NAMPT inhibitors and their uses

Abstract

Disclosed are compounds, methods, compositions, uses, and kits that modulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide mononucleotide (NMN) production, nicotinamide adenine dinucleotide (NAD) production, NAMPT signaling, the NAMPT pathway, and / or cellular metabolism. In some embodiments, the compounds are used to treat a disease or disorder. The compounds may treat cancer by targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, liver cancer, endometrial cancer, leukemia, or multiple myeloma. Additionally, methods of making a compound of formula (V) are provided. Compounds of the present disclosure are of formula (I), (II), (III), and (IV). [Formula 1] JPEG2024518089000393.jpg96163

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application USSN 63 / 188,399, filed May 13, 2021, which is incorporated herein by reference. [Background technology]

[0002] Cancer is ubiquitous and, despite medical advances, 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 expected to increase by approximately 70% over the next 20 years. The economic impact of cancer is significant and growing: in 2010, the total annual economic cost of cancer was estimated to be approximately US$1.16 trillion. 2

[0003] Cancer is a general term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumor and neoplasm. Cancer results from the transformation of normal cells into tumor cells in a multistep process, which generally progresses from a precancerous lesion to a malignant tumor. One of the defining characteristics of cancer is the rapid creation of abnormal cells, which can grow beyond their normal boundaries and invade adjacent parts of the body, spreading to other organs. This latter process is called metastasis. Metastasis is the leading cause of cancer death. The most common causes of cancer death are cancer of the lung, liver, colorectum, stomach, and breast.

[0004] While progress has been made in treating a subset of cancer types, average cancer mortality rates remain extremely high, and little overall improvement has been made in the ongoing cancer crisis. Nearly all modern cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on tumor debulking and fail to target the most dangerous cells within tumors: cancer stem cells, which 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 Current treatments do not target cancer stem cell populations, often leading to the proliferation of resistant tumors and continued cancer spread. Summary of the Invention

[0005] The discovery of cancer stem cells provides an opportunity to integrate the fields of oncology and stem cell biology. 5、6 The development of effective, non-toxic therapies can be achieved through a strategy called cancer containment therapy by targeting what makes cancer so dangerous: the embryonic or adult stem cell properties of cancer stem cells that form the basis for cancer growth, spread, and resistance. A therapy that can both reduce tumor size and destroy cancer stem cells would transform cancer treatment. 7 Examples of such cancer treatments can be found, for example, in PCT Publication No. WO2019 / 213570 and PCT Application No. PCT / US2020 / 059329, both of which are incorporated by reference herein in their entireties.

[0006] The compounds herein may force cancer stem cells to differentiate and inhibit signaling pathways required for metastasis (the same pathways used by stem cells during differentiation and development). 8、9 These pathways can be safely targeted because they occur only in stem cells and not in healthy adult tissues.

[0007] Described herein are compounds that modulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide mononucleotide (NMN) production, nicotinamide adenine dinucleotide (NAD) production, NAMPT signaling, the NAMPT pathway, and / or cellular metabolism. Additional NAMPT inhibitors can be found, for example, in PCT Application No. PCT / US2020 / 059329, which is incorporated herein by reference in its entirety. Elevated levels of NAMPT have been described in (a) metabolic / inflammatory conditions, including obesity, type 2 diabetes, metabolic syndrome, atherogenic inflammatory disease, and cardio / cerebrovascular disease; (b) non-metabolic chronic inflammatory diseases, including osteoarthritis and acute lung injury; (c) infectious diseases, such as sepsis or intrauterine infection; and (d) autoimmune inflammatory diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. 15 .

[0008] Enzymatic inhibition of NAMPT has effects on the immune system, including suppression and stimulatory effects. NAMPT has been implicated in acute respiratory distress syndrome, inflammatory bowel disease, inflammatory arthritis, hepatitis, neuroinflammation, diabetes, vascular inflammation, and stimulation of the immune microenvironment. 20~36 Inhibition of intracellular NAMPT reduced intracellular NAD levels in lung tissue, leading to inflammatory cell infiltration and lung injury in rodents, and enhanced apoptosis in inflammatory polymorphonuclear neutrophils. 20、21 NAMPT inhibition inhibited IL-8 production and NF-kB activation in human alveolar epithelial cells exposed to hypoxia-reoxygenation. 21 Blockade of NAMPT activity ameliorates experimental colitis, biases monocyte / macrophage biology toward an anti-inflammatory M2 phenotype, and reduces cytokine release from human IBD-derived lamina propria mononuclear cells. 22 NAMPT inhibition or deficiency reduces synovial inflammation and cartilage destruction and prevents bone erosion in mice with collagen-induced arthritis. 23、24、25 Inhibiting NAMPT reduced the expression of proinflammatory cytokines and protected mice from experimental hepatitis. 26Pharmacological inhibition of NAMPT prevented the recruitment of myeloid-derived suppressor cells, reactivated antitumor immunity, and enhanced the antitumor activity of immune checkpoint inhibitors. 27 Several studies have found that in rats with ischemic injury, NAMPT inhibition reduced the levels of TNF-α, NAMPT, and IL-6 in ischemic brain tissue, improved neuronal dysfunction, reduced infarct volume and neuronal loss, and inhibited microgliosis and astrogliosis. 28 On the other hand, another study showed that pharmacological inhibition of NAMPT exacerbated cerebral infarction in rats with cerebral ischemia. 29 In an experimental compression model of spinal cord injury, inhibition of NAMPT also reduced secondary inflammatory damage and partially reduced permanent injury. 30 Although inhibition of NAMPT prevented eNAMPT-induced vascular inflammation 31、32 , inhibition of iNAMPT in leukocytes reversed its antiatherogenic effect. 33 Adipocyte-specific deletion of Nampt causes severe insulin resistance accompanied by adipose tissue inflammation, an effect that was ameliorated by NMN. 34 Enzymatic inhibition of exogenous NAMPT suppressed the pro-inflammatory effects on renal tubular cells, whereas inhibition of endogenous NAMPT promoted inflammation in the inflammatory environment of diabetic rats. 35 On the other hand, another study suggested that the pro-inflammatory role of endogenous NAMPT in diabetic kidney cells was suppressed by inhibiting the enzymatic activity of NAMPT. 36

[0009] Described herein are compounds, methods, methods of synthesizing compounds, uses, kits, and compositions for treating an inflammatory disease, a proliferative disease, an autoimmune disease, a hematological disease, a neurological disease, a pain condition, a metabolic disorder, an infectious disease, a cardiovascular disease, a cerebrovascular disease, a tissue repair disorder, a pulmonary disease, a skin disease, a bone disease, or a hormonal disease disclosed herein.

[0010] In some embodiments, these compounds are more effective than conventional cancer treatments in reducing tumor growth, extending lifespan, and / or preventing metastasis and recurrence. Additionally, because the reactivation of embryonic characteristics in cell populations is a common property of many tumor types, cancer containment therapies are expected to be effective against many different types of cancer, including leukemia and cancers of the colon, stomach, prostate, testicle, and breast.

[0011] Disclosed herein are compounds, methods, compositions, uses, and kits that allow for the treatment of inflammatory diseases, proliferative diseases, autoimmune diseases, hematological diseases, neurological diseases, pain conditions, metabolic disorders, infectious diseases, cardiovascular diseases, cerebrovascular diseases, tissue repair disorders, pulmonary diseases, skin diseases, bone diseases, or hormonal diseases.

[0012] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; and R 2 , R 3 , L 1 , R 9 and n is defined herein. Subgenuses of Formula (I) (e.g., compounds of Formula (Ia) and Formula (Ib)) are also provided herein.

[0013] In another aspect, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ring B is a 3- to 13-membered carbocyclyl ring, a 6- to 12-membered aryl ring, or an aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2 ,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzo Thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepine pyranyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzo a heterocyclyl or heteroaryl ring selected from the group consisting of dibenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl; R, 2 , R 3 , L 2 , R 9 and n is defined herein. Subgenus of Formula (II) (e.g., compounds of Formula (IIa) and Formula (IIb)) are also provided herein.

[0014] In a further aspect, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 2 , R 3 , L 3 , ring A, R 9 and n are defined herein. Subgenuses of Formula (III) (e.g., compounds of Formula (IIIa), Formula (IIIb), Formula (IIIc), and Formula (IIId)) are also provided herein.

[0015] In an additional aspect, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ring D is a 3- to 13-membered heterocyclyl or a 5- to 14-membered heteroaryl ring; and R 2 , R 3 , R 9 and n is defined herein.

[0016] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0017] In another aspect, the 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 (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables described in Formula (I), (II), (III), or (IV) are as described herein. In certain embodiments, the cancer comprises cancer stem cells. In certain embodiments, the cancer involves or is associated with cancer stem cells. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, testicular cancer, prostate cancer, liver cancer, or endometrial cancer. In certain embodiments, the cancer is leukemia (e.g., acute myeloid leukemia). In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the subject is in need of a regenerative medicine or therapy.

[0018] In yet another aspect, the disclosure provides methods and uses comprising contacting a cell with an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0019] In certain aspects, the present disclosure provides methods and uses that include killing a cell with an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0020] In certain aspects, the present disclosure provides methods and uses that include contacting a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, with a cell, tissue, or biological sample to inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic or adult stem cell characteristics of one or more cells, reduce cell viability, and / or prevent cell proliferation.

[0021] In certain aspects, the present disclosure provides a method of inhibiting NAMPT in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0022] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting NAMPT in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0023] In certain aspects, the present disclosure provides a method of inhibiting the production of nicotinamide adenine dinucleotide in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0024] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0025] In certain aspects, the disclosure provides a method of inhibiting the production of nicotinamide mononucleotide in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0026] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0027] In certain aspects, the present disclosure provides a method of reducing inflammatory cell infiltration in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0028] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by reducing inflammatory cell infiltration in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0029] In certain aspects, the present disclosure provides a method of reducing cell proliferation in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0030] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject by reducing cell proliferation in the subject, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0031] In certain aspects, the present disclosure provides a method of reducing cellular metabolic activity in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0032] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject by reducing cellular metabolic activity in the subject, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0033] In certain aspects, the present disclosure provides a method of reducing inflammatory activity in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0034] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by reducing inflammatory activity in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0035] In certain aspects, the present disclosure provides a method of reducing NAMPT signaling in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0036] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by decreasing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0037] In certain aspects, the present disclosure provides a method of inhibiting the NAMPT pathway in a subject, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0038] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject by inhibiting the NAMPT pathway in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III) or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0039] In certain aspects, the present disclosure provides methods for inhibiting NAMPT in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0040] In certain aspects, the present disclosure provides methods for reducing NAMPT signaling in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0041] In certain aspects, the present disclosure provides methods of reducing inflammatory activity in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0042] In certain aspects, the present disclosure provides methods of reducing cellular metabolic activity in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0043] In certain aspects, the present disclosure provides methods of reducing cell proliferation in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0044] In certain aspects, the present disclosure provides methods of reducing inflammatory cell infiltration in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0045] In certain aspects, the present disclosure provides methods for inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0046] In certain aspects, the present disclosure provides methods of inhibiting the production of nicotinamide mononucleotide in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0047] In certain aspects, the present disclosure provides methods for inhibiting NAMPT in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0048] In some embodiments, the contacting step is carried out in vitro or ex vivo.

[0049] In some aspects, the present disclosure provides a composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the composition further comprises an additional pharmaceutical agent.

[0050] In certain aspects, the disclosure provides methods of treating a disease or disorder in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition disclosed herein, and an additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent is administered before, simultaneously with, or after a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition disclosed herein.

[0051] In a further aspect, the disclosure provides kits comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or a composition described herein; and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

[0052] Also provided herein are compounds disclosed herein (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, for use in any of the methods described herein. Also provided herein are compounds disclosed herein (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, for preparing a medicament (e.g., for treating and / or preventing any of the diseases or conditions described herein).

[0053] Further, as used herein, there is provided a compound of formula (V): [ka] or a salt thereof, wherein the rings M, q, R 3S , and R 2S is defined herein. In some embodiments, Route A is used to synthesize a compound of Formula (V). In some embodiments, Route B is used to synthesize a compound of Formula (V). In some embodiments, Route B and Route C are used to synthesize a compound of Formula (V). In some embodiments, Route D is used to synthesize a compound of Formula (V). In some embodiments, Route E is used to synthesize a compound of Formula (V).

[0054] The details of certain embodiments of the invention are set forth in the detailed description set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, examples, and claims.

[0055] definition For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0056] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0057] The phrases "in some embodiments" and "in one particular embodiment" are used interchangeably.

[0058] The following definitions are of more general terms used throughout this application.

[0059] The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0060] Except in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." "About" and "approximately" are generally intended to refer to the degree of error acceptable for the measured quantity given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0061] Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th (ed.) (back cover), and specific functional groups are generally defined as described therein. For general principles of organic chemistry and specific functional moieties and reactivities, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7 th 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,3 rdEdition, Cambridge University Press, Cambridge, 1987.

[0062] The compounds described herein may contain 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 individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or 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, ELS Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0063] In the formula: [ka] is a single bond with no specified stereochemistry at the directly attached moiety, [ka] is absent or a single bond, [ka] or [ka] is a single or double bond.

[0064] Unless otherwise specified, formulas set forth herein include compounds that do not contain isotopically enriched atoms and also include compounds that contain isotopically enriched atoms, which may be useful, for example, as analytical tools and / or as probes in biological assays.

[0065] The term "aliphatic" includes both saturated and unsaturated, non-aromatic, straight-chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, aliphatic groups are optionally substituted with one or more functional groups (e.g., halo, such as fluorine). As one of ordinary skill in the art would understand, "aliphatic," as used herein, is intended to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0066] When a range of values ​​("range") is listed, it is intended to encompass each value and subrange within the range. A range includes the values ​​at both ends of the range unless otherwise indicated. For example, "an integer between 1 and 4" means 1, 2, 3, and 4; for example, "C 1~6 "Alkyl" refers to 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 , C4~5 , and C 5~6 Alkyl is intended to be included.

[0067] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), and n-octyl (C10). 12 Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~12 Alkyl (e.g., —CH(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, e.g., unsubstituted N-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1~12 Alkyl (e.g., substituted C 1~6 Alkyl, for example, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, or benzyl (Bn). The point of attachment of the alkyl can be a single bond (e.g., as in -CH), a double bond (e.g., as in =CH), or a triple bond (e.g., as in ≡CH). Moieties such as =CH and ≡CH are also alkyls.

[0068] In some embodiments, an alkyl group is substituted with one or more halogens. A "perhaloalkyl" is a substituted alkyl group, as defined herein, in which all hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C1~8 In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C 1~2 In some embodiments, all hydrogen atoms are replaced with fluoro. In some embodiments, all hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include -CF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0069] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, internally (e.g., inserted between adjacent carbon atoms) and / or located at one or more terminal position(s) of the parent chain. In certain embodiments, heteroalkyl groups are saturated groups having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC"). 1~20 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~12 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~11 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~9In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~12 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~12 It is alkyl.

