic efficacy of another therapeutic agent.

[0176] The “preventatively effective amount” of a compound described herein is an amount sufficient to prevent the symptoms or one or more symptoms associated with the symptoms, or to prevent their recurrence. The preventatively effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides preventative benefit in the prevention of symptoms. The term “preventatively effective amount” may also include amounts that improve overall prevention or enhance the preventative efficacy of another preventative agent.

[0177] The term "gene" refers to a nucleic acid fragment that provides a template for producing a gene product. In some embodiments, the nucleic acid fragment includes regulatory sequences preceding and following the coding sequence. "Natural gene" refers to a gene found in nature that has its own regulatory sequences. "Chimeric gene" or "chimeric construct" refers to any gene or construct that contains regulatory and coding sequences not found in nature, rather than a natural gene. Therefore, a chimeric gene or chimeric construct may contain regulatory and coding sequences derived from different sources, or regulatory and coding sequences derived from the same source but arranged differently from those found in nature. "Endogenous gene" refers to a natural gene located at its natural position in the genome of an organism. "Exogenous" gene refers to a gene that is not normally found in a host organism but is introduced into a host organism through gene transfer. Exogenous genes may include natural genes or chimeric genes inserted into non-natural organisms. "Transgenic" is a gene introduced into the genome through a transformation procedure.

[0178] The terms “nucleic acid” or “nucleic acid sequence,” “nucleic acid molecule,” “nucleic acid fragment,” or “polynucleotide” are used interchangeably. A polynucleotide molecule is a biopolymer composed of nucleotide monomers covalently bonded together in a chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two polynucleotide chains, each helical. In nature, RNA typically occurs as a single-stranded fold. Exemplary types of RNA include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0179] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissues); cell samples (e.g., cytological smears (such as Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirations, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from the first biological sample.

[0180] The phrases “compounds of this disclosure”, “compounds as disclosed herein”, etc., refer to any compound disclosed herein, including (i) compounds of formula (0), (ii) formula (I), (iii) all subclasses and (iv) all compound species, including compounds as provided in the separate Compounds section and the Examples section including Tables E1, E2 and E3, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof. The specified compounds are not included in the phrases “compounds of this disclosure”, “compounds as disclosed herein”, etc.

[0181] This disclosure is not intended to be limited in any way by the exemplary list of substituents provided above. Additional terms may be defined in other parts of this disclosure. Detailed Implementation

[0182] Before describing the disclosed systems, compounds, compositions, methods, uses, and kits in more detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, apparatus, or constructions, and therefore are subject to variation. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting unless specifically defined herein.

[0183] The compounds, compositions thereof, and kits disclosed herein can be used for cancer treatment and the treatment of proliferative diseases or for regenerative medicine. The compounds can differentiate embryonic-like cancer stem cells, kill differentiated cancer stem cells, disrupt their proliferation, and / or inhibit their ability to form new tumors. The compounds can inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce the embryonic or adult stem cell characteristics of one or more cells, reduce cell viability, and / or prevent cell proliferation. Embryonic-like characteristics, including embryonic gene expression patterns, are reactivated in many different types of cancer. Additionally, the compounds can differentiate into adult-like cancer stem cells, kill differentiated adult cancer stem cells, disrupt their proliferation, and / or inhibit their ability to form new tumors. Adult stem cells are also associated with many different types of cancer. In 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, leukemia, or liver cancer. For example, embryonic-like characteristics have been found in cancer stem cells derived from solid tumors, such as colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer. 10 Embryonic-like characteristics have also been found in cancer stem cells derived from hematopoietic system cancers such as leukemia and lymphoma. 14

[0184] Without being bound by any particular theory, it is believed that the compounds and compositions disclosed herein regulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), also known as endothelin and pre-B cell colony enhancer 1 (PBEF). NAMPT is an enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. 15 Nicotinamide adenine dinucleotide is an essential cofactor for cellular metabolism. Nicotinamide mononucleotide (NMN) is a product of the NAMPT enzymatic reaction. NAMPT has been indicated in a variety of diseases and conditions; therefore, regulation (i.e., inhibition) of NAMPT can be used to treat a wide range of indications. 15，16，17 In addition, NAMPT is involved in signal transduction, demonstrating its role as an adipocyte kinase. 18 and immune-regulating cytokines 19 The activity of NAMPT has been described in (i) metabolic / inflammatory conditions, including obesity, type 2 diabetes, metabolic syndrome, atherosclerotic inflammatory diseases and cardiovascular diseases, (ii) non-metabolic chronic inflammatory diseases, including osteoarthritis and acute lung injury, (iii) infections, such as sepsis or intrauterine infections, and (iv) autoimmune inflammatory diseases, including psoriasis, rheumatoid arthritis, Crohn's disease and ulcerative colitis. 15 Therefore, the compounds, compositions thereof, and kits disclosed herein can be used to treat or prevent a variety of diseases and conditions.

[0185] compound

[0186] In some respects, this disclosure provides compounds of formula (0) or (I). Other compounds are also provided herein.

[0187] In some embodiments, the compounds disclosed herein are compounds (e.g., compounds of formula (0) or (I), or compounds described in a further compound section below) or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. In some embodiments, the compounds disclosed herein are compounds (e.g., compounds of formula (0) or (I), or compounds described in a further compound section below) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In some embodiments, the compounds disclosed herein are compounds (e.g., compounds of formula (0) or (I), or compounds described in a further compound section below) or pharmaceutically acceptable salts thereof.

[0188] The compounds disclosed herein can have high water solubility. Compared with certain similar known compounds, the compounds disclosed herein can have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000%) water solubility.

[0189] The compounds disclosed herein can have high microparticle stability. Compared with certain similar known compounds, the compounds disclosed herein can have higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000%) microparticle stability.

[0190] The compounds disclosed herein can treat cancer. Compared with certain similar known compounds, the compounds disclosed herein can have a 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%) therapeutic effect on cancer, which can be demonstrated by the reduction of cancer symptoms and / or the reduction of tumor size.

[0191] Compounds of formulas (0) and (I)

[0192] In some embodiments, compounds of formula (0) are provided herein:

[0193]

[0194] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0195] R 1 C is either replaced or not replaced. 1-12 Alkyl, or substituted or unsubstituted C 1-12 Heteroalkyl;

[0196] R 2 It is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 Heteroalkyl, substituted or unsubstituted 3 to 13-membered heterocyclic -C 1-12 -alkyl, substituted or unsubstituted 3 to 13-membered carbocyclic group -C 1-12 -alkyl or nitrogen-protecting group;

[0197] When R 2 When it is an unsubstituted methyl group, R 1 It is not an unsubstituted ethyl group;

[0198] R 3 It is hydrogen, halogen, substituted or unsubstituted carbon.1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0199] R a Each example is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0200] R 4 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0201] R 5 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0202] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups;

[0203] R 8 Each example is independently hydrogen, halogen, or C that is substituted or unsubstituted. 1-6 alkyl;

[0204] R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2, or R 9 Two examples are linked to form a 3- to 13-membered heterocyclic group, a 3- to 13-membered heterocyclic group, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring;

[0205] n is an integer from 0 to 4, including the end value;

[0206] m is an integer from 0 to 3, including the endpoints;

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

[0208] q is an integer selected from 0 and 1.

[0209] In some embodiments, the compound of formula (0) has formula (0a):

[0210]

[0211] In some embodiments, the compound of formula (0) has formula (0b):

[0212]

[0213] In some embodiments, the compound of formula (0) has formula (0c):

[0214]

[0215] In some embodiments, compounds of formula (I) are provided herein:

[0216]

[0217] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, wherein:

[0218] R 1 C is either replaced or not replaced. 1-12 Alkyl, or substituted or unsubstituted C 1-12 Heteroalkyl;

[0219] R 2 It is hydrogen, substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted C 1-12 Heteroalkyl, substituted or unsubstituted 3 to 13-membered heterocyclic -C 1-12 -alkyl, substituted or unsubstituted 3 to 13-membered carbocyclic group -C 1-12 -alkyl or nitrogen-protecting group;

[0220] When R 2 When it is an unsubstituted methyl group, R 1 It is not an unsubstituted ethyl group;

[0221] R 3 It is hydrogen, halogen, substituted or unsubstituted carbon.1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0222] R a Each example is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl groups, oxygen-protecting groups when bonded to oxygen atoms, or nitrogen-protecting groups when bonded to nitrogen atoms;

[0223] R 4 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0224] R 5 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0225] R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups;

[0226] R 8 Each example is independently hydrogen, halogen, or C that is substituted or unsubstituted. 1-6 alkyl;

[0227] R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2;

[0228] n is an integer from 0 to 4, including the end value;

[0229] m is an integer from 0 to 3, inclusive; and

[0230] p is an integer from 0 to 3, inclusive.

[0231] In some embodiments, the compound of formula (I) has formula (Iz):

[0232]

[0233] In some embodiments, the compound of formula (I) has formula (Ia):

[0234]

[0235] In some embodiments, the compound of formula (I) has formula (Ib):

[0236]

[0237] In some embodiments, the compound of formula (I) has formula (Ic):

[0238]

[0239] In some implementations, R 1 C is either replaced or not replaced. 1-12 Alkyl group. In some embodiments, R 1 The C that was replaced 1-12 Alkyl group. In some embodiments, R 1 It is the unreplaced C 1-12 Alkyl group. In some embodiments, R 1 C is either replaced or not replaced. 1-6 Alkyl group. In some embodiments, R 1 It is the unreplaced C 1-6 Alkyl group. In some embodiments, R 1 It is an unsubstituted C1 alkyl group. In some embodiments, R 1 It is an unsubstituted C2 alkyl group. In some embodiments, R 1 It is an unsubstituted C3 alkyl group. In some embodiments, R 1 It is an unsubstituted C4 alkyl group. In some embodiments, R 1 It is an unsubstituted C5 alkyl group. In some embodiments, R 1 It is an unsubstituted C6 alkyl group. In some embodiments, R 1 The C that was replaced 1-6 Alkyl group. In some embodiments, R 1 It is a substituted C1 alkyl group. In some embodiments, R 1It is a substituted C2 alkyl group. In some embodiments, R 1 It is a substituted C3 alkyl group. In some embodiments, R 1 It is a substituted C4 alkyl group. In some embodiments, R 1 It is a substituted C5 alkyl group. In some embodiments, R 1 It is a substituted C6 alkyl group. In some embodiments, R 1 It is fluorinated C 1-6 Alkyl groups (e.g., -CF3, -CHF2, -CH2F). In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 It is propyl. In some embodiments, R 1 C is either replaced or not replaced. 1-12 Heteroalkyl. In some embodiments, R 1 It is the unreplaced C 1-12 Heteroalkyl. In some embodiments, R 1 The C that was replaced 1-12 Heteroalkyl. In some embodiments, R 1 C is either replaced or not replaced. 1-6 Heteroalkyl. In some embodiments, R 1 It is the unreplaced C 1-6 Heteroalkyl. In some embodiments, R 1 It is an unsubstituted C1 heteroalkyl group. In some embodiments, R 1 It is an unsubstituted C2 heteroalkyl group. In some embodiments, R 1 It is an unsubstituted C3 heteroalkyl group. In some embodiments, R 1 It is an unsubstituted C4 heteroalkyl group. In some embodiments, R 1 It is an unsubstituted C5 heteroalkyl group. In some embodiments, R 1 It is an unsubstituted C6 heteroalkyl group. In some embodiments, R 1 The C that was replaced 1-6 Heteroalkyl. In some embodiments, R 1 It is a substituted C1 heteroalkyl group. In some embodiments, R 1 It is a substituted C2 heteroalkyl group. In some embodiments, R 1 It is a substituted C3 heteroalkyl group. In some embodiments, R 1 It is a substituted C4 heteroalkyl group. In some embodiments, R 1 It is a substituted C5 heteroalkyl group. In some embodiments, R 1 It is a substituted C6 heteroalkyl group. In some embodiments, R1 It is methoxy, ethoxy, or propoxy. In some embodiments, R 1 Replaced by: halogenated group, -CN, -NR a 2. -CO2R aa -C(=O)R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa , or -NR bb C(=O)N(R bb 2. In some implementations, R 1 Replaced by: -CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa , or -NR bb C(=O)N(R bb )2.

[0240] In some implementation schemes, R bb It can be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or pentyl.

[0241] In some implementations, R 1 The substituents on the group are -CN, -F, -Cl, -N(R) a (C=O)OR a 、or -COOR a In some implementations, R 1 The substituents on the group are -CN, -F, -Cl, and -NR. a 2. -N(R) a (C=O)OR a -COOR a 、or -(C=O)R a In some implementations, R 1 The substituents on the group are -CN, -F, -Cl, -NH2, -NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)Ot Bu, or -C(=O)CH3.

[0242] In some implementations, R 2 It is hydrogen. In some implementations, R 2 It is not hydrogen. In some implementations, R 2 C is either replaced or not replaced. 1-12 Alkyl group. In some embodiments, R 2 It is the unreplaced C 1-12 Alkyl group. In some embodiments, R 2 The C that was replaced 1-12 Alkyl group. In some embodiments, R 2 It is Me. In some implementations, R 2 It is Et, Pr, or Bu. In some implementations, R 2 It is a nitrogen protecting group.

