COMPOUNDS FOR ACTIVATING INVARIANT NATURAL KILLER T CELLS AND METHODS OF USE IN ELIMINATING INFLAMMATORY SENESCENT CELLS - Patent application

Abstract

Compounds for activating invariant natural killer T cells (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 with an inflammatory secretome (SASP). Methods for activating iNKT cells by contacting the iNKT cells with an amount of a compound of the invention and selectively reducing or eliminating the presence of senescent cells with the activated iNKT cells are also described. Compositions for carrying out the methods of the invention 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 lead to numerous different diseases. Invariant natural killer T (iNKT) cells are a subset of T cells that recognize glycolipid antigens bound to cluster of differentiation (CD)1d molecules expressed by surface antigen-presenting cells. Recognition of exogenous and endogenous lipids can aid in immune responses against diseases such as autoimmune diseases, allergic diseases, metabolic syndrome, cancer, and pathogen infections. While iNKT cells have been shown to mediate immune responses based on cytokine release, they can also function as effectors through cytotoxicity. Summary of the Invention [Means for solving the problem]

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

[0003] In some embodiments, the compound of interest is a compound of formula DCD-(I): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0004] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In some cases, R 1 , R 2 , R 3 , R 4 are each hydrogen. In one particular case, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0005] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In one particular case, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl.

[0007] In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R iis hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I.

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

[0009] In some embodiments, X is -NH. In some instances, X, X and R a together form an amide, e.g., X1 is -NH, X2 is carbon, and R a is oxygen. In other cases, X1, X2 and R a together form a sulfoximine, e.g., X1 is -NH and X2 is -SR k and R a is oxygen. In some cases, R k is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. k is methyl. In other cases, X1, X2 and R a taken together form a trifluoromethylaminomethyl, e.g., where X1 is -NH and X2 is carbon and R a In other cases, X1, X2 and R are trifluoromethyl. a together form a vinyl fluoride, e.g., X1 is carbon, X2 is carbon, and R a In certain cases, X1, X2 and R a together form an aminooxetane, e.g., X1 is -NH and R a together with X2 to form an oxacyclobutane. In embodiments, R e may be alkyl or substituted alkyl. In some cases, R e is a C8-C20 alkyl. In some cases, R e is a substituted C8-C20 alkyl. In certain instances, R eis a C13 alkyl.

[0010] In some embodiments, R b is hydrogen. In some cases, R b is C1-C16 alkyl. In some cases, R b is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. b teeth, [ka] is selected from [ka] indicates a bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl.

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

[0012] In some embodiments, R dis a C5-C25 alkyl or a 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. d teeth, [ka] [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] indicates a bond to a C5-C25 alkyl, and R m and R n is 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 a halogen. In some cases, R mis selected from fluorine, bromine, or iodine. In some cases, R n is hydrogen. In some cases, R n is a halogen. In some cases, R n is fluorine, bromine or iodine.

[0014] In some embodiments, the compound of interest is a compound of formula DCD-(II): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0015] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In some cases, R 1 , R 2 , R 3 , R 4 are each hydrogen.

[0016] In one particular case, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 Ha-NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0017] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In one particular case, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl; R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, Ri is I. In other cases, R i is Br.

[0019] In some embodiments, X1, X2, X3, X4, and X5 together form a pyrazole, e.g., 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, e.g., 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, e.g., X1 is nitrogen, X2 is nitrogen, X3 is nitrogen, X4 is nitrogen, and X5 is carbon. In certain embodiments, X1, X2, X3, X4, and X5 together form a tetrazolone, e.g., X1 is nitrogen, X2 is nitrogen, X3 is nitrogen, X4 is nitrogen, and X5 is carbon, and R a is oxygen.

[0020] In embodiments, R e may be alkyl or substituted alkyl. In some cases, R e is a C8-C20 alkyl. In some cases, R e is a substituted C8-C20 alkyl. In certain instances, R e is a C13 alkyl.

[0021] In some embodiments, R b is hydrogen. In some cases, R b is C1-C16 alkyl. In some cases, R b is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. b teeth, [ka] is selected from [ka] indicates a bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl.

[0022] In some embodiments, R c is C1-C16 alkyl. In some cases, R c 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 is a C5-C25 alkyl or a 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. d teeth, [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] indicates a bond to a 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.

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

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

[0026] Embodiments of the present disclosure also include methods for activating iNKT cells by contacting the iNKT cells with an amount of a 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 comprises contacting one or more compounds described herein with iNKT cells and T HIn other instances, the method includes contacting one or more compounds described herein with iNKT cells in a manner sufficient to elicit a type 1 cytokine response (e.g., increasing 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). H The method includes contacting in a manner sufficient to induce a type 2 cytokine response (e.g., increasing 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 the 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 produce a cytokine response. In some cases, the at least one other lymphocyte is a T helper cell.

[0027] In certain instances, the method includes contacting activated iNKT cells with a composition comprising senescent cells, wherein contacting with the 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 comprises healthy cells. In some instances, contacting with the 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 the activated iNKT cells reduces or eliminates the presence of senescent cells in the composition, and the presence of healthy cells is reduced by 5% or less when the composition is contacted with the activated iNKT cells.

[0028] In some embodiments, the method includes administering one or more compounds described herein to a subject, e.g., to reduce the presence of or eliminate senescent cells in the subject. In some cases, the method includes administering one or more compounds described herein to a subject, for example, to treat an autoimmune disease, a fibrotic disorder (lung, kidney, liver), an allergic disease, metabolic syndrome, type 2 diabetes, NAFLD, NASH, cancer, eye disease, heart disease, kidney disease, pathogen infection, rheumatoid arthritis, ulcerative colitis, multiple sclerosis, familial hypercholesterolemia, giant cell arteritis, idiopathic pulmonary fibrosis, systemic lupus erythematosus, cachexia, glaucoma, chronic kidney disease, or other conditions. The methods include administering one or more compounds to treat a subject for chronic obstructive pulmonary disease, systemic sclerosis, pulmonary arterial hypertension, lipodystrophy, sarcopenia, alopecia, post-myocardial infarction, vitiligo, POTS, MCAD, Sjogren's, scleroderma, Hashimoto's thyroiditis, ankylosing spondylitis, fibromyalgia, sarcoidosis, hepatitis, Raynaud's syndrome, mold disease, celiac disease, Crohn's disease, pemphigus, SPS, PBC, psoriatic arthritis, CIDP, motor neuron disease, GPA, ALS, myasthenia gravis, and presbyopia. [Brief explanation of the drawings]

