Compounds for activating invariant natural killer T cells and methods for their use in eliminating inflammatory senescent cells.

Abstract

This invention provides compounds for activating invariant natural killer T cells (iNKTs) and methods for their use in eliminating inflammatory senescent cells. [Solution] Compounds for activating iNKT cells are provided. Compounds according to certain embodiments activate iNKT cells and induce increased production of one or more cytokines, such as IFNγ, IL-2, IL-4, IL-6, and TNFα. In some embodiments, activated iNKT cells are used to selectively reduce or eliminate the presence of inflammatory senescent cells, such as senescent cells having an inflammatory secretome (SASP). Methods for activating iNKT cells by contacting them with a certain amount of the compound of the present invention, and for selectively reducing or eliminating the presence of senescent cells in the activated iNKT cells, are also described.

Description

[Background technology]

[0001] Introduction In a healthy system, the immune system naturally (endogenously) removes senescent cells. When this immune function is impaired, senescent cells accumulate and can propagate to numerous different diseases. Invariant natural killer T (iNKT) cells are a subset of T cells that recognize glycolipid antigens bound to surface antigen classification (CD) 1d molecules expressed by surface antigen-presenting cells. Recognition of exogenous and endogenous lipids can aid in immune responses to diseases such as autoimmune diseases, allergic diseases, metabolic syndrome, cancer, and pathogen infections. While iNKT cells have been shown to mediate cytokine-based immune responses, they can also function as effectors through cytotoxicity. [Overview of the project] [Means for solving the problem]

[0002] overview Compounds for activating invariant natural killer T cells (iNKT cells) are provided. In certain embodiments, the compounds activate iNKT cells and induce increased production of one or more cytokines, such as IFNγ, IL-2, IL-4, IL-6, and TNFα. In some embodiments, activated iNKT cells are used to selectively reduce or eliminate the presence of inflammatory senescent cells, such as senescent cells having an inflammatory secretome (SASP). Methods for activating iNKT cells by contacting them with a certain amount of the compounds of the present invention, and for selectively reducing or eliminating the presence of senescent cells in the activated iNKT cells, are also described. Compositions for carrying out the methods of the present invention are also described.

[0003] In some embodiments, the target compound is a compound of formula DCD-(I): [ka] [In the formula, Z is [Chemical formula] selected from [Chemical formula] represents a Z-O bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, X1 and X2 are each independently selected from -C, -NR j , -O, -SR k , -Si, and R j and R k are each independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, R a is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 forms cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [Chemical formula] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0004] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 It is hydrogen. In some cases, R 1 , R 2 , R 3 , R 4 Each of them is hydrogen. In a particular case, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0005] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In a particular case, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0006] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl.

[0007] In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R iIt is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I.

[0008] In other cases, R i It is Br.

[0009] In some embodiments, X1 is -NH. In some cases, X1, X2 and R a They come together to form an amide, for example, if X1 is -NH and X2 is carbon, R a This is oxygen. In other cases, X1, X2 and R a These combine to form a sulfoximine, for example, if X1 is -NH and X2 is -SR k And R a That is oxygen. In some cases, R k The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R k It is methyl. In other cases, X1, X2 and R a They combine to form trifluoromethylaminomethyl, for example, X1 is -NH and X2 is carbon, R a This is trifluoromethyl. In other cases, X1, X2 and R a They come together to form a vinyl fluoride, for example, if X1 is carbon and X2 is carbon, R a fluorine is fluorine. In certain cases, X1, X2 and R a They combine to form an aminooxetane, for example, X1 is -NH and R a It combines with X2 to form oxacyclobutane. In this embodiment, R e R may be an alkyl group or a substituted alkyl group. In some cases, R e It is a C8-C20 alkyl group. In some cases, R e is a substituted C8-C20 alkyl group. In certain cases, R eIt is a C13 alkyl group.

[0010] In some embodiments, R b It is hydrogen. In some cases, R b It is a C1-C16 alkyl group. In some cases, R b The group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some cases, R b teeth, [ka] Selected from, [ka] This indicates a bond to Y, and R z R is hydrogen, alkyl, or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In certain cases, R z This is an alkyl group, for example, a C1-C16 alkyl group or a C1-C16 substituted alkyl group.

[0011] In some embodiments, R c It is a C1-C16 alkyl group. In some cases, R c The methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl compounds are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl compounds.

[0012] In some embodiments, R dis C5-C25 alkyl or C5-C25 alkyl substituted with a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, an aryl group, a substituted aryl group, an arylalkyl group, a substituted arylalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroarylalkyl group, or a substituted heteroarylalkyl group. In some cases, R d is [Chemical formula] [Chemical formula] [Chemical formula] is C5-C25 alkyl substituted with a moiety selected from the group consisting of [Chemical formula] represents a bond to C5-C25 alkyl, and R m and R n are independently selected from hydrogen, halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine, substituted sulfoximine, acyl, aminoacyl, alkyl, substituted alkyl; heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, spiroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0013] In some cases, R m is hydrogen. In some cases, R m is halogen. In some cases, R m is selected from fluorine, bromine or iodine. In some cases, R nis hydrogen. In some cases, R n is a halogen. In some cases, R n is fluorine, bromine or iodine.

[0014] In some embodiments, the target compound is a compound of formula DCD-(II): [Chemical formula] [wherein, Z is [Chemical formula] is selected from [Chemical formula] represents a Z-O bond, X is -NHCO- or oxygen, R 1 R 2 R 3 and R 4 are each independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, X1, X2, X3, X4 and X5 are each independently selected from carbon, nitrogen, oxygen or sulfur, R a is optionally absent or, if present, is selected from hydrogen or oxygen, [Chemical formula] represents a double bond or a single bond, n is an integer from 2 to 25, Y is selected from carbon, nitrogen or silicon, R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0015] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 It is hydrogen. In some cases, R 1 , R 2 , R 3 , R 4 Each of them is hydrogen.

[0016] In a particular case, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0017] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R gThis is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In a particular case, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0018] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And, R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I. In other cases, Ri It is Br.

[0019] In some embodiments, X1, X2, X3, X4, and X5 together form a pyrazole, for example, X1 is carbon, X2 is nitrogen, X3 is nitrogen, X4 is carbon, and X5 is carbon. In other embodiments, X1, X2, X3, X4, and X5 together form an imidazole, for example, X1 is carbon, X2 is nitrogen, X3 is carbon, X4 is carbon, and X5 is nitrogen. In other embodiments, X1, X2, X3, X4, and X5 together form a tetrazole, for example, X1 is nitrogen, X2 is nitrogen, X3 is nitrogen, X4 is nitrogen, and X5 is carbon. In a particular embodiment, X1, X2, X3, X4, and X5 together form a tetrazole, for example, X1 is nitrogen, X2 is nitrogen, X3 is nitrogen, X4 is nitrogen, and X5 is carbon, R a That is oxygen.

[0020] In this embodiment, R e R may be an alkyl group or a substituted alkyl group. In some cases, R e It is a C8-C20 alkyl group. In some cases, R e is a substituted C8-C20 alkyl group. In certain cases, R e It is a C13 alkyl group.

[0021] In some embodiments, R b It is hydrogen. In some cases, R b It is a C1-C16 alkyl group. In some cases, R b The group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some cases, R b teeth, [ka] Selected from, [ka] This indicates a bond to Y, and R z R is hydrogen, alkyl, or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In certain cases, R z This is an alkyl group, for example, a C1-C16 alkyl group or a C1-C16 substituted alkyl group.

[0022] In some embodiments, R c It is a C1-C16 alkyl group. In some cases, R c The compound is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.

[0023] In some embodiments, R d This is a C5-C25 alkyl group, or a C5-C25 alkyl group that is substituted with a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, an aryl group, a substituted aryl group, an arylalkyl group, a substituted arylalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroarylalkyl group, or a substituted heteroarylalkyl group. In some cases, R d teeth, [ka] [ka] A C5-C25 alkyl group that is substituted with a portion selected from the group consisting of the following: [ka] This indicates bonding to C5-C25 alkyl groups, and R m and R n These are independently selected from hydrogen, halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine, substituted sulfoximine; acyl, aminoacyl, alkyl, substituted alkyl; heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, spiroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0024] In some cases, R m It is hydrogen. In some cases, R m It is a halogen. In some cases, R m This is selected from fluorine, bromine, or iodine. In some cases, R n It is hydrogen.

[0025] In some cases, R n It is a halogen. In some cases, R n These are fluorine, bromine, or iodine.

[0026] Aspects of this disclosure also include methods for activating iNKT cells by contacting them with a certain amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some cases, the iNKT cells are contacted with the compound in vitro. In other cases, the iNKT cells are contacted with the compound in vivo. In some cases, the method involves contacting iNKT cells with one or more of the compounds described herein, and T HThe method involves contacting iNKT cells in a manner sufficient to induce a type 1 cytokine response (e.g., increasing the production of one or more cytokines selected from IFNγ, IL-1B, IL-2, IL-3, IL-8, IL-12, IL-15, TNFα, GM-CSF, RANTES, MIP-1α, and MCP-1). In other cases, the method involves contacting one or more of the compounds described herein with iNKT cells and T H This involves contact in a manner sufficient to induce a type 2 cytokine response (e.g., increasing the production of one or more cytokines selected from IL-4, IL-6, IL-8, IL-10, IL-13, RANTES, MIP-1α, and MCP-1). In some cases, the compound forms a complex with a CD1 molecule on an antigen-presenting cell. In certain cases, the CD1 molecule is a CD1d molecule. In some cases, the receptor on a T lymphocyte is a T cell receptor. In some cases, the compound stimulates at least one other lymphocyte to produce a cytokine response. In some cases, the at least one other lymphocyte is a T helper cell.

[0027] In certain cases, the method involves contacting activated iNKT cells with a composition containing senescent cells, and contacting with activated iNKT cells reduces or eliminates the presence of senescent cells in the composition. In some embodiments, the senescent cells have an inflammatory secretome. In some embodiments, the composition further contains healthy cells. In some cases, contacting with activated iNKT cells reduces or eliminates the presence of senescent cells in the composition without reducing the presence of healthy cells. For example, contacting with activated iNKT cells reduces or eliminates the presence of senescent cells in the composition, and when the composition is contacted with activated iNKT cells, the presence of healthy cells is reduced by 5% or less.

[0028] In some embodiments, the method involves administering one or more compounds described herein to a subject, for example, to reduce or eliminate the presence of senescent cells in the subject. In some cases, the method may be used for autoimmune diseases, fibrotic disorders (lung, kidney, liver), allergic diseases, metabolic syndrome, type 2 diabetes, NAFLD, NASH, cancer, eye diseases, heart diseases, kidney diseases, pathogen infections, rheumatoid arthritis, ulcerative colitis, multiple sclerosis, familial hypercholesteremia, giant cell arteritis, idiopathic pulmonary fibrosis, systemic lupus erythematosus, cachexia, glaucoma, and chronic diseases. The treatment involves administering one or more compounds to treat the following conditions: obstructive pulmonary disease, systemic sclerosis, pulmonary arterial hypertension, lipodystrophy, muscle loss, alopecia, post-myocardial infarction, vitiligo, POTS, MCAD, Sjögren's disease, scleroderma, Hashimoto's disease, ankylosing spondylitis, fibromyalgia, sarcoidosis, hepatitis, Raynaud's syndrome, fungal diseases, celiac disease, Crohn's disease, pemphigus, SPS, PBC, psoriatic arthritis, CIDP, motor neuron disease, GPA, ALS, myasthenia gravis, and presbyopia. [Brief explanation of the drawing]

[0029] [Figure 1A]Figure 1A shows different concentrations of compounds DCD-101, DCD-102, DCD-103, DCD-104, DCD-105, DCD-106, DCD-108, DCD-112, DCD-113, DCD-114, DCD115, and DCD-116, DCD118, DC D-119, DCD-120, DCD-121, DCD-122, DCD-123, DCD-124, DCD-125, DCD-126, DCD-127, DCD-128, DCD-129, DCD-130, DCD-131, DCD-132, DCD-133, DCD- This shows the GFP+ percentage of cells at different concentrations of 134, DCD-135, DCD-136, DCD-137, DCD-138, DCD-139, DCD-140, DCD-141, DCD-142, DCD-143, DCD-144, DCD-145, DCD-146, DCD-147, DCD-148, DCD-149, DCD-150, DCD-151, DCD-152, DCD-153, DCD-154, DCD-155, DCD-156, DCD-157, DCD-158, DCD-159 and α-GalCer. [Figure 1B] Figure 1B shows the EC50 of the dose-response relationship shown in Figure 1A. [Figure 2A] Figure 2A shows the interleukin-2 (IL-2) secretion levels in response to 48-hour incubation with compounds DCD-101, DCD-102, DCD-104, DCD-105, DCD-106, and α-GalCer in dose-response situations of 0.01, 0.1, 1, and 10 ug / mL. [Figure 3A] Figure 3A shows the secretion of the cytokine interferon gamma (IFNγ) in response to activation by compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 3B] Figure 3B shows the secretion of the cytokine interleukin-6 (IL-6) in response to activation by compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 3C]Figure 3C shows the secretion of the cytokine tumor necrosis factor alpha (TNFα) in response to activation by compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 4A] Figure 4A shows the activation of C57BL / 6J immune cells in response to injection of compounds DCD-101, DCD-119, DCD-123, DCD125, DCD127, DCD-128, DCD-134, DCD-142, DCD-145, DCD-146, DCD-147, DCD-148, DCD-149, DCD-150, DCD-151, DCD-152, DCD-153, DCD-154, DCD-155, DCD-156, and DCD-157, DCD-158, and DCD-159, as measured by serum IFNγ using ELISA 20 hours after injection, compared to α-GalCer. [Figure 4B] Figure 4B shows the increase in iNKT cells in the spleen of C57BL / 6J mice in response to injection of compounds DCD-101, DCD-104, DCD-106, DCD-119, DCD-142, DCD-145, DCD-146, DCD-147, DCD-148, DCD-149, DCD-150, DCD-151, DCD-152, DCD-153, DCD-154, DCD-155, DCD-156, DCD-157, DCD-158, and DCD-159, compared to α-GalCer. [Figure 5A] Figure 5A shows the increase in iNKT cells induced by α-GalCer or DCD-101 in the spleen of HFD model mice, as measured by flow cytometry. [Figure 5B] Figure 5B shows the increase in iNKT cells induced by α-GalCer or DCD-154 in the HFD mouse model eWAT, as measured by flow cytometry. [Figure 5C] Figure 5C shows the amount of serum IFNγ produced in the HFD mouse model in response to α-GalCer or DCD-101, 2 hours after injection. [Figure 5D]Figure 5D shows the amount of serum IFNγ produced in the HFD mouse model in response to α-GalCer or DCD-154 20 hours after injection. [Figure 5E] Figure 5E shows the reduction in accumulated senescent cells in eWAT in response to treatment with compounds DCD-101, DCD-154, and α-GalCer. Values ​​were collected from numerous experiments and normalized for HFD-vehicle conditions. [Figure 6A] Figure 6A shows the expression of GFP in compounds GVK1a, GVK1b, GVK1c, and GVK1f in response to incubation with BWSTIM and JiNKT cells. [Figure 6B] Figure 6B shows the IL-2 expression induced by compounds GVK1a, GVK1b, and GVK1f in the DN3.2 cell line when added to BWSTIM CD1d. [Figure 6C] Figure 6C shows the secretion of cytokines interferon-gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin-4 (IL-4), and interleukin-6 (IL-6) in response to incubation with compounds GVK1a, GVK1b, GVK1c, and GVK1f and α-GalCer. [Figure 7A] Figure 7A shows the effects of activated iNKT cells on senescent and non-senescent cells over an 18-hour period. [Figure 7B] Figure 7B shows a comparison of cell lysis of senescent and healthy cells by activated iNKT cells after 8 and 18 hours of incubation. [Modes for carrying out the invention]

[0030] definition The following terms have the meanings set forth below unless otherwise noted. Any undefined term has the meaning known to those skilled in the art.

[0031] As used herein, the term “alkyl” refers to a saturated, branched, or linear monovalent hydrocarbon group obtained by the removal of one hydrogen atom from a single carbon atom of a parent alkane, either by itself or as part of another substituent. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, e.g., propan-1-yl or propan-2-yl; and butyl, e.g., butane-1-yl, butane-2-yl, 2-methyl-propan-1-yl or 2-methyl-propan-2-yl. In some embodiments, the alkyl group contains 1 to 20 carbon atoms. In other embodiments, the alkyl group contains 1 to 10 carbon atoms. In yet another embodiment, the alkyl group contains 1 to 6 carbon atoms, e.g., 1 to 4 carbon atoms.

[0032] "Alkanyl" refers to a saturated, branched, linear, or cyclic alkyl group obtained by removing one hydrogen atom from a single carbon atom of an alkane, either by itself or as part of another substituent. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyl, e.g., propan-1-yl, propan-2-yl(isopropyl), ggregate e-1-yl; and butanyl, e.g., butan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl(isobutyl), 2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl.

[0033] "Alkylene" refers to a branched or unbranched saturated hydrocarbon chain typically having 1 to 40 carbon atoms, more typically 1 to 10 carbon atoms, and even more typically 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), and propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-).

[0034] "Alkenyl" refers to an unsaturated, branched, linear, or cyclic alkyl group having at least one carbon-carbon double bond, obtained by removing one hydrogen atom from a single carbon atom of an alkene, either by itself or as part of another substituent. The group may have either a cis or trans structure with respect to the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl;propenyl, e.g., propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl), propa-2-en-2-yl, cyclopropa-1-en-1-yl;cyclopropa-2-en-1-yl;butenyl, e.g., buta-1-en-1-yl, buta-1-en-2-yl, 2-methylpropa-1-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobuta-1-en-1-yl, cyclobuta-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.

[0035] "Alkynyl" refers to an unsaturated, branched, linear, or cyclic alkyl group having at least one carbon-carbon triple bond, obtained by removing one hydrogen atom from a single carbon atom of an alkyne, either by itself or as part of another substituent. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, e.g., propa-1-in-1-yl, propa-2-in-1-yl, etc.; and butynyl, e.g., buta-1-in-1-yl, buta-1-in-3-yl, buta-3-in-1-yl, etc.

[0036] "Acyl" can be used by itself or as part of another substituent, -C(O)R 30 group (in the formula, R 30This refers to hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl (as defined herein, and their substituted versions). Typical examples, but not limited to, include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, succinyl, and malonyl.

[0037] The term "aminoacyl" is -C(O)NR 21 R 22 group (in the formula, R 21 and R 22 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle. 21 and R 22 This refers to a group that, if necessary, links together with the nitrogen atom bonded to it to form a heterocyclic or substituted heterocyclic group, where these alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0038] "Alkoxy" can be -OR, either by itself or as part of another substituent. 31 group (in the formula, R 31 (wherein is an alkyl or cycloalkyl group, as defined herein). Typical examples, but not limited to, include methoxy, ethoxy, propoxy, butoxy, and cyclohexyloxy.

[0039] "Alkoxycarbonyl" can be C(O)OR, either by itself or as part of another substituent.31 group (in the formula, R 31 (wherein is an alkyl or cycloalkyl group, which are as defined herein). Typical examples, but not limited to, include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and cyclohexyloxycarbonyl.

[0040] "Aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom in an aromatic ring system, either by itself or as part of another substituent. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and others. In certain embodiments, the aryl group contains 6 to 20 carbon atoms. In certain embodiments, the aryl group contains 6 to 12 carbon atoms. Examples of aryl groups are phenyl and naphthyl.

[0041] "Arylalkyl" refers to carbon atoms, typically terminal or sp, either by themselves or as part of another substituent. 3This refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl. When a specific alkyl moiety is intended, the nomenclature arylalkanyl, arylalkenyl, and / or arylalkynyl is used. In certain embodiments, the arylalkyl group is (C7~C 30 ) Arylalkyl, for example, the alkanyl, alkenyl or alkynyl portion of an arylalkyl group is (C1~C 10 ) and the aryl portion is (C6~C 20 ) In certain embodiments, the arylalkyl group is (C7~C 20 ) Arylalkyl, for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is (C1-C8), and the aryl portion is (C6-C 12 )

[0042] "Arylaryl" refers to a monovalent hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of a ring system, in which two or more identical or non-identical aromatic ring systems are directly linked together by single bonds, either by themselves or as part of another substituent, and the number of such direct ring junctions is one less than the number of aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, and biphenyl-naphthyl. When the number of carbon atoms in a reelaryl group is specified, this number refers to the carbon atoms that make up each aromatic ring. For example, (C5~C 14) Arylaryl groups are arylaryl groups in which each aromatic ring contains 5 to 14 carbon atoms, such as biphenyl, triphenyl, binaphthyl, and phenylnaphthyl. In certain embodiments, each aromatic ring system of the arylaryl group is independently (C5~C 14 ) is aromatic. In certain embodiments, each aromatic ring system of the arylaryl group is independently (C5~C 10 ) are aromatic. In certain embodiments, each aromatic ring system is identical, for example, biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

[0043] "Cycloalkyl" refers to a saturated or unsaturated cyclic alkyl group, either by itself or as part of another substituent. The nomenclature "cycloalkanyl" or "cycloalkenyl" is used when a specific level of saturation is intended. Typical cycloalkyl groups include, but are not limited to, cyclopropane, ggregate e, cyclopentane, and groups derived from cyclohexane. In certain embodiments, the cycloalkyl group is (C3~C 10 ) is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a (C3-C7) cycloalkyl group.