[0070] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., 2, 3, or 4, valences permitting) carbon-carbon double bonds and no triple bonds ("C 2~20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4In addition to alkenyl groups, examples include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 In alkenyl groups, a C=C double bond with no specified stereochemistry (e.g., -CH=CHCH3, [ka] can be in the (E) or (Z) configuration.

[0071] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more (e.g., two, three, or four, valences permitting) carbon-carbon triple bonds, and optionally one or more double bonds ("C 2~20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of the alkynyl group include the above-mentioned C 2~4 In addition to alkynyl groups, examples include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0072] "Carbocyclyl" or "carbocyclic" means a radical of a non-aromatic cyclic hydrocarbon group having 3 to 13 ring carbon atoms ("C 3~13 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C3~6 Carbocyclyl groups include cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 As the carbocyclyl group, the aforementioned C 3~6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 As the carbocyclyl group, the aforementioned C 3~8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the preceding examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"). A carbocyclyl can be saturated, and saturated carbocyclyls are referred to as "cycloalkyls." In some embodiments, a carbocyclyl is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 In addition to alkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are included. 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10It is a cycloalkyl. A carbocyclyl may be partially unsaturated. A carbocyclyl may contain zero, one, or more (e.g., two, three, or four, valences permitting) C=C double bonds in all rings of a carbocyclic ring system that is neither aromatic nor heteroaromatic. A carbocyclyl containing one or more (e.g., two or three, valences permitting) C=C double bonds in a carbocyclic ring is referred to as a "cycloalkenyl." A carbocyclyl containing one or more (e.g., two or three, valences permitting) C≡C triple bonds in a carbocyclic ring is referred to as a "cycloalkynyl." Carbocyclyl includes aryl. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring; in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 In certain embodiments, the carbocyclyl is substituted or unsubstituted, 3-7 membered, and monocyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 5-13 membered, and bicyclic.

[0073] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 In addition to alkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are included. 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 In certain embodiments, a carbocyclyl contains, where valence allows, 0, 1, or 2 C=C double bonds in the carbocyclic ring system.

[0074] "Carbocyclylalkyl", "X-X membered carbocyclyl-C x~x alkyl," or "X-X membered carbocyclyl-C x~x "-alkyl" (each instance of X is an integer) is a subset of "alkyl" and refers to an alkyl group substituted by a carbocyclyl group, where the point of attachment is on the alkyl portion. For example, 3- to 13-membered carbocyclyl-C 1~12 -Alkyl groups include C substituted with 3- to 13-membered carbocyclyl groups (e.g., cyclopropyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl). 1~12 It refers to an alkyl group (eg, methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0075] "Heterocyclyl" or "heterocyclic" means the radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclyl"). For heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")). Heterocyclic groups can be saturated or partially unsaturated. A heterocyclyl can contain zero, one, or more (e.g., two, three, or four, where valence allows) double bonds in any ring of a heterocyclic ring system that is neither aromatic nor heteroaromatic. Partially unsaturated heterocyclyl groups include heteroaryl. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring defined above is fused to one or more carbocyclyl groups, with the point of attachment either on the carbocyclyl ring or on the heterocyclyl ring, or in which the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment on the heterocyclyl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl in which one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence allows.

[0076] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0077] Exemplary 3-membered heterocyclyl groups containing one heteroatom include aziridinyl, oxiranyl, or thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrole, and 1H-benzo[e][1,4]diazepinyl. Examples include pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0078] "Heterocyclylalkyl", "X-X membered heterocyclyl-C x~x alkyl," or "X-X membered heterocyclyl-C x~x "-alkyl" (each instance of X is an integer) is a subset of "alkyl" and refers to an alkyl group substituted by a heterocyclyl group, where the point of attachment is on the alkyl portion. For example, 3- to 13-membered heterocyclyl-C 1~12 -alkyl groups are C substituted with 3- to 13-membered heterocyclyl groups (e.g., oxiranyl, oxetanyl, oxadiazolinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl); 1~12 It refers to an alkyl group (eg, methyl, ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl).

[0079] "Aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl"). 10 Aryl," for example, naphthyl (e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the radical or point of attachment being on the aryl ring; in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0080] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, where the point of attachment is on the alkyl portion.

[0081] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., a ring system having 6 or 10 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5- to 10-membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the point of attachment being on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being either on the aryl ring or the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the fused (aryl / heteroaryl) ring system. The point of attachment of a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be on either ring, for example, on a ring with a heteroatom (e.g., 2-indolyl) or on a ring without a heteroatom (e.g., 5-indolyl). In certain embodiments, a heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl in which 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, a heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl in which 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0082] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl portion.

[0083] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0084] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0085] "Partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0086] In some embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents at each position are the same or different. Unless otherwise specified, substituents on a polycyclic ring may be at any substitutable position of any one monocyclic ring in the polycyclic ring. The term "substituted" is intended to include any of the substituents described herein that result in the formation of a stable compound, including substitution with all permissible substituents of organic compounds. The present disclosure contemplates all such combinations to arrive at stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0087] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(Rbb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa, -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is a counter ion), Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group), R bb Each instance of is independently 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 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is a counter ion), R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group), R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee, -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5-10 membered heteroaryl (wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be linked to form =O or =S, and X - is a counter ion; R ee Each instance of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group), R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may be linked to form =O or =S (wherein X - is the counterion).

[0088] In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bbIn certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb )2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2. In certain embodiments, the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2, where R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0089] As used herein, a "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. Anionic counterions can be monovalent (i.e., containing one formal negative charge). Anionic counterions can also be polyvalent (i.e., containing multiple formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid ions, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid ions, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4-, BPh4 -, Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylate, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0090] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0091] Nitrogen atoms may be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc, -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined above.

[0092] In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 In certain embodiments, the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0093] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroalkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc, and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0094] Amide nitrogen protecting groups (e.g., -C(=O)R aa ) include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0095] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl Ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0096] Sulfonamide nitrogen protecting groups (e.g., -S(=O)R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts ), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0097] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilyla. 1,3-Dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) Amines, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthio Methyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, two instances of the nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, are N,N'-isopropylidenediamine.

[0098] In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0099] In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group. In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 In certain embodiments, the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or oxygen protecting group.

[0100] In certain embodiments, the substituent present on the oxygen atom is a nitrogen 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, wherein X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0101] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 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- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formyl Benzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate Examples of suitable amines include nitrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0102] In certain embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0103] In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 In certain embodiments, the sulfur atom substituents are independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 It is an alkyl or sulfur protecting group.

[0104] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). In some embodiments, each sulfur protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -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(wherein, R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0105] Additional exemplary substituents include hydrogen, halogen, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl), C 1~6 Alkoxy, partially or fully halogenated C 1~6 Alkyl (e.g., -CF3, -CHF2, -CH2F), -CN, -NO2, -OR a (e.g., -OMe, -OEt), -SR a , -N(R a )2 (e.g., -NH2, -NMe2), -NR a (C=O)OR a (e.g. -NH(C=O)OMe, -NH(C=O)OEt, -NH(C=O)O t Bu), COOR a (e.g., -COOH, -COOMe, -COOEt), and -COR aFurther examples include aryl and heteroaryl.

[0106] Additional exemplary substituents include hydrogen, halogen, C 1~6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl), C 1~6 Alkoxy, partially or fully halogenated C 1~6 Alkyl (e.g., -CF3, -CHF2, -CH2F), -CN, -NO2, -OR aa (e.g., -OMe, -OEt), -SR aa , -N(R aa )2 (e.g., -NH2, -NMe2), -NR aa (C=O)OR aa (e.g. -NH(C=O)OMe, -NH(C=O)OEt, -NH(C=O)O t Bu), -COOR aa (e.g., -COOH, -COOMe, -COOEt), and -COR aa Further examples include aryl and heteroaryl.

[0107] The "molecular weight" of -R (where -R is any monovalent moiety) is calculated by subtracting the atomic weight of the hydrogen atom from the molecular weight of the molecule RH. The "molecular weight" of -L- (where -L- is any divalent moiety) is calculated by subtracting the combined atomic weight of the two hydrogen atoms from the molecular weight of the molecule HLH.

[0108] In certain embodiments, the molecular weight of the substituent is less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, less than 50 g / mol, or less than 25 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, and / or fluorine atoms. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond donors. In certain embodiments, the substituent does not contain one or more, two or more, or three or more hydrogen bond acceptors.

[0109] The suffix "ene" when added to a group indicates that the group is a multivalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In certain embodiments, the suffix "ene" when added to a group indicates that the group is a divalent moiety.

[0110] The term "hydroxy" or "hydroxyl" refers to an --OH group.

[0111] The terms "thiol" or "thio" refer to an --SH group.

[0112] The term "amine" or "amino" refers to the group --NH-- or --NH.sub.2.

[0113] The term "acyl" refers to a group having the 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, wherein R X1 is hydrogen, halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or diarylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc. (each of which may or may not be further substituted)).

[0114] The term "salt" refers to an ionic compound resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), and therefore is electrically neutral (has no net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lanthanide, thiazolinone ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts. + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0115] The term "pharmaceutically acceptable salt" means a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response, or the like, and that is commensurate with 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 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts. + (C 1~4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate ions.

[0116] The term "solvent" refers to a substance that dissolves one or more solutes to form a solution. A solvent can function as a medium for any reaction or transformation described herein. A solvent can dissolve one or more reactants or reagents in a reaction mixture. A solvent can facilitate mixing of one or more reagents or reactants in a reaction mixture. A solvent can also function to increase or decrease the rate of a reaction compared to a reaction in a different solvent. A solvent can be polar or nonpolar, protic or aprotic. Common solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, Examples of suitable solvents include hexane, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.

[0117] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0118] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including monohydrates (x is 1), hypohydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0119] The term "crystalline" or "crystalline form" refers to a solid form that substantially exhibits three-dimensional order. In certain embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more sharply defined peaks.

[0120] The terms "amorphous" or "amorphous form" refer to a solid form ("solid form") that is substantially devoid of three-dimensional order. In certain embodiments, a solid amorphous form is a solid form that is not substantially crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form comprises a broad, disperse band with peaks at 2θ between 20 and 70° (inclusive), e.g., using CuKα radiation. In certain embodiments, the XRPD pattern of the amorphous form further comprises one or more peaks attributable to crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks attributable to crystalline structure observed at 2θ between 20 and 70° (inclusive) is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broad, disperse band. In certain embodiments, the XRPD pattern of the amorphous form does not comprise peaks attributable to crystalline structure.

[0121] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0122] The term "co-crystal" refers to a crystal structure comprising at least two different components (e.g., a compound of Formula (I), (II), (III), or (IV) and an acid), where each component is independently an atom, ion, or molecule. In certain embodiments, neither component is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound of Formula (I), (II), (III), or (IV) and an acid is different from a salt formed from a compound of Formula (I), (II), (III), or (IV) and an acid. In a salt, the compound disclosed herein is complexed with the acid in a manner such that proton transfer (e.g., complete proton transfer) from the acid to the compound disclosed herein occurs readily at room temperature. However, in a co-crystal, the compound disclosed herein is complexed with the acid in a manner such that proton transfer from the acid to the compound disclosed herein does not occur readily at room temperature. In certain embodiments, in a co-crystal, proton transfer from the acid to the compound disclosed herein does not occur. In certain embodiments, co-crystals involve partial proton transfer from the acid to the compounds disclosed herein and can be useful in improving the properties (e.g., solubility, stability, and ease of formulation) of compounds of Formula (I), (II), (III), or (IV).

[0123] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction resulting in a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0124] It should also be understood that compounds that have the same molecular formula but differ in the nature or bond order of their atoms or the spatial arrangement of their atoms are referred to as "isomers." A "rotational isomer" or "rotamer" is an isomer resulting from restricted rotation about a single bond. The compounds disclosed herein include all rotamers of the isomer shown. The compounds disclosed herein include all rotamers, including but not limited to the rotamers shown. In some embodiments, the compounds disclosed herein include all rotamers. In certain embodiments, the present disclosure provides a compound, or a rotamer thereof. Isomers that differ in the spatial arrangement of their atoms are referred to as "stereoisomers." In certain embodiments, if a phenyl group contains two substituents attached to adjacent carbons, the compound can be referred to as an ortho isomer. In certain embodiments, if a phenyl group contains two substituents attached to carbons separated by one ring carbon, the compound can be referred to as a meta isomer. In certain embodiments, when a phenyl group contains two substituents, each attached to a carbon separated by two ring carbons, the compound can be referred to as a para isomer.

[0125] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center and is bonded to, for example, four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0126] As used herein, the term "agent" refers to a molecule, group of molecules, complex, or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent). In certain embodiments, the compositions disclosed herein include agent(s), e.g., a first therapeutic agent (e.g., at least one (e.g., at least two, including at least three). In some embodiments, the composition further includes a second therapeutic agent, a targeting moiety, a diagnostic moiety, as described herein.

[0127] As used herein, the term "therapeutic agent" includes an agent capable of producing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. For example, a therapeutic agent can control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and enhance bone growth, among other functions. Other suitable therapeutic agents can include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active upon administration but are converted by metabolism or some other mechanism into a biologically active agent upon administration to a subject.

[0128] Agents (e.g., therapeutic agents) can include a wide variety of different compounds, including chemical compounds and mixtures of chemical compounds (e.g., small organic or inorganic molecules), compounds such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)); targeted agents; isotopically labeled chemical compounds; Included are agents useful in bioprocessing; carbohydrates; saccharin; monosaccharides; oligosaccharides; polysaccharides; biopolymers (e.g., peptides, proteins, and peptide analogs and derivatives); peptidomimetics; antibodies and antigen-binding fragments thereof; nucleic acids (e.g., DNA or RNA); nucleotides; nucleosides; oligonucleotides; antisense oligonucleotides; polynucleotides; nucleic acid analogs and derivatives; nucleoproteins; mucoproteins; lipoproteins; synthetic polypeptides or proteins; small molecules bound to proteins; glycoproteins; steroids; lipids; hormones; vitamins; vaccines; immunological agents; extracts made from biological materials such as bacteria, plants, fungi, animal cells, and the like; animal tissue; natural or synthetic compositions; and any combination thereof.

[0129] In some embodiments, the drug is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, e.g., by solvolysis, reduction, oxidation, or under physiological conditions, to yield a pharmaceutically active compound, e.g., in vivo. Prodrugs include derivatives of pharmaceutically active compounds, such as esters formed by reaction of the acid, anhydride, or mixed anhydride portion of the prodrug moiety with a hydroxyl moiety of the pharmaceutically active compound, or amides prepared by reaction of the acid, anhydride, or mixed anhydride portion of the prodrug moiety with a substituted or unsubstituted amine of the pharmaceutically active compound. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups may comprise prodrugs. In some embodiments, the compositions described herein incorporate one therapeutic agent or a prodrug thereof. In some embodiments, the compositions described herein incorporate two or more therapeutic agents or prodrugs.