[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- 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 GFP+ percentage of cells at different concentrations of α-GalCer. [Figure 1B] FIG. 1B depicts the EC50 of the dose response shown in FIG. 1A. [Figure 2A] Figure 2A shows the amount of interleukin-2 (IL-2) secretion in response to 48 hours of incubation with compounds DCD-101, DCD-102, DCD-104, DCD-105, DCD-106, and α-GalCer at dose responses of 0.01, 0.1, 1, and 10 μg / mL. [Figure 3A] FIG. 3A depicts the secretion of the cytokine interferon gamma (IFNγ) in response to activation with compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 3B] FIG. 3B depicts the secretion of the cytokine interleukin-6 (IL-6) in response to activation with compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 3C]FIG. 3C depicts the secretion of the cytokine tumor necrosis factor alpha (TNFα) in response to activation with compounds DCD-101, DCD-104, DCD-106, and α-GalCer. [Figure 4A] FIG. 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 compared to α-GalCer, as measured by serum IFNγ using ELISA 20 hours after injection. [Figure 4B] Figure 4B shows the expansion of 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] FIG. 5A shows the expansion of iNKT cells induced by α-GalCer or DCD-101 in the spleens of HFD model mice, as measured by flow cytometry. [Figure 5B] Figure 5B shows the expansion of iNKT cells induced by α-GalCer or DCD-154 in the eWAT of HFD mouse model, 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]FIG. 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 of accumulated senescent cells in eWAT in response to treatment with compounds DCD-101, DCD-154, and α-GalCer. Values ​​were pooled from multiple experiments and normalized to the HFD-vehicle condition. [Figure 6A] FIG. 6A depicts GFP expression in response to incubation of compounds GVK1a, GVK1b, GVK1c, and GVK1f with BWSTIM and JiNKT cells. [Figure 6B] FIG. 6B shows IL-2 expression by compounds GVK1a, GVK1b, and GVK1f in the DN3.2 cell line when loaded onto BWSTIM CD1d. [Figure 6C] Figure 6C depicts 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] FIG. 7A depicts the effect of activated iNKT cells on senescent and non-senescent cells over an 18-hour period. [Figure 7B] Figure 7B depicts a comparison of cytolysis of senescent and healthy cells by activated iNKT cells after 8 and 18 hours of incubation. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition The following terms have the following meanings unless otherwise indicated: Any undefined term has its art-recognized meaning.

[0031] As used herein, the term "alkyl," by itself or as part of another substituent, refers to a saturated, branched, or straight-chain monovalent hydrocarbon group derived by removal of one hydrogen atom from a single carbon atom of a parent alkane. 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., butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, or 2-methyl-propan-2-yl. In some embodiments, an alkyl group contains 1 to 20 carbon atoms. In other embodiments, an alkyl group contains 1 to 10 carbon atoms. In yet other embodiments, an alkyl group contains 1 to 6 carbon atoms, e.g., 1 to 4 carbon atoms.

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

[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 (-CH-), ethylene (-CHCH-), propylene isomers (e.g., -CHCHCH- and -CH(CH)CH-).

[0034] "Alkenyl," by itself or as part of another substituent, refers to an unsaturated, branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of an alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl, e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like.

[0035] "Alkynyl" by itself or as part of another substituent refers to an unsaturated, branched, straight-chain, 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. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like.

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

[0037] The term "aminoacyl" refers to -C(O)NR 21 R 22 group (in the formula, R 21 and R 22 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, heterocyclic, and substituted heterocyclic; R 21 and R 22 refers to a group, taken together with the nitrogen attached thereto, which optionally joins to form a heterocyclic or substituted heterocyclic group, wherein 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 are as defined herein.

[0038] "Alkoxy" by itself or as part of another substituent means -OR 31 group (in the formula, R 31 represents an alkyl or cycloalkyl group, as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like.

[0039] "Alkoxycarbonyl" by itself or as part of another substituent refers to C(O)OR31 group (in the formula, R 31 represents an alkyl or cycloalkyl group, as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, and the like.

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

[0041] "Arylalkyl" by itself or as part of another substituent refers to an alkyl group having a carbon atom, typically a terminal or sp 3It refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. When specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, and / or arylalkynyl is used. In certain embodiments, arylalkyl groups are (C7-C 30 ) arylalkyl, e.g., the alkanyl, alkenyl, or alkynyl portion of an arylalkyl group (C1-C 10 ), and the aryl moiety is (C6-C 20 In certain embodiments, the arylalkyl group is (C7-C 20 ) arylalkyl, e.g., the alkanyl, alkenyl, or alkynyl portion of the arylalkyl group is (C1-C8) and the aryl portion is (C6-C 12 )

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

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

[0044] "Cycloheteroalkyl" or "heterocyclyl," by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms. Typical heteroatoms replacing a carbon atom(s) include, but are not limited to, N, P, O, S, Si, and the like. Where 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, azirines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, quinuclidines, and the like.

[0045] "Heteroalkyl, heteroalkanyl, heteroalkenyl, and heteroalkynyl," by themselves or as part of another substituent, refer to alkyl, alkanyl, alkenyl, and alkynyl groups, respectively, in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom groups. Exemplary heteroatom groups that may be included in these groups include, but are not limited to, -O-, -S-, -SS-, -OS-, -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. (wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 44 are 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] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic group obtained by the removal of one hydrogen atom from a single atom of an aromatic heterocyclic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole, and the like. In certain embodiments, the heteroaryl group is a 5- to 20-membered heteroaryl. In certain embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl. In certain embodiments, the heteroaryl group is a group derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.

[0047] A "heteroarylalkyl" by itself or as part of another substituent refers to a heteroaryl group having a carbon atom, typically a terminal or sp 3" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. When specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl, and / or heteroarylalkynyl is used. In certain embodiments, the heteroarylalkyl group is a 6- to 30-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl portion of the heteroarylalkyl is 1- to 10-membered, and the heteroaryl portion is a 5- to 20-membered heteroaryl. In certain embodiments, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl portion of the heteroarylalkyl is 1- to 8-membered, and the heteroaryl portion is a 5- to 12-membered heteroaryl.

[0048] "Aromatic ring system," by itself or as part of another substituent, refers to an unsaturated cyclic or polycyclic ring system having a conjugated π-electron system. Specifically included within the definition of "aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indane, indene, phenalene, and the like. Exemplary aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0049] "Aromatic heterocyclic ring system," by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, and the like. Specifically included within the definition of "aromatic heterocyclic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as arsindole, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, and the like. Exemplary aromatic heterocyclic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0050] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s). Exemplary substituents include, but are not limited to, alkylenedioxy (e.g., methylenedioxy), -M, -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 (wherein M is a halogen and R 60 , R 61 , R 62 and R 63 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 60 and R 61 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, and R 64 and R 65 are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 64 and R 65together with the nitrogen atom to which they are attached 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 In certain embodiments, the substituents include -M, -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 - In certain embodiments, the substituents include -M, -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 is as defined above. For example, the substituted group may carry a methylenedioxy substituent or one, two or three substituents selected from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group.

[0051] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with or in which a compound is administered.