[0044] A "cycloheteroalkyl" or "heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and any accompanying hydrogen atoms) are independently replaced by the same or different heteroatoms, either by themselves or as part of another substituent. Typical heteroatoms that replace carbon atoms (may be multiple) include, but are not limited to, N, P, O, S, and Si. When a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirine, thiirane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, and quinuclidine.

[0045] "Heteroalkyl, heteroalkanyl, heteroalkenyl, and heteroalkynyl" refers to alkyl, alkanyl, alkenyl, and alkynyl groups, respectively, in which one or more carbon atoms (and any accompanying hydrogen atoms) are independently replaced by the same or different heteroatomic groups, either by themselves or as part of another substituent. Typical heteroatomic groups that may be included in these groups include, but are not limited to, -O-, -S-, -SS-, -OS-, and -NR. 37 R 38 -, .=NN=, -N=N-, -N=N-NR 39 R 40 ,-PR 41 -, -P(O)2-, -POR 42 -, -OP(O)2-, -SO-, -S-(O)-, -SO2-, -SnR 43 R 44 -etc. (In the formula, R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 44 These can be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0046] A "heteroaryl" refers to a monovalent heteroaromatic group obtained by removing one hydrogen atom from a single atom of an aromatic heterocyclic system, either by itself or as part of another substituent. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindol, carbazole, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indidine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and benzodioxole. In certain embodiments, the heteroaryl group is a 5- to 20-membered heteroaryl group. In certain embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In certain embodiments, the heteroaryl group is a group derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.

[0047] "Heteroarylalkyl" refers to carbon atoms, typically terminal or sp, either by themselves or as part of another substituent. 3This refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. When a specific alkyl moiety is intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl, and / or heteroarylalkynyl is used. In certain embodiments, a heteroarylalkyl group is a 6- to 30-membered heteroarylalkyl, for example, the alkanyl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to 10 members and the heteroaryl moiety is a 5- to 20-membered heteroaryl. In certain embodiments, a heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, for example, the alkanyl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to 8 members and the heteroaryl moiety is a 5- to 12-membered heteroaryl.

[0048] An "aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system that has a conjugated π-electron system, either by itself or as part of another substituent. Specifically included in the definition of an "aromatic ring system" are condensed ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indane, indene, and phenalene. Typical aromatic ring systems, though not limited to these, include acetantrylene, acenaphthylene, acephenantrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalen, ovalen, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0049] An "aromatic heterocyclic system" refers to an aromatic ring system in which one or more carbon atoms (and any accompanying hydrogen atoms) are independently replaced by the same or different heteroatoms, either by themselves or as part of another substituent. Typical heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. Specifically included within the definition of an "aromatic heterocyclic system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as arsindol, benzodioxane, benzofuran, chroman, chromene, indole, indoline, and xanthene. Typical aromatic heterocyclic systems, though not limited to these, include arsindol, carbazole, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indoridine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinoridine, quinoxaline, tetrazoline, thiadiazole, thiazole, thiophene, triazole, and xanthene.

[0050] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituent(s). Typical substituents include, but are not limited to, alkylenedioxy (e.g., methylenedioxy), -M, and -R. 60 , -O - ,=O,-OR 60 , -SR 60 , -S - ,=S,-NR 60 R 61 ,=NR 60 , -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O - -S(O)2OH, -S(O)2R 60-OS(O)2O - -OS(O)2R 60 ,-P(O)(O - )2, -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 ,-C(S)R 60 , -C(O)OR 60 -C(O)NR 60 R 61 ,-C(O)O - , -C(S)OR 60 , -NR 62 C(O)NR 60 R 61 , -NR 62 C(S)NR 60 R 61 , -NR 62 C(NR 63 )NR 60 R 61 and -C(NR 62 )NR 60 R 61 (In the formula, M is a halogen, and R 60 , R 61 , R 62 and R 63 These are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or R as needed. 60 and R 61 These, together with the nitrogen atom to which they are bonded, form a cycloheteralkyl or substituted cycloheteralkyl ring, R 64 and R 65 These are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R as needed. 64 and R 65Examples include (these, together with the nitrogen atom to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring). In certain embodiments, substituents include -M, -R 60 ,=O,-OR 60 , -SR 60 , -S - ,=S,-NR 60 R 61 ,=NR 60 , -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R 60 -OS(O)2° - -OS(O)2R 60 ,-P(O)(O - )2, -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 ,-C(S)R 60 , -C(O)OR 60 -C(O)NR 60 R 61 ,-C(O)O - , -NR 62 C(O)NR 60 R 61 Examples include -M and -R. In certain embodiments, substituents include -M and -R. 60 ,=O,-OR 60 , -SR 60 , -NR 60 R 61 , -CF3, -CN, -NO2, -S(O)2R 60 , -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(O)OR 60 -C(O)NR 60 R 61 ,-C(O)O - Examples include -M and -R. In certain embodiments, substituents include -M and -R. 60 ,=O,-OR 60 , -SR 60 , -NR 60 R61 , -CF3, -CN, -NO2, -S(O)2R 60 , -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(O)OR 60 ,-C(O)O - (In the formula, R 60 , R 61 and R 62 Examples include the above definitions. For example, the substituted group may retain one, two, or three substituents selected from methylenedioxy substituents or halogen atoms, (1-4C) alkyl groups, and (1-4C) alkoxy groups.

[0051] "Pharmacologically acceptable carriers" refer to diluents, adjuvants, excipients, or vehicles, which are administered together with or containing the compound.

[0052] In certain embodiments, “treating” or “treatment” any condition, e.g., autoimmune, metabolic, allergic, cancerous, or infectious disease, means improving the condition (i.e., stopping or reducing the onset of the condition). In certain embodiments, “treating” or “treatment” means improving at least one physical parameter, which may not be perceived by the patient. In certain embodiments, “treating” or “treatment” means inhibiting the condition either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both.

[0053] In certain embodiments, “to treat” or “to treat” means to delay the onset of a condition.

[0054] "Therapeutic dose" refers to the amount of compound sufficient to perform a treatment when administered to a patient to prevent or treat a condition, such as an autoimmune, metabolic, allergic, cancerous, or infectious disease. The therapeutic dose varies depending on the compound, the condition and its severity, as well as the patient's age, weight, etc. Detailed explanation

[0055] Compounds for activating invariant natural killer T cells (iNKT cells) are provided. In certain embodiments, the compounds activate iNKT cells and induce increased production of one or more cytokines, such as IFNγ, IL-2, IL-4, IL-6, and TNFα. In some embodiments, activated iNKT cells are used to selectively reduce or eliminate the presence of inflammatory senescent cells, such as senescent cells having an inflammatory secretome (SASP). Methods for activating iNKT cells by contacting them with a certain amount of the compounds of the present invention, and for selectively reducing or eliminating the presence of senescent cells in the activated iNKT cells, are also described. Compositions for carrying out the methods of the present invention are also described.

[0056] Before the present invention is described in more detail, it should be understood that the invention is not limited to the specific embodiments described and is therefore naturally subject to change. It should also be understood that the scope of the invention is limited solely by the appended claims, and that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit them.

[0057] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that each value between the upper and lower limits of that range, up to one-tenth of the lower limit unit, and any other stated or intermediate values ​​within that stated range are included within the invention. The upper and lower limits of these smaller ranges may independently be included within the smaller range and are also included within the invention, depending on any boundaries specifically excluded within the stated range. If the stated range includes one or both boundaries, the range excluding one or both of these included boundaries is also included within the invention.

[0058] In this specification, certain ranges are presented preceded by the term “approximately.” The term “approximately” is used herein to provide verbal support for the exact number that follows, and to provide numbers that are close to or approximate the number that follows. In determining whether a number is close to or approximates a specifically listed number, a close or approximate, unlisted number may be a number that, in the context in which it is presented, results in a number that is substantially equivalent to a specifically listed number.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein may also be used in carrying out or testing the invention, but representative exemplary methods and materials are described herein.

[0060] All publications and patents cited herein are incorporated by reference as if each individual publication or patent were specifically and individually shown and incorporated by reference, and methods and / or materials are incorporated by reference as if they were disclosed and described in relation to the cited publications. Any citation of a publication is for its disclosure prior to the filing date and should not be construed as acknowledging that the present invention does not have prior rights to such publication by prior invention. Furthermore, the dates of the publications provided may differ from the actual publication dates, and these dates may need to be verified independently.

[0061] In use herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the context explicitly indicates otherwise. Furthermore, claims may be constructed to exclude any element as needed. Thus, this statement is intended to function as a precedent against the use of exclusive terms such as “simply,” “only,” or “negative” limitations relating to the enumeration of claim elements.

[0062] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that can be readily separated from or combined with any of the features of several other embodiments without departing from the scope or spirit of the invention. Any of the listed methods can be carried out in the order of the listed events, or in any other logically possible order.

[0063] Compounds and methods, for the sake of grammatical fluidity, have or are described using functional descriptions; however, claims should not necessarily be construed as being limited in any way by constructing limitations on “means” or “steps” unless expressly provided under 35 U.S. SC § 112, and should be permitted to the full extent of the meaning and equivalents of the definitions provided by the claims under the doctrine of judicial equivalents, and in cases where the claims are expressly provided under 35 U.S. SC § 112, it should be expressly understood that sufficient legal equivalents should be permitted under 35 U.S. SC § 112.

[0064] The publications discussed herein are provided only for disclosures prior to the filing date of this application. Nothing in this specification should be construed as an acknowledgment that the present invention does not have prior rights to such publications by prior inventions. Furthermore, the dates of the publications provided may differ from the actual publication dates and should be verified independently.

[0065] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. Any methods and materials similar or equivalent to those described herein may also be used in carrying out or testing the present invention, but preferred methods and materials are described herein. All publications described herein are incorporated herein by reference to disclose and describe methods and / or materials in relation to cited publications.

[0066] Certain features of the present invention are described in the context of separate embodiments for clarity, but it should be recognized that they can also be combined and provided in a single embodiment. Conversely, various features of the present invention are described in the context of a single embodiment for brevity, but they can also be provided separately or in any suitable sub-combination. All combinations of embodiments relating to the chemical groups represented by the variable elements are specifically encompassed by the present invention and disclosed herein as if every possible combination were individually and expressly disclosed, to the extent that such combinations encompass compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested with respect to biological activity). In addition, all sub-combinations of the chemical groups enumerated in embodiments describing such variable elements are also specifically encompassed by the present invention as if every such sub-combination of the chemical groups disclosed herein were individually and expressly disclosed herein.

[0067] Various embodiments will be described in detail here. It should be understood that the present invention is not limited to these embodiments. Rather, it is intended to cover alternative forms, variations, and equivalents that may fall within the spirit and scope of the permitted claims.

[0068] Compounds that activate iNKT cells and selectively eliminate senescent cells Formula DCD-(I) According to a particular embodiment, an aspect of this disclosure is: Compounds of formula DCD-(I): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R dis independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0069] In embodiments, the “salt” of the compounds of the present disclosure may include: (1) an acid addition salt formed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid Acid addition salts formed with folic acid, camphor sulfonic acid, 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic proton present in the compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0070] As used herein, the term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as DCD-(I) or a salt thereof, and one or more molecules of a solvent. Such a solvate may be a crystalline solid having a substantially fixed molar ratio of solute to solvent. Typical examples of solvents include water, methanol, ethanol, isopropanol, and acetic acid. When the solvent is water, the solvate formed is a hydrate.

[0071] Formula DCD-(IA-1) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IA-1): [ka] [In the formula, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R dis independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0072] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f ORf And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0073] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0074] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl.

[0075] In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I. In other cases, R i It is Br.

[0076] Formula DCD-(IA-2) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IA-2): [ka] [In the formula, X is -NHCO- or oxygen, R 1 , R 2 and R 3 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0077] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 is hydrogen. In certain cases, R 1 , R 2 and R 3 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0078] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0079] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I. In other cases, R i It is Br.

[0080] Formula DCD-(IA-3) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IA-3): [ka] [In the formula, X is -, NHCO-, or oxygen. R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof. In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0081] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R gThis is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0082] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl.

[0083] In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, Ri It is I. In other cases, R i It is Br.

[0084] Formula DCD-(IA-4) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IA-4): [ka] [In the formula, X is -NHCO- or oxygen, R 1 and R 2 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0085] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 1 and R 2 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0086] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R gR is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0087] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I. In other cases, R i It is Br.

[0088] Formula DCD-(IB-1) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IB-1): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and Rd Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0089] Formula DCD-(IB-2) In certain embodiments, aspects of the present disclosure relate to compounds of formula DCD-(IB-2). [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R kThe is selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In some cases, R k The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R k It is methyl. N is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0090] Formula DCD-(IB-3) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IB-3): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0091] Formula DCD-(IB-4) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IB-4): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R dTogether with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0092] Formula DCD-(IB-5) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IB-5): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R dis independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0093] In embodiments of compounds of formula DCD-(I), DCD-(IA), and DCD-(IB), in some cases, R e R may be an alkyl group or a substituted alkyl group. In some cases, R e It is a C8-C20 alkyl group. In some cases, R e is a substituted C8-C20 alkyl group. In certain cases, R e It is a C13 alkyl group.

[0094] In some cases, n is an integer between 2 and 25, for example, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0095] In some cases, Y is carbon. In some cases, Y is nitrogen. In some cases, Y is silicon. In some cases, R b It is hydrogen. In some cases, R b It is alkyl. In some cases, R b It is a C1-C16 alkyl group. In some cases, R bR is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some cases, R b teeth, [ka] Selected from, [ka] This indicates a bond to Y, and R z R is hydrogen, alkyl, or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In certain cases, R z This is an alkyl group, for example, a C1-C16 alkyl group or a C1-C16 substituted alkyl group. In some cases, R c It is hydrogen. In some cases, R c It is alkyl. In some cases, R c It is a C1-C16 alkyl group. In some cases, R c The methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl compounds are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl compounds.

[0096] In some embodiments, R d This is a C5-C25 alkyl group, or a C5-C25 alkyl group that is substituted with a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, an aryl group, a substituted aryl group, an arylalkyl group, a substituted arylalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroarylalkyl group, or a substituted heteroarylalkyl group. In some cases, R d teeth, [ka] [ka] A C5-C25 alkyl group that is substituted with a portion selected from the group consisting of the following: [ka] This indicates bonding to C5-C25 alkyl groups, and R m and R n These are independently selected from hydrogen, halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine, substituted sulfoximine, acyl, aminoacyl, alkyl, substituted alkyl; heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, spiroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0097] In some cases, R m It is hydrogen. In some cases, R m It is a halogen. In some cases, R m This is selected from fluorine, bromine, or iodine. In some cases, R n It is hydrogen.

[0098] In some cases, R n It is a halogen. In some cases, R n These are fluorine, bromine, or iodine.

[0099] Formula DCD-(II) In a particular embodiment, aspects of this disclosure relate to compounds of formula DCD-(II): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1, X2, X3, X4, and X5 are each independently selected from carbon, nitrogen, oxygen, or sulfur. R a It is either absent as needed, or if present, selected from hydrogen or oxygen. [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, Rd It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0100] Formula DCD-(IIA-1) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIA-1): [ka] [In the formula, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1, X2, X3, X4, and X5 are each independently selected from carbon, nitrogen, oxygen, or sulfur. R a It is either absent as needed, or if present, selected from hydrogen or oxygen. [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R dis independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0101] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f ORf And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0102] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0103] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I. In other cases, R i It is Br.

[0104] Formula DCD-(IIA-2) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIA-2): [ka] [In the formula, X is -NHCO- or oxygen, R 1 , R 2 and R 3 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1, X2, X3, X4, and X5 are each independently selected from carbon, nitrogen, oxygen, or sulfur. R a It is either absent as needed, or if present, selected from hydrogen or oxygen. [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R dTogether with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0105] In some cases, R 1 It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 is hydrogen. In certain cases, R 1 , R 2 and R 3 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0106] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I.

[0107] In other cases, R i It is Br. Formula DCD-(IIA-3) In a particular embodiment, the present disclosure relates to a compound of formula DCD-(IIA-3): [ka] [In the formula, X is -NHCO- or oxygen, R 1 , R2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1, X2, X3, X4, and X5 are each independently selected from carbon, nitrogen, oxygen, or sulfur. R a It is either absent as needed, or if present, selected from hydrogen or oxygen. [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl group] or a salt, solvate, or hydrate thereof.

[0108] In some cases, R 1It is hydrogen. In some cases, R 2 It is hydrogen. In some cases, R 3 It is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R fTogether, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R i It is I.

[0109] In other cases, R i It is Br. Formula DCD-(IIA-4) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIA-4): [ka] [In the formula, X is -NHCO- or oxygen, R 1 and R 2 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1, X2, X3, X4, and X5 are each independently selected from carbon, nitrogen, oxygen, or sulfur. R a It is either absent as needed, or if present, selected from hydrogen or oxygen. [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0110] In some cases, R 1 It is hydrogen. In some cases, R 2 is hydrogen. In certain cases, R 1 and R 2 Each of them is hydrogen. In other cases, R 1 teeth, [ka] And, [ka] R 1 - Represents an O bond, R 8is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 The element is selected from hydrogen, methyl, ethyl, and cyclopropyl. R 9 -NR f OR f And R f is an alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f R 10 Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 R f Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0111] In a particular case, R 1 teeth, [ka] Selected from, [ka] R 1 - Represents an O bond, R 8 These are hydrogen, alkyl, and substituted alkyl. R g This is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. In other cases, R 1 teeth, [ka] And, R 11 is an alkyl or substituted alkyl, R 12 This is an alkyl, or an alkyl that is substituted with a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0112] In some cases, R 11 The following are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. In certain cases, R 11 It is isopropyl. In a particular case, R 1 teeth, [ka] And R h and R i Each is independently selected from hydrogen, hydroxyl, or halogen. In some cases, R h It is hydroxyl. In some cases, R h It is F. In some cases, R h It is Cl. In some cases, R h It is I. In some cases, R h It is Br. In some cases, R i It is hydroxyl. In some cases, R i In other cases, R i It is Cl. In other cases, R iIt is I. In other cases, R i teeth,

[0113] Formula DCD-(IIB-1) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIB-1): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, Rd It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0114] Formula DCD-(IIB-2) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIB-2): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , R c and R dis independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0115] Formula DCD-(IIB-3) In a particular embodiment, aspects of this disclosure relate to a compound of formula DCD-(IIB-3): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. n is an integer between 2 and 25; Y is selected from carbon, nitrogen, or silicon. R b , R c and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or a salt, solvate, or hydrate thereof.

[0116] In embodiments of the compounds of formulas DCD-(II), DCD-(IIA), and DCD-(IIB), in some cases, R e R may be an alkyl group or a substituted alkyl group. In some cases, R e It is a C8-C20 alkyl group. In some cases, R e is a substituted C8-C20 alkyl group. In certain cases, R e It is a C13 alkyl group.

[0117] In some cases, n is an integer from 2 to 25. For example, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0118] In some cases, Y is carbon. In some cases, Y is nitrogen. In some cases, Y is silicon. In some cases, R b is hydrogen. In some cases, R b is alkyl. In some cases, R b is C1 - C16 alkyl. In some cases, R b is selected from methyl, ethyl, propyl, isopropyl, n - butyl, isobutyl, tert - butyl, pentyl, hexyl, heptyl, and octyl. In some cases, R b is

Chemical formula

Chemical formula

[0119] In some embodiments, R d This is a C5-C25 alkyl group, or a C5-C25 alkyl group that is substituted with a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, an aryl group, a substituted aryl group, an arylalkyl group, a substituted arylalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroarylalkyl group, or a substituted heteroarylalkyl group. In some cases, R d teeth, [ka] [ka] A C5-C25 alkyl group that is substituted with a portion selected from the group consisting of the following: [ka] This indicates bonding to C5-C25 alkyl groups, and R m and R n These are independently selected from hydrogen, halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfoximine, substituted sulfoximine, acyl, aminoacyl, alkyl, substituted alkyl; heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, spiroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0120] In some cases, R m It is hydrogen. In some cases, R mIt is a halogen. In some cases, R m This is selected from fluorine, bromine, or iodine. In some cases, R n It is hydrogen.