[0130] 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 compound that is "natural product-like." However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, small molecules are typically characterized by containing several carbon-carbon bonds and have a molecular weight of less than 5,000 daltons (5 kDa), preferably less than 3 kDa, even more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases, it is preferred that the molecular weight of a small molecule be 700 daltons or less.

[0131] Exemplary agents (e.g., therapeutic agents) in the composition include, but are not limited to, those listed in Harrison's Principles of Internal Medicine, 13th Edition, Eds. 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 all of which are incorporated herein by reference.

[0132] In some embodiments, exemplary therapeutic agents in the composition include, but are not limited to, one or more of the agents listed in paragraph

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

[0133] In other embodiments, exemplary therapeutic agents in the compositions include, but are not limited to, one or more of the therapeutic agents listed in International Publication No. WO2013 / 169739, published November 14, 2013 (hereby incorporated by reference), including antihypertensive agents and / or collagen modifying agents ("AHCMs") (e.g., as disclosed in paragraphs 40-49, 283, 286-295), microenvironment modulators (e.g., as disclosed in paragraphs 113-121 of WO2013 / 169739). In some embodiments, a composition comprising AHCM and / or a microenvironment modulator causes one or more of the following in a subject: a reduction in solid stress (e.g., tumor growth-induced solid stress); a reduction in tumor fibrosis; a reduction in interstitial hypertension or interstitial fluid pressure (IFP); an increase in interstitial tumor transport; an increase in tumor or vascular perfusion; an increase in vascular diameter and / or dilation of compressed or collapsed blood vessels; a reduction or depletion of one or more of cancer cells or stromal cells (e.g., tumor-associated fibroblasts or immune cells); an increase in extracellular matrix components, such as fibers (e.g., collagen, procollagen), and reducing the levels or production of tumor cells and / or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid); reducing the levels or production of collagen or procollagen; reducing the levels or production of hyaluronic acid; increasing tumor oxygenation; reducing tumor hypoxia; reducing tumor acidosis; enabling immune cell infiltration; reducing immunosuppression; increasing anti-tumor immunity; reducing the production of cancer stem cells (also referred to herein as tumor-initiating cells); or enhancing the effectiveness (e.g., penetration or spread) of a therapy, e.g., a cancer therapy (e.g., radiation, photodynamic therapy, chemotherapy, and immunotherapy) in the tumor or tumor vasculature.

[0134] Agents, e.g., therapeutic agents, include the categories and specific examples disclosed herein. It is not intended that the category be limited by the specific examples. Those of skill in the art will recognize numerous other compounds that fall within this category and are useful according to the present disclosure.

[0135] Examples of therapeutic agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, counterirritants, coagulation modifiers, diuretics, sympathomimetics, appetite suppressants, antacids and other gastrointestinal agents, anthelmintics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetics, dopaminergic agents, antiemetics, muscle relaxants, parasympathomimetics, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast media, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antivirals, antineoplastic or cytostatic or other agents with anticancer properties, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins, as well as micronutrients and macronutrients. Still other examples include anti-infectives, e.g., antibiotics and antivirals; analgesics and analgesic combinations; appetite suppressants; anthelmintics; anti-arthritics; anti-asthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antiemetics; antinicotnauseants; antineoplastic agents; antiparkinsonian agents; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations (including calcium channel blockers and beta blockers) vasodilators (including general coronary, peripheral, and cerebrovascular); central nervous system stimulants; cough and cold preparations (including decongestants); hormones, e.g., estradiol and other steroids (including corticosteroids); hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally occurring or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0136] "Composition" and "formulation" are used interchangeably.

[0137] A "subject" to which administration is contemplated means a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey)), a commercially important mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal.

[0138] The terms "administer," "administering," or "administration" mean implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0139] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have occurred or are observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of a disease. For example, treatment can be administered to a susceptible subject before symptoms develop (e.g., based on a history of treatment for the condition). Treatment can also be continued after symptoms have resolved to delay and / or prevent the recurrence of a disease or disorder.

[0140] The terms "prevent," "preventing," or "prevention" refer to prophylactic treatment of a subject who does not currently have or has not previously had the disease but is at risk of developing the disease, or who has previously had the disease but does not currently have the disease but is at risk of relapse. In certain embodiments, the subject is at higher risk of developing or relapsing from the disease than the average healthy member of a population of subjects.

[0141] The term "NAMPT" or "nicotinamide phosphoribosyltransferase" refers to a key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from the natural precursor nicotinamide. NAMPT catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways for salvaging NAD. NAMPT specifically produces nicotinamide mononucleotide (NMN) as the product of the NAMPT enzymatic reaction. NAMPT is found both extracellularly and intracellularly. Thus, in some embodiments, NAMPT is intracellular. In certain embodiments, NAMPT is extracellular. NAMPT can be found in various intracellular compartments, both in the nucleus and the cytosol. NAMPT is expressed throughout the body, including, but not limited to, the heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. NAMPT can also be referred to as pre-B cell colony-enhancing factor (PBEF) and visfatin. The protein is also known as NAmPRTase. NAMPT can lead to changes in downstream signaling molecules such as sirtuins, PARPs, and NADases. 15 NAMPT plays a role in a variety of diseases and disorders, see, for example, (i) WO97 / 48696 concerning the involvement of NAMPT in the treatment of cancer, (ii) WO97 / 48397 concerning the involvement of NAMPT in immunosuppression, (iii) WO2003 / 80054 concerning the involvement of NAMPT in the treatment of diseases involving angiogenesis, (iv) WO2008 / 025857 concerning the involvement of NAMPT in the treatment of rheumatoid arthritis and septic shock, and (v) WO2009 / 109610 concerning the involvement of NAMPT in the prevention and treatment of ischemia.

[0142] The terms "modulate," "modulating," "modulation," or "modulator" refer to the ability of a compound to reduce / increase, delay / accelerate, stop / start, inhibit / stimulate, or prevent / cause the activity of a particular biological target (e.g., NAMPT) in a cell relative to a vehicle. In some embodiments, "modulate," "modulating," "modulation," or "modulator" refers to inhibiting. In some embodiments, "modulate," "modulating," "modulation," or "modulator" refers to activating.

[0143] As used herein, the terms "activate," "activator," "stimulate," or "stimulator" in the context of an enzyme, e.g., NAMPT, refer to an increase in the activity of the enzyme. In some embodiments, the terms refer to an increase in the level of enzyme activity, e.g., NAMPT activity, to a level that is statistically significantly higher than a starting level, which may be, e.g., a baseline level of enzyme activity. In some embodiments, the terms refer to an increase in the level of enzyme activity, e.g., NAMPT activity, to a level that is greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.1%, greater than 99.5%, greater than 99.9%, greater than 99.99%, or greater than 99.999% of the starting level, which may be, e.g., a baseline level of enzyme activity. In some embodiments, the NAMPT activators cause weight loss, treat obesity, treat diabetes, treat aging, treat neurodegenerative diseases, treat neurodegeneration, treat stroke, treat Alzheimer's disease, treat Parkinson's disease, or treat amyotrophic lateral sclerosis (ALS). In some embodiments, the compounds provided herein are useful for treating a disease or disorder selected from weight loss, obesity, diabetes, aging, neurodegenerative diseases, neurodegeneration, stroke, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis (ALS). In some embodiments, the NAMPT activators provided herein are useful for treating a disease or disorder selected from weight loss, obesity, diabetes, aging, neurodegenerative diseases, neurodegeneration, stroke, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis (ALS). In some embodiments, NAMPT activators result in improved glucose tolerance and insulin sensitivity, reduce damage from ischemia or reperfusion, restore physical activity, improve protection from retinal degeneration or light-induced damage, improve memory, reduce cell death after cerebral edema and intracerebral hemorrhage, reduce effects on white blood cell counts, lymphocytes, and hemoglobin after radiation, protect kidney function from cisplatin-induced damage, and increase physical activity.In some embodiments, the compounds provided herein are useful for improving glucose tolerance and insulin sensitivity, reducing ischemia or reperfusion damage, restoring physical activity, improving protection from retinal degeneration or light-induced damage, improving memory, reducing cerebral edema and cell death after intracerebral hemorrhage, reducing the effects of radiation on white blood cell counts, lymphocytes, and hemoglobin, protecting kidney function from cisplatin-induced damage, and increasing physical activity. NAMPT activators can be used to treat diseases and conditions associated with impaired NAD homeostasis. Replenishing NAD corrects bioenergetic or metabolic defects and is useful in treating neurodegenerative diseases or conditions associated with reduced NAD levels.

[0144] The terms "inhibition," "inhibiting," "inhibit," or "inhibitor" refer to the ability to reduce, delay, stop, or prevent the activity of a particular biological target (e.g., NAMPT) in a cell relative to a vehicle.

[0145] As used herein, the term "inhibit" or "inhibition" in the context of an enzyme, e.g., NAMPT, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction in the level of enzyme activity, e.g., NAMPT activity, to a level that is statistically significantly lower than a starting level, which may be, e.g., a baseline level of enzyme activity. In some embodiments, the term refers to a reduction in the level of enzyme activity, e.g., NAMPT activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the starting level, which may be, e.g., a baseline level of enzyme activity.

[0146] The terms "condition," "disease," and "disorder" are used interchangeably.

[0147] "Proliferative disease" refers to a disease caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with 1) pathological proliferation of normally quiescent cells; pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis-related diseases, inflammatory diseases, and autoimmune diseases.

[0148] The terms "inflammatory disease" and "inflammatory condition" are used interchangeably herein and refer to diseases or conditions caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders, or conditions characterized by symptoms of pain (from the production of noxious substances and nerve irritation), hot flashes (heat from blood vessel dilation), redness (redness from blood vessel dilation and increased blood flow), swelling (from excessive inflow or restricted outflow of fluid), and / or loss of function (loss of function that can be partial or complete, temporary or permanent). Inflammation takes many forms, including, but not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, scattered, exudative, fibrotic, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obstructive, parenchymal, plastic, productive, proliferative, pseudomembranous, purulent, sclerosing, serous-fibrinous, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term "inflammatory disease" can also refer to an uncontrolled inflammatory response that causes an exaggerated response by macrophages, granulocytes, and / or T lymphocytes, leading to abnormal tissue damage and / or cell death. Inflammatory diseases can be either acute or chronic inflammatory conditions and can result from infectious or non-infectious etiologies.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type 1), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpastis disease, and the like. ulcerative colitis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talc, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial 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 skin diseases, hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia , airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reaction, asthma, hay fever, allergy, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, These include fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. Ocular inflammatory diseases include, but are not limited to, postoperative inflammation.

[0149] Additional exemplary inflammatory conditions include acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis nodosa, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas' disease, chronic obstructive pulmonary disease, and the like. Disease, dermatomyositis, diverticulitis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin conditions (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itching)), endometriosis, Guillain-Barré syndrome, infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine, tension headache), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, acidophilic gastric Intestinal 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., selected from Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, primary These include, but are not limited to, inflammation associated with chronic biliary cirrhosis, neuroinflammatory 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 enterocolitis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthropathy, Sjogren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis.In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis, and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation caused by, for example, an infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions caused by asthma, arthritis, and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory muscle pain. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0150] "Autoimmune disease" refers to a disease resulting from an inappropriate immune response of a subject's body to substances and tissues normally present in the body. That is, the immune system mistakes some parts of the body as pathogens and attacks its own cells. This may be limited to specific organs (e.g., in the case of autoimmune thyroiditis) or may involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membrane of both the lungs and kidneys). Treatment for autoimmune diseases is typically immunosuppressive, e.g., treatment that reduces the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0151] In certain embodiments, the inflammatory and / or immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from gastrointestinal disorders (e.g., peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., selected from Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis), and inflammatory bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD). In certain embodiments, the inflammatory condition and / or immune disorder is a skin condition. In some embodiments, the skin condition is pruritus (itch), psoriasis, eczema, burns, or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritus.

[0152] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue that exceeds and is out of step with normal tissue growth. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. Benign neoplasms are generally well differentiated, characteristically slower growing than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors may subsequently give rise to malignant neoplasms. This may result from additional genetic alterations in a subpopulation of the tumor's neoplastic cells; such tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, a "malignant neoplasm" is generally poorly differentiated (anaplastic) and characteristically fast-growing, with progressive invasion, infiltration, and destruction of surrounding tissue. Furthermore, a malignant neoplasm generally has the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, typically distinguishable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor, rather than the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is considered metastatic prostate cancer, and includes cancerous prostate cancer cells growing within bone tissue.

[0153] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct adenocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, carcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, neuroblastoma, thyroid cancer ... Glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., , esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); lung cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma); hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic 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), as well as non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Barton's lymphoma, Kitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, cutaneous ... subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma; mixed leukemia / lymphoma of one or more of the above; and multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma (also known as Wilms' tumor), renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mast cell myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myelofibrosis (AMM) (also known as myelofibrosis), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic endocrine tumors (GEP-NETs), carcinoid tumors), osteosarcomas (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA)) ), melanoma, basal cell carcinoma (BCC); small intestine cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva);

[0154] As used herein, the term "cell" may refer to any cell, including, but not limited to, a cancer cell, a stem cell, a cancer stem cell, a blood cell, a bone cell, a muscle cell, a skin cell, an adipocyte, or a nerve cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a stem cell.

[0155] Cancer cells may exhibit characteristics similar to those of embryonic stem cells and / or adult stem cells. As used herein, cancer stem cells (CSCs) are cancer cells that possess one or more embryonic or adult stem cell characteristics. CSCs are generally considered problematic cancer cells due to their ability to metastasize to other sites in the body and form tumors. As used herein, "embryonic characteristics," "embryonic characteristics," and the like refer to gene, ncRNA, and / or miRNA expression and / or similar biological characteristics of embryonic cells. Undifferentiated cancer cells with embryonic characteristics have the ability to metastasize, are resistant to chemotherapy and radiation therapy, and have the ability to regrow tumors after surgery and / or additional cancer therapeutic treatments have removed or reduced the majority of the tumor. As used herein, "adult stem cell characteristics," "adult stem cell characteristics," and the like refer to gene, ncRNA, and / or miRNA expression and / or similar biological characteristics of adult stem cells. Cancer cells with adult stem cells may have the ability to metastasize, divide, and differentiate, may exhibit plasticity, high rates of cell turnover, may be resistant to chemotherapy and radiation therapy, and may have the ability to regrow tumors after most of the tumor has been removed or reduced following surgery and / or additional cancer therapeutic treatments.

[0156] In some embodiments, cancer stem cells are characterized by expression of genes, ncRNAs, and / or miRNAs associated with an embryonic state, hi some embodiments, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes, miRNAs, or ncRNAs associated with an embryonic state.