[0052] "Treating" or "treatment" of any condition, e.g., an autoimmune, metabolic, allergic, cancer, or infectious disease, in certain embodiments refers to improving the condition (i.e., halting or reducing the onset of the condition). In certain embodiments, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the patient. In certain embodiments, "treating" or "treatment" refers to inhibiting the condition either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both.

[0053] In certain embodiments, "treating" or "treatment" refers to delaying the onset of the condition.

[0054] A "therapeutically effective amount" means the amount of a compound that, when administered to a patient for preventing or treating a condition, such as an autoimmune, metabolic, allergic, cancer, or infectious disease, is sufficient to effect such treatment. The "therapeutically effective amount" varies depending on the compound, the condition and its severity, and the patient's age, weight, etc. Detailed Description

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

[0056] Before the present invention is described in more detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0057] Where a range of values ​​is provided, it is understood that, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0058] Certain ranges are presented herein with the term "about" preceding the numerical value. The term "about" is used herein to provide verbal support for the exact number that follows, and a number that is near or approximately the number that follows. In determining whether a number is near or approximately a specifically recited number, the near or approximately unrecited number may be a number that, in the context in which it is presented, results in a number that is substantially equivalent to the specifically recited number.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, 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 was specifically and individually indicated to be incorporated by reference, and the methods and / or materials are incorporated by reference as if disclosed and described in connection with the cited publication. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0061] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to operate on a precedential basis over the use of exclusive terminology such as "solely," "only," and the like, or the use of a "negative" limitation in connection with the recitation 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 which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0063] Although compounds and methods may have or be described using functional descriptions for the sake of grammatical fluidity, the claims should not necessarily be construed as being limited in any way by the construction of "means" or "step" limitations unless expressly recited under 35 U.S.C. § 112, but rather shall allow the full range of meaning and equivalents of the definitions provided by the claims under the doctrine of judicial equivalents, and in instances where the claims are expressly recited under 35 U.S.C. § 112, it shall be expressly understood to allow the full legal equivalents under 35 U.S.C. § 112.

[0064] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0065] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used to practice or test the present invention, preferred methods and materials are described herein. All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with the cited publications.

[0066] It will be appreciated that, while certain features of the invention are described, for clarity, in the context of separate embodiments, they can also be provided in combination in a single embodiment. Conversely, while various features of the invention are described, for brevity, in the context of a single embodiment, they can also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables are specifically embraced by the invention and disclosed herein, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), just as if each and every combination were individually and explicitly disclosed. In addition, all subcombinations of chemical groups listed in embodiments describing such variables are also specifically embraced by the invention, just as if each and every such subcombination of chemical groups disclosed herein were individually and explicitly disclosed herein.

[0067] Reference will now be made in detail to various embodiments. It is to be understood that the invention is not limited to these embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the appended claims.

[0068] Compounds for activating iNKT cells and selectively eliminating senescent cells Formula DCD-(I) According to certain embodiments, aspects of the present disclosure include: Compounds of formula DCD-(I): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or single bond, n is an integer from 2 to 25, Y is selected from carbon, nitrogen or silicon; R b , R cand 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0069] In embodiments, "salts" of the compounds of the present disclosure may include the following: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids 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, and the like. or (2) salts formed when an acidic proton present in the compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated to an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0070] The term "solvate," as used herein, refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound of DCD-(I) or its salt, with 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. Examples of representative solvents include water, methanol, ethanol, isopropanol, acetic acid, etc. When the solvent is water, the solvate formed is a hydrate.

[0071] Formula DCD-(IA-1) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IA-1): [ka] [In the formula, 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or single bond, n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0072] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -ORf and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0073] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl.

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

[0076] Formula DCD-(IA-2) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IA-2): [ka] [In the formula, X is -NHCO- or oxygen; R 1 , R 2 and R 3 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0077] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In certain cases, R 1 , R 2 and R 3 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0078] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I. In other cases, R i is Br.

[0080] Formula DCD-(IA-3) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IA-3): [ka] [In the formula, 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof. In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0081] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R gis hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl.

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

[0084] Formula DCD-(IA-4) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IA-4): [ka] [In the formula, X is -NHCO- or oxygen; R 1 and R 2 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0085] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 1 and R 2 are each hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0086] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R gis hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I. In other cases, R i is Br.

[0088] Formula DCD-(IB-1) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IB-1): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; 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; when Y is nitrogen, R d does not exist or R c and Rd together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0089] Formula DCD-(IB-2) According to certain embodiments, an aspect of the present disclosure is a compound of formula DCD-(IB-2) [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; R kis 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. k is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. k is methyl. 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0090] Formula DCD-(IB-3) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IB-3): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0091] Formula DCD-(IB-4) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IB-4): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; 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; when Y is nitrogen, R d does not exist or R c and R dtogether with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0092] Formula DCD-(IB-5) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IB-5): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

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

[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 is hydrogen. In some cases, R b is alkyl. In some cases, R b is C1-C16 alkyl. In some cases, R bis selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. b teeth, [ka] is selected from [ka] indicates a bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. In some cases, R c is hydrogen. In some cases, R c is alkyl. In some cases, R c is C1-C16 alkyl. In some cases, R c is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

[0096] In some embodiments, R d is a C5-C25 alkyl or a 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. d teeth, [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] indicates a bond to a C5-C25 alkyl, and R m and R n is 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 is hydrogen. In some cases, R m is a halogen. In some cases, R m is selected from fluorine, bromine, or iodine. In some cases, R n is hydrogen.

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

[0099] Formula DCD-(II) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(II): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; [ka] indicates a double or single bond, n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0100] Formula DCD-(IIA-1) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IIA-1): [ka] wherein 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; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0101] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0102] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, Ri is Cl. In other cases, R i is I. In other cases, R i is Br.

[0104] Formula DCD-(IIA-2) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(IIA-2): [ka] wherein X is —NHCO— or oxygen; R 1 , R 2 and R 3 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; [ka] indicates a double or single bond, n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0105] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In certain cases, R 1 , R 2 and R 3 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R fis alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0106] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is 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 some cases, R 11 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I.

[0107] In other cases, R i is Br. Formula DCD-(IIA-3) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(IIA-3): [ka] wherein 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; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R eis alkyl or substituted alkyl] or a salt, solvate or hydrate thereof.

[0108] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In some cases, R 3 is hydrogen. In some cases, R 4 is hydrogen. In certain cases, R 1 , R 2 , R 3 and R 4 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is 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 some cases, R 11 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I.