[0121] In some cases, R n It is a halogen. In some cases, R n These are fluorine, bromine, or iodine.

[0122] In some embodiments, the target compounds include those shown in Tables 1-9, and these are not to be construed as limiting. Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0123] Table 2 - Amide Analogues [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0124] Table 3 - Trifluoromethylaminomethyl analog [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0125] Table 4 - Sulfoximine Analogues [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10]

[0126] Table 5 - Vinyl Fluoride Analogue [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0127] Table 6 - Aminooxetane Analogues [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0128] Table 7 - Pyrazole Analogues [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] Table 8 - Tetrazolon Analogues [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9]

[0129] Table 9 - Imidazole Analogues [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7]

[0130] A method for activating iNKT cells and selectively eliminating senescent cells. As outlined above, aspects of this disclosure also include methods for activating iNKT cells. In embodiments, the method involves contacting iNKT cells with one or more of the compounds described herein or pharmaceutically acceptable salts thereof in an amount sufficient to activate the iNKT cells. In some cases, the iNKT cell source is contacted in vitro. In other cases, the iNKT cell source is contacted in vivo (e.g., by administration to subjects described in more detail below). In yet another case, the iNKT cell source is contacted ex vivo.

[0131] In some embodiments, the method involves contacting iNKT cells with one or more of the compounds described herein in a manner sufficient to activate the iNKT cells, the activated iNKT cells inducing a TH1 cytokine response (e.g., increasing the production of one or more cytokines selected from IFN-γ, IL-1β, IL-2, IL-3, IL-8, IL-12, IL-15, TNF-α, GM-CSF, RANTES, MIP-1α, and MCP-1). In other embodiments, the activated iNKT cells inducing a TH2 cytokine response (e.g., increasing the production of one or more cytokines selected from IL-4, IL-6, IL-8, IL-10, IL-13, RANTES, MIP-1α, and MCP-1). In some cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase cytokine production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or the control compound).

[0132] In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase interleukin-2 (IL-2) production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or a control compound). In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase interleukin-4 (IL-4) production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or a control compound).In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase interleukin-6 (IL-6) production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or a control compound). In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase interferon-gamma (IFNγ) production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or a control compound).In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase tumor necrosis factor (TNFα) production by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more, compared to a suitable control (e.g., iNKT cells not in contact with the compound or the control compound).

[0133] In certain cases, activation of iNKT cells with one or more compounds of the present invention is sufficient to increase cytokine production, for example, by increasing cytokine production (e.g., increasing one or more IFN-γ, IL-1β, IL-2, IL-3, IL-8, IL-12, IL-15, TNF-α, GM-CSF, RANTES, MIP-1α and MCP-1 or IL-4, IL-6, IL-8, IL-10, IL-13, RANTES, MIP-1α and MCP-1) compared to contacting iNKT cells with α-galactosylceramide (α-GalCer). In some embodiments, the compounds of the Disclosure increase cytokine production by 1% or more compared to α-galactosylceramide, for example, 2% or more, for example, 3% or more, for example, 4% or more, for example, 5% or more, for example, 10% or more, for example, 15% or more, for example, 20% or more, for example, 25% or more, for example, 50% or more, for example, 75% or more, for example, 90% or more, for example, 95% or more, including an increase of 99% or more compared to α-galactosylceramide.

[0134] In some cases, the compound forms a complex with a CD1 molecule on an antigen-presenting cell. In certain cases, the CD1 molecule is a CD1d molecule. In some cases, the receptor on the T lymphocyte is a T cell receptor. In some cases, the compound stimulates at least one other lymphocyte to generate a cytokine response, and in some cases, at least one other lymphocyte is a T helper cell. In some embodiments, the method involves activating iNKT cells using the compound of the present invention in a manner sufficient to modulate an immune response in a subject.

[0135] When carrying out the method of the present invention, iNKT cells can be exposed to the compound of the present invention for a period of time including 1 minute or longer, for example, 2 minutes or longer, for example, 3 minutes or longer, for example, 4 minutes or longer, for example, 5 minutes or longer, for example, 10 minutes or longer, for example, 15 minutes or longer, for example, 30 minutes or longer, for example, 60 minutes or longer, for example, 2 hours or longer, for example, 6 hours or longer, for example, 12 hours or longer, for example, 18 hours or longer, 24 hours or longer. In certain embodiments, the production of one or more cytokines can be evaluated (e.g., quantified) after the compound has been exposed to the iNKT cells. In some cases, cytokine production is evaluated in real time (i.e., continuously monitored). In other cases, cytokine production is evaluated at predetermined time intervals, such as every minute, every 15 minutes, every 30 minutes, every 60 minutes, every 2 hours, every 4 hours, every 6 hours, every 12 hours, every 18 hours, including every 24 hours.

[0136] In some embodiments, contact with iNKT cells with one or more compounds of the present disclosure is sufficient to activate the iNKT cells and reduce the presence of senescent cells or induce the death of senescent cells. In certain embodiments, senescent cells are those having an inflammatory secretome. For example, activating iNKT cells with the compounds of the present invention according to these embodiments results in a cytotoxic effect on senescent cells. In some cases, the method involves activating iNKT cells with the compounds of the present invention in a manner sufficient to reduce the presence of senescent cells or induce the death of senescent cells in vitro. In some cases, the method involves activating iNKT cells with the compounds of the present invention in a manner sufficient to reduce the presence of senescent cells or induce the death of senescent cells in vivo (for example, by administering the compounds as part of the pharmaceutical compositions described below). In some cases, activating iNKT cells with the compounds of the present invention is sufficient to reduce the presence of senescent cells by 1% or more, e.g., 2% or more, e.g., 3% or more, e.g., 4% or more, e.g., 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 20% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, e.g., 99% or more. In certain specific cases, the compounds of the present invention eliminate the presence of senescent cells (e.g., activation of iNKT cells reduces the presence of senescence by 100%). The reduction in the presence of senescent cells can be evaluated (e.g., quantified) after contact of the compounds with iNKT cells.

[0137] In some embodiments, iNKT cells activated by contact with the compounds described herein selectively reduce the presence of senescent cells or selectively induce senescent cell death while maintaining healthy cells (i.e., not killing them). In some cases, contact with iNKT cells activated with the compounds of the Disclosure is sufficient to reduce the presence of senescent cells while maintaining 75% or more of healthy cells, e.g., 80% or more, e.g., 85% or more, e.g., 90% or more, e.g., 95% or more, e.g., 97% or more, e.g., 99% or more, e.g., 99.9% or more, and 99.99% or more. In certain specific cases, iNKT cells activated by contact with the compounds of the Disclosure selectively reduce the presence of senescent cells without any effect on healthy cells (i.e., 100% healthy cells are maintained).

[0138] In some cases, the reduction of senescent cells can be assessed in real time (i.e., by continuous monitoring). In other cases, the reduction of senescent cells is assessed at predetermined time intervals, such as every minute, every 15 minutes, every 30 minutes, every 60 minutes, every 2 hours, every 4 hours, every 6 hours, every 12 hours, every 18 hours, including every 24 hours.

[0139] Aspects of this disclosure also include administering one or more of the compounds described herein to a subject in need thereof. In embodiments, the term “subject” means a human or organism to which the compound is administered. Thus, subjects of this disclosure may include, but are not limited to, mammals, such as humans and other primates, such as chimpanzees and other apes and monkey species, dogs, rabbits, cats and other domesticated pets, and in certain embodiments, the subject is human.

[0140] The term “subject” is also intended to include any human or living being of any age, weight or other physical characteristics, and the subject may be an adult, child, infant or newborn.

[0141] In certain embodiments, subjects are diagnosed with autoimmune diseases, fibrous disorders (lung, kidney, liver), allergic diseases, metabolic syndrome, type 2 diabetes, NAFLD, NASH, cancer, pathogen infections, rheumatoid arthritis, ulcerative colitis, multiple sclerosis, familial hypercholesterolemia, giant cell arteritis, idiopathic pulmonary fibrosis, systemic lupus erythematosus, cachexia, glaucoma, chronic obstructive pulmonary disease, systemic sclerosis, pulmonary arterial hypertension, lipodystrophy, muscle loss, alopecia, post-myocardial infarction, vitiligo, POTS, MCAD, Sjögren's disease, scleroderma, Hashimoto's disease, ankylosing spondylitis, fibromyalgia, sarcoidosis, hepatitis, Raynaud's syndrome, fungal diseases, celiac disease, Crohn's disease, pemphigus, SPS, PBC, psoriatic arthritis, CIDP, motor neuron disease, GPA, ALS, myasthenia gravis, and presbyopia. In some embodiments, subjects are diagnosed with or exhibiting symptoms of at least one of the following conditions: multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, vitiligo, Behçet's disease, collagen disease, type 1 diabetes mellitus, uveitis, Sjögren's syndrome, autoimmune myocarditis (cardiomyotitis), autoimmune liver disease, autoimmune gastritis, pemphigus, Guillain-Barré syndrome, HTLV-1-associated myelopathy, or fulminant hepatitis (e.g., by clinical laboratory testing or by a qualified healthcare professional).

[0142] In some embodiments, the method involves administering one or more compounds to treat a target for an infectious disease caused by a pathogenic microorganism, such as a virus, bacteria, fungi, protozoa, and multicellular parasites. In one example, the infectious disease is caused by a virus selected from Retroviridae, Picornaviridae, Caliciviridae, Togaviridae, Flaviviridae, Coronaviridae, Rhabdoviridae, Filoviridae, Paramyxoviridae, Orthomyxoviridae, Bunyaviridae, Arena viridae, Reoviridae, Birnaviridae, Hepadnaviridae, Parvoviridae, Papovaviridae, Adenoviridae, Herpesviridae, Poxviridae, and Iridoviridae.Its ingredients include Helicobacter pylori, Borrelia burgdorferi, Legionella pneumophilia, Klebsiella Pneumoniae, Mycobacteria sps, Staphylococcus aureus, and Neisseria gonorrhoeae、Neisseria meningitidis、Listeria monocytogenes、Streptococcus pyogenes、Streptococcus agalactiae、Streptococcus、Streptococcus faecalis、Streptococcus bovis、Streptococcus pneumoniae Campylobacter sp. Enterococcus sp. Chlamydia sp. Haemophilus influenzae Bacillus anthracis Corynebacterium diphtheriae Corynebacterium sp. Erysipelothrix rhusiopathiae Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasteurella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidum, Treponema belonging to Leptospira, Actinomyces israelii, Sphingomonas capsulata, and Francisella tularensis.

[0143] The compounds described herein may be administered to a subject by any convenient protocol, including, but not limited to, intraperitoneal, topical, oral, sublingual, parenteral, intravenous, transvaginal, rectal, and transdermal protocols. In certain embodiments, the compounds of the present invention are administered by intravenous injection. In certain embodiments, the compounds of the present invention are administered by intraperitoneal injection.

[0144] Depending on the condition being treated, the amount of compound administered to the subject may vary within a range including, for example, approximately 100 mg / day to approximately 10,000 mg / day, approximately 10 mg / day to approximately 9,000 mg / day, approximately 50 mg / day to approximately 8,000 mg / day, approximately 100 mg / day to approximately 7,000 mg / day, and approximately 500 mg / day to approximately 6,000 mg / day, including approximately 600 mg / day to approximately 5,000 mg / day. Each dose of the compound or pharmaceutically acceptable salt administered to the subject may vary within a range including approximately 1 mg / kg to approximately 1000 mg / kg, for example, approximately 2 mg / kg to approximately 900 mg / kg, for example, approximately 3 mg / kg to approximately 800 mg / kg, for example, approximately 4 mg / kg to approximately 700 mg / kg, for example, approximately 5 mg / kg to approximately 600 mg / kg, for example, approximately 6 mg / kg to approximately 500 mg / kg, for example, approximately 7 mg / kg to approximately 400 mg / kg, for example, approximately 8 mg / kg to approximately 300 mg / kg, for example, approximately 9 mg / kg to approximately 200 mg / kg, and including approximately 10 mg / kg to approximately 100 mg / kg.

[0145] In certain embodiments, the protocol may include multiple dosing intervals. “Multiple dosing intervals” means that two or more doses of the compound are administered to the subject in a sequential manner. In carrying out the methods of the present disclosure, the treatment regimen may include dosing intervals that include two or more dosing intervals, e.g., three or more dosing intervals, e.g., four or more dosing intervals, e.g., five or more dosing intervals, ten or more dosing intervals. The duration between dosing intervals in a multiple dosing interval treatment protocol may vary depending on the physiological function of the subject or the treatment protocol as determined by the healthcare professional. For example, the duration between dosing intervals in a treatment protocol with multiple dosing doses may be predetermined and follow regular intervals. Therefore, the time between dose intervals may vary and may include intervals of 1 day or longer, for example, 2 days or longer, for example, 4 days or longer, for example, 6 days or longer, for example, 8 days or longer, for example, 12 days or longer, for example, 16 days or longer, or 24 days or longer. In certain embodiments, multiple dose interval protocols are provided with intervals of 1 week or longer, for example, 2 weeks or longer, for example, 3 weeks or longer, for example, 4 weeks or longer, for example, 5 weeks or longer, or 6 weeks or longer.

[0146] The drug administration cycle may consist of 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 drug administration cycles, repeated over a total period of 6 months, 1 year, 2 years, 3 years, 4 years, or longer. In certain embodiments, one or more compounds of the present invention are administered for the remainder of the subject's life.

[0147] In certain embodiments, the compounds of the Disclosure may be administered before, concurrently with, or after other therapeutic agents for treating the same or unrelated conditions. When provided concurrently with another therapeutic agent, the compounds of the Disclosure may be administered in the same or different compositions. Thus, the compounds of interest and other therapeutic agents may also be administered to a subject as concurrent therapy. "Concurrent therapy" means that the substances are administered to a subject in such a way that the therapeutic effect of the combination of substances occurs in the subject receiving therapy. For example, concurrent therapy can be achieved by administering the compounds of the Disclosure together with at least one other agent, for example, a pharmaceutical composition having an anti-inflammatory agent, immunosuppressant, steroid, analgesic, anesthetic, antihypertensive, or chemotherapeutic agent among other types of therapeutic agents, and combining them according to a specific dosing regimen to create a therapeutically effective dose. The administration of separate pharmaceutical compositions may be carried out simultaneously or at different times (i.e., sequentially, in any order, on the same day or on different days), insofar as the therapeutic effect of the combination of these substances is induced in the subject receiving therapy.

[0148] When the compounds of the present disclosure are administered in parallel with a second therapeutic agent for treating the same condition (e.g., a chemotherapeutic agent, an antiviral agent, etc.), the weight ratio of the compounds of the present invention to the second therapeutic agent may be in the range of 1:2, and 1:2.5; 1:2.5 and 1:3; 1:3 and 1:3.5; 1:3.5 and 1:4; 1:4 and 1:4.5; 1:4.5 and 1:5; 1:5 and 1:10; and 1:10 and 1:25, or within these ranges. For example, the weight ratio of the compounds of the present invention to the second therapeutic agent may be in the range of 1:1 to 1:5; 1:5 to 1:10; 1:10 to 1:15; or 1:15 to 1:25. Alternatively, the weight ratio of the second therapeutic agent to the compound of the present invention may be in the range of 2:1 to 2.5:1; 2.5:1 to 3:1; 3:1 to 3.5:1; 3.5:1 to 4:1; 4.1 to 4.5:1; 4.5:1 to 5:1; 5:1 to 10:1; and 10:1 to 25:1, or a range of these. For example, the ratio of the second therapeutic agent to the compound of the present invention may be in the range of 1:1 to 5:1; 5:1 to 10:1; 10:1 to 15:1; or 15:1 to 25:1.

[0149] Aspects of this disclosure also include compositions having a pharmaceutically acceptable carrier and one or more of the compounds described above. A wide variety of pharmaceutically acceptable excipients are known in the art and do not need to be discussed in detail herein. Examples of pharmaceutically acceptable excipients are, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, & Wilkins;Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) HC Ansel et al., eds 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients This is well described in various publications, including (2000) AH Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc. For example, one or more excipients are used in Crowth, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate, binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, poly(ethylene glycol), sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., magnesium stearate) It may contain light anhydrous silicic acid, talc, or sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol).

[0150] The compound can be formulated into pharmaceutical compositions in combination with a suitable, pharmaceutically acceptable carrier or diluent, and can be formulated into preparations in the form of solids, semi-solids, liquids, or gases, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols. In certain embodiments, the conjugate compound is formulated for injection. For example, the composition of interest can be formulated for intravenous or intraperitoneal administration.

[0151] In certain embodiments, the composition of interest comprises a liposome or micelle composition in which the compound described herein is a liposome-based formulation or a micelle-based formulation. The liposome-based or micelle-based formulations of the compound of the present invention can be prepared by any convenient protocol for forming liposomes or micelles, such as mechanical dispersion, solvent dispersion, or detergent removal. In certain cases, liposomes are formed by mechanical dispersion, including sonication, French press cell extrusion, freeze-thaw, lipid film hydration (e.g., by manual shaking, mechanical agitation, or freeze-drying), microemulsification, membrane extrusion, or the use of dried and reconstituted vesicles. In certain embodiments, liposome-based formulations of the compounds described herein are prepared by rehydrating a thin film, followed by extrusion (e.g., extrusion through a filter larger than 5 nm, e.g., 10 nm or larger, e.g., 25 nm or larger, e.g., 50 nm or larger, e.g., 100 nm or larger, e.g., 150 nm or larger, e.g., 200 nm or larger, e.g., 250 nm or larger, e.g., 300 nm or larger, e.g., extrusion through a filter larger than 500 nm).

[0152] In some embodiments, liposome-based or micelle-based formulations may include, but are not limited to, sterols such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; C 12 ~C 24 Fatty acids, such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C 18 ~C 36Mono-, di-, and triacylglycerides, e.g., glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate, and mixtures thereof; sucrose fatty acid esters, e.g., sucrose distearate and sucrose palmitate; sorbitan fatty acid esters, e.g., sorbitan monostearate, sorbitan monopalmitate, and sorbitan tristearate; C 16 ~C 18 Aliphatic alcohols, e.g., cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of aliphatic alcohols and fatty acids, e.g., cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids, e.g., stearic acid anhydride; phospholipids, e.g., phosphatidylcholine (lecithin), phosphatidylserine, phosphoethanolamine, phosphoethanolamine-PEG(2000), phosphatidylethanolamine, phosphatidylinositol, and their lyso derivatives; sphingosine and its derivatives; sphingomyelins, e.g., stearyl, palmitoyl, and tricho The liposome formulation may be formed from nonpolymeric carrier materials comprising sanilsphingomyelin; ceramides, such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof. In certain embodiments, the liposome formulation compound comprises phosphatidylcholine and cholesterol.

[0153] Each component used to prepare a liposome or micelle formulation may vary as desired, and may be present in amounts of 0.001% by weight or more, e.g., 0.005% by weight or more, e.g., 0.010% by weight or more, e.g., 0.05% by weight or more, e.g., 0.1% by weight or more, e.g., 0.5% by weight or more, e.g., 1% by weight or more, e.g., 2% by weight or more, e.g., 3% by weight or more, e.g., 4% by weight or more, including cases where each component is present in an amount of 5% by weight or more. If there are more than one component (e.g., phospholipids, e.g., phosphatidylcholine and cholesterol), the ratio of the components may be in the range of 0.001:1 to 1:0.001, e.g., 0.005:1 to 1:0.005, e.g., 0.01:1 to 1:0.01, e.g., 0.05:1 to 1:0.05, e.g., 0.1:1 to 1:0.1, e.g., 0.5:1 to 1:0.5, e.g., 0.6:1 to 1:0.6, e.g., 0.7:1 to 1:0.7, e.g., 0.8:1 to 1:0.8, e.g., 0.9:1 to 1:0.9, and also include the case where the ratio of the components is 1:1 (e.g., the ratio of phosphatidylcholine to cholesterol is 1:1). In one example, a liposome or micelle formulation may contain phospholipid components (e.g., phosphatidylcholine) and cholesterol in ratios ranging from, for example, 0.001:1 to 1:0.001, 0.005:1 to 1:0.005, 0.01:1 to 1:0.01, 0.05:1 to 1:0.05, 0.1:1 to 1:0.1, 0.5:1 to 1:0.5, 0.6:1 to 1:0.6, 0.7:1 to 1:0.7, 0.8:1 to 1:0.8, 0.9:1 to 1:0.9, and a range including cases where the ratio of components is 1:1. In a particular case, the ratio of phospholipid components to cholesterol is approximately 2:1.