[0157] In some embodiments, cancer stem cells are characterized by one or more embryonic characteristics, including, but not limited to, cellular self-renewal properties, hyperproliferative activity, multipotency, pluripotency, expression of embryonic markers, lack of differentiation markers, resistance to chemotherapy, motility, and the ability to give rise to different cell lineages.

[0158] In some embodiments, cancer stem cells are characterized by expression of genes, ncRNAs, and / or miRNAs associated with an adult stem cell state, ie, cancer stem cells express one or more (e.g., 1, 2, 3, 4, 5, 6, or more) genes, ncRNAs, or miRNAs associated with an adult stem cell state.

[0159] In some embodiments, cancer stem cells are characterized by one or more adult stem cell characteristics, examples of which include, but are not limited to, one or more of the following (depending on the cell type): cellular self-renewal properties, proliferative and / or hyperproliferative activity, multipotency, plasticity, pluripotency, resistance to chemotherapy, and the ability to give rise to different cell lineages (transdifferentiation).

[0160] As used herein, the term "regenerative medicine" or "regenerative therapy" refers to promoting the regenerative capacity of cells, tissues, and / or organs. Regenerative medicine encompasses the manipulation of cells and / or tissues to replace, manipulate, or regenerate cells, tissues, and / or organs, and / or to repair or improve one or more biological functions of dysfunctional or abnormal cells, tissues, and / or organs, as well as tissue engineering and organ regeneration. As used herein, "regenerative capacity" refers to the conversion of cells, such as stem cells, into dividing progenitor cells and differentiated tissue-specific cells. Regenerative capacity can additionally or alternatively refer to the ability of cells, tissues, and / or organs to replicate, proliferate, restore function, and / or regenerate.

[0161] An "effective amount" of a composition described herein means an amount sufficient to elicit a desired biological response. The effective amount of a composition described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the composition, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount in a single administration of a composition or pharmaceutical composition described herein. In certain embodiments, the effective amount is the total amount in multiple administrations of a composition or pharmaceutical composition described herein.

[0162] A "therapeutically effective amount" of a composition described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with that condition. A therapeutically effective amount of a composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or conditions, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0163] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition, or to prevent its recurrence. A prophylactically effective amount of a compound is an amount of a therapeutic agent alone, or in combination with other agents, that provides a prophylactic benefit in prophylaxis. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0164] The term "gene" refers to a nucleic acid fragment that provides a template that can be used to produce a gene product. In certain embodiments, the nucleic acid fragment includes regulatory sequences that precede and follow the coding sequence. "Native gene" refers to a gene found in nature with its own regulatory sequences. "Chimeric gene" or "chimeric construct" refers to any gene or construct that is not a natural gene, containing regulatory and coding sequences that are not found together in nature. Thus, a chimeric gene or chimeric construct can contain regulatory and coding sequences that are derived from different sources, or regulatory and coding sequences that are derived from the same source but that are arranged in a manner different from that found in nature. "Endogenous gene" refers to a native gene in its natural location within the genome of an organism. "Foreign" gene refers to a gene that is not normally found in a host organism but that is introduced into the host organism by gene transfer. A foreign gene can include a native gene inserted into a non-native organism, or a chimeric gene. A "transgene" is a gene that has been introduced into a genome by a transformation procedure.

[0165] The terms "nucleic acid," "nucleic acid sequence," "nucleic acid molecule," "nucleic acid fragment," or "polynucleotide" are used interchangeably. A polynucleotide molecule is a biopolymer composed of nucleotide monomers covalently linked in a chain. DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are examples of polynucleotides with different biological functions. DNA consists of two strands of a polynucleotide, each in the form of a helix. RNA is more frequently found in nature as a single strand folded back on itself. Exemplary RNA types include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin (shRNA), microRNA (miRNA), non-coding RNA (ncRNA), messenger RNA (mRNA), antisense RNA, transfer RNA (tRNA), small nuclear RNA (snRNA), and ribosomal RNA (rRNA).

[0166] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any substance containing biomolecules derived from an initial biological sample.

[0167] The phrases "compounds of the disclosure," "compounds disclosed herein," and the like, mean any compound disclosed herein, including in the specification and claims, including (a) Formula (I), (b) Formula (II), (c) Formula (III), (d) Formula (IV), (e) all subgenera, and (f) all compound species, including the compounds provided in the Additional Compounds section and in the Examples, including Tables E1 and E2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0168] The present disclosure is not intended to be limited in any manner by the above list of exemplary substituents. Additional terms may be defined in other sections of this disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0169] Before describing the disclosed systems, compounds, compositions, methods, uses, and kits in more detail, it is to be understood that the aspects described herein are not limited to specific embodiments, methods, devices, systems, or configurations, which, as such, can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and unless specifically defined herein, such terms are not intended to be limiting.

[0170] The disclosed compounds, as well as compositions and kits thereof, are useful for treating inflammatory, proliferative, autoimmune, hematological, neurological, pain, metabolic, infectious, cardiovascular, cerebrovascular, tissue repair, pulmonary, skin, bone, or hormonal disorders disclosed herein. In some embodiments, the compounds are useful for cancer therapy and the treatment of proliferative disorders, or used for regenerative medicine. The compounds can differentiate embryonic-like cancer stem cells, kill cells, prevent 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 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 across a variety of different types of cancer. The compounds can also differentiate adult-like cancer stem cells, kill differentiated adult cells, prevent their proliferation, and / or inhibit their ability to form new tumors. Adult stem cells are also associated with a variety of different types of cancer. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, leukemia, or liver cancer. For example, embryonic-like characteristics have been found in cancer stem cells from solid tumors (e.g., colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer). 10 Embryonic-like properties have also been found in cancer stem cells from hematopoietic cancers (eg, leukemia and lymphoma). 14

[0171] Without wishing to be bound by any particular theory, the compounds and compositions disclosed herein are believed to modulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin and pre-B cell colony-enhancing factor 1 (PBEF), which is an enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. 15 Nicotinamide adenine dinucleotide is an essential cofactor for cellular metabolism. Nicotinamide mononucleotide (NMN) is the product of the NAMPT enzymatic reaction. NAMPT has been implicated in a variety of diseases and disorders, and thus modulation (i.e., inhibition) of NAMPT can be used to treat a wide range of indications. 15,16,17 Furthermore, NAMPT is also involved in signal transduction and adipocytokine 18 and immunoregulatory cytokines 19 Elevated levels of NAMPT have been described in (a) metabolic / inflammatory conditions including obesity, type 2 diabetes, metabolic syndrome, atherogenic inflammatory diseases, and cardio / cerebrovascular disorders, (b) non-metabolic chronic inflammatory diseases including osteoarthritis and acute lung injury, (c) infectious diseases such as sepsis or intrauterine infection, and (d) autoimmune inflammatory diseases including psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. 15 .

[0172] Enzymatic inhibition of NAMPT has effects on the immune system, including suppression and stimulatory effects. NAMPT has been implicated in acute respiratory distress syndrome, inflammatory bowel disease, inflammatory arthritis, hepatitis, neuroinflammation, diabetes, vascular inflammation, and stimulation of the immune microenvironment. 20~36 Inhibition of intracellular NAMPT reduced intracellular NAD levels in lung tissue, leading to inflammatory cell infiltration and lung injury in rodents, and enhanced apoptosis in inflammatory polymorphonuclear neutrophils. 20、21 NAMPT inhibition inhibited IL-8 production and NF-kB activation in human alveolar epithelial cells exposed to hypoxia-reoxygenation. 21Blockade of NAMPT activity ameliorates experimental colitis, biases monocyte / macrophage biology toward an anti-inflammatory M2 phenotype, and reduces cytokine release from human IBD-derived lamina propria mononuclear cells. 22 NAMPT inhibition or deficiency reduces synovial inflammation and cartilage destruction and prevents bone erosion in mice with collagen-induced arthritis. 23、24、25 Inhibiting NAMPT reduced the expression of proinflammatory cytokines and protected mice from experimental hepatitis. 26 Pharmacological inhibition of NAMPT prevented the recruitment of myeloid-derived suppressor cells, reactivated antitumor immunity, and enhanced the antitumor activity of immune checkpoint inhibitors. 27 Several studies have found that in rats with ischemic injury, NAMPT inhibition reduced the levels of TNF-α, NAMPT, and IL-6 in ischemic brain tissue, improved neuronal dysfunction, reduced infarct volume and neuronal loss, and inhibited microgliosis and astrogliosis. 28 On the other hand, another study showed that pharmacological inhibition of NAMPT exacerbated cerebral infarction in rats with cerebral ischemia. 29 In an experimental compression model of spinal cord injury, inhibition of NAMPT also reduced secondary inflammatory damage and partially reduced permanent injury. 30 Although inhibition of NAMPT prevented eNAMPT-induced vascular inflammation 31、32 , inhibition of iNAMPT in leukocytes reversed its antiatherogenic effect. 33 Adipocyte-specific deletion of Nampt causes severe insulin resistance accompanied by adipose tissue inflammation, an effect that was ameliorated by NMN. 34 Enzymatic inhibition of exogenous NAMPT suppressed the pro-inflammatory effects on renal tubular cells, whereas inhibition of endogenous NAMPT promoted inflammation in the inflammatory environment of diabetic rats. 35 On the other hand, another study suggested that the pro-inflammatory role of endogenous NAMPT in diabetic kidney cells was suppressed by inhibiting the enzymatic activity of NAMPT. 36

[0173] Thus, the compounds of the present disclosure, and compositions and kits thereof, are useful for treating or preventing a wide variety of diseases and disorders.

[0174] compound In certain aspects, the present disclosure provides compounds of formula (I), (II), (III), and (IV). Additional compounds are also provided herein.

[0175] In certain embodiments, a compound of the present disclosure is a compound (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound of the present disclosure is a compound (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a compound of the present disclosure is a compound (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, [ka] is.

[0177] In some embodiments, [ka] is.

[0178] Compounds of formula (I) In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, L 1 is a substituted or unsubstituted C 2~4 Alkylene, substituted or unsubstituted C 2~4 Alkenylene, substituted or unsubstituted C 2~4 alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 12 (inclusive), as far as valence permits.

[0179] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, or -COOCH3, L 1 is a substituted or unsubstituted C 2~4 Alkylene, substituted or unsubstituted C 2~4 Alkenylene, substituted or unsubstituted C 2~4 alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 12 (inclusive), as far as valence permits.

[0180] In some embodiments, L 1 is a substituted or unsubstituted C 2~4 Alkylene, substituted or unsubstituted C 2~4 Alkenylene, substituted or unsubstituted C 2~4 In some embodiments, L is alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene. 1 is the unsubstituted C 2~4Alkylene, unsubstituted C 2~4 Alkenylene, unsubstituted C 2~4 It is alkynylene, unsubstituted heteroalkylene, or unsubstituted carbocyclylene.

[0181] In some embodiments, L 1 is a substituted or unsubstituted C 2~4 In some embodiments, L is alkylene. 1 is the unsubstituted C 2~4 In certain embodiments, L 1 is ethylene. In some embodiments, L 1 is propylene. In certain embodiments, L 1 is butylene.

[0182] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0183] In some embodiments, the present disclosure provides a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0184] In some embodiments, the present disclosure provides a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0185] In some embodiments, the present disclosure provides a compound of formula (Id): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0186] In some embodiments, the present disclosure provides a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0187] In some embodiments, the present disclosure provides a compound of formula (If): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0188] In some embodiments, the present disclosure provides a compound of formula (Ig): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0189] In some embodiments, the present disclosure provides a compound of formula (Ih): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0190] In some embodiments, the present disclosure provides a compound of formula (Ii): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0191] In some embodiments, the present disclosure provides a compound of formula (Ij): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0192] In some embodiments, the present disclosure provides a compound of formula (Ik): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0193] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0194] In certain embodiments, R 2is cyclopropylmethyl or 2,2-difluoroethyl. In some embodiments, R 2 is cyclopropylmethyl. In some embodiments, R 2 is 2,2-difluoroethyl.

[0195] In some embodiments, R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 3 is chloro. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is -COOCH3.

[0196] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R3 is chloro.

[0197] In some embodiments, L 1 is a substituted or unsubstituted C 2~4 In certain embodiments, L 1 is C alkenylene. In some embodiments, L 1 is -CH=CH-. In certain embodiments, L 1 is C alkenylene. In certain embodiments, L 1 is -CH=CHCH2-. In certain embodiments, L 1 is -CHCH=CH-. In certain embodiments, L 1 is C4 alkenylene. In certain embodiments, L 1 is -CH=CHCHCH-. In certain embodiments, L 1 is —CH2CH2CH═CH—. In certain embodiments, L 1 is -CHCH=CHCH-. In certain embodiments, L 1 is -CH2CH2CH=CH-.

[0198] In certain embodiments, L 1 is C2 alkynylene. In certain embodiments, L 1 is C alkynylene. In certain embodiments, L 1 is a C4 alkynylene.

[0199] In some embodiments, L 1 is heteroalkylene. In certain embodiments, L 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains 1, 2, 3, or 4 atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains 4 atoms.1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains four atoms selected from three carbon atoms and one oxygen atom, or two carbon atoms and two oxygen atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes three carbon atoms and one oxygen atom. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes two carbon atoms and two oxygen atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains three atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains three atoms selected from two carbon atoms and one oxygen atom. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes two carbon atoms and one oxygen atom. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes one carbon atom and two oxygen atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains two atoms. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes one carbon atom and one oxygen atom. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A contains one atom. 1 is a substituted or unsubstituted heteroalkylene, and the shortest path between the nitrogen atom (N) and ring A includes one oxygen atom.1 is —O—. In certain embodiments, L 1 is —OCH—. In certain embodiments, L 1 is —CH2O—. In certain embodiments, L 1 is —OCH2CH2—. In certain embodiments, L 1 is —CH2OCH2—. In certain embodiments, L 1 is —CH2CH2O—. In certain embodiments, L 1 is —CH2CH2CH2O—. In certain embodiments, L 1 is —CH2CH2OCH2—. In certain embodiments, L 1 is —CH2OCH2CH2—. In certain embodiments, L 1 is -OCH2CH2CH2-.

[0200] In some embodiments, L 1 is a substituted or unsubstituted carbocyclylene. In certain embodiments, L 1 is cyclopropylene. In certain embodiments, L 1 is cyclobutylene.