[0109] In other cases, R i is Br. Formula DCD-(IIA-4) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(IIA-4): [ka] wherein X is —NHCO— or oxygen; R 1 and R 2are 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; [ka] indicates a double or 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0110] In some cases, R 1 is hydrogen. In some cases, R 2 is hydrogen. In certain cases, R1 and R 2 Each of is hydrogen. In other cases, R 1 teeth, [ka] and [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl. In some cases, R 8 is selected from hydrogen, methyl, ethyl and cyclopropyl. R 9 is -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f is R 10 together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 is R f together form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

[0111] In one particular case, R 1 teeth, [ka] is selected from [ka] is R 1 represents an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. In other cases, R 1 teeth, [ka] and R 11 is alkyl or substituted alkyl, R 12 is alkyl or alkyl substituted with 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 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl. 11 is isopropyl. In one particular case, R 1 teeth, [ka] and R h and R iare each independently selected from hydrogen, hydroxyl, or halogen. h is hydroxyl. In some cases, R h is F. In some cases, R h is Cl. In some cases, R h is I. In some cases, R h is Br. In some cases, R i is hydroxyl. In some cases, R i is F. In other cases, R i is Cl. In other cases, R i is I. In other cases, R i teeth,

[0113] Formula DCD-(IIB-1) Aspects of the present disclosure, according to certain embodiments, include compounds of formula DCD-(IIB-1): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0114] Formula DCD-(IIB-2) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(IIB-2): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO bond, X is -NHCO- or oxygen; R 1 , R 2 , R 3 and R 4are 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; 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

[0115] Formula DCD-(IIB-3) According to certain embodiments, aspects of the present disclosure include a compound of formula DCD-(IIB-3): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof.

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

[0117] 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.

[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. b teeth, [ka] is selected from [ka] indicates a bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. In some cases, R c is hydrogen. In some cases, R cis alkyl. In some cases, R c is C1-C16 alkyl. In some cases, R c is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

[0119] In some embodiments, R d is a C5-C25 alkyl or a 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. d teeth, [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] indicates a bond to a C5-C25 alkyl, and R m and R n is 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 is hydrogen. In some cases, R m is a halogen. In some cases, R m is selected from fluorine, bromine, or iodine. In some cases, R n is hydrogen.

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

[0122] In some embodiments, compounds of interest include those shown in Tables 1-9, which 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 analogs [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 Analogues [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0127] Table 6 - Aminoxetane 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 - Tetrazolone 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] Method for activating iNKT cells and selectively eliminating senescent cells As outlined above, aspects of the present disclosure also include methods for activating iNKT cells. In embodiments, the methods include contacting iNKT cells with one or more compounds described herein or pharmaceutically acceptable salts thereof in an amount sufficient to activate the iNKT cells. In some cases, the source of iNKT cells is contacted in vitro. In other cases, the source of iNKT cells is contacted in vivo (e.g., by administration to a subject, as described in more detail below). In still other cases, the source of iNKT cells is contacted ex vivo.

[0131] In some embodiments, the method includes contacting iNKT cells with one or more of the compounds described herein in a manner sufficient to activate the iNKT cells, wherein the activated iNKT cells induce a TH1-type cytokine response (e.g., increased 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 cases, the activated iNKT cells induce a TH2-type cytokine response (e.g., increased 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 invention is sufficient to increase cytokine production by 1% or more, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a 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, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a control compound). In certain cases, activation of iNKT cells with one or more compounds of the invention is sufficient to increase interleukin-4 (IL-4) production by 1% or more, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a control compound).In certain cases, activation of iNKT cells with one or more compounds of the invention is sufficient to increase interleukin-6 (IL-6) production by 1% or more, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a control compound). In certain cases, activation of iNKT cells with one or more compounds of the invention is sufficient to increase interferon gamma (IFNγ) production by 1% or more, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a control compound).In certain cases, activation of iNKT cells with one or more compounds of the invention is sufficient to increase tumor necrosis factor (TNFα) production by 1% or more, 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 a suitable control (e.g., iNKT cells not contacted with a compound or a control compound).

[0133] In certain cases, activation of iNKT cells with one or more compounds of the invention is sufficient to increase cytokine production compared to contacting iNKT cells with α-galactosylceramide (α-GalCer), such as when cytokine production (e.g., increased one or more of 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) is greater upon activation of iNKT cells with one or more compounds of the invention compared to contacting iNKT cells with α-galactosylceramide. In some embodiments, compounds of the present disclosure increase cytokine production by 1% or more, 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 a 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, the at least one other lymphocyte is a T helper cell. In some embodiments, the method includes using a compound of the present invention to activate iNKT cells 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 contacted with the compound of the present invention for 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, including 24 hours or longer. In certain embodiments, the production of one or more cytokines can be assessed (e.g., quantified) after the compound is contacted with iNKT cells. In some cases, cytokine production is assessed in real time (i.e., continuously monitored). In other cases, cytokine production is assessed at predetermined time intervals, for example, every 1 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, contacting 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 their death. In certain embodiments, the senescent cells are senescent cells with an inflammatory secretome. For example, according to these embodiments, activating iNKT cells with a compound of the present invention results in a cytotoxic effect on the senescent cells. In some cases, the method includes activating iNKT cells with a compound of the present invention in a manner sufficient to reduce the presence of senescent cells or induce their death in vitro. In some cases, the method includes activating iNKT cells with a compound of the present invention in a manner sufficient to reduce the presence of senescent cells or induce their death in vivo (e.g., by administering the compound to a subject as part of a pharmaceutical composition 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, 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 99% or more.In certain cases, the compounds of the present invention eliminate the presence of senescent cells (for example, activating iNKT cells reduces the presence of senescent cells by 100%).The reduction in the presence of senescent cells can be evaluated (for example, quantified) after contacting the compound with iNKT cells.

[0137] In some embodiments, iNKT cells activated by contact with a compound described herein selectively reduce the presence of or selectively induce the death of senescent cells while preserving (i.e., not killing) healthy cells. In some cases, contacting activated iNKT cells with a compound of the present disclosure is sufficient to reduce the presence of senescent cells while preserving 75% or more, 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 including preservation of 99.99% or more of healthy cells. In certain cases, iNKT cells activated by contact with a compound of the present disclosure selectively reduce the presence of senescent cells without causing any effect on healthy cells (i.e., 100% healthy cells are preserved).

[0138] In some cases, the reduction of senescent cells can be assessed in real time (i.e., continuously monitored), while in other cases, the reduction of senescent cells is assessed at predetermined time intervals, such as every 1 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 the present disclosure also include administering one or more compounds described herein to a subject in need thereof.In embodiments, the term "subject" refers to a human or living organism to which the compound is administered.Thus, the subject of the present disclosure can include, but is not limited to, mammals, for example, humans and other primates, for example, chimpanzees and other apes and monkeys, dogs, rabbits, cats and other domesticated pets, and the like, and in certain embodiments, the subject is a human.

[0140] The term "subject" is also intended to include a human being or organism of any age, weight, or other physical characteristic; a subject may be an adult, a child, an infant, or a newborn.