[0154] The compounds described herein (for example, compounds of formula DCD-(I) or DCD-(II)) may be present in liposomes or micelle formulations in an amount of 0.001% by weight or more of the formulation, for example, 0.005% by weight or more, for example, 0.010% by weight or more, for example, 0.05% by weight or more, for example, 0.1% by weight or more, for example, 0.5% by weight or more, for example, 1% by weight or more, for example, 2% by weight or more, for example, 3% by weight or more, for example, 4% by weight or more, including the presence of 5% by weight or more of the activating compound in an amount of 5% by weight or more of the formulation. The ratio of the activating compound (e.g., a compound for activating invariant natural killer T cells, e.g., a compound of formula DCD-(I) to DCD-(II)) to each liposome component may be in the range of 0.001:1 to 1:0.001, e.g., 0.005:1 to 1:0.005, e.g., 0.01:1 to 1:0.01, e.g., 0.05:1 to 1:0.05, e.g., 0.1:1 to 1:0.1, e.g., 0.5:1 to 1:0.5, e.g., 0.6:1 to 1:0.6, e.g., 0.7:1 to 1:0.7, e.g., 0.8:1 to 1:0.8, e.g., 0.9:1 to 1:0.9, and may include the case where the ratio of the components is 1:1. In certain cases, the ratio is 1:0.15 or 2:0.15. For example, the composition may contain phosphatidylcholine, cholesterol, and an activating compound in a ratio of 2:1:0.15.

[0155] In certain embodiments, the liposome or micelle formulation may contain organic solvents, e.g., sterols, e.g., cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters, e.g., cholesteryl stearate; C12-C24 fatty acids, e.g., lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C18-C36 mono-, di-, and triacylglycerides, e.g., glyceryl monooleate, monolino Glyceryl glycerate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters, e.g., sucrose distearate and sucrose palmitate; sorbitan fatty acid esters The organic solvent may include, for example, sorbitan monostearate, sorbitan monopalmitate, and sorbitan tristearate; C16-C18 aliphatic alcohols, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of aliphatic alcohols and fatty acids, for example, cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids, for example, stearic acid anhydride; phospholipids containing phosphatidylcholine (lecithin), phosphatidylserine, phosphoethanolamine, phosphoethanolamine-PEG(2000), phosphatidylethanolamine, phosphatidylinositol, and their lyso derivatives; sphingosine and its derivatives; sphingomyelin, for example, stearyl, palmitoyl, and tricosanylsphingomyelin; ceramides, for example, stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohol; and one or more organic solvents selected from combinations and mixtures thereof.

[0156] In pharmaceutical dosage forms, compounds may be administered in the form of their pharmaceutically acceptable salts, or used alone, in appropriate combinations, or in combination with other pharmaceutically active compounds. The following methods and excipients are merely illustrative and not limiting.

[0157] In some embodiments, the composition of interest comprises an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetates, succinates, citrates, and phosphate buffers of varying strengths from about 5 mM to about 100 mM. In some embodiments, the aqueous buffer comprises a reagent that provides an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars, such as mannitol, glucose, sucrose, etc. In some embodiments, the aqueous buffer further comprises a nonionic surfactant, such as polysorbate 20 or 80. In some cases, the composition of interest further comprises a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, and benzalkonium chloride. Often, the composition is stored at about 4°C. The formulation may also be lyophilized, in which case the formulation generally comprises an antifreeze agent, such as sucrose, trehalose, lactose, maltose, mannitol, etc. Lyophilized formulations can be stored for long periods, even at ambient temperature.

[0158] In some embodiments, the composition includes other additives, such as lactose, mannitol, corn starch, or potato starch, together with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatin; together with disintegrants, such as corn starch, potato starch, or sodium carboxymethylcellulose; together with lubricants, such as talc or magnesium stearate; and optionally, together with diluents, buffers, humectants, preservatives, and flavorings.

[0159] When a composition is formulated for injection, the compounds can be formulated by dissolving, suspending or emulsifying them in aqueous or non-aqueous solvents, such as plant or other similar oils, synthetic aliphatic acid glycerides, higher aliphatic acids or esters of propylene glycol, and, if desired, with conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

[0160] The dosage used for the treatment may vary depending on the clinical goal to be achieved, but the appropriate dosage range for a compound is from approximately 0.0001 mg to approximately 5000 mg, for example, doses that provide the activator from approximately 1 mg to approximately 25 mg, approximately 25 mg to approximately 50 mg, approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 200 mg, approximately 200 mg to approximately 250 mg, approximately 250 mg to approximately 500 mg, approximately 500 mg to approximately 1000 mg, or approximately 1000 mg to approximately 5000 mg, which can be administered as a single dose. Those skilled in the art will readily recognize that dose levels may vary as a function of the particular compound, the severity of the symptoms, and the subject's susceptibility to side effects.

[0161] In some embodiments, a single dose of the compound is administered. In other embodiments, multiple doses of the compound are administered. When multiple doses are administered over a period of time, the compound may be administered, for example, twice daily (qid), daily (qd), every other day (qod), every three days, three times a week (tiw), or twice a week (biw) over a period of time. For example, the compound may be administered qid, qd, qod, tiw, or biw over a period of time from one day to about two years or longer. For example, the compound may be administered at any of the above frequencies for one week, two weeks, one month, two months, six months, one year, or two years or longer, depending on various factors.

[0162] The dose units of this disclosure can be prepared using manufacturing methods available in the art and may be in various forms suitable for administration by injection (including topical, intracapsular, intrathecal, intravenous, intramuscular, subcutaneous, and cutaneous), such as solutions, suspensions, liquids, lyophilized products, or emulsions. The dose units may contain components conventional in pharmaceutical preparations, such as one or more carriers, binders, lubricants, excipients (e.g., to impart controlled-release characteristics), pH adjusters, colorants, or further activators.

[0163] The dose unit may contain components in any relative amount. For example, the dose unit may contain about 0.1% to 99% by weight of the active ingredient (i.e., the compound described herein) per total weight of the dose unit. In some embodiments, the dose unit may contain 10% to 50% by weight, 20% to 40% by weight, or about 30% by weight of the active ingredient per total weight of the dose unit.

[0164] The aspects of the subject matter described herein, including embodiments, may be useful individually or in combination with one or more other aspects or embodiments. Without limiting the scope of this description, certain non-limiting aspects of the present disclosure, numbered 1 to 99, are provided below. As will be apparent to those skilled in the art through reading this disclosure, each individually numbered aspect may also be used or combined with any aspect preceding or following the individually numbered aspect. This is intended to provide support for all such combinations of aspects, and is not limited to the combinations of aspects expressly provided below: 1. Compounds of formula DCD-(I): [ka] [In the formula, Z is [ka] Selected from, [ka] This shows a ZO bond, X is -NHCO- or oxygen, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. X1 and X2 are independently set to -C and -NR, respectively. j -O, -SR k Selected from -Si, R j and R k Each is independently selected from hydrogen, alkyl or substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R a It is selected from hydrogen, oxygen, fluorine, -CF3, or together with X2 to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, [ka] This indicates a double bond or a single bond. n is an integer between 2 and 25. Y is selected from carbon, nitrogen, or silicon. R b , Rc and R d is independently selected from hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, and when Y is nitrogen, R d It does not exist, or R c and R d Together with Y, it forms a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. R e [is an alkyl or substituted alkyl] or its salt, solvate, or hydrate. 2.R 1 , R 2 , R 3 and R 4 However, each of these compounds is hydrogen, as described in 1. 3.R 1 The compound described in 1, wherein the hydrogen atom is hydrogen. 4.R 1 but, [ka] And, [ka] However, R 1 -O bond is shown, R 8 However, these are hydrogen, alkyl, and substituted alkyl. R 9 However, -NR f OR f And R f However, it is alkyl, substituted alkyl, acyl, alkylacyl or substituted alkylacyl, or R f However, R 10Together, they form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. R 10 However, is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R 10 However, R f The compound according to any one of 1 to 3, which, together with the above, forms a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. 5.R 1 but, [ka] Selected from, [ka] However, R 1 -O bond is shown, R 8 However, these are hydrogen, alkyl, and substituted alkyl. R g The compound according to 4, wherein the compound is hydrogen, or a halogen selected from fluorine, chlorine, bromine, or iodine. 6.R 1 but, [ka] And, R 11 However, it is an alkyl or substituted alkyl, R12 The compound according to any one of 1 to 3, wherein R is alkyl or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl. 7.R 1 is

Chemical Structure

Chemical Structure

Chemical Structure

[0165] The following embodiments are proposed to provide a complete disclosure and description of how the present invention is generated and used, and are not intended to limit the scope of what the inventors consider to be their invention, nor are they intended to indicate that the following experiments are all or only those that have been conducted. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), some experimental errors and deviations are to be expected.

[0166] (Example 1) Compound Synthesis General synthesis procedure Many common references are available that provide generally known chemical synthesis schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, (See New York: Longman, 1978).

[0167] The compounds described herein can be purified by any chromatographic means known in the art, such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion-exchange chromatography. Any suitable stationary phase, including normal phase, reversed phase, and ionic resins, can be used. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. LR Snyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed. E. Stahl, Springer-Verlag, New York, 1969.

[0168] During any of the steps for preparing the compounds of this disclosure, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules involved. This is based on standard research, e.g., TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Fourth edition, Wiley, New York 2006. As described, this can be achieved by conventional protecting group means. The protecting group can be removed at a convenient subsequent step using methods known from the art.

[0169] The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Thus, all possible enantiomers and stereoisomers of the compounds, including pure forms as stereoisomers (e.g., geometrically pure, pure as an enantiomer, or pure as a diastereomer) and mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and stereoisomers can be separated into their constituent enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in several tautomer forms, including enol forms, keto forms, and mixtures thereof. Therefore, the chemical structures shown herein encompass all possible tautomer forms of the exemplified compounds. The compounds described also include isotopically labeled compounds in which one or more atoms have atomic weights different from those conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 Examples include O. Compounds can exist in solvated and non-solvated forms, including hydrated forms. Generally, compounds may be hydrated or solvated. Some compounds can exist in a number of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses envisioned herein and are intended to be within the scope of this disclosure.

[0170] The nomenclature used herein to name the compounds of the present invention is illustrated in the examples herein. Where possible, this nomenclature is generally derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0171] The compounds of this disclosure can be prepared by a variety of methods. This specification includes exemplary methods for preparing the compounds described herein.

[0172] Synthesis of (2S,3S,4R)-2-azidooctadecane-1,3,4-triol ChemBioChem 2012, 13, 1689-1697 and Eur. J. Org. Chem. 1998, 291-229 This will be mentioned. [ka]

[0173] A mixture of DCM (25 mL) containing NaN3 (10 g, 153 mmol) and H2O (25 mL), cooled to 0°C, and Tf2O (5.5 mL, 31.5 mmol) were added dropwise over 20 minutes. After addition, the resulting mixture was stirred at room temperature for 3 hours. The organic layer was separated, and the aqueous portion was extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated aqueous Na2CO3 and used directly in the next step.

[0174] The above organic DCM layer was added to a suspension of (2S,3S,4R)-2-aminooctadecane-1,3,4-triol (5 g, 15.5 mmol), K2CO3 (10.9 g, 79.0 mmol), and CuSO4 (100 mg) in a mixture of MeOH (30 mL) and H2O (30 mL). This organic DCM layer contained TfN3. Further MeOH was added to make the mixture a homogeneous solution. The reaction mixture was stirred overnight at room temperature. The organic solvent was removed under vacuum, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography (PE / ethyl acetate 1:1) to obtain (2S,3S,4R)-2-azidooctadecane-1,3,4-triol (4.5 g, 83%) as an oily substance.

[0175] Synthesis of (2S,3S,4R)-2-azide-1-(trityloxy)octadecane-3,4-diol [ka] A mixture of (2S,3S,4R)-2-azidooctadecane-1,3,4-triol (6.00 g, 17.5 mmol, 1.0 equivalent), TrtCl (6.8 g, 24.4 mmol, 1.4 equivalent), and DMAP (213 mg, 1.74 mmol, 0.1 equivalent) in dried pyridine (100 mL) was stirred overnight at 50°C. The pyridine was removed under reduced pressure, the residue was diluted with siRNA (200 mL), washed with water (2 × 50 mL) and brine (2 × 50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g; siRNA / PE1:2) to obtain (2S,3S,4R)-2-azido-1-(trityloxy)octadecane-3,4-diol (9 g, 88%) as an oily substance. Synthesis of (((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)methanetriyl)tribenzene [ka]

[0176] To a solution of (2S,3S,4R)-2-azido-1-(trityloxy)octadecane-3,4-diol (9.0 g, 15.4 mmol, 1.0 equivalent) in dry DMF (120 mL), a dispersion of 60% NaH in oil (2.2 g, 55.0 mmol, 3.5 equivalents) was gradually added at 0°C. After complete addition, the mixture was stirred at 0°C for 10 minutes. BnBr (9.2 g, 53.8 mmol, 3.5 equivalents) was added, and the mixture was warmed to room temperature and stirred for a further 5 hours. This was poured into ice / water (200 mL), diluted with siRNA (1 L), the organic layer was washed with water (4 × 200 mL) and brine (2 × 200 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (120 g; Â1:15) on silica gel to obtain (((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)methanetriyl)tribenzene (10 g, 85%) as an oily substance. LC / MS:C 51 H 63 Calculated mass value for N3O3: 765.49, measured value: 788.50 [M+Na] + . Synthesis of (2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecane-1-ol [ka]

[0177] (((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)methanetriyl)tribenzene (10 g, 13.1 mmol, 1.0 equivalent) was mixed in toluene (60 mL) and MeOH (60 mL) to which aqueous concentrated HCl (2 mL; 12 M) was added. The mixture was heated to 60 °C and stirred overnight. The pH of the aqueous phase was adjusted to approximately 7 using 1 M NaOH, and the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (120 g; HCl / PE: 1:10) to obtain (2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecane-1-ol (5 g, 73%) as an oily substance. LC / MS: C 32 H 49 Calculated mass value for N3O3: 523.38, measured value: 546.25 [M+Na] + . Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ylacetate [ka] A mixture of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol (25 g, 9.24 mmol), pyridine (60 mL), and Ac2O (120 mL) was stirred overnight at room temperature. The reaction mixture was quenched with crushed ice, and the resulting mixture was extracted with DCM (3 × 300 mL). The combined organic layer was concentrated under reduced pressure, and the crude residue was purified by column chromatography (PE / Â1:1) on silica gel to obtain (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl acetate (20 g, 74%) as an oily substance. Synthesis of (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodotetrahydro-2H-pyran [ka]

[0178] (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl acetate (20.0 g, 34.3 mmol, 1.0 equivalent) was mixed in DCM (150 mL) and TMSI (6.9 g, 34.5 mmol, 1.0 equivalent) at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 40 minutes, then benzene (50 mL) was added, and the mixture was concentrated under reduced pressure to obtain (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodotetrahydro-2H-pyran (19 g, 85%) as an oily substance.

[0179] Synthesis of (2S,3R,4S,5S,6R)-2-((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran [ka] A mixture of (2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecane-1-ol (3.0 g, 5.7 mmol, 1.0 equivalent), TBAI (19.0 g, 51.4 mmol, 9.0 equivalents), DIPEA (2.2 g, 17.0 mmol, 3.0 equivalents), and 4Å-MS (2 g) in benzene (80 mL) was stirred at 65°C for 20 minutes under an atmosphere of N2. To this mixture, a solution of (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodotetrahydro-2H-pyran (18.6 g, 17.2 mmol, 3.0 equivalents) in benzene (30 mL) was added. The mixture was stirred at 65°C for a further 2 hours, cooled to room temperature, and toluene (150 mL) was added. The mixture was filtered, and the filtrate was washed with saturated sodium thiosulfate solution (2 × 80 mL) and brine (2 × 80 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (120 g; toluene / PE₁:5) to obtain (2S,3R,4S,5S,6R)-2-((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran (3 g, 50%) as an oily substance. LC / MS:C 66 H 83 Calculated mass for N3O8: 1045.62, measured mass: 1068.60 [M+Na] + .

[0180] Synthesis of (2S,3S,4R)-3,4-bis(benzyloxy)-1-((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yloxy)octadecane-2-amine [ka] A mixture of (2S,3R,4S,5S,6R)-2-((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran (3.0 g, 2.9 mmol, 1.0 equivalent) in THF (30 mL) was mixed with 1 M PMe3 (3.2 mL, 3.2 mmol, 1.1 equivalent) in THF at room temperature. The mixture was stirred at room temperature for 5 hours, then H2O (10 mL) was added, the mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH / DCM1:20) on silica gel to obtain (2S,3S,4R)-3,4-bis(benzyloxy)-1-((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yloxy)octadecane-2-amine (2g, 68%) as an oily substance. LC / MS:C 66 H 85 Calculated mass for NO8: 1019.63, measured mass: 1020.60 [M+H] + . Synthesis of (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka]

[0181] (2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-amine (200 mg, 0.2 mmol, 1.0 equivalent) was mixed in EtOH (10 mL) and DCM (3 mL) with 20% Pd(OH)2 / C (0.2 g). The mixture was hydrogenated at room temperature for 16 hours (1 atm), and the catalyst was then removed by filtration through a Celite pad, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (75 mg, 80%) as an oily substance.

[0182] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide Synthesis of 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde [ka] To a mixture of oxalyl chloride (164 mg, 1.29 mmol, 1.5 equivalents) in DCM (5 mL), DMSO (202 mg, 2.58 mmol, 3.0 equivalents) was added dropwise at -78°C under an N2 atmosphere. The mixture was stirred at -78°C for 15 minutes, and then (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (100 mg, 0.86 mmol, 1.0 equivalent) was added dropwise in DCM (1 mL). The mixture was stirred at -78°C for 50 minutes, and then Et3N (1 mL) was added. Stirring was continued for a further 5 minutes at -78°C, and then the mixture was warmed to room temperature. H2O (10 mL) was added, and the mixture was extracted with DCM (3 × 20 mL). The combined organic layer was washed with H2O (20 mL) and brine (20 mL), then dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde (70 mg, 71%) as an oily substance. The compound was used without further purification. f = 0.3, PE / .'' 1:3. Synthesis of (10-carboxydecyl)triphenylphosphonium bromide

[0183] To a mixture of 11-bromoundecanoic acid (3.0 g, 11.3 mmol, 1.0 equivalent) in CH3CN (100 mL), PPh3 (3.0 g, 11.31 mmol, 1.0 equivalent) was added under an N2 atmosphere. The mixture was heated to 90°C, stirred for 72 hours, and then concentrated under reduced pressure. The crude product crystallized from siRNA yielded (10-carboxydecyl)triphenylphosphonium bromide (5.8 g, 97%) as a solid. LC / MS:C 29 H 36 Calculated mass relative to BrO2P: 526, measured mass: 447 [M-Br] + . Synthesis of (E)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undeca-10-enoic acid [ka]

[0184] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (315 mg, 0.61 mmol, 1.0 equivalent) in THF (5 mL), NaHMDS in 2 M THF (0.61 mL, 1.22 mmol, 2 equivalents) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde (70 mg, 0.61 mmol, 1.0 equivalent) in THF (1 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O (10 mL) was added, and the pH was adjusted to 4-5 with 2N HCl. The mixture was extracted with ELISA (20 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on a silica gel column to obtain (E)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undeca-10-enoic acid (120 mg, 73%) as a solid. LC / MS:C 16 H 25 Calculated mass for FO2: 268, measured mass: 267 [MH] - . Synthesis of 11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanoic acid [ka]

[0185] A mixture of (E)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanoic acid (60 mg, 0.22 mmol, 1.0 equivalent) and PtO2 (5 mg, 0.022 mmol, 0.1 equivalent) in EtOH (50 mL) was hydrogenated at room temperature for 1 hour (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was rinsed with EtOH. The filtrate was concentrated under reduced pressure to obtain 11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanoic acid (55 mg, 91%) as a solid. LC / MS:C 16 H 27 Calculated mass for FO2: 270, measured mass: 269 [MH] - .