[0243] In some implementations, R 2 C is either replaced or not replaced. 1-12 Alkyl group. In some embodiments, R 2 It is the unreplaced C 1-12 Alkyl group. In some embodiments, R 2 The C that was replaced 1-12 Alkyl group. In some embodiments, R 2 C is either replaced or not replaced. 1-6 Alkyl group. In some embodiments, R 2 It is the unreplaced C 1-6 Alkyl group. In some embodiments, R 2 It is an unsubstituted C1 alkyl group. In some embodiments, R 2 It is an unsubstituted C2 alkyl group. In some embodiments, R 2 It is an unsubstituted C3 alkyl group. In some embodiments, R 2 It is an unsubstituted C4 alkyl group. In some embodiments, R 2 It is an unsubstituted C5 alkyl group. In some embodiments, R 2 It is an unsubstituted C6 alkyl group. In some embodiments, R 2 The C that was replaced 1-6 Alkyl group. In some embodiments, R 2 It is a substituted C1 alkyl group. In some embodiments, R 2 It is a substituted C2 alkyl group. In some embodiments, R 2 It is a substituted C3 alkyl group. In some embodiments, R 2 It is a substituted C4 alkyl group. In some embodiments, R 2It is a substituted C5 alkyl group. In some embodiments, R 2 It is a substituted C6 alkyl group. In some embodiments, R 2 It is halogenated C 1-12 Alkyl group. In some embodiments, R 2 It is a substituted C6 alkyl group. In some embodiments, R 2 It is fluorinated C 1-6 Alkyl groups (e.g., -CF3, -CHF2, -CH2F). In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is propyl. In some embodiments, R 2 C is either replaced or not replaced. 1-12 Heteroalkyl. In some embodiments, R 2 The C that was replaced 1-12 Heteroalkyl. In some embodiments, R 2 It is the unreplaced C 1-12 Heteroalkyl. In some embodiments, R 2 C is either replaced or not replaced. 1-6 Heteroalkyl. In some embodiments, R 2 It is the unreplaced C 1-6 Heteroalkyl. In some embodiments, R 2 It is an unsubstituted C1 heteroalkyl group. In some embodiments, R 2 It is an unsubstituted C2 heteroalkyl group. In some embodiments, R 2 It is an unsubstituted C3 heteroalkyl group. In some embodiments, R 2 It is an unsubstituted C4 heteroalkyl group. In some embodiments, R 2 It is an unsubstituted C5 heteroalkyl group. In some embodiments, R 2 It is an unsubstituted C6 heteroalkyl group. In some embodiments, R 2 The C that was replaced 1-6 Heteroalkyl. In some embodiments, R 2 It is a substituted C1 heteroalkyl group. In some embodiments, R 2 It is a substituted C2 heteroalkyl group. In some embodiments, R 2 It is a substituted C3 heteroalkyl group. In some embodiments, R 2 It is a substituted C4 heteroalkyl group. In some embodiments, R 2 It is a substituted C5 heteroalkyl group. In some embodiments, R 2 It is a substituted C6 heteroalkyl group. In some embodiments, R 2It is methoxy, ethoxy, or propoxy.

[0244] In some implementations, R 2 It is a substituted or unsubstituted 3- to 13-membered heterocyclic group -C 1-12 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 13-membered heterocyclic group -C 1-12 Alkyl group. In some embodiments, R 2 It is the substituted 3 to 13-membered heterocyclic group -C 1-12 Alkyl group. In some embodiments, R 2 It is a substituted or unsubstituted 3- to 13-membered heterocyclic group -C 1-6 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic group -C 1-6 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic -C1 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic C2 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic -C3 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic -C4 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic C5 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered heterocyclic -C6 alkyl group. In some embodiments, R 2 It is the substituted 3- to 6-membered heterocyclic group -C 1-6 Alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered heterocyclic -C1 alkyl group. In some embodiments, R 2 It is a substituted C2 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered heterocyclic -C3 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered heterocyclic C4 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered heterocyclic C5 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered heterocyclic -C6 alkyl group. In some embodiments, R 2 It is a halogenated 3 to 6-membered heterocyclic group -C 1-12 Alkyl group. In some embodiments, R 2 It is a substituted 3 to 6-membered heterocyclic C6 alkyl group.

[0245] In some implementations, R2 It is a substituted or unsubstituted 3 to 13-membered carbon cyclogroup -C 1-12 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 13-membered carbon cyclogroup -C 1-12 Alkyl group. In some embodiments, R 2 The replaced 3 to 13-membered carbon cyclogroups -C 1-12 Alkyl group. In some embodiments, R 2 It is a substituted or unsubstituted 3 to 13-membered carbon cyclogroup -C 1-6 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cyclogroup -C 1-6 Alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloalkyl-C1 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloalkyl-C2 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloalkyl group (C3 alkyl). In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloalkyl-C4 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloalkyl-C5 alkyl group. In some embodiments, R 2 It is an unsubstituted 3- to 6-membered carbon cycloyl-C6 alkyl group. In some embodiments, R 2 The replaced 3- to 6-membered carbon cyclogroups -C 1-6 Alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered carbon cycloalkyl group (C1 alkyl group). In some embodiments, R 2 It is a substituted C2 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered carbon cycloyl-C3 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered carbon cycloyl-C4 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered carbon cycloyl-C5 alkyl group. In some embodiments, R 2 It is a substituted 3- to 6-membered carbon cycloyl-C6 alkyl group. In some embodiments, R 2 It is a halogenated 3- to 6-membered carbon cyclogroup -C 1-12 Alkyl group. In some embodiments, R 2 It is a substituted 3 to 6-membered carbon cycloalkyl-C6 alkyl group.

[0246] In some implementations, R 2 It is a substituted C6 heteroalkyl group. In some embodiments, R 2 It is methoxy, ethoxy, or propoxy.

[0247] In some implementations, R 2 Replaced by: halogenated group, -CN, -NR a 2. -CO2R aa -C(=O)R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa , or -NR bb C(=O)N(R bb 2. In some implementations, R 2 Replaced by: -CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa , or -NR bb C(=O)N(R bb )2.

[0248] In some implementation schemes, R bb It can be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or pentyl.

[0249] In some implementations, R 2 The substituents on the group are -CN, -F, -Cl, -N(R) a (C=O)OR a or COOR a .

[0250] In some implementations, R 2 The substituents on the group are -CN, -F, -Cl, -N(R) a (C=O)OR a 、or -COOR a In some implementations, R 2 The substituents on the group are -CN, -F, -Cl, and -NR. a 2. -N(R) a (C=O)OR a-COOR a 、or -(C=O)R a In some implementations, R 1 The substituents on the group are -CN, -F, -Cl, -NH2, -NHC(=O)OEt, -NHC(=O)OMe, -NHC(=O)O t Bu, or -C(=O)CH3.

[0251] In some implementations, when R 2 When it is an unsubstituted methyl group, R 1 Not an unsubstituted ethyl. In some embodiments, when R 2 When it is methyl, R 1 It is not ethyl.

[0252] In some implementations, when R 2 When it is an unsubstituted methyl group, R 1 It is not the unsubstituted n-propyl group. In some embodiments, when R... 2 When it is methyl, R 1 It's not propyl.

[0253] In some implementations, when R 2 When it is an unsubstituted methyl group, R 1 It is not an unsubstituted ethoxy group. In some embodiments, when R... 2 When it is methyl, R 1 It is not ethoxylated.

[0254] In some implementations, R 1 It is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a methoxy group, or an ethoxy group; and R 2 It is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted isopropyl group, a substituted or unsubstituted butyl group, a substituted or unsubstituted sec-butyl group, a substituted or unsubstituted 3- to 6-membered carbon cycloalkyl group -C1 alkyl group, a substituted or unsubstituted 3- to 6-membered carbon cycloalkyl group -C2 alkyl group, a substituted or unsubstituted 3- to 6-membered heterocyclic group -C1 alkyl group, or a substituted or unsubstituted 3- to 6-membered heterocyclic group -C2 alkyl group.

[0255] In some implementations, R 2 The C that was replaced 1-6 Alkyl group. In some embodiments, R 2 It is a haloalkyl group. In some embodiments, R 2 It is difluoroethyl. In some embodiments, R 2 It is 2,2-difluoroethyl.

[0256] In some implementation schemes, R 2 It is a substituted or unsubstituted 3- to 6-membered carbon cyclogroup -C 1-6 Alkyl group. In some embodiments, R 2 It is a substituted or unsubstituted 3- to 6-membered carbon cycloalkyl group (C1 alkyl group). In some embodiments, R 2 It is cyclopropylmethyl.

[0257] In some implementation schemes, R 3 It is hydrogen, halogen, substituted or unsubstituted carbon. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a 2. In some implementation schemes, R 3 It is a hydrogen, chlorinated, bromo, or iodinated carbon group, substituted or unsubstituted. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a 2. In some implementation schemes, R 3 It 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.

[0258] In some implementation schemes, R 3 It is hydrogen. In some implementations, R 3 It is a halogen. In some implementations, R 3 It is a chlorinated, brominated, or iodinated group. In some embodiments, R 3 It is a chlorinated group. In some embodiments, R 3 It is a fluorinated group. In some embodiments, R 3 Yes -CN. In some implementations, R 3 C is either replaced or not replaced. 1-6 Alkyl groups (e.g., unsubstituted C14) 1-6 Alkyl). In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3It is propyl or butyl. In some embodiments, R 3 It is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 3 Yes - OR a In some implementations, R 3 It is -OH. In some embodiments, R 3 It is -O (substituted or unsubstituted C) 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 3 Yes - COOR a In some implementations, R 3 Yes - COOR a , where R a It is either hydrogen or a substituted or unsubstituted C. 1-6 Alkyl groups (e.g., -COOMe, -COOEt, -COO(CH2)2CH3, -COO(CH2)3CH3, or -COOC(CH3)3. In some embodiments, R...) 3 It is -COR a In some implementations, R 3 It is -COR a , where R a It is either hydrogen or a substituted or unsubstituted C. 1-6 Alkyl groups (e.g., -COMe, -COEt, -CO(CH2)2CH3, -CO(CH2)3CH3, or -COC(CH3)3). In some embodiments, R 3 It is -N(R) a 2. In some implementations, R 3 It is -NH2. In some implementations, R 3 Yes - NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 3 It is -N (substituted or unsubstituted C) 1-6 Alkyl group (e.g., -N(Me)2). In some embodiments, R 3 It is -C(=O)N(R) a 2. In some implementations, R 3 It is -C(=O)NH2. In some implementations, R 3 It is -C(=O)NHR a (For example, -C(=O)NH(C with or without substitution) 1-6 Alkyl groups, for example, -C(=O)NHMe. In some embodiments, R3 It is -C(=O)N (C that has been substituted or not substituted) 1-6 Alkyl group 2, for example, -C(=O)N(Me)2). In some embodiments, R 3 It is a halogenated group or -COOR a In some implementations, R 3 It is a chlorinated group or -COOMe.

[0259] In some implementations, R a Each example is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, an oxygen-protecting group when attached to an oxygen atom, or a nitrogen-protecting group when attached to a nitrogen atom. In some embodiments, R a Each example is hydrogen. In some implementations, R a The example is not hydrogen. In some implementations, R a At least one example is C, whether it has been replaced or not. 1-6 Alkyl groups (e.g., unsubstituted C14) 1-6 Alkyl). In some embodiments, R a At least one example is Me. In some implementations, R a At least one example is Et, Pr, or Bu. In some implementations, R a At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, e.g., -CF3).

[0260] In some implementation schemes, R 4 It is hydrogen, halogen, substituted or unsubstituted carbon. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a 2. In some implementation schemes, R 4 It is hydrogen. In some implementations, R 4 It is a halogen. In some implementations, R 4 It is a chlorinated group. In some embodiments, R 4 It is a fluorinated group. In some embodiments, R 4 Yes -CN. In some implementations, R 4 C is either replaced or not replaced. 1-6 Alkyl groups (e.g., unsubstituted C14) 1-6 Alkyl). In some embodiments, R 4 It is methyl. In some embodiments, R 4It is ethyl. In some embodiments, R 4 It is propyl or butyl. In some embodiments, R 4 It is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 4 Yes - OR a In some implementations, R 4 It is -OH. In some embodiments, R 4 It is -O (substituted or unsubstituted C) 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 4 Yes - COOR a In some implementations, R 4 Yes - COOR a , where R a It is either hydrogen or a substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R 4 It is -COR a In some implementations, R 4 It is -COR a , where R a It is either hydrogen or a substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R 4 It is -N(R) a 2. In some implementations, R 4 It is -NH2. In some implementations, R 4 Yes - NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups). In some embodiments, R 4 It is -N (substituted or unsubstituted C) 1-6 Alkyl group (e.g., -N(Me)2). In some embodiments, R 4 It is -C(=O)N(R) a 2. In some implementations, R 4 It is -C(=O)N(R) a )2, where R a It is either hydrogen or a substituted or unsubstituted C. 1-6 alkyl.