[0201] In some embodiments, n is an integer from 0 to 12, inclusive, valence permitting. In some embodiments, n is an integer from 0 to 6, inclusive. In some embodiments, n is an integer from 0 to 5, inclusive. In some embodiments, n is an integer from 0 to 4, inclusive. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0202] In some embodiments, ring A is a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. In some embodiments, ring A is a 3- to 6-membered carbocyclyl, a 3- to 6-membered heterocyclyl, a 6-membered aryl, or a 5- to 9-membered heteroaryl ring, pyridinyl, pyrazolyl, thiazolyl, imidazolyl, imidazo[1,2-a]pyrimidinyl, phenyl, thiophenyl, cyclohexyl, or piperidinyl. In some embodiments, ring A is pyridinyl, pyrazolyl, imidazolyl, imidazo[1,2-a]pyrimidinyl, phenyl, thiophenyl, cyclohexyl, or piperidinyl. In some embodiments, ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, ring A is [ka] In some embodiments, ring A is pyridinyl.

[0203] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0204] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0205] In some embodiments, R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(Ra )2, -CN, or -C(=O)N(R a )2. R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , or -N(R a )2. In certain embodiments, R 9 At least one instance of R is hydrogen. 9 Each instance of R is hydrogen. 9 At least one instance of R is not hydrogen. 9 In certain embodiments, R 9 At least one instance of R is halogen. 9 At least one instance of R is F. In certain embodiments, 9 At least one instance of R is Cl. 9 At least one instance of 1~6 Alkyl (e.g., unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of R is Me. 9 At least one instance of is Et. In certain embodiments, R 9 At least one instance of R is Pr or Bu. 9 At least one instance of fluorinated C 1~6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 9 At least one instance of -OR a In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of -O(substituted or unsubstituted C 1~6 In certain embodiments, R9 At least one instance of is -OMe. 9 At least one instance of -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH. In certain embodiments, R 9 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1~6 alkyl), for example, -NHMe). In certain embodiments, R 9 At least one instance of -NHR a and R a is a substitution C 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is C substituted with -NH2, -NHMe, or -NMe2 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is the unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of -N (substituted or unsubstituted C 1~6 alkyl). In certain embodiments, R 9 is —N(Me)2. In certain embodiments, R 9 At least one instance of is -CN. In certain embodiments, R 9 At least one instance of 1~6 Alkyl, or -OR a In certain embodiments, R 9 Multiple instances of C 1~6 alkyl (e.g., R 9 In certain embodiments, R 9 Several instances of are halogens (e.g., R9 In some embodiments, R 9 The first example is C 1~6 alkyl, and R 9 A second instance of is halogen. In some embodiments, R 9 The first example is methyl, R 9 The second example is fluoro.

[0206] In some embodiments, R 9 two instances of are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 are linked to form a 3- to 6-membered carbocyclyl, a 3- to 6-membered heterocyclyl, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring. 9 are linked to form a phenyl ring. 9 are linked to form a 6-membered heteroaryl ring. 9 are linked to form a pyridinyl ring. 9 are linked to form a 5-membered heteroaryl ring. 9 are linked to form a 5-membered heterocyclyl ring. 9 two instances of R are linked to form pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl, or imidazolinyl. 9 are linked to form a 5-membered heteroaryl or heterocyclyl ring, and R 9 When viewed together with the ring A to which the group is attached, the group [ka] is expressed by

[0207] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro.

[0208] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 1 is propylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 1 is propylene.

[0209] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 1 is propylene. In certain embodiments, R 2 is cyclopropylmethyl and R 3 is chloro and L 1 is propylene.

[0210] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 1 is propylene. In certain embodiments, R 2 is 2,2-difluoroethyl, and R3 is chloro and L 1 is propylene.

[0211] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 1 is propylene. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 1 is ethylene.

[0212] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3is chloro, fluoro, -CN, -CF3, or -COOCH3, and ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0213] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is cyclopropylmethyl, and R 3 is chloro and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is cyclopropylmethyl, and R 3 is chloro and ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0214] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3is chloro and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro and ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0215] In some embodiments, Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl, and R 3 In some embodiments, Ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl, and R 3 In some embodiments, Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl, and L 1 In some embodiments, ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl, and L 1 is propylene.

[0216] In certain embodiments, ring A is [ka] and L 1 is propylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 1 is propylene.

[0217] In certain embodiments, ring A is [ka] and R 3 In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0218] In certain embodiments, ring A is [ka] and L 1 is propylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 1 is propylene.

[0219] In certain embodiments, ring A is [ka] and R 3 In some embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In some embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0220] In certain embodiments, ring A is [ka] and L 1 is propylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 1 is propylene.

[0221] In certain embodiments, ring A is [ka] and R 3 In certain embodiments, ring A is [ka] and R2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0222] Compound of formula (II) In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, L 2 is a bond or a substituted or unsubstituted methylene; Ring B is a 3- to 13-membered carbocyclyl ring, a 6- to 12-membered aryl ring, or aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, or thiadiazolinyl. Linyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydro Quinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro Pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, a heterocyclyl or heteroaryl ring selected from the group consisting of benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0223] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, or -COOCH3, L 2 is a bond or a substituted or unsubstituted methylene; Ring B is a 3- to 13-membered carbocyclyl ring, a 6- to 12-membered aryl ring, or aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, or thiadiazolinyl. Linyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydro Quinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro Pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, a heterocyclyl or heteroaryl ring selected from the group consisting of benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0224] In some embodiments, L 2 is a bond. In some embodiments, the present disclosure provides a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0225] In some embodiments, L 2 is substituted or unsubstituted methylene. In some embodiments, L 2 is a substituted methylene. In some embodiments, L is a methylene substituted with methyl, halo, or two bonds on the same carbon are joined to form a ring. In some embodiments, L is [ka] In some embodiments, L 2 is unsubstituted methylene. In some embodiments, the present disclosure provides a compound of formula (IIb): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0226] In some embodiments, the present disclosure provides a compound of formula (IId): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0227] In some embodiments, the present disclosure provides a compound of formula (IIe): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0228] In some embodiments, the present disclosure provides a compound of formula (IIf): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0229] In some embodiments, the present disclosure provides a compound of formula (IIg): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0230] In some embodiments, the present disclosure provides a compound of formula (IIh): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0231] In some embodiments, the present disclosure provides a compound of formula (IIi): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0232] In some embodiments, the present disclosure provides a compound of formula (IIj): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0233] In some embodiments, the present disclosure provides a compound of formula (IIk): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0234] In some embodiments, the present disclosure provides a compound of formula (IIl): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0235] In some embodiments, the present disclosure provides a compound of formula (IIm): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0236] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl. In some embodiments, R 2 is cyclopropylmethyl. In some embodiments, R 2 is 2,2-difluoroethyl.

[0237] In some embodiments, R 3is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 3 is chloro. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is -COOCH3. In certain embodiments, R 3 is -CN. In certain embodiments, R 3 is -CF3.

[0238] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0239] In some embodiments, n is an integer from 0 to 12, inclusive, valence permitting. In some embodiments, n is an integer from 0 to 6, inclusive. In some embodiments, n is an integer from 0 to 5, inclusive. In some embodiments, n is an integer from 0 to 4, inclusive. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0240] In some embodiments, Ring B is a 3- to 13-membered carbocyclyl ring, a 6- to 12-membered aryl ring, or a 3- to 13-membered aryl ring, such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadia Zolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolinyl tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetra ... 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, In some embodiments, Ring B is a heterocyclyl or heteroaryl ring selected from the group consisting of benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. In some embodiments, Ring B is a 3- to 13-membered carbocyclyl ring. In certain embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some embodiments, Ring B is a 6- to 12-membered aryl ring. In some embodiments, Ring B is phenyl. In some embodiments, the heterocyclyl or heteroaryl ring is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl , decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b ]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophene In some embodiments, Ring B is selected from the group consisting of phenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. In some embodiments, Ring B is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, [ka] In some embodiments, Ring B is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring B is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In certain embodiments, Ring B is phenyl, tetrahydrofuranyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, [ka] In certain embodiments, ring B is [ka] In certain embodiments, Ring B is phenyl, tetrahydrofuranyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring B is [ka] is.

[0241] In some embodiments, R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2. R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , or -N(R a )2. In certain embodiments, R 9 At least one instance of R is hydrogen.9 Each instance of R is hydrogen. 9 At least one instance of R is not hydrogen. 9 In certain embodiments, R 9 At least one instance of R is halogen. 9 At least one instance of R is F. In certain embodiments, 9 At least one instance of R is Cl. 9 At least one instance of 1~6 Alkyl (e.g., unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of R is Me. 9 At least one instance of is Et. In certain embodiments, R 9 At least one instance of R is Pr or Bu. 9 At least one instance of fluorinated C 1~6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 9 At least one instance of -OR a In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of -O(substituted or unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of is -OMe. 9 At least one instance of -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH. In certain embodiments, R 9 At least one instance of -NHR a(e.g., -NH(substituted or unsubstituted C 1~6 alkyl), for example, -NHMe). In certain embodiments, R 9 At least one instance of -NHR a and R a is a substitution C 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is C substituted with -NH2, -NHMe, or -NMe2 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is the unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of -N (substituted or unsubstituted C 1~6 alkyl). In certain embodiments, R 9 is —N(Me)2. In certain embodiments, R 9 At least one instance of is -CN. In certain embodiments, R 9 At least one instance of 1~6 Alkyl, or -OR a In certain embodiments, R 9 Multiple instances of C 1~6 alkyl (e.g., R 9 In certain embodiments, R 9 Several instances of are halogens (e.g., R 9 In some embodiments, R 9 The first example is C 1~6 alkyl, and R 9 A second instance of is halogen. In some embodiments, R 9 The first example is methyl, R 9 The second example is fluoro.

[0242] In some embodiments, R 9 two instances of are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 are linked to form a 3- to 6-membered carbocyclyl, a 3- to 6-membered heterocyclyl, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring. 9 are linked to form a 5-membered heteroaryl ring. 9 The two instances of are linked to form a 5-membered heterocyclyl ring.

[0243] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3 and Ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0244] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is cyclopropylmethyl, and R 3is chloro and ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0245] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 2 is a bond. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 2 is a bond. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro and L 2 is -CH2-.

[0246] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R3 is chloro and ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0247] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 2 is a bond. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 2 is a bond. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro and L 2 is -CH2-.

[0248] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 2 is a bond. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 2 is CH2-.

[0249] In some embodiments, Ring B is imidazo[1,2-a]pyrimidinyl and R 3 In some embodiments, Ring B is imidazo[1,2-a]pyrimidinyl and L 2 In some embodiments, Ring B is imidazo[1,2-a]pyrimidinyl and L 2 is a bond.

[0250] In certain embodiments, ring B is [ka] and L 2 is a bond. In some embodiments, ring B is [ka] and R 3 is chloro and L 2 is a bond.

[0251] In certain embodiments, ring B is [ka] and L 2 is methylene. In certain embodiments, ring B is [ka] and R 3 is chloro and L 2 is methylene.

[0252] In certain embodiments, ring B is [ka] and R 3 In some embodiments, ring B is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In some embodiments, Ring B is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, Ring B is [ka] and R 2 is cyclopropylmethyl, and R 3 In certain embodiments, ring B is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, Ring B is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, Ring B is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0253] Compound of formula (III) In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, L 3 is a bond, substituted or unsubstituted C 1~4 Alkylene, substituted or unsubstituted C 2~4Alkenylene, substituted or unsubstituted C 2~4 alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0254] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, or -COOCH3, L 3 is a bond, substituted or unsubstituted C 1~4 Alkylene, substituted or unsubstituted C 2~4 Alkenylene, substituted or unsubstituted C2~4 alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0255] In some embodiments, L 3 is a bond. In some embodiments, the present disclosure provides a compound of formula (IIIa): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0256] In some embodiments, L 3 is a substituted or unsubstituted C 1~4 In some embodiments, L is alkylene. 3 is a substitution C 1~4 In some embodiments, L is alkylene. 3 is the unsubstituted C1~4 In certain embodiments, L 3 is methylene. In certain embodiments, L 3 is ethylene. In some embodiments, L 3 is propylene. In certain embodiments, L 3 is butylene. In some embodiments, L 3 is methylene substituted with halo or methyl. In some embodiments, L 3 teeth, [ka] is.

[0257] In some embodiments, the present disclosure provides a compound of formula (IIIb): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0258] In some embodiments, the present disclosure provides a compound of formula (IIIc): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0259] In some embodiments, the present disclosure provides a compound of formula (IIId): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0260] In some embodiments, the present disclosure provides a compound of formula (IIIe): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0261] In some embodiments, the present disclosure provides a compound of formula (IIIf): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0262] In some embodiments, the present disclosure provides a compound of formula (IIIg): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0263] In some embodiments, the present disclosure provides a compound of formula (IIIh): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0264] In some embodiments, the present disclosure provides a compound of formula (IIIi): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0265] In some embodiments, the present disclosure provides a compound of formula (IIIj): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0266] In some embodiments, the present disclosure provides a compound of formula (IIIk): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0267] In some embodiments, the present disclosure provides a compound of formula (IIIl): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0268] In some embodiments, the present disclosure provides a compound of formula (IIIm): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0269] In some embodiments, the present disclosure provides a compound of formula (IIIn): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0270] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl. In some embodiments, R 2 is cyclopropylmethyl. In some embodiments, R 2 is 2,2-difluoroethyl.

[0271] In some embodiments, R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 3 is chloro. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is -COOCH3. In some embodiments, R 3 is -CN. In certain embodiments, R 3 is -CF3.

[0272] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro. In some embodiments, R 2is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0273] In some embodiments, L 3 is a substituted or unsubstituted C 2~4 In certain embodiments, L 3 is C alkenylene. In some embodiments, L 3 is -CH=CH-. In certain embodiments, L 3 is C alkenylene. In certain embodiments, L 3 is -CH=CHCH2-. In certain embodiments, L 3 is -CHCH=CH-. In certain embodiments, L 3 is C4 alkenylene. In certain embodiments, L 3 is -CH=CHCHCH-. In certain embodiments, L 3 is —CH2CH2CH═CH—. In certain embodiments, L 3 is -CHCH=CHCH-. In certain embodiments, L 3 is -CH2CH2CH=CH-.

[0274] In certain embodiments, L 3 is C2 alkynylene. In certain embodiments, L 3 is C alkynylene. In certain embodiments, L 3 is a C4 alkynylene.

[0275] In some embodiments, L 3is heteroalkylene. In certain embodiments, L 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains 1, 2, 3, or 4 atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains 4 atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains four atoms selected from three carbon atoms and one oxygen atom, or two carbon atoms and two oxygen atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains three carbon atoms and one oxygen atom. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A includes two carbon atoms and two oxygen atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains 3 atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains three atoms selected from two carbon atoms and one oxygen atom. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains two carbon atoms and one oxygen atom. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A includes one carbon atom and two oxygen atoms. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains two atoms. 3is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains one carbon atom and one oxygen atom. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains one atom. 3 is a substituted or unsubstituted heteroalkylene, and the shortest path between the carbonyl moiety and ring A contains one oxygen atom. 3 is —O—. In certain embodiments, L 3 is —OCH—. In certain embodiments, L 3 is —CH2O—. In certain embodiments, L 3 is —OCH2CH2—. In certain embodiments, L 3 is —CH2OCH2—. In certain embodiments, L 3 is —CH2CH2O—. In certain embodiments, L 3 is —CH2CH2CH2O—. In certain embodiments, L 3 is —CH2CH2OCH2—. In certain embodiments, L 3 is —CH2OCH2CH2—. In certain embodiments, L 3 is -OCH2CH2CH2-.