[0186] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide [ka] To a mixture of 11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanoic acid (55 mg, 0.20 mmol) and (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (98 mg, 0.20 mmol, 1.0 equivalent) in THF (5 mL), HBTU (154 mg, 0.41 mmol, 2.0 equivalents), Et3N (41 mg, 0.41 mmol, 2.0 equivalents), and NMM (41 mg, 0.41 mmol, 2.0 equivalents) were added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH9:1) and preparative HPLC on silica to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanamide (12.5 mg, 8%) as a solid. LC / MS:C 40 H 74 Calculated mass for FNO9: 731.53, measured mass: 732.45 [M+H] + ; 1 H NMR (300 MHz, MeOH-d4) δ 4.21 (d, J = 6.0 Hz, 1H), 3.81-3.89 (m, 3H), 3.76-3.79 (m, 2H), 3.68-3.74 (m, 3H), 3.62-3.65 (m, 1H), 3.53-3.59 (m, 1H), 2.24 (t, J = 7.5 Hz, 2H), 1.88 (d, J = 2.7 Hz, 6H), 1.57-1.66 (m, 6H), 1.29-1.34 (m, 39H), 0.92 (t, J = 6.7 Hz, 3H); 19 F NMR (282 MHz, MeOH-d4) δ -146.5.

[0187] Synthesis of (10-carboxydecyl)triphenylphosphonium bromide [ka] To a mixture of 11-bromoundecanoic acid (3.0 g, 11.3 mmol, 1.0 equivalent) in CH3CN (100 mL), PPh3 (3.0 g, 11.31 mmol, 1.0 equivalent) was added under an N2 atmosphere. The mixture was heated to 90°C, stirred for 72 hours, and then concentrated under reduced pressure. The crude product crystallized from siRNA yielded (10-carboxydecyl)triphenylphosphonium bromide (5.8 g, 97%) as a solid. LC / MS:C 29 H 36 Calculated mass relative to BrO2P: 526, measured mass: 447 [M-Br] + .

[0188] Synthesis of (E)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodeca-11-enoic acid [ka] To a mixture of (10-carboxydecyl)triphenylphosphonium bromide (0.4 g, 0.76 mmol, 1.0 equivalent) in THF (10 mL), 2 M NaHMDS in THF (0.8 mL, 1.6 mmol, 2.1 equivalents) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde (87 mg, 0.76 mmol, 1.0 equivalent) in THF (1 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O (10 mL) was added, and the pH was adjusted to 4-5 with 2N HCl. The mixture was extracted with siRNA (30 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â1:1) on silica gel to obtain (E)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodeca-11-enoic acid (0.11 g, 51%) as a solid. LC / MS:C 17 H 27 Calculated mass for FO2: 282, measured mass: 281 [MH] - .

[0189] Synthesis of 12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanoic acid [ka] A mixture of (E)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanoic acid (0.11 g, 0.39 mmol, 1.0 equivalent) and PtO2 (10 mg, 0.04 mmol, 0.1 equivalent) in EtOH (70 mL) was hydrogenated at room temperature for 1 hour (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to obtain 12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanoic acid (0.1 g, 90%) as a solid. LC / MS:C 17 H 29 Calculated mass for FO2: 284, measured mass: 283 [MH] - .

[0190] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecaneamide [ka] To a mixture of 12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanoic acid (0.1 g, 0.35 mmol, 1.0 equivalent) and (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-bis(benzyloxy)octadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (232 mg, 0.35 mmol, 1.0 equivalent) in THF (6 mL), HBTU (267 mg, 0.70 mmol, 2.0 equivalent), Et3N (71 mg, 0.70 mmol, 2.0 equivalent), and NMM (71 mg, 0.70 mmol, 2.0 equivalent) were added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH8:1) on a silica gel column and preparative HPLC to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanamide (15.7 mg, 6%) as a solid. LC / MS:C 41 H 76 Calculated mass for FNO9: 745.55, measured mass: 746.45 [M+H] + ; 1 1H NMR (300 MHz, MeOH-d4) δ 4.17 (t, J = 5.5 Hz, 1H), 3.81-3.89 (m, 3H), 3.74-3.77 (m, 2H), 3.66-3.72 (m, 3H), 3.59-3.63 (m, 1H), 3.52-3.57 (m, 1H), 2.22 (t, J = 7.4 Hz, 2H), 1.86 (d, J = 2.7 Hz, 6H), 1.56-1.65 (m, 6H), 1.27-1.35 (m, 41H), 0.95-0.85 (m, 3H); 19 F NMR (282 MHz, MeOH-d4) δ -146.5.

[0191] Synthesis of 11-(bicyclo[2.2.2]octan-1-yl)-N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide Synthesis of (E)-11-(bicyclo[2.2.2]octan-1-yl)undeca-10-enoic acid [ka] To a mixture of 9-carboxynonyl(triphenyl)phosphonium bromide (371 mg, 0.72 mmol, 1.0 equivalent) in THF (5 mL), 2 M NaHMDS in THF (0.72 mL, 1.44 mmol, 2 equivalents) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then bicyclo[2.2.2]octane-1-carboaldehyde (0.1 g, 0.72 mmol, 1.0 equivalent) in THF (1 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O was added, and the pH was adjusted to approximately 4-5 with 2N HCl. The mixture was extracted with siRNA (30 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on silica gel to obtain (E)-11-(bicyclo[2.2.2]octan-1-yl)undeca-10-enoic acid (0.15 g, 71%) as a solid. LC / MS:C 19 H 32 Calculated mass relative to O2: 292, measured value: 291 [MH] - .

[0192] Synthesis of 11-(bicyclo[2.2.2]octan-1-yl)undecanoic acid [ka] A mixture of (E)-11-(bicyclo[2.2.2]octan-1-yl)undecanoic acid (0.15 g, 0.51 mmol, 1.0 equivalent) and 10% Pd / C (20 mg) in MeOH (10 mL) was hydrogenated at room temperature for 1 hour (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain 11-(bicyclo[2.2.2]octan-1-yl)undecanoic acid (130 mg, 86%) as a solid. LC / MS: C 19 H 34 Calculated mass value for O2: 294, measured value: 293 [MH] - .

[0193] Synthesis of 11-(bicyclo[2.2.2]octan-1-yl)-N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide [ka] To a mixture of 11-(bicyclo[2.2.2]octan-1-yl)undecanoic acid (130 mg, 0.44 mmol, 1.0 equivalent) and (2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-amine (450 mg, 0.44 mmol, 1.0 equivalent) in DCM (5 mL), EDCI (127 mg, 0.66 mmol, 1.5 equivalents) and DMAP (11 mg, 0.09 mmol, 0.2 equivalents) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ELISA (10 mL) and washed with brine (5 mL). The aqueous layer was extracted with ELISA (10 mL x 2), the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / ELISA 3:1) on silica gel to obtain 11-(bicyclo[2.2.2]octan-1-yl)-N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide (0.2 g, 35%) as a solid. LC / MS:C 85 H 117 Calculated mass of NO9: 1296, measured mass: 1297 [M+H] + .

[0194] Synthesis of 11-(bicyclo[2.2.2]octane-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide [ka] A mixture of 11-(bicyclo[2.2.2]octan-1-yl)-N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide (0.1 g, 0.08 mmol, 1.0 equivalent) and 20% Pd(OH)2 / C (0.2 g) in EtOH / DCM (10 mL / 3 mL) was hydrogenated at room temperature for 16 hours (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, and the crude residue was purified by column chromatography (chromatography) on a silica gel column (DCM / MeOH) and preparative HPLC. The compound obtained was 11-(bicyclo[2.2.2]octan-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide (8.9 mg, 15%). LC / MS:C 43 H 81 Calculated mass for NO9: 755.59, measured mass: 756.50 [M+H] + ; 1 H NMR (300 MHz, CDCl3+ MeOH-d4) δ 4.88 (d, J = 3.7 Hz, 1H), 4.18 (d, J = 5.0 Hz, 1H), 3.67-3.89 (m, 8H), 3.53-3.59 (m, 2H), 2.20 (t, J = 7.7 Hz, 2H),1.49-1.62 (m, 12 H), 1.12-1.30 (m, 43H), 0.93-0.99 (m, 2H), 0.87 (t, J = 6.4 Hz, 3H).

[0195] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(2-methylcyclopropyl)undecaneamide Synthesis of (E)-11-(2-methylcyclopropyl)undeca-10-enoic acid [ka] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (488 mg, 0.95 mmol, 1.0 equivalent) in THF (5 mL), 2M NaHMDS in THF (1.0 mL, 2.0 mmol, 2.0 equivalent) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then 2-methylcyclopropane-1-carboaldehyde (80 mg, 0.95 mmol, 1.0 equivalent) in THF (1 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O (10 mL) was added, and the pH was adjusted to approximately 4-5 with 2N HCl. The mixture was extracted with siRNA (30 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on silica gel to obtain (E)-11-(2-methylcyclopropyl)undeca-10-enoic acid (120 mg, 53%) as a solid. LC / MS:C 15 H 26 Calculated mass relative to O2: 238, measured value: 237 [MH] - .

[0196] Synthesis of 11-(2-methylcyclopropyl)undecanoic acid [ka] (E)-11-(2-methylcyclopropyl)undecanoic acid (120 mg, 0.50 mmol, 1.0 equivalent) was mixed in THF (5 mL) and H2O (5 mL) at room temperature with p-MeC6H4SO2NHNH2 (938 mg, 5.0 mmol, 10 equivalents) and KOAc (642 mg, 6.6 mmol, 13 equivalents). The mixture was heated under reflux, stirred for 5 hours, cooled, and H2O was added. The mixture was extracted with  (30 mL × 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â) on a silica gel column to obtain 11-(2-methylcyclopropyl)undecanoic acid (90 mg, 74%) as an oily substance. LC / MS:C 15 H 28 Calculated mass value for O2: 240, measured value: 239 [MH] - .

[0197] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(2-methylcyclopropyl)undecaneamide [ka] To a mixture of 11-(2-methylcyclopropyl)undecanoic acid (80 mg, 0.33 mmol, 1.0 equivalent) and (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (160 mg, 0.33 mmol, 1.0 equivalent) in THF (6 mL), HBTU (252 mg, 0.66 mmol, 2.0 equivalent), Et3N (67 mg, 0.66 mmol, 2.0 equivalent), and NMM (67 mg, 0.66 mmol, 2.0 equivalent) were added at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH8:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(2-methylcyclopropyl)undecanamide (20.7 mg, 9%) as a solid. LC / MS:C 39 H 75 NO9: Calculated mass value for 701.54, measured value: 702.45 [M+H] + ; 1 1H NMR (300 MHz, MeOH-d4) δ 4.18 (dd, J = 6.5, 4.4 Hz, 1H), 3.80-3.89 (m, 3H), 3.74-3.78 (m, 2H), 3.66-3.72 (m, 3H), 3.60-3.64 (m, 1H), 3.52-3.57 (m, 1H), 2.22 (t, J = 7.5 Hz, 2H), 1.50-1.67 (m, 4H), 1.24-1.38 (m, 41H), 1.15-1.23 (m, 2H), 0.99-1.02 (m, 3H), 0.95-0.85 (m, 3H), 0.29-0.44 (m, 1H), 0.09-0.18 (m, 1H).

[0198] Synthesis of 11-(kuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide Synthesis of (E)-11-(kuban-1-yl)undeca-10-enoic acid [ka] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (0.4 g, 0.8 mmol, 1.0 equivalent) in THF (6 mL), 2 M NaHMDS in THF (0.8 mL, 1.6 mmol, 2.0 equivalent) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then cubane-1-carbaldehyde (0.1 g, 0.8 mmol, 1.0 equivalent) in THF (1 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O (10 mL) was added, and the pH was adjusted to approximately 4-5 with 2N HCl. The mixture was extracted with siRNA (20 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on a silica gel column to obtain (E)-11-(cuban-1-yl)undeca-10-enoic acid (0.11 g, 49%) as a solid. LC / MS:C 19 H 26 Calculated mass relative to O2: 286, measured value: 285 [MH] - .

[0199] Synthesis of 11-(cuban-1-yl)undecanoic acid [ka] A mixture of (E)-11-(cuban-1-yl)undecanoic acid (0.1 g, 0.4 mmol, 1.0 equivalent) and PtO2 (8 mg, 0.04 mmol, 0.1 equivalent) in EtOH (10 mL) was hydrogenated at room temperature for 1 hour (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to obtain 11-(cuban-1-yl)undecanoic acid (80 mg, 79%) as a solid. LC / MS:C 19 H 28 Calculated mass relative to O2: 288, measured value: 287 [MH] - .

[0200] Synthesis of 11-(kuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide [ka] To a mixture of 11-(cuban-1-yl)undecanoic acid (80 mg, 0.3 mmol, 1.0 equivalent) and (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (130 mg, 0.3 mmol, equivalent) in THF (6 mL), HBTU (210 mg, 0.55 mmol, 2.0 equivalent), Et3N (56 mg, 0.55 mmol, 2.0 equivalent), and NMM (56 mg, 0.55 mmol, 2.0 equivalent) were added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) and preparative HPLC on silica gel to obtain 11-(cuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide as a solid. LC / MS:C 43 H 75 Calculated mass for NO9: 749.54, measured mass: 750.60 [M+H] + .

[0201] Synthesis of 12-(kuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecanamide Synthesis of (E)-12-(kuban-1-yl)dodeca-11-enoic acid [ka] To a mixture of (10-carboxydecyl)triphenylphosphonium bromide (319 mg, 0.6 mmol, 1.0 equivalent) in THF (6 mL), 2 M NaHMDS in THF (0.6 mL, 1.2 mmol, 2.0 equivalent) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour, and then cubane-1-carbaldehyde (80 mg, 0.6 mmol, 1.0 equivalent) in THF (1 mL) was added. The mixture was warmed to room temperature and stirred for 16 hours, and then H2O (10 mL) was added, and the pH was adjusted to approximately 4-5 with 2N HCl. The mixture was extracted with siRNA (20 mL x 3), and the combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on silica to obtain (E)-12-(cuban-1-yl)dodeca-11-enoic acid (110 mg, 60%) as a solid. LC / MS:C 20 H 28 Calculated mass value for O2: 300, measured value: 299 [MH] - .

[0202] Synthesis of 12-(cuban-1-yl)dodecanoic acid [ka] A mixture of (E)-12-(cuban-1-yl)dodecanoic acid (110 mg, 0.37 mmol, 1.0 equivalent) and PtO2 (8 mg, 0.04 mmol, 0.1 equivalent) in EtOH (70 mL) was hydrogenated at room temperature for 1 hour (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to obtain 12-(cuban-1-yl)dodecanoic acid (0.1 g, 90%) as a solid. LC / MS:C 20 H 30 Calculated mass value for O2: 302, measured value: 301 [MH] - .

[0203] Synthesis of 12-(kuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecanamide [ka] To a mixture of 12-(cuban-1-yl)dodecanoic acid (80 mg, 0.26 mmol, 1.0 equivalent) and (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-bis(benzyloxy)octadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (175 mg, 0.26 mmol, 1.0 equivalent) in THF (6 mL), HBTU (201 mg, 0.53 mmol, 2.0 equivalent), TEA (53 mg, 0.53 mmol, 2.0 equivalent), and NMM (53 mg, 0.53 mmol, 2.0 equivalent) were added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) and preparative HPLC on silica gel to obtain 12-(cuban-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecanamide (8.6 mg, 4%) as a solid. LC / MS:C 44 H 77 Calculated mass for NO9: 763.56, measured mass: 764.60 [M+H] + ; 1 1H NMR (300 MHz, MeOH-d4) δ 4.86-4.89 (m, 1H), 4.14-4.20 (m, 1H), 4.02-4.08 (m, 1H), 3.80-3.88 (m, 6H), 3.68-3.77 (m, 7H), 3.50-3.65 (m, 3H), 2.22 (t, J = 7.5 Hz, 2H), 1.48-1.62 (m, 6H), 1.27-1.35 (m, 40H), 0.95-0.85 (m, 3H).

[0204] Synthesis of (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(5-(diheptylamino)pentyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol Synthesis of N,N-diheptylhepta-6-in-1-amine [ka] To a mixture of hepta-6-inal (0.7 g, 6.4 mmol, 1.0 equivalent) in DCE (10 mL), diheptylamine (1.3 g, 6.4 mmol, 1.0 equivalent) was added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 15 minutes, then NaBH(OAc)3 (2.0 g, 9.5 mmol, 1.5 equivalent) and AcOH (0.1 mL) were added. The mixture was stirred at room temperature for 3 hours, then H2O (10 mL) was added, and the mixture was extracted with RINKAN (30 mL × 3). The combined organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH / DCM1:8) on a silica gel column to obtain N,N-diheptylhepta-6-in-1-amine (0.7 g, 36%) as an oily substance. LC / MS:C 21 H 41 Calculated mass value for N: 307, measured value: 308 [M+H] + .

[0205] Synthesis of N-(5-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)pentyl)-N-heptylheptan-1-amine [ka] N,N-diheptylhepta-6-in-1-amine (38 mg, 0.12 mmol, 1.3 equivalents) and (2S,3R,4S,5S,6R)-2-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (0.1 g, 0.1 mmol, 1.0 equivalent) t To a mixture in BuOH (3 mL) and H2O (3 mL), CuSO4 (5 mg, 0.03 mmol, 0.3 equivalents) and sodium ascorbate (6 mg, 0.03 mmol, 0.3 equivalents) were added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours, then diluted with HCl (10 mL), washed with brine (5 mL), and the aqueous layer was extracted with HCl (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / siRNA3:1) on silica gel to obtain N-(5-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)pentyl)-N-heptylheptan-1-amine (0.1g, 77%) as an oily substance. LC / MS:C 87 H 124 Calculated mass of N4O8: 1353, measured mass: 1354 [M+H] + .

[0206] Synthesis of (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(5-(diheptylamino)pentyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] A mixture of N-(5-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)pentyl)-N-heptylheptan-1-amine (0.1 g, 0.07 mmol, 1.0 equivalent) in EtOH (10 mL) and DCM (3 mL), and 20% Pd(OH)2 / C (0.2 g) were hydrogenated at room temperature for 16 hours (1 atm). The catalyst was removed by filtration through a Celite pad and washed with filter cake EtOH / DCM (3:1). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH8:1) and preparative HPLC on silica gel to obtain (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(5-(diheptylamino)pentyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (16.2 mg, 35%) as a solid. LC / MS:C 45 H 88 Calculated mass for N4O8: 812.66, measured mass: 813.70 [M+H] + ; 1 1H NMR (300 MHz, DMSO-d6) + D2O) δ 7.86 (s, 1H), 4.90-4.96 (m, 1H), 4.63 (d, J = 3.7 Hz, 1H), 4.01-4.06 (m, 1H), 3.87-3.92 (m, 1H), 3.47-3.63 (m, 2H), 3.35-3.45 (m, 2H), 3.10-3.18 (m, 1H), 2.93-2.99 (m, 6H), 2.55-2.60 (m, 2H), 1.50-1.58 (m, 9H), 1.15-1.26 (m, 46H), 0.76-0.83 (m, 9H).

[0207] Synthesis of (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(6-(diheptylamino)hexyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol Synthesis of N,N-diheptylocta-7-in-1-amine [ka] To a mixture of octa-7-inal (0.7 g, 5.6 mmol, 1.0 equivalent) in DCE (10 mL), diheptylamine (1.2 g, 5.6 mmol, 1.0 equivalent) was added at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 15 minutes, then NaBH(OAc)3 (1.8 g, 8.5 mmol, 1.5 equivalent) and AcOH (0.1 mL) were added. The mixture was stirred at room temperature for 3 hours, then H2O (10 mL) was added, and the mixture was extracted with RINKAN (30 mL × 3). The combined organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH / DCM1:8) on silica gel to obtain N,N-diheptylocta-7-in-1-amine (0.6 g, 33%) as an oily substance. LC / MS:C 22 H 43 Calculated mass value for N: 321, measured value: 322 [M+H] + .

[0208] Synthesis of N-(6-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)hexyl)-N-heptylheptan-1-amine [ka] N,N-diheptylocta-7-in-1-amine (40 mg, 0.12 mmol, 1.0 equivalent) and (2S,3R,4S,5S,6R)-2-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (130 mg, 0.12 mmol, 1.0 equivalent) t To a mixture in BuOH (3 mL) and H2O (3 mL), CuSO4 (6 mg, 0.04 mmol, 0.3 equivalents) and sodium ascorbate (7 mg, 0.04 mmol, 0.3 equivalents) were added at room temperature. The mixture was stirred at room temperature for 1 day, then diluted with HCl (10 mL), washed with brine, and the aqueous layer was extracted with HCl (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â3:1) on silica gel to obtain N-(6-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)hexyl)-N-heptylheptan-1-amine (0.1g, 59%) as an oily substance. LC / MS:C 88 H 126 Calculated mass for N4O8: 1367, measured mass: 1368 [M+H] + .