[0141] In certain embodiments, the subject has been diagnosed with an autoimmune disease, a fibrotic disorder (lung, kidney, liver), an allergic disease, metabolic syndrome, type 2 diabetes, NAFLD, NASH, cancer, a pathogen infection, 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, sarcopenia, alopecia, post-myocardial infarction, vitiligo, POTS, MCAD, Sjogren's, scleroderma, Hashimoto's disease, ankylosing spondylitis, fibromyalgia, sarcoidosis, hepatitis, Raynaud's syndrome, a mold disease, celiac disease, Crohn's disease, pemphigus, SPS, PBC, psoriatic arthritis, CIDP, motor neuron disease, GPA, ALS, myasthenia gravis, and presbyopia. In some embodiments, the subject has been diagnosed (e.g., by clinical laboratory test or by a qualified health care professional) as having or exhibiting at least one symptom of multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, vitiligo, Behcet's disease, collagen disease, type 1 diabetes mellitus, uveitis, Sjogren's syndrome, autoimmune cardiomyotitis, autoimmune liver disease, autoimmune gastritis, pemphigus, Guillain-Barré syndrome, HTLV-1 associated myelopathy, or fulminant hepatitis.

[0142] In some embodiments, the method comprises administering one or more compounds to treat an infectious disease, for example, an infectious disease caused by a pathogenic microorganism, including a virus, a bacterium, a fungus, a protozoan, and a multicellular parasite. 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 can be administered to subjects by any convenient protocol, including but not limited to intraperitoneal, topical, oral, sublingual, parenteral, intravenous, vaginal, 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 a subject may vary, for example, from about 100 mg / day to about 10,000 mg / day, e.g., from about 10 mg / day to about 9000 mg / day, e.g., from 50 mg / day to about 8000 mg / day, e.g., from about 100 mg / day to about 7000 mg / day, e.g., from about 500 mg / day to about 6000 mg / day, inclusive of about 600 mg / day to about 5000 mg / day. Each dosage of the compound or pharmaceutically acceptable salt administered to a subject may vary in the range of about 1 mg / kg to about 1000 mg / kg, for example, about 2 mg / kg to about 900 mg / kg, for example, about 3 mg / kg to about 800 mg / kg, for example, about 4 mg / kg to about 700 mg / kg, for example, 5 mg / kg to about 600 mg / kg, for example, 6 mg / kg to about 500 mg / kg, for example, 7 mg / kg to about 400 mg / kg, for example, about 8 mg / kg to about 300 mg / kg, for example, about 9 mg / kg to about 200 mg / kg, and inclusive of about 10 mg / kg to about 100 mg / kg.

[0145] In certain embodiments, the protocol may include multiple dosing intervals. "Multiple dosing intervals" means that two or more dosages of a compound are administered to a subject in a continuous manner. In the practice of the method of the present disclosure, the treatment regimen may include two or more dosing intervals, for example, three or more dosing intervals, for example, four or more dosing intervals, for example, five or more dosing intervals, including ten or more dosing intervals. In a multiple dosing interval treatment protocol, the duration between dosing intervals may vary depending on the subject's physiology or the treatment protocol determined by a health care professional. For example, the duration between dosing intervals in a multiple dosage treatment protocol may be predetermined and follow regular intervals. Thus, the time between doses may vary, including 1 day or more, e.g., 2 days or more, e.g., 4 days or more, e.g., 6 days or more, e.g., 8 days or more, e.g., 12 days or more, e.g., 16 days or more, 24 days or more, hi certain embodiments, multiple dose interval protocols are provided with times between doses of 1 week or more, e.g., 2 weeks or more, e.g., 3 weeks or more, e.g., 4 weeks or more, e.g., 5 weeks or more, including 6 weeks or more.

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

[0147] In certain embodiments, the compounds of the present disclosure can be administered before, simultaneously with, or after other therapeutic agents for treating the same or unrelated conditions. When provided simultaneously with another therapeutic agent, the compounds of the present disclosure may be administered in the same or different compositions. Thus, the compound of interest and the other therapeutic agent can be administered to a subject as simultaneous therapy. By "simultaneous therapy," it is intended to mean administration to a subject so that the therapeutic effects of the combination of substances are achieved in the subject receiving therapy. For example, simultaneous therapy can be achieved by administering a compound of the present disclosure together with a pharmaceutical composition having at least one other agent, such as an anti-inflammatory agent, an immunosuppressant, a steroid, an analgesic, an anesthetic, an antihypertensive, or a chemotherapeutic agent, among other types of therapeutic agents, according to a specific dosing regimen, to create a therapeutically effective dose in combination. The separate pharmaceutical compositions can be administered simultaneously or at different times (i.e., sequentially, in any order, on the same day, or on different days), as long as the therapeutic effects of the combination of substances are achieved in the subject receiving therapy.

[0148] When a compound of the present disclosure is administered concurrently with a second therapeutic agent for treating the same condition (e.g., a chemotherapeutic agent, an antiviral agent, etc.), the weight ratio of the compound of the present disclosure to the second therapeutic agent can be in the range of 1:2, 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 any of these ranges. For example, the weight ratio of the compound of the present disclosure to the second therapeutic agent can 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 invention is in the range of, or between, 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. For example, the ratio of the second therapeutic agent to the compound of the 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] The present disclosure also includes compositions comprising 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 here.Pharmaceutically acceptable excipients are fully described in various publications, including, 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 (2000) AH Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.For example, the one or more excipients may be sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate, a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, poly(ethylene glycol), sucrose or starch), a disintegrant (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., stearic acid, cellulose acetate, cellulose acetate esters ... Magnesium phosphate, 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), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and basic waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol).

[0150] Compound can be formulated into pharmaceutical compositions by combining with suitable pharmaceutically acceptable carrier or diluent, and can be formulated into solid, semi-solid, liquid or gas form preparation, for example, tablet, capsule, powder, granule, ointment, liquid, suppository, injection, inhalant and aerosol.In certain embodiments, conjugate compound is formulated for injection.For example, target composition can be formulated for intravenous or intraperitoneal administration.

[0151] In certain embodiments, the composition of interest comprises a liposome or micelle composition, wherein the compound described herein is in a liposome-based or micelle-based formulation.The liposome-based or micelle-based formulation of the compound of the present invention can be prepared by any convenient liposome or micelle-forming protocol, such as mechanical dispersion, solvent dispersion, or detergent removal.In certain cases, liposomes are formed by mechanical dispersion, including sonication, French pressure cell extrusion, freeze-thawing, lipid thin film hydration (e.g., by manual shaking, mechanical agitation, or lyophilization), 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 thin film rehydration followed by extrusion (e.g., including extrusion through a 5 nm or larger, 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 filter, including extrusion through a 500 nm or larger filter).