[0276] In some embodiments, L 3 is a substituted or unsubstituted carbocyclylene. In certain embodiments, L 3 is cyclopropylene.

[0277] In some embodiments, n is an integer from 0 to 12, inclusive, valence permitting. In some embodiments, n is an integer from 0 to 6, inclusive. In some embodiments, n is an integer from 0 to 5, inclusive. In some embodiments, n is an integer from 0 to 4, inclusive. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0278] In some embodiments, ring A is a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. In some embodiments, ring A is a 3- to 6-membered carbocyclyl, a 3- to 6-membered heterocyclyl, a 6-membered aryl, or a 5- to 9-membered heteroaryl ring. In certain embodiments, ring A is phenyl, cyclohexyl, pyridinyl, pyrazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, ring A is pyridinyl, pyrazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, ring A is [ka] In some embodiments, ring A is pyridinyl.

[0279] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0280] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0281] In some embodiments, R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a)2, -CN, or -C(=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2. R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , or -N(R a )2. In certain embodiments, R 9 At least one instance of R is hydrogen. 9 Each instance of R is hydrogen. 9 At least one instance of R is not hydrogen. 9 In certain embodiments, R 9 At least one instance of R is halogen. 9 At least one instance of R is F. In certain embodiments, 9 At least one instance of R is Cl. 9 At least one instance of 1~6 Alkyl (e.g., unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of R is Me. 9 At least one instance of is Et. In certain embodiments, R 9 At least one instance of R is Pr or Bu. 9At least one instance of fluorinated C 1~6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 9 At least one instance of -OR a In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of -O(substituted or unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of is -OMe. 9 At least one instance of -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH. In certain embodiments, R 9 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1~6 alkyl), for example, -NHMe). In certain embodiments, R 9 At least one instance of -NHR a and R a is a substitution C 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is C substituted with -NH2, -NHMe, or -NMe2 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is the unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of -N (substituted or unsubstituted C 1~6 alkyl). In certain embodiments, R 9 is —N(Me)2. In certain embodiments, R 9At least one instance of is -CN. In certain embodiments, R 9 At least one instance of 1~6 Alkyl, or -OR a In certain embodiments, R 9 Multiple instances of C 1~6 alkyl (e.g., R 9 In certain embodiments, R 9 Several instances of are halogens (e.g., R 9 In some embodiments, R 9 The first example is C 1~6 alkyl, and R 9 A second instance of is halogen. In some embodiments, R 9 The first example is methyl, R 9 The second example is fluoro.

[0282] In some embodiments, R 9 are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 are linked to form a phenyl ring. 9 are linked to form a 6-membered heteroaryl ring. 9 are linked to form a pyridinyl ring. 9 are linked to form a 5-membered heteroaryl ring. 9 are linked to form a 5-membered heterocyclyl ring. 9two instances of R are linked to form pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl, or imidazolinyl. 9 are linked to form a 5-membered heteroaryl or heterocyclyl ring, and R 9 When viewed together with the ring A to which the group is attached, the group [ka] is expressed by

[0283] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyridinyl. 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyridinyl. 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyridinyl. 2 is cyclopropylmethyl, and R 3 is chloro and ring A is pyridinyl.

[0284] In some embodiments, R 2 is cyclopropylmethyl, and R 3is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is propylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is ethylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is methylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is a bond.

[0285] In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is propylene. In certain embodiments, R 2 is cyclopropylmethyl and R 3 is chloro and L 3 is propylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is ethylene. In certain embodiments, R 2 is cyclopropylmethyl and R 3 is chloro and L 3 is ethylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is methylene. In certain embodiments, R 2 is cyclopropylmethyl and R3 is chloro and L 3 is methylene. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is a bond. In certain embodiments, R 2 is cyclopropylmethyl and R 3 is chloro and L 3 is a bond.

[0286] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and Ring A is pyridinyl, pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro and ring A is pyridinyl. 2 is 2,2-difluoroethyl, and R 3is chloro, fluoro, —CN, —CF, or —COOCH, and Ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl. 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and ring A is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl.

[0287] In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is propylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is ethylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is methylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, and L 3 is a bond. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is propylene. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro and L 3 is propylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L3 is ethylene. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro and L 3 is ethylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is methylene. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro and L 3 is methylene. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3, and L 3 is a bond. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro and L 3 is a bond.

[0288] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 3 is propylene. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 3 is a bond. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 3 is methylene. In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro and L 3 is ethylene.

[0289] In some embodiments, ring A is pyridinyl and R 3 In some embodiments, ring A is pyridinyl and L 3 In some embodiments, ring A is pyridinyl and L 3 In some embodiments, ring A is pyridinyl and L 3 In some embodiments, ring A is pyridinyl and L 3 is a bond.

[0290] In certain embodiments, ring A is [ka] and L 3 is propylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 3 is propylene. In certain embodiments, ring A is [ka] and L 3 is ethylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 3 is ethylene. In certain embodiments, ring A is [ka] and L 3 is methylene. In certain embodiments, ring A is [ka] and R 3 is chloro and L 3 is methylene. In certain embodiments, ring A is [ka] and L 3 is a bond. In certain embodiments, ring A is [ka] and R 3 is chloro and L 3 is a bond.

[0291] In certain embodiments, ring A is [ka] and R 3 In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is cyclopropylmethyl, and R 3 In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH3. In certain embodiments, ring A is [ka] and R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0292] Compound of formula (IV) In some embodiments, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, -CN, -CF3, or -COOCH3, Ring D is a 3- to 13-membered heterocyclyl or a 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0293] In some embodiments, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 2 is cyclopropylmethyl or 2,2-difluoroethyl, R 3 is chloro, fluoro, or -COOCH3, Ring D is a 3- to 13-membered heterocyclyl or a 5- to 14-membered heteroaryl ring; R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -(C=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R a Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), as far as valence permits.

[0294] In some embodiments, the present disclosure provides a compound of formula (IVa): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0295] In some embodiments, the present disclosure provides a compound of formula (IVb): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0296] In some embodiments, the present disclosure provides a compound of formula (IVc): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0297] In some embodiments, the present disclosure provides a compound of formula (IVd): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0298] In some embodiments, the present disclosure provides a compound of formula (IVe): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0299] In some embodiments, the present disclosure provides a compound of formula (IVf): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0300] In one aspect, the present disclosure provides a compound of formula (IVg): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0301] In some embodiments, the present disclosure provides a compound of formula (IVh): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0302] In some embodiments, the present disclosure provides a compound of formula (IVi): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0303] In some embodiments, the present disclosure provides a compound of formula (IVj): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0304] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl. In some embodiments, R 2 is cyclopropylmethyl. In some embodiments, R 2 is 2,2-difluoroethyl.

[0305] In some embodiments, R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 3 is chloro. In certain embodiments, R 3 is fluoro. In some embodiments, R 3 is -COOCH3. In some embodiments, R 3 In some embodiments, R 3 is -CF3.

[0306] In certain embodiments, R 2 is cyclopropylmethyl or 2,2-difluoroethyl, and R 3 is chloro. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is cyclopropylmethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is cyclopropylmethyl, and R 3is chloro. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, —CN, —CF, or —COOCH. In some embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro, fluoro, or -COOCH. In certain embodiments, R 2 is 2,2-difluoroethyl, and R 3 is chloro.

[0307] In some embodiments, ring D is a 3- to 13-membered heterocyclyl or a 5- to 14-membered heteroaryl ring. In some embodiments, ring D is a 3- to 13-membered heterocyclyl. In some embodiments, ring D is a 4- to 6-membered heterocyclyl. In some embodiments, ring D is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In some embodiments, ring D is pyridinyl.

[0308] In some embodiments, n is an integer from 0 to 12, inclusive, valence permitting. In some embodiments, n is an integer from 0 to 6, inclusive. In some embodiments, n is an integer from 0 to 5, inclusive. In some embodiments, n is an integer from 0 to 4, inclusive. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0309] In some embodiments, R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a, -N(R a )2, -CN, or -C(=O)N(R a )2 or R 9 are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , -COOR a , -COR a , -N(R a )2, -CN, or -C(=O)N(R a )2. R 9 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -OR a , or -N(R a )2. In certain embodiments, R 9 At least one instance of R is hydrogen. 9 Each instance of R is hydrogen. 9 At least one instance of R is not hydrogen. 9 In certain embodiments, R 9 At least one instance of R is halogen. 9 At least one instance of R is F. In certain embodiments, 9 At least one instance of R is Cl. 9 At least one instance of 1~6 Alkyl (e.g., unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of R is Me. 9 At least one instance of is Et. In certain embodiments, R 9 At least one instance of R is Pr or Bu.9 At least one instance of fluorinated C 1~6 alkyl (e.g., fluorinated methyl, e.g., —CF). In certain embodiments, R 9 At least one instance of -OR a In certain embodiments, R 9 At least one instance of is -OH. In certain embodiments, R 9 At least one instance of -O(substituted or unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of is -OMe. 9 At least one instance of -N(R a )2. In certain embodiments, R 9 At least one instance of is -NH. In certain embodiments, R 9 At least one instance of -NHR a (e.g., -NH(substituted or unsubstituted C 1~6 alkyl), for example, -NHMe). In certain embodiments, R 9 At least one instance of -NHR a and R a is a substitution C 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is C substituted with -NH2, -NHMe, or -NMe2 1~6 In certain embodiments, R 9 At least one instance of -NHR a and R a is the unsubstituted C 1~6 In certain embodiments, R 9 At least one instance of -N (substituted or unsubstituted C 1~6 alkyl). In certain embodiments, R 9 is —N(Me)2. In certain embodiments, R9 At least one instance of is -CN. In certain embodiments, R 9 At least one instance of 1~6 Alkyl, or -OR a In certain embodiments, R 9 Multiple instances of C 1~6 alkyl (e.g., R 9 In certain embodiments, R 9 Several instances of are halogens (e.g., R 9 In some embodiments, R 9 The first example is C 1~6 alkyl, and R 9 A second instance of is halogen. In some embodiments, R 9 The first example is methyl, R 9 The second example is fluoro.

[0310] In some embodiments, R 9 two instances of are linked to form a 3- to 13-membered carbocyclyl, a 3- to 13-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 14-membered heteroaryl ring. 9 are linked to form a 3- to 6-membered carbocyclyl, a 3- to 6-membered heterocyclyl, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring. 9 are linked to form a phenyl ring. 9 are linked to form a 6-membered heteroaryl ring. 9 are linked to form a pyridinyl ring. 9 are linked to form a 5-membered heteroaryl ring. 9 are linked to form a 5-membered heterocyclyl ring. 9are linked to form pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, pyrrolinyl, pyrazolinyl, or imidazolinyl.

[0311] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] is.

[0312] Compound species In certain embodiments, the compound of formula (I) has the formula: [ka] [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0313] In certain embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0314] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0315] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0316] In certain embodiments, the compound of formula (II) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0317] In certain embodiments, the compound of formula (II) has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0318] In certain embodiments, the compound of formula (II) has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0319] In certain embodiments, the compound of formula (II) has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0320] In certain embodiments, the compound of formula (II) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0321] In certain embodiments, the compound of formula (II) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0322] In certain embodiments, the compound of formula (II) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0323] In certain embodiments, the compound of formula (III) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0324] In some embodiments, the compound of formula (III) has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0325] In some embodiments, the compound of formula (III) has the formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0326] In some embodiments, the compound of formula (III) has the formula: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0327] In certain embodiments, the compound of formula (IV) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0328] In certain embodiments, the compound of formula (IV) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0329] In certain embodiments, the compound of formula (IV) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0330] In certain embodiments, the compound of formula (IV) has the formula: [ka] or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0331] formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0332] formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0333] In certain embodiments, provided herein are compounds of the formula: [ka] Also provided is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0334] Compositions and Kits The present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), or (IV), or any compound described herein) and an excipient (e.g., a pharmaceutically acceptable excipient). In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the excipient is a pharmaceutically acceptable excipient.

[0335] The present disclosure also provides compositions further comprising an additional pharmaceutical agent.

[0336] The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), or (IV), or any compound described herein) and one pharmaceutical agent. The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), or (IV), or any compound described herein) and two pharmaceutical agents. The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), or (IV), or any compound described herein) and three pharmaceutical agents.

[0337] The compositions described herein can be prepared by any method known in the art. Generally, such preparation methods include bringing the disclosed compounds described herein into association with an excipient, and may also include one or more pharmaceutical or accessory ingredients, and, as necessary and / or desired, shaping and / or packaging the product into a desired single-dose or multi-dose unit. In certain embodiments, the pharmaceutical agent is a pharmaceutical agent.

[0338] In certain embodiments, compounds of the present disclosure are in the form of a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug.

[0339] The compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of the composition comprising a predetermined amount of a drug. The amount of drug is approximately equal to the dose of the drug that would be administered to a subject and / or a convenient fraction of such a dose (e.g., one-half or one-third of such a dose).

[0340] The relative amounts of the disclosed compounds, excipients, drugs, and / or any additional components in the compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. The compositions may contain from 0.1% to 100% (w / w) of drug.

[0341] Excipients and auxiliary ingredients used in the preparation of the provided compositions include diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Excipients and auxiliary ingredients such as cocoa butter, PEGylated lipids, phospholipids, suppository waxes, colorants, coating agents, sweeteners, flavorings, and fragrances 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 and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, 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, tragacanth, chondrux, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., Polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters ( For example, polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate,Examples of suitable anti-inflammatory agents include sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0345] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Chorizoides extract, Panwa gum, Gahatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0346] Non-limiting examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative can be an antioxidant. In other embodiments, the preservative can be a chelating agent.

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

[0348] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0349] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, 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 phenylethyl alcohol.