[0209] Synthesis of (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(6-(diheptylamino)hexyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] A mixture of N-(6-(1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-1H-1,2,3-triazole-4-yl)hexyl)-N-heptylheptan-1-amine (0.1 g, 0.07 mmol, 1.0 equivalent) in EtOH (10 mL) and DCM (3 mL), and 20% Pd(OH)2 / C (0.2 g) were hydrogenated at room temperature for 16 hours (1 atm). The catalyst was removed by filtration through a Celite pad, and the filter cake was washed with EtOH / CH2Cl2 (3:1). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH) and preparative HPLC on silica gel to obtain (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-(4-(6-(diheptylamino)hexyl)-1H-1,2,3-triazole-1-yl)-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (11.1 mg, 18%) as a solid. LC / MS:C 46 H 90 Calculated mass for N4O8: 826.68, measured mass: 827.95 [M+H] + .; 1 H NMR (300 MHz, DMSO-d6+ D2O) δ 7.83 (s, 1H), 4.88-4.94 (m, 1H), 4.63 (d, J = 3.8 Hz, 1H), 3.97-4.12 (m, 1H), 3.86-3.93 (m, 1H), 3.34-3.53 (m, 5H), 3.08-3.14 (m, 1H), 2.93-3.00 (m, 6H), 2.54-2.60 (m, 2H), 1.43-1.59 (m, 10H), 1.18-1.27 (m, 46H), 0.80-0.85 (m, 9H).

[0210] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecane-1-sulfinamide - a mixture of two diastereomers [ka] Synthesis of S-dodecylethanethioate Potassium ethanethioate (274 mg, 2.4 mmol) was added to a mixture of 1-bromododecane (0.5 g, 2.0 mmol) in THF (10 mL) at room temperature. The mixture was heated to 80°C, stirred for 3 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (PE / siRNA) on silica gel to obtain S-dodecylethanethioate (382 mg, 78%) as an oily substance.

[0211] Synthesis of dodecane-1-sulfine chloride To a mixture of S-dodecylethanethioate (0.3 g, 1.2 mmol) in DCM (5 mL), Ac2O (126 mg, 1.2 mmol) and SO2Cl2 (332 mg, 2.5 mmol) were slowly added at -20°C. The mixture was warmed to -5°C, stirred for 2 hours, and then concentrated under reduced pressure to obtain dodecane-1-sulfin chloride (295 mg, 95%) as an oily substance.

[0212] N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecane-1-sulfinamide - Synthesis of a mixture of two diastereomers (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (60 mg, 0.13 mmol) in DMA (3 mL) was mixed with Et3N (25 mg, 0.25 mmol) and dodecane-1-sulfin chloride (47 mg, 0.19 mmol) at room temperature under an N2 atmosphere. The mixture was stirred at room temperature for 3 hours, then H2O was added, and the mixture was extracted with ELISA (3 × 30 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified twice by column chromatography (DCM / MeOH9:1) on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)dodecane-1-sulfinamide (3.4 mg, 3.9%) as a solid. LC / MS:C 36 H 73 Calculated mass of NO9S: 695.50, measured mass: 696.55 [M+H] + .

[0213] N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide - Synthesis of a mixture of two diastereomers [ka] Synthesis of 9-(bromotriphenyl-lambda5-phosphanyl)nonanoic acid A mixture of 9-bromononanoic acid (5.0 g, 21.1 mmol) and Ph3P (5.53 g, 21.1 mmol) in MeCN (50 mL) was heated under reflux and stirred for 3 days. The mixture was concentrated under reduced pressure, the residue was ground with mixture Et2O (200 mL), filtered, and 9-(bromotriphenyl-lambda5-phosphanyl)nonanoic acid (10.0 g, 95%) was obtained as a solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.42-8.28 (m, 15H), 2.17 (t, J = 7.3 Hz, 2H), 1.76 (td, J = 6.6, 5.8, 2.5 Hz, 2H), 1.39-1.56 (m, 6H), 1.14-1.29 (m, 6H).

[0214] Synthesis of (9E)-10-[3-fluorobicyclo[1.1.1]pentan-1-yl]deca-9enoic acid To a mixture of 9-(bromotriphenyl-lambda-5-phosphanyl)nonanoic acid (2.95 g, 5.9 mmol) in THF (50 mL), 2 M NaHMDS (5.9 mL, 11.8 mmol) was added at -10°C under an N2 atmosphere. The mixture was warmed to room temperature and stirred at room temperature for 1 hour, then the mixture of 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde (450 mg, 3.9 mmol) in THF (5 mL) was added. The mixture was stirred overnight at room temperature, then 2 M HCl (20 mL) was added, and the mixture was extracted with  (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / Â1:1) on silica gel to obtain (9E)-10-[3-fluorobicyclo[1.1.1]pentan-1-yl]deca-9-enoic acid (500 mg, 50%) as an oily substance. LC / MS:C 15 H 23 Calculated mass for FO2: 254.2, measured mass: 253.9 [MH] - .

[0215] Synthesis of 10-[3-fluorobicyclo[1.1.1]pentan-1-yl]decanoic acid (9E)-10-[3-fluorobicyclo[1.1.1]pentan-1-yl]decanoic acid (500 mg, 1.96 mmol) and PtO2 (50 mg, 0.22 mmol) were mixed in EtOH (300 mL) and stirred under an H2 atmosphere (balloon) for 2 hours. The mixture was filtered, the filter cake was washed with EtOH (100 mL), and the filtrate was concentrated under reduced pressure to obtain 10-[3-fluorobicyclo[1.1.1]pentan-1-yl]decanoic acid as a solid (500 mg, 99%). LC / MS:C 15 H 25 Calculated mass for FO2: 256.2, measured mass: 255.0 [MH] - . Synthesis of 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-ol

[0216] To a mixture of 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decanoic acid (500 mg, 1.95 mmol) in THF (20 mL), 1 M BH3 (5.9 mL, 5.9 mmol) was added dropwise under an N2 atmosphere. The mixture was stirred at room temperature for 2 hours, then quenched with MeOH (20 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (PE / Â3:1) on silica to obtain 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-ol (430 mg, 91%) as an oily substance. 1 H NMR (300 MHz, DMSO-d6) δ 4.32 (t, J = 5.2 Hz, 1H), 3.37 (td, J = 6.5, 5.1 Hz, 2H), 1.88 (d, J = 2.7 Hz, 6H), 1.60 (d, J = 7.8 Hz, 2H), 1.40 (t, J = 6.5 Hz, 2H), 1.25 (s, 12H). Synthesis of 1-(10-bromodecyl)-3-fluorobicyclo[1.1.1]pentane

[0217] To a mixture of 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-ol (430 mg, 1.77 mmol) in DCM (30 mL), Ph3P (930 mg, 3.54 mmol) and CBr4 (1.18 g, 3.54 mmol) were added under an N2 atmosphere. The mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the residue was purified by column chromatography (PE / Â10:1) on silica gel to obtain 1-(10-bromodecyl)-3-fluorobicyclo[1.1.1]pentane (480 mg, 89%) as an oily substance. 1 H NMR (400 MHz, DMSO-d6) δ 3.53 (t, J = 6.7 Hz, 2H), 1.88 (d, J = 2.8 Hz, 6H), 1.79 (d, J = 6.8 Hz, 2H), 1.59 (t, J = 7.0 Hz, 2H), 1.33-1.41 (m, 2H), 1.26 (d, J = 1.7 Hz, 12H). Synthesis of 1-[(10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decyl)sulfanyl]ethanone

[0218] A mixture of 1-(10-bromodecyl)-3-fluorobicyclo[1.1.1]pentane (480 mg, 1.57 mmol) and 1-(potassiosulfanyl)ethanone (359 mg, 3.14 mmol) in THF (20 mL) was heated to 60°C, stirred for 4 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â10:1) on silica gel to obtain 1-[(10-{3-fluorobicyclo[1.1.1]pentane-1-yl}decyl)sulfanyl]ethanone (450 mg, 95%) as an oily substance. 1 H NMR (300 MHz, CDCl3) δ 2.88 (t, J = 7.3 Hz, 2H), 2.35 (s, 3H), 1.90 (d, J = 2.7 Hz, 6H), 1.50-1.67 (m, 4H), 1.28 (d, J = 2.7 Hz, 14H). Synthesis of 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-sulfinyl chloride

[0219] A mixture of 1-[(10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decyl)sulfanyl]ethanone (50 mg, 0.17 mmol) in DCM (0.5 mL) was mixed with Ac2O (17 mg, 0.17 mmol) and SO2Cl2 (45 mg, 0.33 mmol) at -20°C under an atmosphere of N2. The mixture was stirred at -20°C for 10 minutes and then concentrated under reduced pressure to obtain 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-sulfinyl chloride (50 mg, 97%) as an oily substance.

[0220] N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide - Synthesis of a mixture of two diastereomers (2S,3R,4S,5R,6R)-2-{[(2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl]oxy}-6-(hydroxymethyl)oxan-3,4,5-triol (50 mg, 0.10 mmol) in DMA (3 mL) and DCM (1 mL) was mixed with Et3N (106 mg, 1.0 mmol) and 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-sulfinyl chloride (50 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a solid mixture of two diastereomers of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide (5.1 mg, 7%). LC / MS: 39 H 74 Calculated mass for FNO9S: 751.51, measured mass: 752.07 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.10 (dd, J = 9.5, 2.2 Hz, 1H), 3.85-3.98 (m, 2H), 3.65-3.85 (m, 4H), 3.55-3.65 (m, 2H), 3.45-3.55 (m, 1H), 2.89 (qt, J = 13.0, 7.4 Hz, 2H), 1.88 (d, J = 2.6 Hz, 6H), 1.54-1.73 (m, 6H), 1.23-1.32 (m, 40H), 0.90-0.95 (m, 3H).

[0221] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-[(2S,3S)-2,3,4-trihydroxybutoxy]octadecane-2-yl]-11-[3-fluorobicyclo[1.1.1]pentan-1-yl]undecaneamide [ka] (2S,3S)-4-[[(2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl]oxy]butane-1,2,3-triol[Diaz et al Tetrahedron: To a mixture of [Asymmetry 2009, 20, 747-753 and Jervis et al Bioconjugate Chemistry 2013, 24, 586-594] (50 mg, 0.12 mmol) and 11-[3-fluorobicyclo[1.1.1]pentan-1-yl]undecanoic acid (35.3 mg, 0.13 mmol) in DMF (3 mL), HBTU (90 mg, 0.24 mmol), Et3N (24 mg, 0.24 mmol), and NMM (24 mg, 0.24 mmol) were added at room temperature. The mixture was stirred overnight at room temperature, and then purified by preparative HPLC to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-[(2S,3S)-2,3,4-trihydroxybutoxy]octadecane-2-yl]-11-[3-fluorobicyclo[1.1.1]pentan-1-yl]undecanamide (7.8 mg, 10%) as a solid. LC / MS:C 38 H 72 Calculated mass for FNO7: 673.53, measured mass: 674.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.20 (s, 1H), 3.74-3.84 (m, 1H), 3.52-3.72 (m, 8H), 3.20-3.30 (m, 1H), 2.23 (t, J = 7.5 Hz, 2H), 1.88 (s, 5H), 1.28-1.63 (m, 45H), 0.92 (t, J = 6.4 Hz, 3H).

[0222] Synthesis of ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-(11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide)-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)-L-valinate [ka] Synthesis of ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valinate ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol [Org. Biomol. Chem. 2011, 9, 8413] (0.7g, 0.7mmol) and (((9H-fluorene-9 A mixture of (-yl)methoxy)carbonyl)-L-valine (0.5 g, 1.5 mmol) in THF (20 mL) was mixed with EDCI (210 mg, 1.10 mmol) and DMAP (179 mg, 1.46 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / Â3:1) to obtain ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (0.8 g, 86%) as an oily substance. LC / MS:C 79 H 96 N4O 11 Calculated mass value for this value: 1277, measured value: 1278 [M+H] + .

[0223] Synthesis of ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl L-valinate ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valinate (0.8 g, 0.6 mmol) in DMF (15 mL) was mixed with piperidine (0.3 g, 3.5 mmol). The mixture was stirred at room temperature for 0.5 hours, then quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (PE / siRNA2:1) to obtain ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl L-valinate (0.6g, 91%) as an oily substance. LC / MS:C 64 H 86 Calculated mass of N4O9: 1055, measured mass: 1056 [M+H] + .

[0224] Synthesis of ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)-L-valinate ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl L-valinate (0.6 g, 0.6 mmol) and chenodeoxycholic acid (268 mg, 0.68 mmol) were mixed in DMF (10 mL) at room temperature. HATU (324 mg, 0.85 mmol) and DIPEA (147 mg, 1.14 mmol) were added. The mixture was stirred at room temperature for 6 hours, then H2O was added, and the mixture was extracted with ELISA. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA3:1) to obtain ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-L-valinate (0.6 g, 74%) as an oily substance. LC / MS:C 88 H 124 N4O 12 Calculated mass value for this: 1429, measured value: 1430 [M+H] + .

[0225] Synthesis of ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)-L-valinate ((2R,3S,4S,5R,6S)-6-(((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl)oxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-L-valinate (0.6 g, 0.4 mmol) and 20% Pd(OH)2 / C (0.6 g) were mixed in MeOH (15 mL) and DCM (15 mL) and hydrogenated at room temperature for 16 hours (1 atm). The mixture was filtered through a Celite pad and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)-L-valinate (0.33 g, 83%) as a solid. LC / MS:C 53 H 96 N2O 12 Calculated mass value for this value: 953, measured value: 954 [M+H] + .

[0226] Synthesis of ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-(11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide)-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)-L-valinate ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl A mixture of (100 mg, 0.11 mmol) pentanoyl-L-valinate and 11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanoic acid (31 mg, 0.12 mmol) in THF (5 mL) and DMF (5 mL) was added at room temperature under an N2 atmosphere to HBTU (119 mg, 0.32 mmol), Et3N (0.1 mL), and NMM (0.1 mL). The mixture was stirred at room temperature for 16 hours, then quenched with H2O and extracted with SiO2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was purified by silica gel column chromatography (DCM / MeOH) to obtain the crude product (50 mg), which was further purified by grinding with CH3CN to obtain ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-(11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide)-3,4-dihydroxyoctadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl((4R)-4-((3R,7R,10S,13R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-L-valinate (26 mg, 21%) as a solid. LC / MS:C 69 H 121 FN2O 13 Calculated mass value for this value: 1205, measured value: 1206 [M+H] + .

[0227] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(oxetan-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(oxetan-3-yl)undeca-10-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (565 mg, 1.1 mmol) in THF (20 mL), 2.0 M NaHMDS (1.1 mL, 2.2 mmol) was added at 0°C under an N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 hour, then oxetane-3-carbaldehyde (86 mg, 1.0 mmol) in THF (1 mL) was added. The mixture was stirred overnight at room temperature, then acidified to approximately 1 pH with 1N HCl and extracted with  (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE /  1:1) on silica gel to obtain 11-(oxetane-3-yl)undeca-10-enoic acid (100 mg, 42%) as an oily substance. LC / MS:C 14 H 24 Calculated mass value for O3: 240, measured value: 239 [MH] - .

[0228] Step 2: Synthesis of 11-(oxetan-3-yl)undecanoic acid A mixture of 11-(oxetan-3-yl)undecanoic acid (100 mg, 0.4 mmol), PtO2 (20 mg, 0.1 mmol), and EtOH (30 mL) was stirred under an H2 atmosphere (with a balloon) for 1 hour. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(oxetan-3-yl)undecanoic acid (100 mg, 99%) as a solid. LC / MS:C 14 H 26Calculated mass value for O3: 242, measured value: 241 [MH] - .

[0229] Step 3: Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(oxetan-3-yl)undecaneamide (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (50 mg, 0.1 mmol) in DMF (2 mL) was mixed with 11-(oxetan-3-yl)undecanoic acid (25 mg, 0.1 mmol), Et3N (0.1 mL), NMM (0.1 mL), and HBTU (80 mg, 0.2 mmol) under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then diluted with H2O (10 mL). Extraction was performed with ELISA (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(oxetan-3-yl)undecaneamide (13.8 mg, 19%) as a solid. LC / MS:C 38 H 73 NO 10 Calculated mass value for this value: 703.99, measured value: 704.50 [M+H] + . 1H NMR (300 MHz, CD3OD) δ 4.81 (dd, J = 7.9, 5.8 Hz, 2H), 4.39 (t, J = 6.1 Hz, 2H), 4.21 (d, J = 5.7 Hz, 1H), 3.56-3.91 (m, 10H), 2.99-3.01 (m, 1H), 2.35-2.18 (m, 2H), 1.63-1.70 (m, 6H), 1.33-1.46 (m, 39H), 0.87-0.97 (m, 3H).

[0230] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (564 mg, 1.1 mmol) in THF (20 mL), 2 M NaHMDS (1.1 mL, 2.2 mmol) was added at 0°C under an N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 hour, then methyloxetane-3-carbaldehyde (100 mg, 1.0 mmol) in THF (2 mL) was added. The mixture was stirred overnight at room temperature, then acidified to approximately pH 1 with 1 N HCl and extracted with Âxa (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA1:1) on silica gel to obtain 11-(3-methyloxetane-3-yl)undeca-10-enoic acid (110 mg, 43%) as an oily substance. LC / MS:C 15 H 26 Calculated mass value for O3: 254, measured value: 253 [MH] - . Step 2: Synthesis of 11-(3-methyloxetan-3-yl)undecanoic acid

[0231] A mixture of 11-(3-methyloxetan-3-yl)undecanoic acid (110 mg, 0.4 mmol) and PtO2 (20 mg, 0.1 mmol) in EtOH (30 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(3-methyloxetan-3-yl)undecanoic acid (110 mg, 99%) as a solid. LC / MS:C 15 H 28 Calculated mass value for O3: 256, measured value: 255 [MH] - . Step 3: Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide

[0232] (2S,3R,4S,5R,6R)-2-(((2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (50 mg, 0.1 mmol) in DMF (2 mL) was mixed with 11-(3-methyloxetan-3-yl)undecanoic acid (27 mg, 0.1 mmol), Et3N (0.1 mL), NMM (0.1 mL), and HBTU (80 mg, 0.2 mmol) under an N2 atmosphere. The mixture was stirred at room temperature for 16 hours and then diluted with H2O (10 mL). Extraction was performed with ELISA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide (10.2 mg, 13%) as a solid. LC / MS:C 39 H 75 NO 10 Calculated mass value for this value: 718.01, measured value: 718.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.44 (d, J = 5.6 Hz, 2H), 4.35 (d, J = 5.5 Hz, 2H), 4.15-4.25 (m, 1H), 3.53-3.83 (m, 10H), 3.31-3.32 (m, 1H), 2.24 (t, J = 7.5 Hz, 2H), 1.52-1.65 (m, 6H), 1.28-1.36 (m, 41H), 0.83-0.97 (m, 3H).

[0233] Synthesis of 11-((1r,3s)-adamantan-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide [ka] Step 1: Synthesis of (11-((1s,3s)-adamantane-1-yl)undec-10-enoic acid (11-((1s,3s)-adamantan-1-yl)undeca-10-enoic acid) was prepared using a similar method to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain (11-((1s,3s)-adamantan-1-yl)undeca-10-enoic acid (250 mg, 799%) as a solid. LC / MS:C 21 H 34 Calculated mass relative to O2: 318, measured value: 317 [MH] - .

[0234] Step 2: Synthesis of 11-((1r,3s)-adamantan-1-yl)undecanoic acid A mixture of (11-((1s,3s)-adamantan-1-yl)undecanoic acid (250 mg, 0.7 mmol) and PtO2 (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-((1r,3s)-adamantan-1-yl)undecanoic acid (250 mg, 99.4%) as a solid. LC / MS:C 21 H 36 Calculated mass relative to O2: 320, measured value: 319 [MH] - .

[0235] Step 3: Synthesis of 11-((1r,3s)-adamantan-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) on silica gel. The solution was purified by preparative HPLC to obtain 11-((1r,3s)-adamantan-1-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide (5.4 mg, 6.4%) as a solid. LC / MS:C 45 H 83 Calculated mass for NO9: 782.14, measured mass: 782.65 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.19 (dd, J = 6.7, 4.4 Hz, 1H), 3.54-3.94 (m, 10H), 3.31-3.32 (m, 1H), 2.33 (t, J = 7.4 Hz, 1H), 2.24 (t, J = 7.4 Hz, 1H), 1.99-1.91 (m, 4H), 1.65-1.86 (m, 11H), 1.49-1.53 ​​(m, 7H), 1.26-1.36 (m, 34H), 1.05-1.09 (m, 3H), 0.87-0.91 (m, 3H).

[0236] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydrofuran-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(tetrahydrofuran-3-yl)undeca-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid, and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(tetrahydrofuran-3-yl)undeca-10-enoic acid (250 mg, 79%) as a solid. LC / MS:C 15 H 26 Calculated mass value for O3: 254, measured value: 253 [MH] - .