[0152] In some embodiments, the liposome- or micelle-based formulations may contain, but are not limited to, sterols, such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters, such as cholesteryl stearate; 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, such as 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, such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters, such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C 16 ~C 18 Non-polymeric carrier materials may be formed, including fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; fatty acid anhydrides such as stearic acid anhydride; phospholipids such as phosphatidylcholine (lecithin), phosphatidylserine, phosphoethanolamine, phosphoethanolamine-PEG (2000), phosphatidylethanolamine, phosphatidylinositol, and their lyso-derivatives; sphingosine and its derivatives; sphingomyelins such as stearyl, palmitoyl, and tricosanyl sphingomyelin; ceramides such as stearyl and palmitoyl ceramide; glycosphingolipids; lanolin and lanolin alcohol; and combinations and mixtures thereof. In certain embodiments, the liposome-formulated compound comprises phosphatidylcholine and cholesterol.

[0153] The amount of each component used to prepare the liposome or micellar formulation may be varied, if desired, and may be present in an amount of 0.001% by weight or more, 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 cases where each component is present in an amount of 5% by weight or more of the liposome or micellar formulation. Where more than one component is present (e.g. a phospholipid, e.g. phosphatidylcholine and cholesterol), the ratio of the components may be in the range of 0.001:1 to 1:0.001, such as 0.005:1 to 1:0.005, for example, 0.01:1 to 1:0.01, for example, 0.05:1 to 1:0.05, for example, 0.1:1 to 1:0.1, for example, 0.5:1 to 1:0.5, such as 0.6:1 to 1:0.6, for example, 0.7:1 to 1:0.7, for example, 0.8:1 to 1:0.8, for example, 0.9:1 to 1:0.9, including where the ratio of the components is 1:1 (e.g. a 1:1 ratio of phosphatidylcholine to cholesterol). In one example, the liposome or micelle formulation may comprise a phospholipid component (e.g., phosphatidylcholine) and cholesterol in a ratio ranging from, for example, 0.001:1 to 1:0.001, for example, 0.005:1 to 1:0.005, for example, 0.01:1 to 1:0.01, for example, 0.05:1 to 1:0.05, for example, 0.1:1 to 1:0.1, for example, 0.5:1 to 1:0.5, for example, 0.6:1 to 1:0.6, for example, 0.7:1 to 1:0.7, for example, 0.8:1 to 1:0.8, for example, 0.9:1 to 1:0.9, including when the component ratio is 1:1. In certain instances, the ratio of phospholipid component to cholesterol is about 2:1.

[0154] A compound described herein (e.g., a compound of formula DCD-(I) or DCD-(II)) may be present in a liposome or micelle formulation in an amount of 0.001% by weight or more of the formulation, 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 when the active agent compound is present in an amount of 5% by weight or more. The ratio of activator compound (e.g., a compound for activating invariant natural killer T cells, e.g., a compound of formula 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, including ranges where the component ratio 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 active agent compound in a ratio of 2:1:0.15.

[0155] In certain embodiments, the liposomal or micelle formulations are prepared by dissolving in an organic solvent, 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, glyceryl monolaurate, glyceryl methylcellulose ... Glyceryl laurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodecenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters, for example, sucrose distearate and sucrose palmitate; sorbitan fatty acid esters the fatty acid esters, such as cetyl palmitate and cetearyl palmitate; fatty acid anhydrides, such as stearic acid anhydride; phospholipids, including phosphatidylcholine (lecithin), phosphatidylserine, phosphoethanolamine, phosphoethanolamine-PEG(2000), phosphatidylethanolamine, phosphatidylinositol, and lyso-derivatives thereof; sphingosine and derivatives thereof; sphingomyelins, such as stearyl, palmitoyl, and tricosanyl sphingomyelin; ceramides, such as stearyl and palmitoyl ceramide; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof.

[0156] In pharmaceutical dosage forms, the compounds may be administered in the form of their pharmaceutically acceptable salts, or may be used alone or in appropriate association and combination with other pharmaceutically active compounds. The following methods and excipients are merely illustrative and in no way limiting.

[0157] In some embodiments, the composition of interest comprises an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers of varying strengths, ranging from about 5 mM to about 100 mM. In some embodiments, the aqueous buffer contains a reagent that provides an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars, such as mannitol, glucose, and sucrose. In some embodiments, the aqueous buffer further comprises a non-ionic 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. In most cases, the composition is stored at about 4°C. Formulations may also be lyophilized, in which case the formulation generally includes a cryoprotectant, such as sucrose, trehalose, lactose, maltose, or mannitol. Lyophilized formulations can be stored for extended periods, even at ambient temperatures.

[0158] In some embodiments, the composition contains 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 disintegrating agents such as corn starch, potato starch or sodium carboxymethylcellulose, together with lubricants such as talc or magnesium stearate, and, if desired, together with diluents, buffers, wetting agents, preservatives and flavorings.

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

[0160] Although the dosage used to treat a subject can vary depending on the clinical goal to be achieved, suitable dosage ranges of the compound are those that provide from about 0.0001 mg to about 5000 mg of active agent, e.g., from about 1 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 1000 mg, or from about 1000 mg to about 5000 mg, which can be administered in a single dose. Those skilled in the art will readily recognize that dosage levels can 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 can be administered, for example, twice a day (qid), every day (qd), every other day (qod), every 3 days, 3 times a week (tiw), or twice a week (biw) over a period of time. For example, the compound can be administered qid, qd, qod, tiw, or biw for a period of 1 day to about 2 years or longer. For example, the compound can be administered at any of the above frequencies for 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, 2 years, or longer, depending on various factors.

[0162] The dosage units of the present disclosure can be made using manufacturing methods available in the art and can be in various forms suitable for administration by injection (including topical, intravesical, intrathecal, intravenous, intramuscular, subcutaneous, and cutaneous), such as a solution, suspension, liquid, lyophilizate, or emulsion. The dosage units can 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 additional active agents.