[0261] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0262] In some implementations, with R 3 and optionally with R 4The benzene ring is composed of: Indication. In some implementations, it includes R. 3 and optionally with R 4 The benzene ring is composed of: Indication. In some implementations, it includes R 3 and optionally with R 4 The benzene ring is composed of: Indication. In some implementations, it includes R 3 and optionally with R 4 The benzene ring is composed of: express.

[0263] In some embodiments, each example of R5 is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -N(Ra)2 or -CN. In some implementations, R 5 Each example is independently for -COOR a -COR a or -(C=O)N(R) a 2. In some implementations, R 5 At least one example is hydrogen. In some implementations, R 5 Each example is hydrogen. In some implementations, R 5 At least one example is not hydrogen. In some implementations, R 5 The example is not hydrogen. In some implementations, R 5 At least one example is halogen. In some implementations, R 5 At least one example is F. In some implementations, R 5 At least one example is Cl. In some implementations, R 5 At least one example is C, whether it has been replaced or not. 1-6 Alkyl groups (e.g., unsubstituted C14) 1-6 Alkyl). In some embodiments, R 5 At least one example is Me. In some implementations, R 5 At least one example is Et, Pr, or Bu. In some implementations, R 5 At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 5 At least one example is -OR a In some implementations, R 5 At least one example is -OH. In some implementations, R 5At least one example is -O (substituted or unsubstituted C). 1-6 Alkyl groups (e.g., -OMe). In some embodiments, R 5 At least one example is -N(R) a 2. In some implementations, R 5 At least one example is -NH2. In some implementations, R 5 At least one example is -NHR a (For example, -NH (substituted or unsubstituted C) 1-6 Alkyl groups, for example, -NHMe. In some embodiments, R 5 At least one example is -N (substituted or unsubstituted C). 1-6 Alkyl)2, for example, -N(Me)2. In some embodiments, R 5 At least one example is -CN. In some implementations, R 5 At least one example is halogen, substituted or unsubstituted C. 1-6 Alkyl or -OR a .

[0264] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3.

[0265] In some implementations, m is 0 and p is 0. In some implementations, m is 0 and p is 1. In some implementations, m is 0, p is 0, and n is 0. In some implementations, m is 0, p is 0, and n is 1. In some implementations, m is 0, p is 1, and n is 1.

[0266] In some implementations, R is optionally included. 5 The central pyridine ring is composed of: Indication. In some implementations, optionally with R 5 The central pyridine ring is composed of: Indication. In some implementations, optionally with R 5 The central pyridine ring is composed of: Indication. In some implementations, optionally with R 5 The central pyridine ring is composed of: express.

[0267] In some implementations, R 6 It is hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, R 6 It is hydrogen. In some implementations, R 6 C is either replaced or not replaced.1-6 Alkyl group. In some embodiments, R 6 It is a substituted or unsubstituted methyl group. In some embodiments, R 6 It is a substituted or unsubstituted ethyl group. In some embodiments, R 6 It is a nitrogen protecting group selected from toluenesulfonyl, tert-butoxycarbonyl, acetyl or benzoyl.

[0268] In some implementations, R 8 Each example is independently hydrogen, halogen, or C that is substituted or unsubstituted. 1-6 Alkyl group. In some embodiments, R 8 Each example is hydrogen. In some implementations, R 8 One example is hydrogen. In some implementations, R 8 At least one example is halogen. In some implementations, R 8 At least one example is C, whether it has been replaced or not. 1-6 Alkyl group. In some embodiments, R 8 At least one example is the unreplaced C. 1-6 Alkyl (e.g., methyl, ethyl, propyl). In some embodiments, R 8 At least one example is C replaced by at least one example of a halogen (e.g., F). 1-6 alkyl.

[0269] In some implementations, q is 0. In other implementations, q is 1.

[0270] In some implementations, q is 0 and n is 0, 1, or 2. In some implementations, q is 1 and n is 0, 1, or 2.

[0271] In some implementation schemes, R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -COR a -N(R) a )2、-CN、or-(C=O)N(R a )2, or R 9 Two examples are linked to form a 3- to 13-membered heterocyclic group, a 3- to 13-membered heterocyclic group, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring. In some embodiments, R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a -COOR a -CORa -N(R) a )2、-CN、or-(C=O)N(R a )2. R 9 Each example is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, -OR a 、or -N(R a 2. In some implementations, R 9 At least one example is hydrogen. In some implementations, R 9 Each example is hydrogen. In some implementations, R 9 At least one example is not hydrogen. In some implementations, R 9 The example is not hydrogen. In some implementations, R 9 At least one example is halogen. In some implementations, R 9 At least one example is F. In some implementations, R 9 At least one example is Cl. In some implementations, R 9 At least one example is C, whether it has been replaced or not. 1-6 Alkyl groups (e.g., unsubstituted C14) 1-6 Alkyl). In some embodiments, R 9 At least one example is Me. In some implementations, R 9 At least one example is Et. In some implementations, R 9 At least one example is Pr or Bu. In some implementations, R 9 At least one example is fluorinated C 1-6 Alkyl groups (e.g., fluorinated methyl groups, such as -CF3). In some embodiments, R 9 At least one example is -OR a In some implementations, R 9 At least one example is -OH. In some implementations, R 9 At least one example is -O (substituted or unsubstituted C). 1-6 Alkyl). In some embodiments, R 9 At least one example is -OMe. In some implementations, R 9 At least one example is -N(R) a 2. In some implementations, R 9 At least one example is -NH2. In some implementations, R 9 At least one example is -NHR a (For example, -NH (substituted or unsubstituted C) 1-6Alkyl groups, for example, -NHMe. In some embodiments, R 9 At least one example is -NHR a , where R a The C that was replaced 1-6 Alkyl group. In some embodiments, R 9 At least one example is -NHR a , where R a C is replaced by -NH2, -NHMe or -NMe2 1-6 Alkyl group. In some embodiments, R 9 At least one example is -NHR a , where R a It is the unreplaced C 1-6 Alkyl group. In some embodiments, R 9 At least one example is -N (substituted or unsubstituted C). 1-6 Alkyl)2. In some embodiments, R 9 At least one example is -N(Me)2. In some implementations, R 9 At least one example is -CN. In some implementations, R 9 At least one example is halogen, substituted or unsubstituted C. 1-6 Alkyl or -OR a In some implementations, R 9 More than one example is C 1-6 Alkyl (e.g., R) 9 Two examples are methyl groups. In some implementations, R 9 More than one example is halogens (e.g., R... 9 Two examples are fluorinated groups). In some implementations, R 9 One example is C 1-6 Alkyl, and R 9 The second example is halogens. In some implementations, R... 9 One example is methyl, and R 9 The second example is fluorinated groups.

[0272] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0273] In some implementations, R is optionally included. 9 The terminal pyridine ring is composed of: Indication. In some implementations, optionally with R 9 The terminal pyridine ring is composed of: Indication. In some implementations, optional inclusion of R 9 The terminal pyridine ring is composed of: Indication. In some implementations, optionally with R 9 The terminal pyridine ring is composed of: Indication. In some implementations, optional inclusion of R 9 The terminal pyridine ring is composed of: Indication. In some implementations, optionally with R 9 The terminal pyridine ring is composed of: express.

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

[0275] In some implementation schemes, R 9 Two examples are linked to form a 3- to 13-membered heterocyclic group, a 3- to 13-membered heterocyclic group, a 6- to 12-membered aryl ring, or a 5- to 14-membered heteroaryl ring. In some embodiments, R 9 Two examples are linked to form a 5-membered heteroaryl ring. In some embodiments, R 9 Two examples are linked to form a 5-membered heterocyclic base ring. In some implementations, R 9 Two examples are linked to form pyrrole, imidazole, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophene, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl, or imidazolelinyl. In some embodiments, R 9 Two examples are linked to form a 5-membered heteroaryl or heterocyclic ring, and when combined with R 9 When observed together with the pyridyl ring to which the group is attached, the group consists of: express.

[0276] In some implementations, R 3 It is a halogenated group or -COORa R 2 It is C 1-6 Halogenated alkyl groups or 3 to 6-membered carbocyclic groups -C 1-6 Alkyl, and R 1 C is either replaced or not replaced. 1-6 Alkyl group. In some embodiments, R 3 It is a halogenated group or -COOR a R 2 It is C 1-6 Halogenated alkyl groups or 3 to 6-membered carbocyclic groups -C 1-6 Alkyl, and R 1 It is a substituted or unsubstituted methyl group.

[0277] In some embodiments, the compound of formula (I) has formula (Iz), wherein each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl. In some embodiments, each R 9 Independently selected from methyl, fluorinated, and chloro groups, and R 3 It is methyl. In some embodiments, each R 9 It is methyl, and R 3 It is methyl. In some embodiments, each R 9 It is methyl. In some embodiments, R 3 It is a methyl group.

[0278] In some embodiments, the compound of formula (I) has the following formula:

[0279]

[0280] Each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups; and R 3 It is methyl. In some embodiments, each R 9 Independently selected from methyl, fluorinated, and chloro groups; and R 3 It is methyl. In some embodiments, each R 9 It is methyl; and R 3 It is methyl. In some embodiments, each R 9It is methyl. In some embodiments, R 3 It is a methyl group.

[0281] In some embodiments, the compound of formula (I) has formula (Iz), wherein each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is a chlorinated group. In some implementations, each R 9 Independently selected from methyl, fluorinated, and chloro groups, and R 3 It is a chlorinated group. In some embodiments, each R 9 It is methyl, and R 3 It is a chlorinated group. In some implementations, each R 9 It is methyl. In some embodiments, R 3 It is a chlorinated group.

[0282] In some embodiments, the compound of formula (I) has the following formula:

[0283]

[0284] Each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups; and R 3 It is a chlorinated group. In some implementations, each R 9 R3 is independently selected from methyl, fluorinated, and chloro groups; and R3 is a chloro group. In some embodiments, each R... 9 It is methyl; and R 3 It is a chlorinated group. In some implementations, each R 9 It is methyl. In some embodiments, R 3 It is a chlorinated group.

[0285] In some embodiments, the compound of formula (0) has formula (0a), (0b) or (0c), wherein each R 9 Independently selected from methyl, fluorinated, chloro, methoxy, and amino groups, or R 9 Two examples are connected to form a loop, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is methyl. In some embodiments, each R 9 Independently selected from methyl, fluorinated, and chloro groups, and R 3 It is methyl. In some embodiments, each R 9 It is methyl, and R 3 It is methyl. In some embodiments, each R 9 It is methyl. In some embodiments, R 3 It is a methyl group.

[0286] In some embodiments, the compound of formula (0) has formula (0a), (0b) or (0c), wherein each R 9 Independently selected from methyl, fluorinated, chloro, methoxy, and amino groups, or R 9 Two examples are connected to form a loop, and R 3 It is methyl, fluorinated, or chloro. In some embodiments, each R 9 Independently selected from methyl, fluorinated, chlorolated, methoxy, and amino groups, and R 3 It is a chlorinated group. In some implementations, each R 9 Independently selected from methyl, fluorinated, and chloro groups, and R 3 It is a chlorinated group. In some embodiments, each R 9 It is methyl, and R 3 It is a chlorinated group. In some implementations, each R 9 It is methyl. In some embodiments, R 3 It is a chlorinated group.

[0287] In some embodiments, q is 1 in the compound of formula (0). In some embodiments, q is 1 in the compound of formula (0a). In some embodiments, q is 1 in the compound of formula (0b). In some embodiments, q is 1 in the compound of formula (0c). In some embodiments, q is 1 in the compound of formulas (0), (0a), (0b), or (0c), and R 3 It is methyl, chloro, or -COOR a .

[0288] In some embodiments, q is 0 in the compound of formula (0). In some embodiments, q is 0 in the compound of formula (0a). In some embodiments, q is 0 in the compound of formula (0b). In some embodiments, q is 0 in the compound of formula (0c). In some embodiments, q is 0 in the compounds of formulas (0), (0a), (0b), or (0c), and R 3 It is methyl, chloro, or -COORa .