[0237] Step 2: Synthesis of 11-(tetrahydrofuran-3-yl)undecanoic acid A mixture of 11-(tetrahydrofuran-3-yl)undecanoic acid (200 mg, 0.7 mmol) and PtO2 (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon), then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(tetrahydrofuran-3-yl)undecanoic acid (200 mg, 99%) as a solid. LC / MS:C 15 H 28 Calculated mass value for O3: 256, measured value: 255 [MH] - .

[0238] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydrofuran-3-yl)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydrofuran-3-yl)undecaneamide (9 mg, 8%) as a solid. LC / MS:C 39 H 75 NO 10 Calculated mass value for this value: 717.54, measured value: 718.60 [M+H] + ; 1 H NMR (300 MHz, MeOHl-d4) δ 4.21 (d, J = 5.7 Hz, 1H), 3.56-3.92 (m, 12H), 2.15-2.20 (m, 2H), 1.63-1.70 (m, 5H), 1.33-1.46 (s, 44H), 0.87-0.97 (m, 3H).

[0239] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecaneamide [ka] Step 1: Synthesis of 11-(tetrahydro-2H-pyran-4-yl)undeca-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(tetrahydro-2H-pyran-4-yl)undeca-10-enoic acid (200 mg, 85%) as a solid. LC / MS:C 16 H 28 Calculated mass value for O3: 268, measured value: 267 [MH] - As a solid. Step 2: Synthesis of 11-(tetrahydro-2H-pyran-4-yl)undecanoic acid

[0240] A mixture of 11-(tetrahydro-2H-pyran-4-yl)undecanoic acid (200 mg, 0.7 mmol) and PtO2 (40 mg, 0.2 mmol) in EtOH (50 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(tetrahydro-2H-pyran-4-yl)undecanoic acid (200 mg, 99%) as a solid. LC / MS:C 16 H 30 Calculated mass value for O3: 270, measured value: 269 [MH] - .

[0241] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecaneamide (9.6 mg, 8.7%) as a solid. LC / MS:C 40 H 77 NO 10 Calculated mass value for this value: 731.55, measured value: 732.65 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 3.56-3.91 (m, 10H), 3.51-3.55 (m, 2H), 3.41-3.44 (m, 2H), 2.22-2.23 (m, 2H), 1.65-1.70 (m, 5H), 1.23-1.46 (m, 44H), 0.87-0.97 (m, 3H).

[0242] Synthesis of tert-butyl 4-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)piperidine-4-yl)undec-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(1-(tert-butoxycarbonyl)piperidine-4-yl)undeca-10-enoic acid (280 mg, 76%) as a solid. LC / MS:C 21 H 37 Calculated mass value for NO4: 367, measured value: 366 [MH] - .

[0243] Step 2: Synthesis of 11-(1-(tert-butoxycarbonyl)piperidine-4-yl)undecanoic acid A mixture of 11-(1-(tert-butoxycarbonyl)piperidine-4-yl)undecanoic acid (280 mg, 0.76 mmol) and PtO2 (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain 11-(1-(tert-butoxycarbonyl)piperidine-4-yl)undecanoic acid (280 mg, 99%) as a solid. LC / MS:C 21 H 39 Calculated mass value for NO4: 369, measured value: 368 [MH] - .

[0244] Step 3: Synthesis of tert-butyl4-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) and preparative HPL on silica gel. Purified in C, tert-butyl4-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate (13.6 mg, 6%) was obtained as a solid. LC / MS: C 45 H 86 N2O 11 Calculated mass value for this value: 830.62, measured value: 831.65 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 4.01-4.07 (m, 2H), 3.56-3.91 (m, 10H), 2.65-2.71 (m, 2H), 2.17-2.19 (m, 2H), 1.63-1.70 (m, 6H), 1.54 (s, 9H), 1.33-1.46 (m, 41H), 1.01-1.09 (m, 2H), 0.87-0.97 (m, 3H).

[0245] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(piperidine-4-yl)undecaneamide [ka] A mixture of tert-butyl 4-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate (100 mg, 0.14 mmol) in ELISA (3 mL), with 2N in ELISA (3 mL). HCl was added. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(piperidine-4-yl)undecanamide (10.2 mg, 12.2%) as a solid. LC / MS:C 40 H 78 Calculated mass for N2O9: 730.57, measured mass: 731.60 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 3.46-3.91 (m, 10H), 2.89-2.99 (m, 2H), 2.35-2.41 (m, 2H), 1.90-1.97 (m, 2H), 1.63-1.70 (m, 5H), 1.33-1.46 (m, 45H), 0.87-0.97 (m, 3H).

[0246] Synthesis of tert-butyl 3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)azetidine-3-yl)undec-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(1-(tert-butoxycarbonyl)azetidine-3-yl)undeca-10-enoic acid (180 mg, 33%) as a solid. LC / MS:C 19 H 33 Calculated mass value for NO4: 339, measured value: 338 [MH] - .

[0247] Step 2: Synthesis of 11-[1-(tert-butoxycarbonyl)azetidine-3-yl]undecanoic acid A mixture of 11-(1-(tert-butoxycarbonyl)azetidine-3-yl)undecanoic acid (180 mg, 0.53 mmol) and PtO2 (40 mg, 0.2 mmol) in EtOH (50 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-[1-(tert-butoxycarbonyl)azetidine-3-yl]undecanoic acid (180 mg, 99%) as a solid. LC / MS:C 19 H 35 Calculated mass value for NO4: 341, measured value: 340 [MH] - .

[0248] Step 3: Synthesis of tert-butyl3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel. Purified using LC / MS:C3 43 H 82 N2O 11 Calculated mass value for this value: 802.59, measured value: 803.65 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 3.98-4.05 (m, 2H), 3.46-3.81 (m, 12H), 2.41-2.53 (m, 1H), 2.18-2.25 (m, 2H), 1.63-1.70 (m, 6H), 1.50 (s, 9H), 1.33-1.46 (m, 39H), 0.87-0.97 (m, 3H).

[0249] Synthesis of 11-(azetidine-3-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecaneamide [ka] A mixture of tert-butyl 3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate (100 mg, 0.14 mmol) in HCl (3 mL), with 2N in HCl (3 mL). HCl was added. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain 11-(azetidine-3-yl)-N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)undecanamide (7.6 mg, 8.6%) as a solid. LC / MS:C 38 H 74 Calculated mass for N2O9: 702.54, measured mass: 703.60 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.11-4.21 (m, 2H), 3.46-3.93 (m, 10H), 2.80-2.91 (m, 2H), 2.35-2.41 (m, 1H), 2.25-2.29 (m, 1H), 1.63-1.70 (m, 5H), 1.33-1.46 (m, 42H), 0.87-0.97 (m, 3H).

[0250] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecaneamide [ka] Step 1: Synthesis of 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undeca-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid, and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undeca-10-enoic acid (100 mg, 51%) as a solid. LC / MS:C 16 H 28 Calculated mass value for O4S: 316, Measured value: 315 [MH] - .

[0251] Step 2: Synthesis of 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanoic acid A mixture of 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanoic acid (80 mg, 0.3 mmol) and PtO2 (20 mg, 0.1 mmol) in EtOH (30 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanoic acid (80 mg, 80%) as a solid. LC / MS:C 16 H 30 Calculated mass value for O4S: 318, measured value: 317 [MH] - .

[0252] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecaneamide Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) and preparative HP on silica gel. Purified by LC, the solid obtained was N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanamide (20.7 mg, 21%). LC / MS:C 40 H 77 NO 11 Calculated mass value for S: 779.52, measured value: 780.50 [M+H] + ; 1 H NMR (300 MHz, DMSO- d6) δ 4.65 (s, 1H), 3.33-3.93 (m, 12H), 2.93-3.13 (m, 4H), 2.93 (d, J = 13.5 Hz, 2H), 2.04 (t, J = 7.2 Hz, 2H), 1.94 (d, J = 10.3 Hz, 2H), 1.38-1.53 ​​(m, 8H), 1.10-1.32 (m, 43H), 0.87-0.97 (m, 3H).

[0253] Synthesis of tert-butyl 3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)undec-10-enoic acid It was prepared using a method similar to that of 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)undeca-10-enoic acid (150 mg, 42%) as a solid. LC / MS:C 20 H 35 Calculated mass value for NO4: 353, measured value: 352 [MH] - .

[0254] Step 2: Synthesis of 11-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)undecanoic acid A mixture of 11-[1-(tert-butoxycarbonyl)pyrrolidine-3-yl]undecanoic acid (150 mg, 0.3 mmol) and PtO2 (20 mg, 0.1 mmol) in EtOH (50 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)undecanoic acid (140 mg, 93%) as a solid. LC / MS:C 20 H 37 Calculated mass value for NO4: 355, measured value: 354 [MH] - .

[0255] Step 3: Synthesis of tert-butyl3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel. Purified using LC / MS:C3 44 H 84 N2O 11 Calculated mass value for this: 816.61, measured value: 839.55 [M+Na] + ; 1 H NMR (300 MHz, CD3OD) δ 4.18 (d, J = 5.9 Hz, 1H), 3.35-3.92 (m, 11H), 3.15-3.20 (m, 2H), 2.82 (s, 1H), 1.91-2.34 (m, 4H), 1.02-1.77 (m, 54H), 0.90 (t, J = 6.6 Hz, 3H).

[0256] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(pyrrolidine-3-yl)undecaneamide [ka] A mixture of tert-butyl 3-(11-(((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate (60 mg, 0.07 mmol) in HCl (3 mL) was mixed with 2N HCl in HCl (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and purified by preparative HPLC to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(pyrrolidine-3-yl)undecanamide (15.6 mg, 28%) as an oily substance. LC / MS:C 39 H 76 Calculated mass for N2O9: 716.56, measured mass: 717.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 3.51-3.91 (m, 14H), 3.12-3.21 (m, 4H), 2.74-2.79 (m, 1H), 2.15-2.30 (m, 3H), 1.14-1.61 (m, 42H), 0.87-0.97 (m, 3H).

[0257] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-{2-oxa-6-azaspiro[3,3]heptan-6-yl}undecaneamide [ka] Step 1: Synthesis of tert-butyl11-(2-oxa-6-azaspiro[3,3]heptan-6-yl)undecanoate To a mixture of 2-oxa-6-azaspiro[3.3]heptane (200 mg, 2.0 mmol) in DMF (10 mL), tert-butyl 11-bromo undecanoate (642 mg, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol) were added. The mixture was heated to 100 °C, stirred for 5 hours, then diluted with H2O (20 mL) and extracted with  (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE /  1:1) on silica gel to obtain tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptane-6-yl) undecanoate (339 mg, 50%) as a solid. LC / MS:C 20 H 37 Calculated mass of NO3: 339, measured mass: 340 [M+H] + .

[0258] Step 2: Synthesis of 11-(2-oxa-6-azaspiro[3,3]heptan-6-yl)undecanoic acid A mixture of tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate (220 mg, 0.6 mmol), DCM (4 mL), and TFA (2 mL) was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoic acid (180 mg, 98%) as a solid.

[0259] Step 3: Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-{2-oxa-6-azaspiro[3,3]heptan-6-yl}undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetane-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-{2-oxa-6-azaspiro[3.3]heptan-6-yl}undecaneamide (8.5 mg, 6.8%) as a solid. LC / MS:C 40 H 76 N2O 10 Calculated mass value for this value: 744.55, measured value: 745.55 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.75 (s, 4H), 4.14-4.24 (m, 1H), 3.56-3.87 (m, 15H), 2.68-2.79 (m, 1H), 2.15-2.25 (m, 2H), 1.49-1.66 (m, 5H), 1.33-1.46 (m, 47H), 0.87-0.97 (m, 3H). Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecaneamide [ka] Step 1: Synthesis of tert-butyl-11-morpholinoundecanoate It was prepared using a method similar to that of tert-butyl 11-(2-oxa-6-azaspiro[3,3]heptan-6-yl)undecanoate and purified by column chromatography (PE / ¼1:1) on silica gel to obtain tert-butyl 11-morpholinoundecanoate (450 mg, 88%) as a solid. LC / MS:C 19 H 37 Calculated mass of NO3: 327, measured mass: 328 [M+H] + .

[0260] Step 2: Synthesis of 11-morpholinoundecanoic acid A mixture of tert-butyl 11-(morpholine-4-yl)undecanoate (450 mg, 1.3 mmol) and ethyl acetate (5 mL) was mixed with 2N HCl in ethyl acetate (5 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain 11-morpholinoundecanoic acid (300 mg, 77%) as a solid. Step 3: Synthesis of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecaneamide It was prepared in a manner similar to that of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide. It was purified by column chromatography (PE / ELISA2:1) on silica gel to obtain N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecaneamide (70 mg, 28%) as a solid.

[0261] Step 4: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecaneamide A mixture of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecanamide (70 mg, 0.055 mmol) and Pd(OH)2 / C (20 mg) in DCM (5 mL) and EtOH (5 mL) was stirred for 16 hours under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-morpholinoundecanamide (9.1 mg, 23%) as a solid. LC / MS:C 39 H 76 N2O 10 Calculated mass value for this value: 732.55, measured value: 733.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) 4.21 (d, J = 5.7 Hz, 1H), 4.02-4.09 (m, 2H), 3.63-3.87 (9H), 3.46-3.58 (m, 4H), 3.11-3.16 (4H), 2.22 (t, J = 7.4 Hz, 2H), 1.33-1.70 (m, 43H), 0.87-0.97 (m, 3H).

[0262] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(piperidine-1-yl)undecaneamide [ka] Step 1: Synthesis of tert-butyl-11-(piperidine-1-yl)undecanoate It was prepared using a method similar to that of tert-butyl11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography (PE / SiO2:1) on silica gel to obtain tert-butyl11-(piperidine-1-yl)undecanoate (240 mg, 47%) as a solid. LC / MS:C 20 H 39 Calculated mass value for NO2: 325, measured value: 326 [M+H] + .

[0263] Step 2: Synthesis of 11-(piperidine-1-yl)undecanoic acid A mixture of tert-butyl 11-(piperidine-1-yl)undecanoate (180 mg, 0.5 mmol) and toluene (3 mL) was mixed with 2N HCl in toluene (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain 11-(piperidine-1-yl)undecanoic acid (140 mg, 94%) as a solid.

[0264] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(piperidine-1-yl)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(piperidine-1-yl)undecaneamide (32 mg, 26%) as an oily substance. LC / MS:C 40 H 78 Calculated mass for N2O9: 730.57, measured mass: 731.55 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.23 (q, J = 4.9 Hz, 1H), 3.68-3.92 (m, 7H), 3.50-3.61 (m, 5H), 3.07-3.09 (m, 2H), 2.89-2.97 (m, 2H), 2.18-2.30 (m, 2H), 1.96-1.99 (m, 1H), 1.50-1.87 (m, 11H), 1.30-1.39 (m, 36H), 0.87-0.97 (m, 3H).

[0265] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(pyrrolidine-1-yl)undecaneamide [ka] Step 1: Synthesis of tert-butyl-11-(pyrrolidine-1-yl)undecanoate It was prepared using a method similar to that of tert-butyl11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography (PE / ԅ1:1) on silica gel to obtain tert-butyl11-(pyrrolidine-1-yl)undecanoate (310 mg, 64%) as a solid. LC / MS:C 19 H 37 Calculated mass value for NO2: 311, measured value: 312 [M+H] + .

[0266] Step 2: Synthesis of 11-(pyrrolidine-1-yl)undecanoic acid A mixture of tert-butyl 11-(pyrrolidine-1-yl)undecanoate (310 mg, 0.99 mmol) and ethyl acetate (3 mL) contains 2N ethyl acetate (3 mL). HCl was added. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain 11-(pyrrolidine-1-yl)undecanoic acid (240 mg, 94%) as a solid.

[0267] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(pyrrolidine-1-yl)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(pyrrolidine-1-yl)undecaneamide (15 mg, 12.4%) as an oily substance. LC / MS:C 39 H 76 Calculated mass for N2O9: 716.56, measured mass: 717.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.21 (d, J = 5.7 Hz, 1H), 3.56-3.91 (m, 10H), 3.13-3.18 (m, 2H), 3.02-3.11 (m, 2H), 2.13-2.23 (m, 4H), 1.94-2.06 (m, 2H), 1.54-1.75 (m, 7H), 1.27-1.39 (m, 37H), 0.87-0.97 (m, 3H).

[0268] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-thiomorpholinoundecaneamide [ka] Step 1: Synthesis of tert-butyl-11-thiomorpholinoundecanoate It was prepared using a method similar to that of tert-butyl11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography (PE / SiO2:1) on silica gel to obtain tert-butyl11-thiomorpholinoundecanoate (340 mg, 64%) as a solid. LC / MS:C 19 H 37 Calculated mass of NO2S: 343, measured mass: 344 [M+H] + .

[0269] Step 2: Synthesis of 11-thiomorpholinoundecanoic acid A mixture of tert-butyl 11-thiomorpholino undecanoate (400 mg, 1.2 mmol) and toluene (5 mL) was mixed with 2N HCl in toluene (5 mL). The mixture was stirred at room temperature for 1 hour. It was then concentrated under reduced pressure to obtain 11-thiomorpholino undecanoic acid (318 mg, 95%) as a solid.

[0270] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-thiomorpholinoundecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-thiomorpholinoundecaneamide (17.1 mg, 13.6%) as an oily substance. LC / MS:C 39 H76 N2O9S: 748.53, Measured value: 749.45 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.23 (q, J = 4.9 Hz, 1H), 3.65-3.96 (m, 10H), 3.03-3.29 (m, 6H), 2.87-2.91 (m, 3H), 2.19-2.32 (m, 2H), 1.52-1.79 (m, 6H), 1.30-1.39 (m, 39H), 0.89-0.96 (m, 3H).

[0271] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-[(1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]undecaneamide [ka] Step 1: Synthesis of 11-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)undeca-10-enoic acid It was prepared in a similar manner to 11-(3-methyloxetan-3-yl)undeca-10-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain 11-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)undeca-10-enoic acid (110 mg, 54%) as a solid. LC / MS:C 20 H 32 Calculated mass value for O2: 304, measured value: 303 [MH] - .

[0272] Step 2: Synthesis of 11-((1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)undecanoic acid A mixture of 11-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)undecanoic acid (100 mg, 0.3 mmol) and PtO2 (20 mg, 0.1 mmol) in EtOH (50 mL) was stirred for 1 hour under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 11-((1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)undecanoic acid (80 mg, 79%) as a solid. LC / MS:C 20 H 36 Calculated mass relative to O2: 308, measured value: 307 [MH] - .

[0273] Step 3: Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-[(1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetane-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-[(1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]undecaneamide (14.3 mg, 10.7%) as a solid. LC / MS:C 44 H 83 Calculated mass for NO9: 769.61, measured mass: 792.65 [M+Na] + ; 1H NMR (300 MHz, CD3OD) δ 4.17 (dd, J = 6.7, 4.1 Hz, 1H), 3.51-3.92 (m, 10H), 3.17-3.26 (m, 3H), 2.31-2.38 (m, 1H), 2.18-2.22 (m, 2H), 1.85-1.97 (m, 4H), 1.52-1.62 (m, 5H), 1.22-1.39 (m, 44H), 1.19 (s, 3H), 0.87-0.97 (m, 3H).

[0274] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidethiomorpholino)undecaneamide [ka] Step 1: Synthesis of tert-butyl-11-(2-oxa-6-azaspiro[3,3]heptan-6-yl)undecanoate Prepared using a method similar to that of tert-butyl11-(2-oxa-6-azaspiro[3,3]heptan-6-yl)undecanoate, and purified by column chromatography (PE / ԅ1:1) on silica gel to obtain tert-butyl11-(1,1-dioxidethiomorpholino)undecanoate (320 mg, 55%) as a solid. LC / MS:C 19 H 37 Calculated mass of NO4S: 375, measured mass: 376 [M+H] + .

[0275] Step 2: Synthesis of 11-(1,1-dioxidethiomorpholino)undecanoic acid A mixture of tert-butyl 11-(1,1-dioxide thiomorpholino)undecanoate (300 mg, 0.79 mmol) and toluene (3 mL) was mixed with 2N HCl in toluene (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain 11-(1,1-dioxide thiomorpholino)undecanoic acid (200 mg, 78%) as a solid. LC / MS:C 15 H 29 Calculated mass value for NO4S: 319, measured value: 318 [MH] - .