[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, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0353] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0354] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0355] Exemplary oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea Cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0356] In certain embodiments, the composition further comprises an agent and is useful for delivering the agent (e.g., to a subject, a tissue, a biological sample, or a cell). In certain embodiments, the composition is a pharmaceutical composition useful for treating a disease in a subject in need thereof. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is colorectal cancer (e.g., colon cancer or rectal cancer). In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is gastrointestinal stromal tumor. In certain embodiments, the cancer is ovarian cancer (e.g., ovarian adenocarcinoma). In certain embodiments, the cancer is lung cancer (e.g., small cell lung cancer). In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is pancreatic cancer (e.g., pancreatic cancer or pancreatic adenocarcinoma). In certain embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In certain embodiments, the cancer is testicular cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is endometrial cancer (e.g., uterine cancer). In certain embodiments, the cancer is a lymphoma, e.g., a non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma). In certain embodiments, the cancer is a B-cell lymphoma (e.g., Burkitt's B-cell lymphoma, large B-cell lymphoma). In certain embodiments, the cancer is a T-cell lymphoma. In certain embodiments, the cancer is a Burkitt's lymphoma (e.g., Burkitt's B-cell lymphoma). In certain embodiments, the cancer is a large cell immunoblastic lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML) (also known as acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, acute myelocytic leukemia, and acute nonlymphocytic leukemia), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) (also known as chronic myeloid leukemia).In certain embodiments, the cancer is AML. In some embodiments, the cancer is a subtype of AML selected from undifferentiated acute myeloblastic leukemia (M0), acute myeloblastic leukemia with minimal maturation (M1), acute myeloblastic leukemia with maturation (M2), acute promyelocytic leukemia (APL) (M3), acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with eosinophilia (M4 eos), acute monocytic leukemia (M5), acute erythroleukemia (M6), and acute megakaryoblastic leukemia (M7). In certain embodiments, the cancer is acute monocytic leukemia or acute lymphocytic leukemia (e.g., B-cell acute lymphoblastic leukemia). In certain embodiments, the cancer is acute lymphoblastic leukemia (e.g., B-cell acute lymphoblastic leukemia or T-cell acute lymphoblastic leukemia). In certain embodiments, the cancer is multiple myeloma (e.g., B-cell myeloma).

[0357] The compositions described herein can be administered in combination with one or more additional agents. In certain embodiments, the agent is an organic molecule. In certain embodiments, the agent is an inorganic molecule. In certain embodiments, the agent is a targeting agent. In certain embodiments, the agent is an isotopically labeled chemical compound. In certain embodiments, the agent is an agent useful in bioprocessing. In certain embodiments, the agent is a pharmaceutical agent (e.g., a therapeutically and / or prophylactically active agent). Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, polynucleotides, lipids, hormones, vitamins, vaccines, immunological agents, and cells.

[0358] In certain embodiments, the compound of the present disclosure described herein is provided in an effective amount in the composition.In certain embodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need of cancer treatment.In certain embodiments, the effective amount is an amount effective for inhibiting the signal transduction pathway required for metastasis in a subject or cell.

[0359] In certain embodiments, an effective amount is an amount effective to inhibit the activity of NAMPT by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of NAMPT by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In certain embodiments, an effective amount is an amount effective to inhibit the activity of NAMPT by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0360] In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.5%, at least 99.9%, at least 99.99%, or at least 99.999% of the starting level, which may be, for example, the baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, 98% or less, or 99.9% or less. In certain embodiments, an effective amount is an amount effective to increase the activity of NAMPT to a range between a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0361] In certain embodiments, an effective amount is an amount effective to inhibit NAMPT signaling by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, an effective amount is an amount effective to inhibit NAMPT signaling by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In certain embodiments, an effective amount is an amount effective to inhibit NAMPT signaling by a range between a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0362] In certain embodiments, an effective amount is an amount effective to increase NAMPT signaling by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.5%, at least 99.9%, at least 99.99%, or at least 99.999% of a starting level, which may be, for example, a baseline level of enzyme activity. In certain embodiments, an effective amount is an amount effective to increase NAMPT signaling by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, 98% or less, or 99.9% or less. In certain embodiments, an effective amount is an amount effective to increase NAMPT signaling to a range between a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

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

[0364] The composition can be formulated into a liquid dosage form for oral and parenteral administration, including pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the drug, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, oral compositions may contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents. In certain embodiments of parenteral administration, the compositions described herein are mixed with a solubilizing agent, such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0365] Injectable preparations, for example, aqueous or oily sterile injectable suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents (for example, as a solution in 1,3-butanediol). Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable solutions.

[0366] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0367] In order to prolong the effect of the compound of the present disclosure, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the compound depends on its dissolution rate, which may depend on crystal size and crystalline form.Alternatively, the absorption of parenterally administered drug forms can be delayed by dissolving or suspending the compound in an oil vehicle.

[0368] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the compositions described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax. Such excipients or carriers are solid at ambient temperature but liquid at body temperature and will melt in the rectum or vaginal cavity and release the compounds of the present disclosure.

[0369] Composition can be formulated into the solid dosage form for oral administration, including capsule, tablet, pill, powder and granule.In this solid dosage form, the compound of the present disclosure is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectant, such as glycerol, (d) disintegrant, such as agar, calcium carbonate, Potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can contain buffering agents.

[0370] Solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmacological arts. These dosage forms can optionally contain opacifying agents and can also be of a composition that releases the compounds of the present disclosure only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0371] The compounds of the present disclosure may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the compounds of the present disclosure may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may contain, as is common practice, additional 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 forms may also contain buffering agents. These dosage forms may optionally contain opacifying agents and may be of a composition that releases the compounds of the present disclosure only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0372] Dosage forms for topical and / or transdermal administration of the compositions described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the compounds of the present disclosure are admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as may be required.

[0373] Suitable devices for use in delivering the intradermal compositions described herein include short needle devices. The intradermal compositions can be delivered by devices that limit the effective penetration length of the needle into the skin. Alternatively or additionally, a conventional syringe may be used in the classical Mantoux intradermal administration. Jet injection devices are suitable, delivering liquid formulations to the dermis via a liquid jet injector and / or via a needle that creates a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder / particle delivery devices are suitable, using compressed gas to accelerate a powdered polymer through the outer layer of the skin to the dermis.

[0374] Formulations suitable for topical administration include liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations can contain, for example, about 1% to about 100% (w / w) of a compound of the present disclosure, although the concentration of the compound of the present disclosure can be as high as the solubility limit of the compound in the solvent. Formulations for topical administration can further include one or more of the additional ingredients described herein.

[0375] The compositions described herein can be prepared, packaged, and / or sold in formulations suitable for pulmonary administration via the oral cavity. Such formulations can include dry particles containing a compound of the present disclosure. Such compositions are conveniently in the form of a dry powder and administered using a device equipped with a dry powder reservoir capable of directing a flow of propellant to disperse the powder, and / or using a self-propelling solvent / powder dispensing container (e.g., a device containing the drug dissolved and / or suspended in a low-boiling propellant in a sealed container). Dry powder compositions can include a solid fine powder diluent, such as sugar, and are conveniently provided in unit dosage form.

[0376] Low-boiling propellants generally include liquid propellants having a boiling point at atmospheric pressure below 65° F. Generally, the propellant comprises 50-99.9% (w / w) of the composition, and the compound of the present disclosure can comprise 0.1-100% (w / w) of the composition. The propellant can further comprise additional components, such as a liquid nonionic and / or solid anionic surfactant and / or a solid diluent.

[0377] The compositions described herein formulated for pulmonary delivery can provide the compounds of the present disclosure in the form of liquid and / or suspension droplets. Such formulations can be prepared, packaged, and / or sold in aqueous and / or dilute alcoholic solutions and / or suspensions (optionally sterilized) containing the compounds of the present disclosure, and can be conveniently administered using any spray and / or atomization device. Such formulations can further include one or more additional ingredients, including flavoring agents (e.g., saccharin sodium), volatile oils, buffers, surfactants, and / or preservatives (e.g., methyl hydroxybenzoate).

[0378] The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein.Another formulation suitable for intranasal administration is a coarse powder comprising the compound of the present disclosure.This formulation is administered by rapid inhalation through the nasal cavity from a powder container held near the nostrils.

[0379] Formulations for nasal administration can contain, for example, from as little as about 0.1% (w / w) to 100% (w / w) of a compound of the present disclosure and can include one or more of the additional ingredients described herein. The pharmaceutical compositions described herein can also be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations can take the form of, for example, tablets and / or lozenges made using conventional methods and contain, for example, 0.1-20% (w / w) of the drug, with the remainder comprising an orally dissolvable and / or disintegrable composition, and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration can include a powder and / or an aerosolized and / or atomized solution and / or suspension containing a compound of the present disclosure.

[0380] The compositions described herein can be prepared, packaged, and / or sold in formulations for ophthalmic administration. Such formulations can take the form of, for example, eye drops, comprising, for example, a 0.1-100% (w / w) solution and / or suspension of a compound of the present disclosure in an aqueous or oily liquid carrier or excipient. Such drops can further comprise buffers, salts, and / or one or more of the additional ingredients described herein. Other useful ophthalmically administrable formulations include formulations comprising a compound of the present disclosure in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of the present disclosure.

[0381] While the description of compositions provided herein is primarily directed to compositions suitable for administration to humans, those skilled in the art will understand that such compositions are also broadly suitable for administration to all types of animals. Modifications to compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and such modifications can be designed and / or implemented by a veterinary pharmacologist of ordinary skill, using routine experimentation.

[0382] The compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it should be understood that the total daily amount of the compositions described herein is determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the cancer to be treated and the severity of the cancer, the activity of the specific compound of the present disclosure used, the specific composition used, the subject's age, weight, general health, sex and diet, administration time, administration route, excretion rate of the specific compound of the present disclosure used, duration of treatment, drugs used in combination with or simultaneously with the specific compound of the present disclosure used, and similar factors well known in the medical field.

[0383] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or drop), transmucosal, nasal, buccal, sublingual, by intratracheal instillation, bronchial instillation, and / or inhalation, and / or by oral spray, nasal spray, and / or aerosol. Specifically, contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via the blood and / or lymphatic supply, and / or direct administration to the affected site. Generally, the most appropriate administration route depends on various factors, including the properties of the disclosed compounds (e.g., their stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compositions described herein are suitable for topical administration to the subject's eye.

[0384] In some embodiments, administration of any of the compositions described herein occurs at least 1 hour before treatment with another cancer therapy.

[0385] The compositions can be administered in combination with additional agents that improve their activity (e.g., potency and / or efficacy), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution within a subject or cell in treating a disease or disorder (e.g., cancer) in a subject in need thereof and / or inhibit a signal transduction pathway in a subject or cell. It will also be understood that the therapies used may achieve the desired effect on the same disease and / or may achieve different effects. In certain embodiments, compositions described herein that include a compound of the present disclosure and an agent described herein exhibit a synergistic effect that is not present in compositions that include either a compound of the present disclosure or an agent, but not both.

[0386] The composition may be administered simultaneously with, before, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy, separate from the composition. Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may be administered together with each other and / or with the compounds of the present disclosure or the compositions described herein in a single dose or separately in different doses. The particular combination to be used in the regimen will take into account the compatibility of the compounds of the present disclosure described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0387] Additional pharmaceutical agents include antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, and analgesics. In certain embodiments, the additional pharmaceutical agent is an antiproliferative agent. In certain embodiments, the additional pharmaceutical agent is an anticancer agent. In certain embodiments, the additional pharmaceutical agent is a chemotherapeutic agent. In certain embodiments, the additional pharmaceutical agent is a differentiation agent (e.g., a retinoid, all-trans retinoic acid (ATRA), vitamin D, or a peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibitor). In certain embodiments, the additional pharmaceutical agent is an antiviral agent. In certain embodiments, the additional pharmaceutical agent is a protein kinase binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), inhibitors of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions disclosed herein can be administered in combination with anti-cancer therapies (including surgery, radiation therapy, transplantation (e.g., stem cell transplant, bone marrow transplant), immunotherapy, and chemotherapy). In some embodiments, the subject is administered one or more additional agents (e.g., one or more additional cancer therapies) simultaneously with, before, or after the administration of the one or more additional agents. In some embodiments, the one or more additional cancer therapies include immunotherapy. Broadly speaking, immunotherapy (also called biologic therapy) is a type of cancer treatment that boosts a subject's natural defenses to treat cancer.In certain embodiments, the immunotherapy utilizes a compound biologically produced by the subject. In certain embodiments, the immunotherapy utilizes a compound not biologically produced by the subject. In certain embodiments, the immunotherapy utilizes cells from the subject. In certain embodiments, the immunotherapy utilizes cells not from the subject. In certain embodiments, the immunotherapy utilizes a compound biologically produced by an organism other than the subject. In certain embodiments, the immunotherapy utilizes cells biologically produced by an organism other than the subject. In certain embodiments, the immunotherapy includes at least one chemical modification to a compound or cell from the subject. In certain embodiments, the immunotherapy includes at least one chemical modification to a compound or cell not from the subject.

[0388] In some embodiments, the additional pharmaceutical agent is a NAM.

[0389] In some embodiments, the additional pharmaceutical agent is NMN.

[0390] In some embodiments, the additional pharmaceutical agent is nicotinic acid (e.g., niacin), ibrutinib, idelalisib, lenalidomide, BCL-2 inhibitors, venetoclax, FLT3 inhibitors, IDH1 / 2 inhibitors, glasdegib, azacitidine, cyclophosphamide, decitabine, enasidenib, erastin, gilterinib, idasanutlin, ivosidenib, ixazomib, midostaurin, navitoclax, ombasertib, cyclosporine A, PARP inhibitors, or the like. anti-cancer drugs, pacritinib, phorbol 12-myristate 13-acetate (PMA), ruxolitinib, S055746, selinexor (KPT-330), trametinib, tretinoin, etoposide, P7C3, napabucasin, olaparib, AraC, daunorubicin, 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG), melphalan, verapamil, etoposide, cisplatin, anti-PD1, tumor necrosis factor-related apoptosis-inducing ligand (TNF-α), TRAIL), EX527, sirtinol, cambinol, vorinostat, valproic acid, butyrate, JPH203, L-asparaginase, bortezomib, rituximab, PGP-4008, β-lapachone, β-methylene adenosine 5'-diphosphate (APCP), gemcitabine, Lu-DOTATATE, fluorouracil (5-FU), pemetrexed, ombansertib, cedazuridine, galinpepim-S, cedazuridine / decitabine, cytarabine The agent is selected from the group consisting of rabinostat / daunorubicin, uprolaseran, gedatolisib, devimistat, glasdegib, idasanutlin, ganetespib, tipifarnib, midostaurin, pevonedistat, ivosidenib, crenolanib, quizartinib, prasinostat, guadecitabine, DFP10917, vosaroxin, lexlemestrose-L-mesoblast, treosulfan, sapacitabine, enasidenib, volasertib, and temozolomide.

[0391] In some embodiments, the BCL-2 inhibitor is beneteoclax, navitoclax, oblimersen, APG2575, BCL201, BGB-11417, LP-108, or S65487.

[0392] In some embodiments, the additional pharmaceutical 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, pinocembrine, resatorbid, naloxone, naltrexone, LPS-RS, propentofylline, tapentadol, or palmitoylethanolamide.

[0393] In some embodiments, the additional pharmaceutical agent is a sirtuin inhibitor. In some embodiments, the sirtuin inhibitor is nicotinamide, a nicotinamide derivative, benzamide, a 3'-phenethyloxy-2-anilinobenzamide analog, AK7, 1,4-dihydropyridine, cambinol, EX-527, AGK2, 3'-(3-fluoro-phenethyloxy)-...