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

[0164] Aspects of the subject matter described herein, including embodiments, may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the disclosure, certain non-limiting aspects of the present disclosure, numbered 1 through 99, are provided below. As will be apparent to one of skill in the art upon reading this disclosure, each individually numbered aspect can also be used or combined with any of the aspects 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 explicitly provided below: 1. Compound of formula DCD-(I): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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 each independently represent -C or -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 form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; [ka] indicates a double or single bond, n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof. 2.R 1 , R 2 , R 3 and R 4 10. The compound according to 1, wherein each of 3.R 1 2. The compound according to 1, wherein is hydrogen. 4.R 1 but, [ka] and [ka] But R 1 indicates an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R 9 But, -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f But R 10together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 But R f and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , R 79 , R 79 , R 79 , R 79 , R 79 , R 79 , R 79 , R 7 5.R 1 but, [ka] is selected from [ka] But R 1 indicates an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g 5. The compound according to 4, wherein is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine. 6.R 1 but, [ka] and R 11 is alkyl or substituted alkyl; R12 is alkyl or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. 7.R 1 but, [ka] and R h and R i are each independently selected from hydrogen, hydroxyl, or a halogen selected from F, Cl, I, or Br. 8. The compound according to any one of 1 to 7, wherein X1 is -NH. 9.R a is O, X2 is C, [ka] 9. The compound according to 8, wherein is carbonyl. 10.R a is O, X2 is -SR k and R k is methyl, [ka] 9. The compound according to claim 8, wherein is a sulfur oxide. 11.R a is CF3, 9. The compound according to 8, wherein X2 is C. 12.R a 9. The compound according to 8, wherein X2 together with X2 form a heterocycloalkyl or substituted heterocycloalkyl. 13.R a13. The compound according to 12, wherein X2 together with X2 form an oxacyclobutane. 14.R a is F, X1 is C, X2 is C, [ka] 8. The compound according to any one of 1 to 7, wherein is a double bond. 15.R e is a C8-C20 alkyl or substituted C8-C20 alkyl. 16.R e 20. The compound according to 19, wherein is C13 alkyl. 17.R d is a C5 to C25 alkyl or a C5 to 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. 18.R d but, [ka] [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] represents a bond to a C5-C25 alkyl; R m and Rn 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. 19.R m 19. The compound according to 18, wherein is hydrogen. 20.R m 19. The compound according to 18, wherein is a halogen. 21.R m 21. The compound according to 20, wherein is selected from fluorine, bromine, or iodine. 22.R n 22. The compound according to any one of 18 to 21, wherein is hydrogen. 23.R n 22. The compound according to any one of 18 to 21, wherein is halogen. 24.R n 24. The compound according to 23, wherein is fluorine, bromine or iodine. 25.R b 25. The compound according to any one of 1 to 24, wherein is hydrogen. 26.R b methyl, ethyl, propyl, butyl and [ka] is selected from the group consisting of [ka] indicates the bond to Y, and R zis 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 27.R b but, [ka] and [ka] indicates the bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 28.R b but, [ka] and [ka] indicates the bond to Y, and R zis 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 29.R c The compound according to any one of 1 to 28, wherein is C1 to C10 alkyl. 30.R c 27. The compound according to 26, wherein is selected from the group consisting of methyl, ethyl, propyl, and butyl. 31. [Table 10] 2. The compound according to 1, selected from the group consisting of: 32. A method comprising contacting invariant natural killer T (iNKT) cells with a compound according to any one of 1 to 31. 33. The method according to 32, wherein the iNKT cells are contacted in vitro. 34. The method according to 32, wherein the iNKT cells are contacted in vivo. 35. The method of any one of 32 to 34, wherein contacting the compound with the iNKT cells is sufficient to activate the iNKT cells. 36. The method of 35, wherein activating iNKT cells induces increased production of one or more cytokines selected from the group consisting of IFN-γ, IL-1β, IL-2, IL-3, IL-8, IL-12, IL-15, TNF-α, GM-CSF, RANTES, MIP-1α, and MCP-1. 37. The method of 35, wherein activating iNKT cells induces increased production of one or more cytokines selected from the group consisting of IL-4, IL-6, IL-8, IL-10 and IL-13. 38. The method further comprising contacting the activated iNKT cells with a composition comprising senescent cells; 38. The method of any one of 35 to 37, wherein contacting with activated iNKT cells reduces the presence of or eliminates senescent cells in the composition. 39. The method of claim 39, wherein the senescent cells comprise an inflammatory secretome. 40. The method of any one of 38 to 39, wherein the composition further comprises healthy cells. 41. The method of 40, wherein contacting with activated iNKT cells reduces or eliminates the presence of senescent cells in the composition without reducing the presence of healthy cells. 42. The method of 41, wherein the presence of healthy cells is reduced by 5% or less when the composition contacts activated iNKT cells. 43. A method comprising administering to a subject in need thereof a compound according to any one of 1 to 31. 44. A method for selectively reducing the presence of or eliminating senescent cells in a subject, comprising administering to a subject in need thereof a compound according to any one of 1 to 31. 45. The method of claim 36, wherein the subject has been diagnosed with an autoimmune disease, an allergic disease, a metabolic disorder, cancer, or a pathogen infection. 46. ​​The method of 45, wherein the subject has been diagnosed with one or more of a metabolic disorder, an eye disease, an age-related disease, fibrosis, a cardiac disease, or a renal disease. 47. A compound according to any one of 1 to 31, and Pharmaceutically acceptable carrier A pharmaceutical composition comprising: 48. A pharmaceutical composition for selectively reducing the presence of or eliminating senescent cells in a subject, the composition comprising: 1 to 31, and Pharmaceutically acceptable carrier A pharmaceutical composition comprising: 49. Use of a compound according to any one of 1-31 in the manufacture of a medicament for treating a subject in need thereof. 50. Use of a compound according to any one of 1 to 31 in the manufacture of a medicament for selectively reducing the presence of or eliminating senescent cells in a subject in need thereof. 51. Compound of formula DCD-(II): [ka] [In the formula, Z is [ka] is selected from [ka] indicates a ZO 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; [ka] indicates a double or single bond, n is an integer from 2 to 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; when Y is nitrogen, R d does not exist or R c and R d together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; R e is alkyl or substituted alkyl], or a salt, solvate or hydrate thereof. 52.R 1 , R 2 , R 3 and R 4 52. The compound according to 51, wherein each of 53.R 1 53. The compound according to 52, wherein is hydrogen. 54.R 1 but, [ka] and [ka] But R 1 indicates an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R 9 But, -NR f -OR f and R f is alkyl, substituted alkyl, acyl, alkylacyl, or substituted alkylacyl, or R f But R 10together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R 10 is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R 10 But R f and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , R 79 , R 79 , R 79 , R 79 , R 79 , R 79 , R 70 , R 7 55.R 1 but, [ka] is selected from [ka] But R 1 indicates an -O bond, R 8 is hydrogen, alkyl, or substituted alkyl; R g 55. The compound according to 54, wherein is hydrogen or a halogen selected from F, Cl, I or Br. 56.R 1 but, [ka] and R 11 is alkyl or substituted alkyl; R12 is alkyl or alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. 57.R 1 but, [ka] and R h and R i 57. The compound of 56, wherein each is independently selected from hydrogen, hydroxyl, or a halogen selected from F, Cl, I, or Br. 58. The compound according to any one of 51 to 57, wherein X1, X2, X3, X4 and X5 together form a pyrazole. 59. The compound according to any one of 51 to 57, wherein X1, X2, X3, X4 and X5 together form an imidazole. 60. The compound according to any one of 51 to 57, wherein X1, X2, X3, X4 and X5 together form a tetrazole. 61. X1 is carbon, X2 is nitrogen; X3 is nitrogen; X4 is carbon, 58. The compound according to any one of 51 to 57, wherein X5 is carbon. 62.X1 is carbon, X2 is nitrogen; X3 is carbon, X4 is carbon, 58. The compound according to any one of 51 to 57, wherein X5 is nitrogen. 63.X1 is nitrogen, X2 is nitrogen; X3 is nitrogen; X4 is nitrogen; X5 is carbon, R a is O, [ka] 58. The compound according to any one of 51 to 57, wherein is carbonyl. 64.R e 64. The compound according to any one of 51 to 63, wherein is C8 to C20 alkyl or substituted C8 to C20 alkyl. 65.R e 65. The compound according to 64, wherein is C13 alkyl. 66.R d is a C5 to C25 alkyl or a C5 to 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. 67.R d but, [ka] [ka] and C5-C25 alkyl substituted with a moiety selected from the group consisting of: [ka] represents a bond to a C5-C25 alkyl; R m and R nare 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. 68.R m 68. The compound according to 67, wherein is hydrogen. 69.R m 68. The compound according to 67, wherein is a halogen. 70.R m 70. The compound according to 69, wherein is selected from fluorine, bromine, or iodine. 71.R n 71. The compound according to any one of 67 to 70, wherein is hydrogen. 72.R n 71. The compound according to any one of 67 to 70, wherein is a halogen. 73.R n 73. The compound according to 72, wherein is fluorine, bromine or iodine. 74.R b 74. The compound according to any one of 51 to 73, wherein is hydrogen. 75.R b methyl, ethyl, propyl, butyl and [ka] is selected from the group consisting of [ka] indicates the bond to Y, and R zis 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 76.R b but, [ka] and [ka] indicates the bond to Y, and R z 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 77.R b but, [ka] and [ka] indicates the bond to Y, and R zis 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. z is alkyl, for example, C1 to C16 alkyl or C1 to C16 substituted alkyl. 78.R c 78. The compound according to any one of 51 to 77, wherein is C1 to C10 alkyl. 79.R c 79. The compound according to 78, wherein is selected from the group consisting of methyl, ethyl, propyl, and butyl. 80. Compounds DCD-104 and DCD-105: [ka] 52. The compound according to 51, selected from: 81. A method comprising contacting invariant natural killer T (iNKT) cells with a compound according to any one of 51 to 80. 82. The method according to 81, wherein the iNKT cells are contacted in vitro. 83. The method according to 81, wherein the iNKT cells are contacted in vivo. 84. The method of any one of 81-83, wherein contacting the compound with the iNKT cells is sufficient to activate the iNKT cells. 85. The method of claim 84, wherein activating iNKT cells induces increased production of one or more cytokines selected from the group consisting of IFN-γ, IL-1β, IL-2, IL-3, IL-8, IL-12, IL-15, TNF-α, GM-CSF, RANTES, MIP-1α, and MCP-1. 86. The method of claim 84, wherein activating iNKT cells induces increased production of one or more cytokines selected from the group consisting of IL-4, IL-6, IL-8, IL-10, and IL-13. 87. The method further comprising contacting the activated iNKT cells with a composition comprising senescent cells; 87. The method of any one of 84 to 86, wherein contacting with activated iNKT cells reduces the presence of or eliminates senescent cells in the composition. 88. The method of claim 87, wherein the senescent cells comprise an inflammatory secretome. 89. The method of any one of 87 to 88, wherein the composition further comprises healthy cells. 90. The method of claim 89, wherein contacting with activated iNKT cells reduces or eliminates the presence of senescent cells in the composition without reducing the presence of healthy cells. 91. The method of 90, wherein the presence of healthy cells is reduced by 5% or less when the composition contacts activated iNKT cells. 92. A method comprising administering a compound according to any one of 51 to 80 to a subject in need thereof. 93. A method for selectively reducing the presence of or eliminating senescent cells in a subject, the method comprising administering to a subject in need thereof a compound according to any one of 51-80. 94. The method of 93, wherein the subject has been diagnosed with an autoimmune disease, an allergic disease, a metabolic disorder, cancer, or a pathogen infection. 95. The method of 93, wherein the subject has been diagnosed with one or more of a metabolic disorder, an eye disease, an age-related disease, fibrosis, a heart disease, or a kidney disease. A compound according to any one of 96.51 to 96.80, and Pharmaceutically acceptable carrier A pharmaceutical composition comprising: 97. A pharmaceutical composition for selectively reducing the presence of or eliminating senescent cells in a subject, the composition comprising: A compound according to any one of claims 51 to 80, and Pharmaceutically acceptable carrier A pharmaceutical composition comprising: 98. Use of a compound according to any one of 51 to 80 in the manufacture of a medicament for treating a subject in need thereof. 99. Use of a compound according to any one of 51 to 80 in the manufacture of a medicament for selectively reducing the presence of or eliminating senescent cells in a subject in need thereof. [Example]