[0289] In some embodiments, the compounds of formula (0) or (I) have the following formula:

[0290]

[0291]

[0292]

[0293] Or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0294] In some embodiments, the compound of formula (0) or (I) is a mixture having the following formula:

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] Or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0313] In certain embodiments, the compound is selected from the group consisting of: I-466, I-467, I-468, I-482, I-483, I-484, I-485, I-486, I-487, I-488, I-489, I-491, I-492, I-495, I-497, I-499, I-500, I-501, I-502, I-503, I-510, I-512, I-517, I-593, I-594, I-595, I-596, I-599, I-600, I-601, I-602, I-603 , I-604, I-605, I-606, I-608, I-609, I-610, I-611, I-619, I-620, I-626, I-629, I-631, I-639, I-652, I-658, I-662, I-663, I-6 77. I-685, I-689, I-690, I-T2106, I-T2107, I-T2120, I-T2161, I-T2162, I-T2163, I-T2164, I-T2165, I-T2166, I-T2167, I-T216 8. I-T2169, I-T2170, I-T2171, I-T2172, I-T2174, I-T2175, I-T2176, I-T2177, I-T2178, I-T2179, I-T2180, I-T2181, I-T2182, I-T2183, I-T2184, I-T2185, I-T2186, I-T2187, I-T2188, I-T2206, I-T2211, I-T2212, I-T2213, I-T2217, I-T2218, I-T2219, I-T 2223, 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 pharmaceutically acceptable salts, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0314] In some embodiments, the compound is selected from the group consisting of: I-674, I-676, I-679, I-681, I-683, I-684, I-687, I-T2101, I-T2102, I-T2109, I-T2135, I-T2136, I-T2139, I-T2157, I-T2158, I-T2159, I-T2160, I-T2173, I-T2189, I-T2190, I-T2191, I-T2192, I-T2193, I-T2194, I-T2195, I-T2196, I-T2197, I-T2198, I-T2199, I-T 2200, 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 pharmaceutically acceptable salts, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0315] In certain embodiments, the compound is selected from the group consisting of: 1-403, 1-404, 1-412, 1-453, 1-468, 1-495, 1-594, 1-5 95. I-596, I-599, I-600, I-601, I-602, I-603, I-604, I-606, I-609, I-610, I-611 I-619, I-620, I-626, I-652, I-662, I-677, I-679, I-681, I-683, I-685, I-689, I-690, I-696 and I-697, or pharmaceutically acceptable salts, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0316] In some embodiments, the compounds are selected from the group consisting of:

[0317]

[0318] Or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0319] In some respects, compounds of formula (0) or (I) do not have the following formula:

[0320] In some embodiments, the compounds of formula (0) or (I) are not the compounds disclosed in: International PCT application No. PCT / US2019 / 030664, filed May 3, 2019, which is incorporated herein by reference. In some aspects, the compounds of formula (0) or (I) do not have the following formula:

[0321] Or a compound that is not disclosed in International PCT Application No. PCT / US2019 / 030664 filed on May 3, 2019, which is incorporated herein by reference.

[0322] Other compounds

[0323] This article also provides compounds selected from the following groups:

[0324] Or a pharmaceutically acceptable salt, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0325] This article also provides compounds selected from the following groups:

[0326] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0327] This article also provides compounds selected from the following groups:

[0328] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0329] In some embodiments, the compound is selected from the group consisting of I-481, I-597, I-624, I-630 and I-675, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0330] In some embodiments, the compound is selected from the group consisting of I-331, I-496, I-511, I-450 and I-527, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0331] In some embodiments, the compound is selected from the group consisting of I-331, I-402, I-597, I-624 and I-630, or pharmaceutically acceptable salts, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof.

[0332] This article also provides compounds selected from the following groups:

[0333] Or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0334] Composition and medicine box

[0335] This disclosure provides compositions comprising compounds of this disclosure (e.g., compounds of formula (0) or (I), any compounds described herein, or any compounds appearing in the section entitled "Additional Compounds") and excipients (e.g., pharmaceutically acceptable excipients). In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the excipient is a pharmaceutically acceptable excipient.

[0336] This disclosure also provides compositions that further comprise additional pharmaceutical agents.

[0337] The compositions described herein can be prepared by any method known in the art. Typically, such preparation methods involve associating the compounds of this disclosure with an excipient, and may include one or more agents or auxiliary components, and then, if necessary and / or required, shaping and / or packaging the product into desired single- or multi-dose units. In some embodiments, the agent is a pharmaceutical preparation.

[0338] In some embodiments, the compounds disclosed herein are in the form of pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs.

[0339] The composition may be prepared, packaged, and / or sold as a single unit dose and / or in batches of multiple single unit doses. A “unit dose” is a discrete amount of a composition containing a predetermined amount of the agent. The amount of the agent is generally equal to the dose of the agent to be administered to the subject and / or a suitable portion of that dose, such as half or one-third of the dose.

[0340] The relative amounts of the compounds, excipients, agents, and / or any other components of this disclosure in the compositions described herein will vary depending on the identity, body type, and / or condition of the subject being treated, and also depending on the route of administration of the composition. The compositions may contain from 0.1% to 100% (w / w) of the agent.

[0341] Excipients and auxiliary ingredients used in the manufacture of the provided compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients and auxiliary ingredients such as cocoa butter, polyethylene glycol-modified lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavorings, and aromatizers may also be present in the compositions.

[0342] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0343] Exemplary granulating agents and / or dispersants include potato starch, corn starch, cassava starch, sodium glycolate starch, clay, alginate, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crosspovidone), sodium carboxymethyl starch (sodium glycolate starch), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0344] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, astragalus gum, chondrux, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, glyceryl monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxyethylene polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), and sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol monolaurate). 20) Polyoxyethylene dehydrated sorbitol ( 60), Polyoxyethylene dehydrated sorbitan monooleate ( 80), sorbitol monopalmitate ( 40) Sorbitol monostearate ( 60), sorbitol tristearate ( 65), glyceryl monooleate, sorbitan monooleate ( 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate) 45) Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.) ), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether) 30), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl lauryl sulfate, sodium lauryl sulfate F-68, poloxamer P-188, hexadecyltrimethylammonium bromide, hexadecylpyridine chloride, benzalkonium chloride, sodium docusate and / or mixtures thereof.

[0345] Exemplary adhesives include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, carrageenan extract, panwar gum, agar, isapola shell adhesive, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), and magnesium aluminum silicate. (and larch arabinogalactan), alginate, polyoxyethylene, polyethylene glycol, inorganic calcium salts, silica, polymethyl methacrylate, wax, water, alcohol and / or mixtures thereof.

[0346] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0347] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbate palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0348] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium EDTA, disodium EDTA, trisodium EDTA, calcium disodium EDTA, dipotassium EDTA, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzyl chloride, benzyl alcohol, bromonitrile glycol, cetrimonium bromide, hexadecylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexacodyl, imidazoline, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0349] Exemplary antifungal preservative packages include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0350] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0351] 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.

[0352] Other preservatives include tocopherol, tocopheryl acetate, ferric sulfate methanesulfonate, hexadecyltrimethylammonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, and potassium metabisulfite. Plus Methylparaben, 115. II. Know

[0353] Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginate, pyrogen-free raw water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0354] 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.

[0355] Exemplary natural oils include almonds, avocados, babassu, bergamot, blackcurrant seeds, borage, juniper, chamomile, canola, caraway, palm wax, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, citronellol, gourd, grapeseed, hazelnut, hyacinth, isopropyl myristate, jojoba, macadamia nuts, mixed lavender, lavender, lemon, litsea cubeba, macadamia nuts, mallow, mango seeds, meadowfoam seeds, mink, nutmeg, olives, citrus, orange barnacles, palm, palm kernels, peach kernels, peanuts, poppy seeds, pumpkin seeds, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia, tamarisk, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, ailanthus, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include butyl stearate, octanoic acid triglyceride, caprylic acid triglyceride, cyclomethicone, diethyl sebacate, polydimethylsiloxane 360, isopropyl myristate, mineral oil, octyldodecanool, oleyl alcohol, silicone oil, and mixtures thereof.

[0356] In some embodiments, the composition further comprises an agent and is available for delivery of said agent (e.g., delivery to a subject, tissue, biological sample, or cells). In some embodiments, the composition is a pharmaceutical composition that can be used to treat a disease in a subject with this need. In some embodiments, the disease is cancer. In some embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer). In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is a gastrointestinal stromal tumor. In some embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In some embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic cancer or pancreatic adenocarcinoma). In some embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In some embodiments, the cancer is lymphoma, such as non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma). In some embodiments, the cancer is B-cell lymphoma (e.g., Burkitt B-cell lymphoma, large B-cell lymphoma). In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the cancer is Burkitt lymphoma (e.g., Burkitt B-cell lymphoma). In some embodiments, the cancer is large cell immunoblastic lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) (also known as acute myeloid leukemia, acute medulloblastic leukemia, acute myeloid leukemia, acute myeloid cell leukemia, and acute non-lymphocytic leukemia), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML) (also known as chronic myeloid leukemia). In some embodiments, the cancer is AML. In some embodiments, the cancer is a subtype of AML selected from the following: undifferentiated acute medulloblastic leukemia (M0), minimally mature acute medulloblastic leukemia (M1), mature acute medulloblastic leukemia (M2), acute promyelocytic leukemia (APL) (M3), acute myeloid-monocytic leukemia (M4), acute myeloid-monocytic leukemia with eosinophilia (M4 eos), acute monocytic leukemia (M5), acute erythroblastic leukemia (M6), and acute megakaryoblastic leukemia (M7). In some embodiments, the cancer is acute monocytic leukemia or acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia). In some embodiments, the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia). In some embodiments, the cancer is multiple myeloma (e.g., B-cell myeloma).

[0357] As described herein, the composition may be administered in combination with one or more additional agents. In some embodiments, the agent is an organic molecule. In some embodiments, the agent is an inorganic molecule. In some embodiments, the agent is a targeting agent. In some embodiments, the agent is an isotopically labeled compound. In some embodiments, the agent is an agent that can be used for bioprocessing. In some embodiments, the agent is a pharmaceutical agent (e.g., a therapeutic and / or preventative active agent). Pharmaceutical agents include therapeutic active agents. Pharmaceutical agents also include preventative active agents. Pharmaceutical agents include small organic molecules such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use as provided in U.S. Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunizing agents, and cells.

[0358] In some embodiments, the compounds of this disclosure described herein are provided in the composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is an amount that is effective in treating a subject's cancer in need. In some embodiments, the effective amount is an amount that is effective in inhibiting signaling pathways required for metastasis in a subject or cell.

[0359] In some embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In some embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%. In some embodiments, an effective amount is an amount that effectively inhibits the activity of NAMPT within a range (inclusive) between one percentage described in this paragraph and another percentage described in this paragraph.

[0360] In some embodiments, the effective amount is an amount that effectively increases 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%, said initial level may be, for example, the baseline level of enzyme activity. In some embodiments, the effective amount is an amount that effectively increases the activity of NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, no more than 98%, or no more than 99.9%. In some implementations, the effective amount is an amount that effectively increases the activity of NAMPT within a range (inclusive) between one percentage and another percentage described in this paragraph.

[0361] In some embodiments, the effective amount is an amount that effectively suppresses the signal conduction of the 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 some embodiments, the effective amount is an amount that effectively suppresses the signal conduction of the NAMPT by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%. In some embodiments, the effective amount is an amount that effectively suppresses the signal conduction of the NAMPT within a range (inclusive) between one percentage described in this paragraph and another percentage described in this paragraph.

[0362] In some embodiments, the effective amount is an amount that effectively increases 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%, said initial level may be, for example, the baseline level of enzyme activity. In some embodiments, the effective amount is an amount that effectively increases NAMPT signaling by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, no more than 98%, or no more than 99.9%. In some implementations, the effective amount is the amount that effectively increases the signal conduction of the NAMPT within a range (inclusive) between one percentage described in this paragraph and another percentage described in this paragraph.

[0363] In some embodiments, the cells are in vitro. In some embodiments, the cells are ex vivo. In some embodiments, the cells are in vivo.

[0364] The compositions can be formulated into liquid dosage forms for oral and parenteral administration, including pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to agents, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solvents, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters and mixtures thereof of sorbitol. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers. In some embodiments for parenteral administration, the compositions described herein are combined with a solvent such as... Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof are mixed.

[0365] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in parenteral acceptable non-toxic diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0366] Injectable formulations can be sterilized, for example, by filtration via a bacterial retention filter or by incorporation of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0367] To prolong the effects of the compounds disclosed herein, it is generally desirable to slow the absorption of compounds administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the compound in an oil medium.

[0368] Compositions for rectal or vaginal application are typically suppositories prepared by mixing the composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, and thus melt in the rectal or vaginal cavity and release the compounds disclosed herein.

[0369] The composition can be formulated into solid dosage forms for oral administration, including capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this disclosure are mixed with at least one pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (e) dissolution delayers, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain a buffer.

[0370] Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the field of pharmacology. They may optionally contain light-blocking agents and may have a composition in which they optionally release the compounds of this disclosure in a delayed manner, either only or preferably in a portion of the intestine. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0371] The compounds disclosed herein may be in a microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, lozenges, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the compounds of this disclosure may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may, according to conventional practice, contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may contain a buffer. They may optionally contain a light-blocking agent and may have a composition in which they optionally release the compounds of this disclosure in a delayed manner, either solely or preferentially, in a portion of the intestine. Examples of encapsulating agents that may be used include polymers and waxes.

[0372] Dosage forms for topical and / or transdermal application of the compositions described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, and / or patches. Typically, the compounds disclosed herein are mixed under aseptic conditions with pharmaceutically acceptable carriers or excipients and / or any desired preservatives and / or buffers that may be required.

[0373] Suitable devices for delivering the intradermal compositions described herein include short-needle devices. Intradermal compositions can be administered by devices that limit the effective length of the needle penetration into the skin. Alternatively or additionally, conventional syringes can be used in the classic Mantoux method for intradermal administration. Jet injection devices that deliver liquid formulations to the dermis via liquid jet syringes and / or via needles that puncture the stratum corneum and generate a jet stream reaching the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate polymers in powder form through the outer layer of skin to the dermis are suitable.

[0374] Formulations suitable for topical application include liquid and / or semi-liquid formulations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments and / or pastes, and / or solutions and / or suspensions. Topically applicable formulations may, for example, contain from about 1% to about 100% (w / w) of the compounds disclosed herein, although the concentration of the compounds disclosed herein may be as high as the solubility limits of the compounds disclosed herein in solvents. Formulations for topical application may further contain one or more additional ingredients described herein.