Claims

1. Compounds of formula (I): 【Chemistry 1】 wherein R ２ is cyclopropylmethyl or 2,2-difluoroethyl; R ３ is chloro, fluoro, -CN, -CF ３ , or -COOCH ３ and L １ is a substituted or unsubstituted C ２～４ Alkylene, substituted or unsubstituted C ２～４ Alkenylene, substituted or unsubstituted C ２～４ alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １～６ Alkyl, -OR ａ , -COOR ａ , -COR ａ , -N(R ａ ) ２ , -CN, or -C(=O)N(R ａ ) ２ or R ９ are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ａ Each instance of is independently hydrogen, substituted or unsubstituted C １～６ an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 12 (inclusive), valence permitting; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

2. L １ is unsubstituted C ２～４ Alkylene, unsubstituted C ２～４ Alkenylene, unsubstituted C ２～４ The compound of claim 1 which is an alkynylene, an unsubstituted heteroalkylene, or an unsubstituted carbocyclylene.

3. The compound is (a) Formula (Ia): 【Chemistry 2】 or, (b) Formula (Ib): 【Chemistry 3】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein

4. L １ but, (a) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the nitrogen atom (N) and ring A contains 1, 2, 3, or 4 atoms; (b) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the nitrogen atom (N) and ring A contains four atoms selected from three carbon atoms and one oxygen atom, or two carbon atoms and two oxygen atoms; (c) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the nitrogen atom (N) and ring A contains three atoms selected from two carbon atoms and one oxygen atom; (d) substituted or unsubstituted C ２～４ alkenylene; (e) -CH=CH-; (f) a substituted or unsubstituted carbocyclylene; or (g) cyclopropylene; The compound of claim 1.

5. Ring A is (a) pyridinyl, pyrazolyl, thiazolyl, imidazolyl, imidazo[1,2-a]pyrimidinyl, phenyl, thiophenyl, cyclohexyl, or piperidinyl; (b) 【Chemistry 4】 or (c) pyridinyl, The compound of claim 1.

6. Compound of formula (II): 【Chemistry 5】 wherein R ２ is cyclopropylmethyl or 2,2-difluoroethyl, R ３ is chloro, fluoro, -CN, -CF ３ , or -COOCH ３ and L ２ is a bond or a substituted or unsubstituted methylene; Ring B is a 3- to 13-membered carbocyclyl ring, a 6- to 12-membered aryl ring, or an aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazo, Linyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, cyanyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydro quinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro Pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, a heterocyclyl or heteroaryl ring selected from the group consisting of benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, pteridinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl; R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １～６ Alkyl, -OR ａ , -COOR ａ , -COR ａ , -N(R ａ ) ２ , -CN, or -C(=O)N(R ａ ) ２ or R ９ are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ａ Each instance of is independently hydrogen, substituted or unsubstituted C １～６ an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), valence permitting; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

7. The compound is (a) Formula (IIa): 【Chemistry 6】 or, (b) Formula (IIb): 【Chemistry 7】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, which is:

8. Ring B is (a) phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, or pyridazinyl; (b) phenyl, tetrahydrofuranyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, or pyridazinyl; or (c) 【Chemistry 8】 That is, The compound according to claim 6.

9. Compound of formula (III): 【Chemistry 9】 wherein R ２ is cyclopropylmethyl or 2,2-difluoroethyl, R ３ is chloro, fluoro, -CN, -CF ３ , or -COOCH ３ and L ３ is a bond, substituted or unsubstituted C １～４ Alkylene, substituted or unsubstituted C ２～４ Alkenylene, substituted or unsubstituted C ２～４ alkynylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted carbocyclylene; Ring A is a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １～６ Alkyl, -OR ａ , -COOR ａ , -COR ａ , -N(R ａ ) ２ , -CN, or -C(=O)N(R ａ ) ２ or R ９ are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ａ Each instance of is independently hydrogen, substituted or unsubstituted C １～６ an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), valence permitting; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

10. L ３ is unsubstituted C ２～４ Alkylene, unsubstituted C ２～４ Alkenylene, unsubstituted C ２～４ 10. The compound of claim 9 which is an alkynylene, an unsubstituted heteroalkylene, or an unsubstituted carbocyclylene.

11. The compound is (a) Formula (IIIa): 【Chemistry 10】 (b) Formula (IIIb): 【Chemistry 11】 (c) Formula (IIIc): 【Chemistry 12】 or (d) Formula (IIId): 【Chemistry 13】 10. The compound of claim 9, wherein:

12. L ３ but, (a) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the carbonyl moiety and Ring A contains 1, 2, 3, or 4 atoms; (b) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the carbonyl moiety and Ring A contains four atoms selected from three carbon atoms and one oxygen atom, or two carbon atoms and two oxygen atoms; (c) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the carbonyl moiety and ring A contains three atoms selected from two carbon atoms and one oxygen atom; (d) a substituted or unsubstituted heteroalkylene, wherein the shortest path between the carbonyl moiety and ring A contains two atoms selected from one carbon atom and one oxygen atom; (e) heteroalkylene, wherein the heteroalkylene is —O—; (f) substituted or unsubstituted C ２～４ alkenylene; (g) -CH=CH-; (h) a substituted or unsubstituted carbocyclylene; or (i) cyclopropylene; 10. The compound according to claim 9.

13. Ring A is (a) phenyl, cyclohexyl, pyridinyl, pyrazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl; (b) 【Chemistry 14】 or (c) pyridinyl, 10. The compound according to claim 9.

14. Compound of formula (IV): 【Chemistry 15】 wherein R ２ is cyclopropylmethyl or 2,2-difluoroethyl, R ３ is chloro, fluoro, -CN, -CF ３ , or -COOCH ３ and Ring D is a 3- to 13-membered heterocyclyl or a 5- to 14-membered heteroaryl ring; R ９ Each instance of is independently hydrogen, halogen, substituted or unsubstituted C １～６ Alkyl, -OR ａ , -COOR ａ , -COR ａ , -N(R ａ ) ２ , -CN, or -C(=O)N(R ａ ) ２ or R ９ are linked to form a 3- to 13-membered carbocyclyl, 3- to 13-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 14-membered heteroaryl ring; R ａ Each instance of is independently hydrogen, substituted or unsubstituted C １～６ an alkyl, an oxygen protecting group if attached to an oxygen atom, or a nitrogen protecting group if attached to a nitrogen atom; n is an integer from 0 to 13 (inclusive), valence permitting; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

15. (a) Ring D is pyrrolidinyl; (b) R ９ are linked to form a 6-membered aryl or 6-membered heteroaryl ring; (c) 【Chemistry 16】 or (d) 【Chemistry 17】 That is, 15. The compound of claim 14.

16. (a) R ２ is cyclopropylmethyl, R ３ is chloro, fluoro or -COOCH ３ is; (b) R ２ is cyclopropylmethyl, R ３ is chloro; (c) R ２ is 2,2-difluoroethyl, R ３ is chloro, fluoro or -COOCH ３ or (d) R ２ is 2,2-difluoroethyl, R ３ But it's Chloro. The compound according to any one of claims 1 to 15.

17. Ring A or Ring B is pyrazolyl, imidazolyl, or imidazo[1,2-a]pyrimidinyl; R ３ The compound according to any one of claims 1 to 13 and 16, wherein is chloro.

18. The compound has the formula: 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 【Chemistry 18-5】 【Chemistry 18-6】 【Chemistry 18-7】 【Chemistry 18-8】 【Chemistry 18-9】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein

19. The compound has the formula: 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 20】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, which is:

20. The compound has the formula: 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 【Chemistry 21-7】 10. The compound of claim 9, wherein:

21. The compound has the formula: 【Chemical 22】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein

22. formula: 【Chemistry 23】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

23. 22. The compound of any one of claims 1 to 21, wherein the compound is of formula (I), formula (II), formula (III), or formula (IV), or a pharma- ceutically acceptable salt thereof.

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and, optionally, a pharma- ceutically acceptable excipient. Optionally, the pharmaceutical composition further comprises an additional pharmaceutical agent; Optionally, the additional pharmaceutical agent is a chemotherapeutic agent or a differentiation agent. The pharmaceutical composition.

25. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, for use in treating a disease or disorder in a subject, comprising: Optionally, the disease or disorder is an inflammatory disease, a proliferative disease, an autoimmune disease, a hematological disease, a neurological disease, a pain condition, a metabolic disorder, an infectious disease, a cardiovascular disease, a cerebrovascular disease, a tissue repair disorder, a pulmonary disease, a skin disease, a bone disease, or a hormonal disease; Optionally, the disease or disorder is selected from the group consisting of tumors, acute coronary syndromes, acute lung injury, acute respiratory distress syndrome, severe acute respiratory distress syndrome, adult respiratory distress syndrome, ventilator-induced lung injury, chronic obstructive pulmonary disease (COPD), pulmonary inflammation, Alzheimer's disease, axonal degeneration, arthritis, asthma, ataxia telangiectasia, atherogenic inflammatory disease, atherosclerosis, cachexia, colitis, ulcerative colitis (UC), Crohn's disease (CD), inflammatory bowel disease (IBD), skin diseases, atopic skin. inflammation, psoriasis, diabetes, weight loss, aging, dilated cardiomyopathy, heart failure, inflammation, fibrotic disease, glomerulonephritis, graft versus host disease (GCDH), acquired immune deficiency syndrome (AIDS), inflammation associated with infection, pneumonia, pneumonitis, COVID-19, coronavirus infection, sepsis, septic shock, intrauterine infection, polycystic ovary syndrome, preeclampsia, obesity, osteoarthritis, osteoporosis, pain, restenosis, stroke, ultraviolet light induced skin damage, atherothrombotic disease, or vascular inflammation; Optionally, the disease or disorder is: (a) by inhibiting NAMPT in a subject, (b) inhibiting the NAMPT pathway in a subject, (c) decreasing NAMPT signaling in a subject, (d) inhibiting the production of nicotinamide mononucleotide in a subject, (e) inhibiting the production of nicotinamide adenine dinucleotide in a subject, (f) reducing inflammatory activity in a subject; (g) reducing inflammatory cell infiltration in a subject; (h) by reducing a cellular metabolic activity or condition in a subject; and / or (i) by reducing cell proliferation in a subject; To be treated, The pharmaceutical composition.

26. 26. The pharmaceutical composition of claim 25 further comprising the use of an additional pharmaceutical agent, Optionally, an additional pharmaceutical agent is administered prior to, simultaneously with, or after the compound, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

27. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, for use in treating cancer in a subject, comprising: Optionally, the cancer comprises cancer stem cells; and / or Optionally, the cancer is: (a) hematological cancer, gastric cancer, colorectal cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, liver cancer, breast cancer, pancreatic cancer, uterine cancer, testicular cancer, or prostate cancer; (b) gastric cancer, optionally wherein the gastric cancer is gastric cancer subtype GS or gastric cancer subtype CIN; (c) colorectal cancer, optionally wherein the colorectal cancer is colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4; (d) uterine cancer, optionally wherein the uterine cancer is endometrial cancer; (e) lung cancer, optionally wherein the lung cancer is small cell lung cancer; (f) a hematological cancer, optionally wherein the hematological cancer is: (1) lymphoma, optionally comprising: (i) non-Hodgkin's lymphoma, (ii) B-cell lymphoma, (iii) large B-cell lymphoma, (iv) Burkitt's lymphoma, (v) Burkitt's B-cell lymphoma, or (vi) large cell immunoblastic lymphoma; (2) leukemia, optionally, the leukemia being: (i) acute myeloid leukemia, optionally wherein the acute myeloid leukemia is: (I) anaplastic acute myeloblastic leukemia (M0), (II) acute myeloblastic leukemia with minimal maturation (M1); (III) acute myeloblastic leukemia with maturation (M2); (IV) acute promyelocytic leukemia (APL) (M3), (V) acute myelomonocytic leukemia (M4), (VI) acute myelomonocytic leukemia with eosinophilia (M4 eos); (VII) acute monocytic leukemia (M5), (VIII) acute erythroleukemia (M6), or (IX) acute megakaryoblastic leukemia (M7); (ii) acute monocytic leukemia, acute lymphocytic leukemia, or B-cell acute lymphocytic leukemia; (iii) chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia; or (iv) acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, or T-cell acute lymphoblastic leukemia; or (3) multiple myeloma, optionally wherein the multiple myeloma is B-cell myeloma; Optionally, the subject has or is undergoing one or more additional cancer therapies; and / or Optionally, the subject is in need of regenerative medicine. The pharmaceutical composition.

28. 26. A method comprising contacting a cell, tissue, or biological sample with an effective amount of a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, Optionally, the cells are (i) characterized by one or more embryonic, pluripotent, or adult stem cell properties; and / or (ii) 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; and / or Optionally, said contacting step comprises: (a) reducing one or more embryonic or adult stem cell characteristics of said cells; (b) performed in vitro or ex vivo; (c) reducing cell viability and / or preventing cell proliferation; (d) killing the cells; (e) inhibiting tumor growth; (f) preventing metastasis; (g) differentiating one or more cells; and / or (h) regenerating one or more cells; The method.

29. 26. A method comprising killing a cell with an effective amount of a compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, Optionally, the cells are (i) characterized by one or more embryonic or adult stem cell characteristics; and / or (ii) 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; and / or Optionally, the cell is in vitro or ex vivo, The method.

30. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: (a) inhibiting NAMPT in a subject; (b) inhibiting the NAMPT pathway in a subject; (c) reducing NAMPT signaling in a subject; (d) inhibiting the production of nicotinamide mononucleotide in a subject; (e) inhibiting the production of nicotinamide adenine dinucleotide in a subject; (f) reducing inflammatory cell infiltration in a subject; (g) reducing inflammatory activity in a subject; (h) reducing cell proliferation in a subject; and / or (i) reducing a cellular metabolic activity or condition in a subject The pharmaceutical composition for use in

31. 24. The method of claim 1, comprising contacting a cell, tissue, or biological sample with a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. (a) inhibiting NAMPT in a cell, tissue, or biological sample; (b) inhibiting the NAMPT pathway in a cell, tissue, or biological sample; (c) reducing NAMPT signaling in a cell, tissue, or biological sample; (d) inhibiting the production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample; (e) inhibiting the production of nicotinamide mononucleotide in a cell, tissue, or biological sample; (f) reducing inflammatory activity in a cell, tissue, or biological sample; (g) reducing inflammatory cell infiltration in a cell, tissue, or biological sample; (h) reducing a cellular metabolic activity or state in a cell, tissue, or biological sample; or (i) reducing cell proliferation in a cell, tissue, or biological sample; 1. A method comprising: Optionally, said contacting is carried out in vitro or ex vivo. The method.

32. A compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and Instructions for using said compound, a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug. Including the kit.

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