[0276] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidethiomorpholino)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(1,1-dioxidethiomorpholino)undecaneamide (17.3 mg, 16.2%) as a solid. LC / MS:C 39 H 76 N2O 11 Calculated mass value for S: 780.52, measured value: 704.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.19 (q, J = 4.8 Hz, 1H), 3.93-3.51 (m, 10H), 3.08 (q, J = 4.6 Hz, 4H), 2.97 (dd, J = 6.8, 3.4 Hz, 4H), 2.56-2.45 (m, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.11-1.61 (m, 42H), 0.95-0.85 (m, 3H).

[0277] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(isopropylsulfonyl)undecaneamide [ka] Step 1: Synthesis of tert-butyl 11-(isopropylthio)undecanoate To a mixture of 2-propanthol (3.5 g, 46.6 mmol) and DMF (30 mL), tert-butyl 11-bromoundecanoate (1.0 g, 3.1 mmol) and Cs2CO3 (2.5 g, 7.7 mmol) were added. The mixture was stirred at room temperature for 5 hours, then diluted with H2O (60 mL) and extracted with Depositphotos (3 × 50 mL). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Depositphotos 2:1) on silica gel to obtain tert-butyl 11-(isopropylthio)undecanoate (900 mg, 91%) as a solid.

[0278] Step 2: Synthesis of tert-butyl-11-(isopropylsulfonyl)undecanoate To a mixture of tert-butyl 11-(isopropylthio)undecanoate (800 mg, 2.5 mmol) in DCM (20 mL), m-CPBA (870 mg, 5.0 mmol) was added. The mixture was stirred overnight at room temperature and then diluted with H2O (50 mL). Extraction was performed with à (3 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Ã2:1) on silica gel to obtain tert-butyl 11-(isopropylsulfonyl)undecanoate (600 mg, 68%) as a solid.

[0279] Step 3: Synthesis of 11-(isopropylsulfonyl)undecanoic acid A mixture of tert-butyl 11-(isopropylsulfonyl)undecanoate (300 mg, 0.86 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain 11-(isopropylsulfonyl)undecanoic acid (200 mg, 79%) as a solid. LC / MS:C 14 H 28 Calculated mass for O4S: 292, Measured mass: 291 [MH] - .

[0280] Step 4: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(isopropylsulfonyl)undecaneamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-11-(isopropylsulfonyl)undecaneamide (31.3 mg, 28%) as a solid. LC / MS:C 38 H 75 NO 11 Calculated mass value for S: 753.51, measured value: 754.50 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.89 (d, J = 3.7 Hz, 1H), 4.22 (q, J = 4.8 Hz, 1H), 3.52-3.94 (m, 10H), 3.22-3.28 (m, 1H), 3.02-3.11 (m, 2H), 2.24 (t, J = 7.5 Hz, 2H), 1.88-1.75 (m, 2H), 1.30-1.66 (m, 46H), 0.96-0.88 (m, 3H).

[0281] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanamide [ka] Step 1: Synthesis of methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate To a mixture of 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (200 mg, 1.3 mmol) and THF (10 mL), 2 M NaHMDS (0.65 mL, 1.3 mmol) was added at 0°C under an N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 hour, then a solution of methyl 10-bromodecanoate (235 mg, 0.9 mmol) in THF (1.5 mL) was added. The mixture was stirred overnight at room temperature, then diluted with H2O (20 mL) and extracted with  (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â1:1) on silica gel to obtain methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate (80 mg, 27%) as a solid. LC / MS:C 16 H 30 Calculated mass for O5S: 334, Measured mass: 335 [M+H] + .

[0282] Step 2: Synthesis of 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid Methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate (200 mg, 0.6 mmol) was mixed in MeOH (5 mL), THF (5 mL), and H2O (5 mL) with LiOH (42 mg, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, then acidified to approximately pH 3 with 1N HCl and extracted with  (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH10:1) to obtain 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid (66 mg, 53%) as a solid. LC / MS:C 15 H28 Calculated mass value for O5S: 320, Measured value: 319 [MH] - .

[0283] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanamide Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and obtained by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel. Purified to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanamide (22.2 mg, 14.5%) as an oily substance. LC / MS:C 39 H 75 NO 12 Calculated mass value for S: 781.50, measured value: 782.45 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.20 (dd, J = 6.4, 4.5 Hz, 1H), 3.52-3.89 (m, 10H), 3.46-3.48 (m, 2H), 3.15-3.30 (m, 2H), 2.91-2.95 (m, 2H), 2.08-2.28 (m, 5H), 1.53-1.63 (m, 6H), 1.27-1.39 (m, 36H), 0.94-0.86 (m, 3H).

[0284] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decanamide [ka] Step 1: Synthesis of methyl 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoate It was prepared using a method similar to that for methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate, and purified by column chromatography (PE / siRNA2:1) on silica gel to obtain methyl 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoate (95 mg, 37%) as an oily substance.

[0285] Step 2: Synthesis of 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoic acid Prepared using a method similar to that of 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid, and purified by column chromatography (DCM / MeOH10:1) on silica gel to obtain 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoic acid (65 mg, 80%) as a solid. LC / MS:C 15 H 28 Calculated mass value for O4: 272, measured value: 271 [MH] - .

[0286] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decanamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography (DCM / MeOH5:1) and preparative HPLC on silica gel to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decaneamide (12 mg, 13%) as an oily substance. LC / MS:C 39 H 75 NO 11 Calculated mass value for this value: 733.53, measured value: 734.50 [M+H] + . 1H NMR (300 MHz, CD3OD) 4.19 (q, J = 4.9 Hz, 1H), 3.66-3.90 (m, 9H), 3.37-3.51 (m, 5H), 2.22 (t, J = 7.5 Hz, 2H), 1.89 (dd, J = 13.0, 3.8 Hz, 2H), 1.47-1.62 (m, 5H), 1.26-1.37 (m, 40H), 0.88-0.91 (m, 3H).

[0287] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide [ka] Step 1: Synthesis of ethyl 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoate It was prepared in a similar manner to methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate and purified by column chromatography (PE / siRNA2:1) on silica gel to obtain ethyl 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoate (94 mg, 29%) as an oily substance.

[0288] Step 2: Synthesis of 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoic acid 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid was prepared using a method similar to that of acidic preparation, and purified by column chromatography (DCM / MeOH10:1) on silica gel to obtain 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoic acid (57 mg, 70%) as a solid. LC / MS:C 15 H 28 Calculated mass value for O4: 272, measured value: 271 [MH] - .

[0289] Step 3: Synthesis of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide It was prepared in a similar manner to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and purified by column chromatography (PE / ELISA 5:1) on silica gel to obtain N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide as a solid. LC / MS:C 81 H 111 NO 11 Calculated mass value for this region: 1273.82, measured value: 1274.50 [M+H] + .

[0290] Step 4: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide A mixture of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide (20 mg, 0.013 mmol) and Pd(OH)2 (40 mg) in EtOH (3 mL) and DCM (3 mL) was stirred for 16 hours under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide (6.3 mg, 54%) as a solid. LC / MS:C 39 H 75 NO 11 Calculated mass value for this value: 733.53, measured value: 734.50 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.22 (d, J = 5.8 Hz, 1H), 3.56-3.94 (m, 10H), 3.40-3.48 (m, 3H), 3.28-3.30 (m, 3H), 2.24 (t, J = 7.5 Hz, 2H), 1.54-1.69 (m, 6H), 1.29-1.35 (m, 39H), 0.97-0.87 (m, 3H).

[0291] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanamide [ka] Step 1: Synthesis of ethyl 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoate It was prepared in a similar manner to methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate and purified by column chromatography (PE / siRNA2:1) on silica gel to obtain ethyl 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoate (62 mg, 23%) as an oily substance.

[0292] Step 2: Synthesis of 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoic acid It was prepared in a similar manner to 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid and purified by column chromatography (DCM / MeOH10:1) on silica gel to obtain 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoic acid (47 mg, 86%) as a solid. LC / MS:C 15 H 28 Calculated mass value for O4: 272, measured value: 271 [MH] - .

[0293] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanamide Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and subjected to column chromatography (DCM / MeOH5:1) and preparative H2-1 Purification by PLC yielded N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanamide (7.4 mg, 8.4%) as an oily substance. LC / MS:C 39 H 75 NO 11 Calculated mass value for this value: 733.53, measured value: 734.45 [M+H] + ; 1 H NMR (300 MHz, CD3OD) δ 4.56-4.60 (m, 4H), 4.17-4.23 (m, 1H), 3.66-3.92 (m, 15H), 3.39-3.57 (m, 4H), 2.22 (t, J = 7.5 Hz, 2H), 1.48-1.65 (m, 5H), 1.27-1.37 (m, 33H), 0.84-0.95 (m, 3H).

[0294] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide [ka] Step 1: Synthesis of 7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanoic acid A mixture of 3-(tetrahydro-2H-pyran-4-yl)propan-1-ol (1.0 g, 6.9 mmol) and DMSO (20 mL) was mixed with KOH (320 mg, 5.7 mmol) under an N2 atmosphere. The mixture was heated to 80°C and stirred for 1 hour, then 7-bromo-heptanoic acid (300 mg, 1.4 mmol) was added, and the mixture was stirred at 80°C for a further 2 hours. After cooling, the mixture was acidified to approximately pH 1 with 1N HCl and extracted with Âxa (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH10:1) on silica gel to obtain 7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanoic acid (50 mg, 13%) as an oily substance. LC / MS:C 15 H 28 Calculated mass value for O4: 272, measured value: 271 [MH] - .

[0295] Step 2: Synthesis of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide It was prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except that THF was used as the solvent. Purification by column chromatography (PE / Â3:1) on silica gel yielded N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide (120 mg, 51%) as a solid. LC / MS:C 81 H 111 NO 11 Calculated mass value for this region: 1273.82, measured value: 1274.50 [M+H] + .

[0296] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide A mixture of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide (24 mg, 0.019 mmol), Pd(OH)2 (40 mg), EtOH (3 mL), and DCM (3 mL) was stirred (with a balloon) for 16 hours under an H2 atmosphere. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide (7.1 mg, 51%) as a solid. LC / MS:C 39 H 75 NO 11 Calculated mass value for this value: 733.53, measured value: 734.50 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.23 (q, J = 4.9 Hz, 1H), 3.57-3.96 (m, 10H), 3.40-3.46 (m, 5H), 2.24 (t, J = 7.8 Hz, 2H), 1.55-1.68 (m, 9H), 1.21-1.41 (m, 37H), 0.88-0.96 (m, 3H).

[0297] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide [ka] Step 1: Synthesis of 6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanoic acid It was prepared in a similar manner to 7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanoic acid and purified by column chromatography (PE / Â2:1) on silica gel to obtain 6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanoic acid (42 mg, 15%) as an oily substance. LC / MS:C 15 H 28 Calculated mass value for O4: 272, measured value: 271 [MH] - .

[0298] Step 2: Synthesis of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide It was prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except that THF was used as the solvent. The compound was purified by column chromatography (PE / Â3:1) on silica gel to obtain N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexaneamide (20 mg, 10%) as a solid. LC / MS:C 81 H 111 NO 11 Calculated mass value for this region: 1273.82, measured value: 1274.50 [M+H] + .

[0299] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide A mixture of N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexaneamide (26 mg, 0.02 mmol), Pd(OH)2 (40 mg), EtOH (3 mL), and DCM (3 mL) was stirred for 16 hours under an H2 atmosphere (with a balloon). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide (1.3 mg, 8.5%) as an oily substance. LC / MS:C 39 H 75 NO 11 Calculated mass value for this value: 733.53, measured value: 734.45 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.23 (q, J = 5.0 Hz, 1H), 3.98-3.77 (m, 10H), 3.40-3.47 (m, 5H), 2.26 (t, J = 7.6 Hz, 2H), 1.52-1.68 (m, 10H), 1.21-1.41 (m, 36H), 0.88-0.96 (m, 3H).

[0300] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide [ka] Step 1: Synthesis of (15-carboxypentadecyl)triphenylphosphonium bromide A mixture of 16-bromohexadecanoic acid (2.0 g, 5.9 mmol) and CH3CN (30 mL) was mixed with Ph3P (1.56 g, 5.9 mmol). The mixture was heated to 90°C, stirred for 2 days, then filtered and washed with THF to obtain (15-carboxypentadecyl)triphenylphosphonium bromide (3.0 g, 84%) as a solid.

[0301] Step 2: Synthesis of 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadeca-16-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (800 mg, 1.3 mmol) in THF (15 mL), 2 M NaHMDS (1.65 mL, 3.3 mmol) was added at 0°C under an N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 hour, then 3-fluorobicyclo[1.1.1]pentane-1-carboaldehyde (152 mg, 1.3 mmol) in THF (1 mL) was added. The mixture was stirred overnight at room temperature, then acidified to approximately pH 1 with 1 N HCl and extracted with  (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â2:1) on silica gel to obtain 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadeca-16-enoic acid (140 mg, 30%) as a solid. LC / MS:C 22 H 37Calculated mass for FO2: 352, measured mass: 351 [MH] - .

[0302] Step 3: Synthesis of 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanoic acid A mixture of 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadeca-16-enoic acid (140 mg, 0.39 mmol), PtO2 (20 mg, 0.1 mmol), and EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 1 hour. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanoic acid (140 mg, 99%) as a solid. LC / MS:C 22 H 39 Calculated mass for FO2: 354, measured mass: 353 [MH] - .

[0303] Step 4: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide Prepared in a manner similar to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, and analyzed by column chromatography (DCM / MeOH5:1) and preparative HP on silica gel. Purified by LC, the solid obtained was N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide (18.8 mg, 15.7%). LC / MS:C 46 H 86 Calculated mass for FNO9: 815.63, measured mass: 816.65 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 4.20 (dt, J = 6.7, 4.4 Hz, 1H), 3.73-3.93 (m, 5H), 3.53-3.76 (m, 5H), 2.24 (t, J = 7.5 Hz, 2H), 1.88 (d, J = 2.6 Hz, 6H), 1.58-1.66 (m, 6H), 1.30-1.36 (m, 50H), 0.96-0.88 (m, 3H); 19 F NMR (376 MHz, CD3OD) δ -146.5.

[0304] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosaneamide [ka] Step 1: Synthesis of (21-carboxyhenicosyl)triphenylphosphonium bromide To a mixture of 22-bromodocanoic acid (1.4 g, 3.4 mmol) and CH3CN (30 mL), Ph3P (0.91 g, 3.4 mmol) was added under an N2 atmosphere. The mixture was heated to 90°C, stirred for 2 days, and then concentrated under reduced pressure to obtain (21-carboxyhenicosyl)triphenylphosphonium bromide (1.6 g, 68%) as a solid.

[0305] Step 2: Synthesis of 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid To a mixture of (21-carboxyhenicosyl)triphenylphosphonium bromide (300 mg, 0.4 mmol) in 1,4-dioxane (10 mL), 4A molecular sieve (0.5 g), K2CO3 (245 mg, 1.7 mmol), and 3-fluorobicyclo[1.1.1]pentan-1-carboaldehyde (75 mg, 0.7 mmol) were added under an N2 atmosphere at room temperature. The mixture was heated to 100 °C and stirred for 16 hours, then diluted with H2O, and the pH of the mixture was adjusted to 4-5 with 2N HCl. The mixture was then extracted with siRNA. The combined organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / siRNA 2:1) on silica gel to obtain 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid (50 mg, 26%) as a solid. LC / MS:C 28 H 49 Calculated mass for FO2: 436, measured mass: 435 [MH] - .

[0306] Step 3: Synthesis of 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid A mixture of 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid (50 mg, 0.11 mmol) and PtO2 (5 mg) in EtOH (20 mL) was stirred at room temperature under an H2 atmosphere (1 atm) for 1 hour. The mixture was filtered through a Celite pad and washed with filter cake EtOH. The filtrate was concentrated under reduced pressure to obtain 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid (45 mg, 90%) as a solid. LC / MS:C 28 H 51 Calculated mass for FO2: 438, measured mass: 437 [MH] - .

[0307] Step 4: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosaneamide It was prepared in a similar manner to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except that DMF / THF was used as the solvent. The solution was purified by column chromatography (DCM / MeOH) on silica gel and washed with CH3CN to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosaneamide (5.2 mg, 5.2%) as a solid. LC / MS:C 52 H 98 Calculated mass for FNO9: 899.72, measured mass: 922.65 [M+H] + ; 1H NMR (300 MHz, CD3OD) δ 4.13-4.25 (m, 1H), 3.56-3.93 (m, 10H), 2.24 (t, J = 7.4 Hz, 2H), 1.88 (d, J = 2.6 Hz, 6H), 1.55-1.68 (m, 5H), 1.26-1.42 (m, 63H), 0.92 (t, J = 6.7 Hz, 3H); 19 F NMR (282 MHz, CD3OD) δ -146.5.

[0308] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosaneamide [ka] Step 1: Synthesis of 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosa-20-enoic acid Prepared in a similar manner to 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid, and purified by column chromatography (PE / Â1:1) on silica gel to obtain 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosa-20-enoic acid (65 mg, 35%) as a solid. LC / MS:C 26 H 45 Calculated mass for FO2: 408, measured mass: 407 [MH] - .

[0309] Step 2: Synthesis of 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanoic acid 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanoic acid (60 mg, 92%) was prepared in a similar manner to 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanoic acid as a solid. LC / MS:C 26 H 47 Calculated mass for FO2: 41, measured mass: 409 [MH] - .

[0310] Step 3: Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosaneamide It was prepared in a similar manner to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except that DMF / THF was used as the solvent. The compound was purified by column chromatography (DCM / MeOH9:1) on silica gel and washed with CH3CN to obtain N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosaneamide (4.7 mg, 3.9%) as a solid. LC / MS:C 50 H 94 Calculated mass for FNO9: 871.69, measured mass: 872.70 [M+H] + and 894.65[M+Na] + ; 1 H NMR (300 MHz, CD3OD) δ 4.16-4.23 (m, 1H), 3.56-3.89 (m, 10H), 2.24 (t, J = 7.5 Hz, 2H), 1.88 (d, J = 2.6 Hz, 6H), 1.52-1.69 (m, 6H), 1.23-1.39 (m, 58 H), 0.92 (t, J = 6.4 Hz, 3H); 19 F NMR (282 MHz, CD3OD) δ -146.6.

[0311] Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosaneamide [ka] Step 1: Synthesis of 21-(bromotriphenyl-lambda5-phosphanyl)henicosanoic acid A mixture of 21-bromohenicosanoic acid (1.16 g, 2.86 mmol) and CH3CN (20 mL) was mixed with Ph3P (0.75 g, 2.86 mmol). The mixture was heated to 90°C, stirred for 2 days, and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase HPLC (H2O, 5% HCl) / CH3OH 5%~100% to obtain 21-(bromotriphenyl-lambda 5-phosphanyl)henicosanoic acid (1.27 g, 66%) as a solid.

[0312] Step 2: Synthesis of (E)-22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosa-21-enoic acid (E)-22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosa-21-enoic acid was prepared using a similar method to that of 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosa-21-enoic acid and purified by column chromatography (PE / Â1:1) on silica gel to obtain (E)-22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosa-21-enoic acid (44 mg, 35%) as a solid. LC / MS:C 27 H 47Calculated mass for FO2: 422.36, measured mass: 421.15 [MH] - .

[0313] Step 3: Synthesis of 22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosanoic acid 22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosanoic acid (40 mg, 99%) was prepared using a method similar to that of 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid to obtain 22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosanoic acid as a solid. LC / MS:C 27 H 49 Calculated mass for FO2: 424.37, measured mass: 423.15 [MH] - .

[0314] Step 4: Synthesis of N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosaneamide It was prepared in a similar manner to N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except that DMF / THF was used as the solvent. The solution was purified by column chromatography (DCM / MeOH9:1) on silica gel and washed with CH3CN to obtain N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecane-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosaneamide (22.5 mg, 18%) as a solid. LC / MS:C 51 H 96 Calculated mass for FNO9: 885.71, measured mass: 886.75 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 4.85-4.87 (m, 1H), 4.20 (d, J = 6.6 Hz, 1H), 3.89-3.90 (m, 3H), 3.70-3.85 (m, 5H), 3.63-3.67 (m, 1H), 3.55-3.60 (m, 1H), 2.24 (t, J = 7.5 Hz, 2H), 1.88 (d, J = 2.6 Hz, 6H), 1.56-1.66 (m, 4H), 1.30-1.46 (m, 62H), 0.92 (t, J = 6.8 Hz, 3H); 19 F NMR (376 MHz, CD3OD) δ -146.6.

[0315] Synthesis of N-((2S,3S,4R)-3,4-dihydroxy-1-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)octadecane-2-yl)-24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosaneamide [ka] Step 1: Synthesis of 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)octa-7-enoic acid ...

Claims

[Claim 1] The invention described in the present specification.

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