[0375] The compositions described herein are suitable for preparation, packaging, and / or sale in formulations for intrabuccular administration to the lungs. Such formulations may comprise dry granules containing compounds of this disclosure. These compositions are suitably available as dry powders for administration, administered using a device including a dry powder reservoir that directs the flow of propellant to its dispersed powder and / or using a self-propelled solvent / powder dispersion container, such as a device containing an agent dissolved and / or suspended in a sealed container of a low-boiling-point propellant. The dry powder compositions may include solid fine powder diluents such as sugars and are suitably provided in unit dosage forms.

[0376] Low-boiling-point propellants typically include liquid propellants with a boiling point below 65°F at atmospheric pressure. Typically, the propellant may comprise 50% to 99.9% (w / w) of the composition, and the compounds disclosed herein may comprise 0.1% to 100% (w / w) of the composition. The propellant may further contain additional components such as liquid nonionic and / or solid anionic surfactants and / or solid diluents.

[0377] The compositions described herein for pulmonary delivery may be provided in the form of solutions and / or droplets of suspensions. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the compounds of this disclosure, and may be suitably administered using any spray and / or nebulizer. Such formulations may further comprise one or more additional ingredients, including flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methylparaben.

[0378] The formulations described herein, which can be used for pulmonary delivery, can be used for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the compounds disclosed herein. Such formulations are administered by rapid inhalation via the nasal passage from a container containing the powder, kept close to the nose.

[0379] Formulations for nasal application may, for example, contain as little as 0.1% (w / w) to as much as 100% (w / w) of the compounds disclosed herein, and may contain one or more of the additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in buccal application formulations. Such formulations may be available, for example, in tablets and / or lozenges prepared using conventional methods, and may, for example, contain 0.1% to 20% (w / w) of the compound, the remainder being an orally soluble and / or biodegradable composition and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal application may contain powders and / or aerosolized and / or nebulized solutions and / or suspensions containing the compounds disclosed herein.

[0380] The compositions described herein can be used to prepare, package, and / or market ophthalmic formulations. Such formulations may be available, for example, as eye drops, including, for example, 0.1%–100% (w / w) solutions and / or suspensions of the disclosed compounds in an aqueous or oily liquid carrier or excipient. Such drops may also contain buffers, salts, and / or one or more of the other ingredients described herein. Other ophthalmic-applicable formulations available include those containing compounds of this disclosure in microcrystalline and / or liposome formulations. Ear drops and / or eye drops are also covered within the scope of this disclosure.

[0381] While the descriptions of the compositions provided herein primarily pertain to those intended for human administration, those skilled in the art will understand that such compositions are generally suitable for administration to all species of animals. Modifications to compositions intended for human administration to make them suitable for administration to a wide variety of animals are well known, and such modifications can be designed and / or performed by a general veterinary pharmacologist through routine experiments.

[0382] The compositions described herein are typically formulated in dosage units that facilitate administration and ensure uniform dosing. However, it will be understood that the total daily dosage of the compositions described herein will be determined by a physician within reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the type and severity of the cancer being treated; the activity of the specific compound used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0383] The compositions provided herein can be administered via any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullaryly, intrathecally, subcutaneously, intravenously, percutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and / or drops), mucosally, nasally, buccally, sublingually; by endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specifically, the intended routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topically administered via blood and / or lymphatic supply, and / or directly to the affected site. Generally, the most suitable route of administration will depend on a variety of factors, including the nature of the disclosed compounds (e.g., their stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compositions described herein are suitable for topically administering to the subject's eyes.

[0384] In some embodiments, the administration of any of the compositions described herein occurs at least one hour prior to treatment with another cancer therapy.

[0385] The composition may be administered in combination with other agents that enhance their activity (e.g., potency and / or efficacy) in treating a disease or condition (e.g., cancer) in a subject with this need and / or by inhibiting signaling pathways in the subject or cells, improve bioavailability, enhance safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in the subject or cells. It should also be understood that the therapy employed may achieve the desired effect for the same condition, and / or it may achieve different effects. In some embodiments, the compositions described herein (including the compounds of this disclosure) and agents exhibit a synergistic effect not present in compositions comprising one, but not both, of the compounds or agents of this disclosure.

[0386] The composition may be administered simultaneously with, before, or after one or more additional agents, which are different from the composition and may be used as, for example, a combination therapy. Each additional agent may be administered at a dose and / or schedule determined for that agent. The additional agents may also be administered individually or at different doses, together with each other and / or with the compounds of this disclosure or the compositions described herein. Specific combinations employed in a regimen will take into account the compatibility of the compounds of this disclosure described herein with the additional agents and / or the desired therapeutic and / or preventative effects to be achieved. Generally, the additional agents in the combination are intended to be used at levels not exceeding those used individually. In some embodiments, the level of combination will be lower than that of those used individually.

[0387] Other agents include antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, and analgesics. In some embodiments, the additional agent is an antiproliferative agent. In some embodiments, the additional agent is an anticancer agent. In some embodiments, the additional agent is a chemotherapeutic agent. In some embodiments, the additional agent is a differentiating agent (e.g., retinoids, all-trans retinoic acid (ATRA), vitamin D, peroxisome proliferator-activated receptor gamma (PPARγ) inhibitors). In some embodiments, the additional agent is an antiviral agent. In some embodiments, the additional agent is a protein kinase binder or inhibitor. In some embodiments, the additional agents are selected from the group consisting of: epigenetic or transcriptional regulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other differentiation-promoting agents. In some embodiments, the compounds or pharmaceutical compositions of this disclosure described herein may be administered in combination with anticancer therapies, including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In some embodiments, the subjects are administered one or more additional agents, such as one or more additional cancer therapies, concurrently with, before, or after the cancer therapy. In some embodiments, one or more additional cancer therapies include immunotherapy. Typically, immunotherapy (also known as biotherapy) is a type of cancer treatment that strengthens the subject's natural defenses against cancer. In some embodiments, the immunotherapy utilizes a compound biologically generated by the subject. In some embodiments, the immunotherapy utilizes a compound not biologically generated by the subject. In some embodiments, the immunotherapy utilizes cells derived from the subject. In some embodiments, the immunotherapy utilizes cells not derived from the subject. In some embodiments, the immunotherapy utilizes a compound biologically generated by an organism not belonging to the subject. In some embodiments, the immunotherapy utilizes cells biologically generated by an organism not belonging to the subject. In some embodiments, the immunotherapy includes at least one chemical modification of the compound or cells derived from the subject. In some embodiments, the immunotherapy includes at least one chemical modification of the compound or cells not derived from the subject.

[0388] In some implementation schemes, additional agents are selected from the group consisting of: nicotinic acid, ibrutinib, idelalisib, lenalidomide, BCL-2 inhibitors, venetoclax, FLT3 inhibitors, IDH 1 / 2 inhibitors, glasdegib, azacytidine, cyclophosphamide, decitabine, enasidenib, erastin, gilterinib, idasanutlin, ivosidenib, ixazomib, midostaurin, navitoclax, onvasertib, and cyclosporine A. A) PARP inhibitors, pacritinib, phorbol 12-myristate 13-acetate (PMA), ruxolitinib, S055746, selinexorKPT-330), trametinib, tretinoin, etoposide, P7C3, napabucasin, olaparib, AraC, daunorubicin, MNNG, melphalan, verapamil, etoposide, cisplatin, anti-PD-1, tumor necrosis factor Related apoptosis-inducing ligands (TRAIL), EX527, sirtinol, cambinol, vorinostat, valproic acid, butyric acid, JPH203, L-asparaginase, bortezomib, rituximab, PGP-4008, β-lapachone, β-methylene adenosine 5′-bisphosphate (APCP), gemcitabine, Lu-DOTATATE, fluorouracil (5-FU), pemetrexed, and omeprazole (onv) ansertib), cedazuridine, galinpepimut-S, decitabine, cytarabine / daunorubicin, uproleselan, gedatolisib, devimistat, graziab, edanulin, ganedespib, tipifamib, midotoxin, pevonedistat, ivermectinib, cresol Crenolanib, quizartinib, pracinostat, guadecitabine, DFP10917, vosaroxin, rexlemestrocel-L-mesoblast, treosulfan, sapacitabine, ensiditinib, volasertib, and temozolomide.

[0389] In some implementations, the BCL-2 inhibitor is venetoclax, navittoclax, oblimersen, APG 2575, BCL201, BGB-11417, LP-108, or S65487.

[0390] In some embodiments, the additional agent is a Toll-like receptor 4 (TLR4) inhibitor. In some embodiments, the Toll-like receptor 4 inhibitor is TAK-242, E5564, OM-174, GSK1795091, GLA-SE, NI-0101, AV-411, AS04, amitriptyline, cyclobenzaprine, ketotifen, imipramine, mianserin, ibudilast, pinocembrin, resatorvid, naloxone, naltrexone, LPS-RS, propentofylline, tapentadol, palmitoylethanolamide.

[0391] In some embodiments, the additional agent is a sirtuin inhibitor. In some embodiments, the sirtuin inhibitor is nicotinamide, a nicotinamide derivative, benzamide, a 3′-phenethoxy-2-anilinebenzamide analog, AK7, 1,4-dihydropyridine, cambinol, EX-527, AGK2, 3′-(3-fluoro-phenethoxy)-2-iminobenzamide, SirReal2, UBCS0137, ELT-11c, or a compound containing a thioacyl lysine.

[0392] In some implementations, the additional agent is selected from ibrutinib or ederaris.

[0393] In some implementations, the additional agent is lenalidomide.

[0394] In some implementation schemes, additional agents are selected from the group consisting of: venetoclax, FLT3 inhibitors, IDH1 / 2 inhibitors, graziab, azacytidine, cyclophosphamide, decitabine, entiditinib, ellastatinib, giratetinib, edanulin, evertinib, ixazomib, midotoxorin, navittoclax, amvascitabine, papatetinib, PMA, ruxolitinib, S055746, selinexol (KPT-330), trametinib, retinoic acid, etoposide, and nababufloxacin.

[0395] In some implementations, the additional agent is P7C3.

[0396] In some implementations, the FLT3 inhibitor is selected from the group consisting of: sorafenib, sunitinib, lestaurtinib, tandutinib, ponatinib, midotutolin, gipretinib, quezartinib, clanolanib, cabozantinib, ibrutinib, and KW-2449. In some implementations, the FLT3 inhibitor is sorafenib, sunitinib, ponatinib, cabozantinib, ibrutinib, midotutolin, or gipretinib. In some implementations, the FLT3 inhibitor is midotutolin or gipretinib.

[0397] In some implementations, the IDH 1 / 2 inhibitor is selected from the group consisting of evertinib and ensiditinib.

[0398] In some embodiments, the PARP inhibitor is selected from the group consisting of: olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, CEP-8983, E7016, iniparib, and 3-aminobenzamide. In some embodiments, the PARP inhibitor is selected from the group consisting of: olaparib, rucaparib, niraparib, and talazoparib. In some embodiments, the PARP inhibitor is selected from the group consisting of: veliparib, pamiparib, CEP9722, CEP-8983, E7016, iniparib, and 3-aminobenzamide.

[0399] In some implementations, the additional agent is an HDAC inhibitor.

[0400] In some implementations, the additional agent is hydrochloric acid.

[0401] In some implementation schemes, additional agents include afatinib, afatinib dimaleate, alectinib, atezolizumab, bevacizumab, brigatinib, capmatinib, carmatinib hydrochloride, carboplatin, carboplatin-paclitaxel, ceritinib, crizotinib, dabrafenib, dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin, doxorubicin hydrochloride, durvalumab, entrectinib, erlotinib, erlotinib hydrochloride, and 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.

[0402] In some embodiments, the additional agent is selected from the group consisting of: topoisomerase II inhibitors (e.g., etoposide, doxorubicin), topoisomerase I inhibitors (e.g., irinotecan, CPT-11, camptostar, topotecan), microtubule interactors (e.g., paclitaxel, docetaxel, epothilones), thymidylate synthase inhibitors (e.g., 5-fluorouracil or 5-FU), alkylating agents (e.g., temozolomide, cyclophosphamide), farnesyltransferase inhibitors (e.g., lonafabi, L778,123, BMS214662), signal transduction inhibitors (e.g., gefitinib), EGFR antibodies (e.g., cetuximab), cytarabine, aromatase inhibitors (e.g., exemestance, anastrozole, letrozole)).

[0403] In some implementations, the additional agent is cytarabine.

[0404] In some embodiments, the additional agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 1,4,6-androst-3,17-dione, or 4-androst-3,6,17-trione.

[0405] In some embodiments, additional agents are anticancer agents or anti-growth agents. In some embodiments, additional agents include cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chlormethine, hexamethylmelamine, zevalin, trisenox, xeloda, aminoglutethimide, 6-thioguanine, pentostatin, mithramycin, ifosfamide, pipobroman, triethylenemelamine, methyltestosterone, amsacrine, mitotane, levamisole, triamcinolone, testosterone, fluoxymesterone, and dromostanolone. propionate, triethylenethiophosphoramine, streptozocin, 6-mercaptopurine, deoxycoformycin, mitomycin C, 17α-ethinylestradiol, diethylstilbestrol, testosterone, megestrolacetate, methylprednisolone, chlorotrianisene, hydroxyprogesterone sterone), medroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, reloxafme, droloxafme, porfimer, thiotepa, altretamine, lerozole, fulvestrant, exemestane, 5-HT3 receptor inhibitors (e.g., dolansetron, granisetron, ondansetron) or dexamethasone.

[0406] In some implementation schemes, additional agents include cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chloroform, hexamethylmelamine, zevalin, arsenic trioxide, capecitabine, aminoglutethimide, 6-thioguanine, pentostatin, photomycin, ifosfamide, pyrobromanil, ethyltrimethazine, methyltestosterone, acridine, mitotane, levamisole, triamcinolone, testosterone, fluoxymethyltestosterone, drotaldophenate, ethyltrithiophosphatidylcholine, streptozotocin, 6- Mercaptopurine, deoxymyomycin, mitomycin C, 17α-ethinylestradiol, diethylstilbestrol, testosterone, medroxyprogesterone acetate, methylprednisolone, chlorestradiol, hydroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, lelothione, drolothione, porphyrin, thiotepa, hexamethylmelamine, lenolazole, fulvestrant, exemestane, or dexamethasone, and 5-HT3 receptor inhibitors (e.g., dolansetron, granisetron, ondansetron).

[0407] In some implementation schemes, additional agents include cytarabine, doxorubicin, cyclophosphamide, FX-11, uracil mustard, chloroform, hexamethylmelamine, zevalin, arsenic trioxide, capecitabine, aminoglutethimide, 6-thioguanine, pentostatin, photomycin, ifosfamide, pyrobromanil, ethyltrimethazine, methyltestosterone, acridine, mitotane, levamisole, triamcinolone, testosterone, fluoxymethyltestosterone, drotaldophenate, ethyltrithiophosphatidylcholine, streptozotocin, 6- Mercaptopurine, deoxymyomycin, mitomycin C, 17α-ethinylestradiol, diethylstilbestrol, testosterone, medroxyprogesterone acetate, methylprednisolone, chlorestradiol, hydroxyprogesterone acetate, toremifene, navelbene, anastrozole, letrozole, lelothione, drolothione, porphyrin, thiotepa, hexamethylmelamine, lenolazole, fulvestrant, exemestane, or 5-HT3 receptor inhibitors (e.g., dolansetron, granisetron, ondansetron), and dexamethasone.

[0408] In some embodiments, the additional agent is cytarabine. In some embodiments, the additional agent is doxorubicin. In some embodiments, the additional agent is cyclophosphamide. In some embodiments, the additional agent is FX-11. In some embodiments, the additional agent is uracil mustard. In some embodiments, the additional agent is chloroform. In some embodiments, the additional agent is hexamethylmelamine. In some embodiments, the additional agent is zevalin. In some embodiments, the additional agent is arsenic trioxide. In some embodiments, the additional agent is capedrin. In some embodiments, the additional agent is aminoglutethimide. In some embodiments, the additional agent is 6-thioguanine. In some embodiments, the additional agent is pentostatin. In some embodiments, the additional agent is styromycin. In some embodiments, the additional agent is ifosfamide. In some embodiments, the additional agent is pipbroman. In some embodiments, the additional agent is triethylene melamine. In some embodiments, an additional agent is methyltestosterone. In some embodiments, an additional agent is acridine. In some embodiments, an additional agent is mitotane. In some embodiments, an additional agent is levamisole. In some embodiments, an additional agent is triamcinolone. In some embodiments, an additional agent is testosterone. In some embodiments, an additional agent is fluoxymethyltestosterone. In some embodiments, an additional agent is drotaldophenone propionate. In some embodiments, an additional agent is triethylthiophosphatidylcholine. In some embodiments, an additional agent is streptozotocin. In some embodiments, an additional agent is 6-mercaptopurine. In some embodiments, an additional agent is deoxymyomycin. In some embodiments, an additional agent is mitomycin C. In some embodiments, an additional agent is 17α-ethinyl estradiol. In some embodiments, an additional agent is diethylstilbestrol. In some embodiments, an additional agent is testrolide. In some embodiments, the additional agent is medroxyprogesterone acetate. In some embodiments, the additional agent is methylprednisolone. In some embodiments, the additional agent is chlorestradiol. In some embodiments, the additional agent is hydroxyprogesterone. In some embodiments, the additional agent is medroxyprogesterone acetate. In some embodiments, the additional agent is toremifene. In some embodiments, the additional agent is navelbene. In some embodiments, the additional agent is anastrozole. In some embodiments, the additional agent is letrozole. In some embodiments, the additional agent is lelothione. In some embodiments, the additional agent is drolothione. In some embodiments, the additional agent is porphyrin. In some embodiments, the additional agent is thiotepa. In some embodiments, the additional agent is hexamethylmelamine. In some embodiments, the additional agent is lelothione.In some embodiments, the additional agent is fulvestrant. In some embodiments, the additional agent is exemestane. In some embodiments, the additional agent is a 5-HT3 receptor inhibitor. In some embodiments, the additional agent is dolanisetron. In some embodiments, the additional agent is granisetron. In some embodiments, the additional agent is ondansetron. In some embodiments, the additional agent is dexamethasone.

[0409] In some implementations, additional agents are used to treat small cell lung cancer. In some implementations, these additional agents are everolimus, aratemumab, doxorubicin, doxorubicin hydrochloride, durvalumab, etoposide phosphate, etoposide, topotecan, topotecan hydrochloride, pembrolizumab, rubitidine, methotrexate, methotrexate sodium, or nivolumab.

[0410] In some embodiments, the additional agent is ibrutinib. In some embodiments, the additional agent is edalaris. In some embodiments, the additional agent is lenalidomide. In some embodiments, the additional agent is venetoclax. In some embodiments, the additional agent is an FLT3 inhibitor. In some embodiments, the additional agent is an IDH1 / 2 inhibitor. In some embodiments, the additional agent is grazib. In some embodiments, the additional agent is azacytidine. In some embodiments, the additional agent is cyclophosphamide. In some embodiments, the additional agent is decitabine. In some embodiments, the additional agent is entiditinib. In some embodiments, the additional agent is ellastatin. In some embodiments, the additional agent is giretinib. In some embodiments, the additional agent is edanulin. In some embodiments, the additional agent is everitinib. In some embodiments, the additional agent is ixazomib. In some embodiments, the additional agent is midotrol. In some embodiments, the additional agent is navittox. In some embodiments, the additional agent is fenbentep. In some embodiments, the additional agent is cyclosporine A. In some embodiments, the additional agent is paktinib. In some embodiments, the additional agent is phorbol 12-myristate 13-acetate (PMA). In some embodiments, the additional agent is ruxolitinib. In some embodiments, the additional agent is S055746. In some embodiments, the additional agent is celiniso (KPT-330). In some embodiments, the additional agent is trametinib. In some embodiments, the additional agent is retinoic acid. In some embodiments, the additional agent is etoposide. In some embodiments, the additional agent is P7C3. In some embodiments, the additional agent is nababufloxacin. In some embodiments, the additional agent is olaparib. In some embodiments, the additional agent is AraC. In some embodiments, the additional agent is daunorubicin. In some embodiments, an additional agent is 1-methyl-3-nitro-1-nitroguanidine (MNNG). In some embodiments, an additional agent is melphalan. In some embodiments, an additional agent is verapamil. In some embodiments, an additional agent is etoposide. In some embodiments, an additional agent is cisplatin. In some embodiments, an additional agent is anti-PD-1. In some embodiments, an additional agent is tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL). In some embodiments, an additional agent is EX527. In some embodiments, an additional agent is sirtinol. In some embodiments, an additional agent is cambinol. In some embodiments, an additional agent is vorinostat. In some embodiments, an additional agent is valproic acid. In some embodiments, an additional agent is butyric acid.In some embodiments, an additional agent is JPH203. In some embodiments, an additional agent is L-asparaginase. In some embodiments, an additional agent is bortezomib. In some embodiments, an additional agent is rituximab. In some embodiments, an additional agent is cyclosporine A. In some embodiments, an additional agent is PGP-4008. In some embodiments, an additional agent is β-lapaquinone. In some embodiments, an additional agent is β-methylene adenosine 5′-bisphosphate (APCP). In some embodiments, an additional agent is gemcitabine. In some embodiments, an additional agent is Lu-DOTATATE. In some embodiments, an additional agent is fluorouracil (5-FU). In some embodiments, an additional agent is pemetrexed. In some embodiments, an additional agent is temozolomide. In some embodiments, an additional agent is fenvalerate. In some embodiments, an additional agent is chidamide. In some embodiments, the additional agent is galinpepimut-S. In some embodiments, the additional agent is chidanilide / decitabine. In some embodiments, the additional agent is cytarabine / daunorubicin. In some embodiments, the additional agent is uproleselan. In some embodiments, the additional agent is galdarexi. In some embodiments, the additional agent is daviditol. In some embodiments, the additional agent is grazib. In some embodiments, the additional agent is edanulin. In some embodiments, the additional agent is ganettespib. In some embodiments, the additional agent is tepififib. In some embodiments, the additional agent is midotol. In some embodiments, the additional agent is pectistat. In some embodiments, the additional agent is evertinib. In some embodiments, the additional agent is clanolanib. In some embodiments, the additional agent is quezartinib. In some embodiments, the additional agent is plasinostat. In some embodiments, the additional agent is guadecitabine. In some embodiments, the additional agent is DFP 10917. In some embodiments, the additional agent is vorsalonfloxacin. In some embodiments, the additional agent is rexlemestrocel-L-mesoblast. In some embodiments, the additional agent is susulfan. In some embodiments, the additional agent is sabattabine. In some embodiments, the additional agent is ensiditinib. In some embodiments, the additional agent is voraseti.

[0411] In some implementations, immunotherapy may include one or more of the following steps: preventing or inhibiting the growth of cancer cells; preventing the spread of cancer to other parts of the body; and enhancing the immune system's ability and activity to kill cancer cells. Non-limiting examples of immunotherapy include: monoclonal antibodies, checkpoint inhibitors, nonspecific immunotherapy, oncolytic virus therapy, T-cell therapy, and cancer vaccines.

[0412] In some implementations, immunotherapy utilizes monoclonal antibodies. In some implementations, monoclonal antibodies target (bind to) and / or block abnormal proteins on cancer cells.

[0413] In some implementations, immunotherapy includes immunotherapy strategies for leukemia. In some implementations, immunotherapy includes vaccination with leukemia-associated antigens. In some implementations, immunotherapy includes adoptive transfer of allogeneic natural killer cells.

[0414] In some embodiments, immunotherapy utilizes checkpoint inhibitors. In some embodiments, immune checkpoint inhibitors are monoclonal antibodies. Immune checkpoints are regulators of the immune system by maintaining immune homeostasis and preventing the activation of autoimmunity. In cancer cells, immune checkpoint mechanisms are typically activated to suppress nascent anticancer immune responses. In some embodiments, checkpoint inhibitors are inhibitors of PD-1 (programmed cell death protein 1). In some embodiments, checkpoint inhibitors are inhibitors of PD-L1 (programmed death ligand 1). In some embodiments, checkpoint inhibitors are inhibitors of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Examples of immune checkpoint inhibitors include, but are not limited to, Yervoy, Opdivo, Keytruda, Tecentriq, Bavencio, and Imfinzi.

[0415] In some implementations, the immunotherapy is a nonspecific immunotherapy (e.g., interferon or interleukin). In some implementations, the immunotherapy is an oncolytic virus therapy.

[0416] In some implementations, the immunotherapy is T-cell therapy. In some implementations, the T-cell therapy is chimeric antigen receptor (CAR) T-cell therapy.

[0417] In some implementations, immunotherapy is an anti-cancer vaccine.

[0418] Anticancer agents include biological therapeutic anticancer agents and chemotherapy agents. Exemplary biological therapeutic anticancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulants and / or immunomodulators (e.g., IL-1, 2, 4, 6 or 12), immune cell growth factors (e.g., GM-CSF), and antibodies (e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuzumab), Vectibix (perumumab), Rituxan (rituximab), Bexxar (tosimomab)). Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g., goserelin and leuprorelin), anti-androgens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-2-methylpyrazine (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trefophosphamide, chlorambucil, estradiol, and melphalan), and nitrosoureas (e.g., ...). Examples of alkaloids include carmustine (BCNU) and lomustine (CCNU), alkyl sulfonates (e.g., busulfan and thiosulfate), triazines (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinblastine alkaloids (e.g., vincristine, vinblastine, vinorelbine), taxanes (e.g., paclitaxel or paclitaxel equivalents), docosahexaenoic acid conjugate paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate conjugate paclitaxel (PG-paclitaxel, polyglutamate paclitaxel). poliglumex), CT-2103, XYOTAX), tumor activation prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, such as 2′-paclitaxel methyl 2-pyranose glucosuccinate.Docetaxel, Taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, captopril, irinotecan, irinotecan, Krestor, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethhotrexate, trimethotraxate, idatraxate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), nucleonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), fluorouracil, deoxyfluorouracil, raltitrexed, tegafuridine, capecitabine), cytosine analogs (e.g., cytarabine). C) Cytarabine and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB1089, CB1093 and KH1060), isoprene inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium salt ion), cell cycle inhibitors (e.g., asteroidin), actinomycins (e.g., actinomycin D, styromycin), bleomycins (e.g., bleomycin A2, bleomycin B2, pepromycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, levorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca; 2+ ATPase inhibitors (e.g., carotenoids), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), besutinib (SKI-606), cediranib (RECENTIN) TM AZD2171), dasatinib ( BMS-354825), Erlotinib Gefitinib Imatinib CGP57148B, STI-571, and lapatinib Linatatinib (CEP-701), Linatinib (HKI-272), Nilotinib Semaxinib (SU5416), Sunitinib ( SU11248), toceranib, ), Vandetani ( ZD6474), Vatalani (PTK787, PTK / ZK), Trastuzumab bevacizumab Rituximab cetuximab Parmumab Ranibizumab Nilotinib Sorafenib Everolimus alenzusnezidine Gelatinumab Ozolmicin Sirolimus lipids ENMD-2076, PCI-32765, AC220, Dovirtinib Lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK) TM ), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647 and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, sirolimus ester (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Novartis), XL765 (Sanofi) Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI), oblimersen, gemcitabine, erythromycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, camptothecin, procainamide, asparaginase, aminopterin, methylfolate, methylmitromycin, melphalan, isovincrine, epoxyvincrine, chlorambucil, trabectedin, procarbizine, disccodermolide, erythromycin, aminopterin, and hexamethylmelamine.

[0419] 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 1 part of the compound disclosed herein.

[0420] In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 1% to about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of the composition comprising the compounds of this disclosure is less than about 50%, for example less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 25%, or from about 5% to about 20%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to 90%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to about 75%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 5% to about 50%. In some embodiments, the percentage of the composition comprising the compounds of this disclosure is from about 10% to about 25%.

[0421] In some embodiments, the total amount of the disclosed compounds present in the composition is greater than about 1% of the total size or total weight of the composition (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30% or more). In some embodiments, the total amount of the disclosed compounds present in the composition is greater than about 10% of the total size or total weight of the composition (e.g., about 12%, about 15%, about 20%, about 25%, about 30% or more).

[0422] In some embodiments, the compounds of this disclosure are incorporated into the composition at a dose or amount less than that of the compounds in their free form to achieve the desired effect (e.g., the desired therapeutic effect). In some embodiments, the composition increases the amount of the compounds of this disclosure delivered to the tissues or cells to which they are thus desired, and reduces the amount of the compounds of this disclosure exposed to non-target tissues or cells, compared to the free compound.

[0423] On the other hand, a medicine box is provided containing 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 described herein.

[0424] In some embodiments, the kit also contains additional pharmaceutical agents as described herein. In some embodiments, the kit also contains instructions regarding the order of use of the disclosed compounds or compositions and the additional pharmaceutical agents. In some embodiments, the instructions specify that the disclosed compounds or compositions be administered before the additional pharmaceutical agents. In some embodiments, the instructions specify that the disclosed compounds or compositions be administered simultaneously with the additional pharmaceutical agents. In some embodiments, the instructions specify that the disclosed compounds or compositions be administered after the additional pharmaceutical agents.

[0425] In some embodiments, the instructions for use of the medicine box may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the medicine box is prescribing information. In some embodiments, the medicine box and instructions for use are used to deliver the compound disclosed herein. In some embodiments, the medicine box and instructions for use are used to deliver the composition. In some embodiments, the medicine box and instructions for use are used to treat cancer in a subject with this need. In some embodiments, the medicine box and instructions for use are used to inhibit signaling pathways in a subject or cells.

[0426] Treatment and prevention methods and uses

[0427] This document also provides methods and uses for treating or preventing any of the diseases described herein using the compounds or compositions described herein.

[0428] In some embodiments, this disclosure provides a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (0) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in formula (0) or (I) are as described herein.

[0429] In some implementations, the cancer includes cancer stem cells. In some implementations, the cancer involves or is related to cancer stem cells. In some implementations, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, prostate cancer, liver cancer, or endometrial cancer. In some implementations, the cancer is leukemia (e.g., acute myeloid leukemia). In some implementations, the cancer is lymphoma. In some implementations, the cancer is multiple myeloma. In some implementations, the subject requires regenerative medicine or a therapy.

[0430] In another aspect, this disclosure provides methods and uses comprising contacting cells with an effective amount of a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0431] In some respects, this disclosure provides methods and uses that include killing cells with an effective amount of a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0432] In some respects, this disclosure provides methods and uses comprising contacting a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof with cells, tissues, or biological samples to inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic or adult stem cell characteristics of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0433] In some embodiments, this disclosure provides a method for modulating NAMPT in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0434] In some embodiments, this disclosure provides a method of treating a subject’s disease or condition by modulating the subject’s NAMPT, which includes administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0435] In some embodiments, this disclosure provides a method for inhibiting NAMPT in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0436] In some embodiments, this disclosure provides a method of treating a subject’s disease or condition by inhibiting the subject’s NAMPT, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0437] In some embodiments, this disclosure provides a method for modulating the inflammatory activity of 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.

[0438] In some embodiments, this disclosure provides a method for treating a subject's disease or condition by modulating the subject's inflammatory activity, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0439] In some embodiments, this disclosure provides a method for 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.

[0440] In some embodiments, this disclosure provides a method for treating a subject's disease or condition by reducing the subject's inflammatory activity, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0441] In some embodiments, this disclosure provides a method for modulating the cellular metabolism of 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.

[0442] In some embodiments, this disclosure provides a method for treating a disease or condition of a subject by modulating the subject's cellular metabolism, 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.

[0443] In some embodiments, this disclosure provides a method for reducing cellular metabolism 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.

[0444] In some embodiments, this disclosure provides a method for treating a subject’s disease or condition by reducing the subject’s cellular metabolism, 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.

[0445] In some embodiments, this disclosure provides a method for modulating the cellular metabolic activity or state of 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.

[0446] In some embodiments, this disclosure provides a method for treating a disease or condition of a subject by modulating the subject's cellular metabolic activity or state, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0447] In some embodiments, this disclosure provides a method for reducing the cellular metabolic activity or state of 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.

[0448] In some embodiments, this disclosure provides a method for treating a subject’s disease or condition by reducing the subject’s cellular metabolic activity or state, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof.

[0449] In some embodiments, this disclosure provides a method for 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.

[0450] In some embodiments, this disclosure provides a method for treating a disease or condition of 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.

[0451] In some embodiments, this disclosure provides a method for 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.

[0452] In some embodiments, this disclosure provides a method for treating a subject’s disease or condition by reducing inflammatory cell infiltration, 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.

[0453] In some embodiments, this disclosure provides a method for regulating 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.

[0454] In some embodiments, this disclosure provides a method for treating a disease or condition of 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.

[0455] In some embodiments, this disclosure provides a method for 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.

[0456] In some embodiments, this disclosure provides a method for treating a disease or condition of 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.

[0457] In some embodiments, this disclosure provides a method for regulating 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.

[0458] In some embodiments, this disclosure provides a method for treating a disease or condition of 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.

[0459] In some embodiments, this disclosure provides a method for 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.

[0460] In some embodiments, this disclosure provides a method for treating a disease or condition of a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0461] In some embodiments, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0462] In some embodiments, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0463] In some embodiments, this disclosure provides a method for treating a subject’s disease or condition by modulating the subject’s NAMPT pathway, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

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

[0465] In some embodiments, this disclosure provides a method for 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, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0466] In some embodiments, this disclosure provides a method for treating a disease or condition of a subject by modulating NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0467] In some embodiments, this disclosure provides a method for reducing NAMPT signaling 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.

[0468] In some embodiments, this disclosure provides a method for treating a disease or condition of a subject by reducing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0469] In some embodiments, this disclosure provides a method of treating a subject for a disease or condition, comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, or a composition disclosed herein. In some embodiments, the disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling. In some embodiments, the disease or condition is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling.

[0470] In some embodiments, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, 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. In some embodiments, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of formula (0) or (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug. In some embodiments, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, comprising administering to the subject a therapeutically effective amount of a compound as described in the additional compound portion or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug. In some embodiments, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound as described in the additional compound portion or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug. In some embodiments, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, comprising administering to the subject a therapeutically effective amount of a compound from 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, this disclosure provides methods and uses for treating or preventing the disease or condition described herein in a subject with such need, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound from 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 disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling. In some embodiments, the disease or condition is mediated by NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling.

[0471] In some implementations, the disease or condition is associated with changes in NAMPT, NMN, NAD, cellular metabolism, and / or NAMPT signaling, wherein said disease or condition is cancer, heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), arthritis, rheumatoid arthritis, acute lung injury, pneumonia, localized pneumonia, severe acute respiratory distress syndrome, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopic dermatitis. Dermatitis, UV-induced skin damage, autoimmune diseases, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, nausea, infection-related inflammation, vasculitis, atherosclerotic thrombotic diseases, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, atherosclerotic inflammatory diseases, cardiovascular diseases, cerebrovascular diseases, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), neurodegenerative diseases, COVID-19, lung inflammation, coronavirus infection, and tumors.

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

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

[0474] In some implementations, the disease or condition is selected from heart failure, dilated cardiomyopathy, pain, graft-versus-host disease (GCDH), diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, osteoporosis, fibrotic diseases, skin diseases, psoriasis, atopic dermatitis, UV-induced skin damage, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, nausea, acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome, ataxia-telangiectasia, cardiovascular disease, cerebrovascular disease, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, neurodegenerative diseases, and tumors.

[0475] In some implementations, the disease or condition is selected from diabetes, rheumatoid arthritis, inflammatory bowel disease, acute respiratory distress syndrome, and ventilator-induced lung injury.

[0476] In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is heart failure. In some embodiments, the disease or condition is dilated cardiomyopathy. In some embodiments, the disease or condition is pain. In some embodiments, the disease or condition is acute respiratory distress syndrome. In some embodiments, the disease or condition is ventilator-induced lung injury. In some embodiments, the disease or condition is inflammation. In some embodiments, the disease or condition is graft-versus-host disease (GCDH). In some embodiments, the disease or condition is arthritis. In some embodiments, the disease or condition is acute lung injury. In some embodiments, the disease or condition is colitis. In some embodiments, the disease or condition is inflammatory bowel disease (IBD). In some embodiments, the disease or condition is diabetes. In some embodiments, the disease or condition is obesity. In some embodiments, the disease or condition is axonal degeneration. In some embodiments, the disease or condition is tissue repair disorder. In some embodiments, the disease or condition is asthma. In some embodiments, the disease or condition is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease or condition is osteoarthritis. In some embodiments, the disease or condition is osteoporosis. In some embodiments, the disease or condition is a fibrotic disease. In some embodiments, the disease or condition is a skin disease. In some embodiments, the disease or condition is psoriasis. In some embodiments, the disease or condition is atopic dermatitis. In some embodiments, the disease or condition is ultraviolet-induced skin damage. In some embodiments, the disease or condition is an autoimmune disease. In some embodiments, the disease or condition is Alzheimer's disease. In some embodiments, the disease or condition is stroke. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, the disease or condition is restenosis. In some embodiments, the disease or condition is glomerulonephritis. In some embodiments, the disease or condition is nausea. In some embodiments, the disease or condition is infection-related inflammation. In some embodiments, the disease or condition is vascular inflammation. In some embodiments, the disease or condition is atherosclerotic thrombotic disease. In some embodiments, the disease or condition is acquired immunodeficiency syndrome (AIDS). In some embodiments, the disease or condition is adult respiratory distress syndrome. In some embodiments, the disease or condition is ataxia-telangiectasia. In some embodiments, the disease or condition is an atherosclerotic inflammatory disease. In some embodiments, the disease or condition is a cardiovascular disease. In some embodiments, the disease or condition is a cerebrovascular disease.In some embodiments, the disease or condition is acute coronary syndrome. In some embodiments, the disease or condition is polycystic ovary syndrome. In some embodiments, the disease or condition is preeclampsia. In some embodiments, the disease or condition is sepsis. In some embodiments, the disease or condition is septic shock. In some embodiments, the disease or condition is intrauterine infection. In some embodiments, the disease or condition is Crohn's disease (CD). In some embodiments, the disease or condition is ulcerative colitis (UC). In some embodiments, the condition is a neurodegenerative disease. In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is COVID-19. In some embodiments, the disease or condition is lung inflammation. In some embodiments, the disease or condition is coronavirus infection. In some embodiments, the disease or condition is pneumonia. In some embodiments, the disease or condition is localized pneumonia. In some embodiments, the disease or condition is severe acute respiratory distress syndrome.

[0477] In some implementations, autoimmune diseases include systemic lupus erythematosus, multiple sclerosis, ankylosing spondylitis, tissue and organ rejection, glomerulonephritis, Goodbastien syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Ritter syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy. In some implementations, autoimmune diseases include...

Claims

1. A compound of formula (0): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein: R 1 is the unsubstituted C 1-12 alkyl; R 2 It is C 1-6 Haloalkyl, unsubstituted 4-membered heterocyclic-C 1-2 -alkyl, or unsubstituted or halogen-substituted 3 to 4-membered cycloalkyl-C 1-2 -alkyl; R 3 is hydrogen, halogen, unsubstituted C 1-6 Alkyl, –COOR a , or –CN; R a Each instance of is independently hydrogen or unsubstituted C 1-6 alkyl; R 6 It is hydrogen; R 8 Each example of is hydrogen; R 9 Each example of is independently hydrogen, halogen, unsubstituted C 1-6 Alkyl, –OR a , –N(R a )2 or –CN, or R 9 Two examples of are connected to form a 5- to 14-membered heteroaryl ring; n is an integer from 0 to 2, inclusive; m is 0; p is 0; and q is an integer selected from 0 and 1.

2. The compound of claim 1, wherein the compound has formula (0a): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

3. The compound of claim 1, wherein the compound has formula (0b): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

4. The compound of claim 1, wherein the compound has formula (0c): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein q is 0. 6 . The compound according to claim 1 , or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein q is 1.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 9 The two examples are connected to form a 5-membered heteroaryl ring.

8. A compound of formula (I): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein: R 1 is the unsubstituted C 1-6 alkyl; R 2 It is C 1-6 Haloalkyl, unsubstituted 4-membered heterocyclic-C 1-2 -alkyl, or unsubstituted or halogen-substituted 3 to 4-membered cycloalkyl-C 1-2 -alkyl; R 3 is hydrogen, halogen, unsubstituted C 1-6 Alkyl, -COOR a or -CN; R a Each instance of is independently hydrogen or unsubstituted C 1-6 alkyl; R 6 It is hydrogen; R 8 Each example of is hydrogen; R 9 Each example of is independently hydrogen, halogen, unsubstituted C 1-6 Alkyl, –OR a , –COR a , –N(R a )2, or –CN; n is an integer from 0 to 2, inclusive; m is 0; and p is 0.

9. The compound of claim 1 or 8, wherein the compound has formula (Iz): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. 10 . The compound according to claim 1 or 8 , or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein n is 0.

11. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein n is 1.

12. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein n is 2.

13. The compound of claim 1 or 8, wherein the compound has formula (Ia): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

14. The compound of claim 1 or 8, wherein the compound has formula (Ib): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

15. The compound of claim 1 or 8, wherein the compound has formula (Ic): or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

16. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein each R 9 are independently hydrogen, unsubstituted methyl, chloro, fluoro, methoxy or -NH2.

17. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein each R 9 are independently unsubstituted methyl, chloro, fluoro, methoxy or -NH2.

18. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 9 It's methyl.

19. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 3 is hydrogen, unsubstituted methyl, fluoro, chloro, -CN, or -COOMe.

20. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 3 is hydrogen, unsubstituted methyl, chloro, -CN, or -COOMe.

21. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 3 is hydrogen, unsubstituted methyl, -CN, or -COOMe.

22. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 3 It is methyl or chloro.

23. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 1 is the unsubstituted C 1-6 alkyl.

24. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 1 is the unsubstituted C 1-3 alkyl.

25. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 1 is an unsubstituted methyl group.

26. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 1 It is an unsubstituted ethyl group.

27. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 It is difluoroethyl.

28. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 It is 2,2-difluoroethyl.

29. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 is an unsubstituted or halo-substituted 3- to 4-membered cycloalkyl-C 1-2 -alkyl.

30. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 It is a 3- to 4-membered cycloalkyl-C1-alkyl group which is unsubstituted or substituted by a halo group.

31. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 It is cyclopropylmethyl.

32. The compound of claim 1 or 8, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, wherein R 2 is an unsubstituted 3- to 4-membered cycloalkyl-C 1-2 -alkyl.

33. The compound of claim 8, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

34. The compound of claim 1 or 8, wherein the compound is selected from the group consisting of: Its pharmaceutically acceptable salt or isotope-labeled derivative.

35. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

36. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

37. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

38. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

39. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

40. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

41. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof; and optionally a pharmaceutically acceptable excipient.

43. The pharmaceutical composition of claim 42, further comprising an additional pharmaceutical agent.

44. The pharmaceutical composition of claim 43, wherein the additional agent is a chemotherapeutic agent.

45. The pharmaceutical composition of claim 43, wherein the additional agent is a differentiation agent.

46. ​​Use of a compound as claimed in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as claimed in any one of claims 42 to 45, in the preparation of a medicament for inhibiting NAMPT in a subject.

47. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by inhibiting NAMPT in the subject.

48. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject.

49. The use of claim 48, wherein the disease or condition is pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease, severe acute respiratory distress syndrome, acute lung injury, inflammatory bowel disease, diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease, osteoporosis, fibrotic diseases, skin diseases, autoimmune diseases, Alzheimer's disease, stroke, cachexia, acquired immunodeficiency syndrome, adult respiratory distress syndrome, ataxia-telangiectasia, cardiovascular disease, cerebrovascular disease, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease, neurodegenerative disorders, COVID-19, coronavirus infection, or tumors.

50. Use of a compound as claimed in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as claimed in any one of claims 42 to 45, in the preparation of a medicament for treating cancer in a subject.

51. The use of claim 50, wherein the cancer comprises cancer stem cells.

52. The use of any one of claims 50 to 51, wherein the cancer is gastric cancer, gastrointestinal stromal tumors, ovarian cancer, lung cancer, breast cancer, pancreatic cancer or prostate cancer.

53. The use of claim 50 or 51, wherein the cancer is gastric cancer subtype GS or gastric cancer subtype CIN.

54. The use of claim 50 or 51, wherein the cancer is colorectal cancer.

55. The use of claim 54, wherein the cancer is colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4.

56. The use of any one of claims 50 to 51, wherein the cancer is testicular cancer.

57. The use of any one of claims 50 to 51, wherein the cancer is liver cancer.

58. The use of any one of claims 50 to 51, wherein the cancer is endometrial cancer.

59. The use according to claim 58, wherein the cancer is uterine cancer.

60. The use of any one of claims 50 to 51, wherein the cancer is small cell lung cancer.

61. The use of any one of claims 50 to 51, wherein the cancer is lymphoma.

62. The use of claim 61, wherein the cancer is non-Hodgkin lymphoma, B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, Burkitt B-cell lymphoma or large cell immunoblastic lymphoma.

63. The use of any one of claims 50 to 51, wherein the cancer is leukemia.

64. The use of claim 63, wherein the cancer is acute myeloid leukemia.

65. The use of claim 63, wherein the cancer is undifferentiated acute myeloblastic leukemia M0, minimal mature acute myeloblastic leukemia M1, mature acute myeloblastic leukemia M2, acute promyelocytic leukemia M3, acute myelomonocytic leukemia M4, acute myelomonocytic leukemia with eosinophilia M4eos, acute monocytic leukemia M5, acute erythroblastic leukemia M6, or acute megakaryoblastic leukemia M7.

66. The use of claim 63, wherein the cancer is acute monocytic leukemia, acute lymphoblastic leukemia, or B-cell acute lymphoblastic leukemia.

67. The use of claim 63, wherein the cancer is chronic myeloid leukemia (CML) or chronic lymphocytic leukemia.

68. The use of claim 63, wherein the cancer is acute lymphoblastic leukemia.

69. The method of claim 63, wherein the acute lymphoblastic leukemia is B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia.

70. The use of any one of claims 50 to 51, wherein the cancer is multiple myeloma.

71. The use of claim 70, wherein the cancer is B-cell myeloma.

72. The use of any one of claims 50, 51, 55, 59, 62, 64-69 or 71, wherein the subject has undergone or is undergoing one or more additional cancer therapies.

73. The use of any one of claims 50, 51, 55, 59, 62, 64-69 or 71, wherein the subject is in need of regenerative medicine.

74. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for contact with a cell, tissue or biological sample, wherein the contacting: reducing one or more embryonic or adult stem cell properties of the cell; reduce cell viability and / or prevent cell proliferation; killing the cells; Inhibit tumor growth; prevent transfer; Differentiate one or more cells; and / or Regenerate one or more cells.

75. The use of claim 74, wherein the cells are characterized by one or more embryonic, pluripotent or adult stem cell properties.

76. The use of claim 74 or 75, wherein the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, a differentiated cancer cell, or an adult stem cell.

77. The use of claim 74 or 75, wherein the contacting reduces one or more embryonic or adult stem cell properties of the cell.

78. The use of claim 74 or 75, wherein the contacting is performed in vitro or ex vivo.

79. The use of claim 74 or 75, wherein the contacting reduces cell viability and / or prevents cell proliferation.

80. The use of claim 74 or 75, wherein the contacting kills the cell.

81. The use of claim 74 or 75, wherein the contacting inhibits tumor growth.

82. The use of claim 74 or 75, wherein the contacting prevents metastasis.

83. The use of claim 74 or 75, wherein the contacting differentiates one or more cells.

84. The use of claim 74 or 75, wherein the contacting regenerates one or more cells.

85. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for killing cells.

86. The use of claim 85, wherein the cells are characterized by one or more embryonic properties or adult stem cell properties.

87. The use of claim 85 or 86, wherein the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, an adult stem cell, or a differentiated cancer cell.

88. The use of claim 85 or 86, wherein the killing reduces one or more embryonic or adult stem cell properties of the cells.

89. The method of claim 85 or 86, wherein the killing is performed in vitro or ex vivo.

90. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for inhibiting the production of nicotinamide adenine dinucleotide in a subject.

91. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject.

92. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for inhibiting the production of nicotinamide mononucleotide in a subject.

93. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by inhibiting the production of nicotinamide mononucleotide in the subject.

94. A compound as described in any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or an isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, for use in the preparation of a medicament for reducing inflammatory cell infiltration in a subject.

95. The compound as described in any one of claims 1 to 41, or its pharmaceutically acceptable salt or isotope-labeled derivative, or the compositions as described in any one of claims 42 to 45, for preparing a drug for treating a disease or illness of the experimenter by reducing the inflammatory cell infiltration of the experimenter.

96. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing cell proliferation in a subject.

97. The use of a compound as described in any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or an isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or illness of the experimenter by reducing the cell proliferation of the experimenter.

98. Use of a compound as described in any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or an isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for reducing a subject's cellular metabolic activity or state.

99. The compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof or an isotope-labeled derivative thereof, or the compositions of any one of claims 42 to 45, in the preparation of a medicament for treating a disease or illness of the subject by reducing the cellular metabolic activity or state of the subject.

100. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing inflammatory activity in a subject.

101. Use of a compound as described in any one of claims 1 to 41, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by reducing the inflammatory activity of the subject.

102. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing NAMPT signaling in a subject.

103. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by reducing NAMPT signaling in the subject.

104. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for inhibiting the NAMPT pathway in a subject.

105. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for treating a disease or disorder in a subject by inhibiting the NAMPT pathway in the subject.

106. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for inhibiting the NAMPT pathway in a cell, tissue or biological sample.

107. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing NAMPT signaling in a cell, tissue or biological sample.

108. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing the inflammatory activity of a cell, tissue or biological sample.

109. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing the cellular metabolic activity or state of a cell, tissue or biological sample.

110. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing cell proliferation of a cell, tissue or biological sample.

111. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for reducing inflammatory cell infiltration of a cell, tissue or biological sample.

112. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue or biological sample.

113. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, in the preparation of a medicament for inhibiting the production of nicotinamide mononucleotide in a cell, tissue or biological sample.

114. Use of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45 in the preparation of a medicament for inhibiting NAMPT in a cell, tissue or biological sample.

115. The use according to any one of claims 106 to 114, wherein the use is performed in vitro or ex vivo.

116. Use of a combination of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a composition as described in any one of claims 42 to 45, and an additional agent in the preparation of a medicament for treating a disease or condition in a subject.

117. The use of claim 116, wherein the additional agent is administered before, simultaneously with or after the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or the composition of any one of claims 42 to 45.

118. The use of any one of claims 47, 91, 93, 95, 97, 99, 101, 103, 105, and 116 to 117, wherein the disease or condition is pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease, severe acute respiratory distress syndrome, acute lung injury, inflammatory bowel disease, diabetes, obesity, axonal degeneration, tissue repair disorders, asthma, chronic obstructive pulmonary disease, osteoporosis, fibrotic diseases, skin diseases, autoimmune diseases, Alzheimer's disease, stroke, cachexia, acquired immunodeficiency syndrome, adult respiratory distress syndrome, ataxia-telangiectasia, cardiovascular disease, cerebrovascular disease, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, intrauterine infection, Crohn's disease, neurodegenerative disorders, COVID-19, coronavirus infection, or tumors.

119. The use of claim 49 or 118, wherein the disease or condition is heart failure, dilated cardiomyopathy, pneumonia, pneumonitis, arthritis, colitis, psoriasis, atopic dermatitis, UV-induced skin damage, atherosclerosis, restenosis, inflammation associated with infection, vascular inflammation, atherothrombotic disease, ulcerative colitis, lung inflammation, glomerulonephritis, or an atherogenic inflammatory disease.

120. The use of claim 119, wherein the disease or disorder is osteoarthritis.

121. A medicine kit comprising: A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof; Or a pharmaceutical composition as described in any one of claims 42 to 45; as well as Instructions for using the compound, pharmaceutically acceptable salt or isotope-labeled derivative or pharmaceutical composition.

Images