[0165] The following examples are put forward so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0166] Example 1 Compound synthesis General synthetic procedure Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, 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, New York: Longman, 1978).

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

[0168] During any of the processes for the preparation of the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, as described in standard works, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Fourth edition, Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0169] The compounds described herein may contain one or more chiral centers and / or double bonds and therefore can exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the exemplified compounds. The compounds described also include isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O and the like. Compounds can exist in unsolvated and solvated forms, including hydrated forms. Generally, compounds can be hydrated or solvated. Some compounds can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

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

[0171] The compounds of the present disclosure can be prepared in a variety of ways. Included herein are exemplary methods for making the compounds described herein.

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

[0173] A mixture of DCM (25 mL) and HO (25 mL) containing NaN (10 g, 153 mmol) and TfO (5.5 mL, 31.5 mmol) cooled to 0 °C was added dropwise over 20 min. After the addition, the resulting mixture was stirred at room temperature for 3 h. 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 NaCO and used directly in the next step.

[0174] The 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 HO (30 mL). This organic DCM layer contained TfN3. Additional MeOH was added to make the mixture a homogeneous solution. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo, and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (PE / EtOAc 1:1) to give (2S,3S,4R)-2-azidooctadecane-1,3,4-triol (4.5 g, 83%) as an oil.

[0175] Synthesis of (2S,3S,4R)-2-azido-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 equiv.), TrtCl (6.8 g, 24.4 mmol, 1.4 equiv.), and DMAP (213 mg, 1.74 mmol, 0.1 equiv.) in dry pyridine (100 mL) was stirred at 50 °C overnight. The pyridine was removed under reduced pressure, and the residue was diluted with EtOAc (200 mL), washed with water (2 × 50 mL), brine (2 × 50 mL), dried over Na SO , and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g; EtOAc / PE 1:2) to give (2S,3S,4R)-2-azido-1-(trityloxy)octadecane-3,4-diol (9 g, 88%) as an oil. 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 equiv) in dry DMF (120 mL) was added a 60% oil dispersion of NaH (2.2 g, 55.0 mmol, 3.5 equiv) in portions at 0 °C. After complete addition, the mixture was stirred at 0 °C for 10 min. BnBr (9.2 g, 53.8 mmol, 3.5 equiv) was added, and the mixture was allowed to warm to room temperature and stirred for an additional 5 h. It was poured into ice / water (200 mL) and diluted with EtOAc (1 L). The organic layer was washed with water (4 × 200 mL), brine (2 × 200 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g; EtOAc / PE 1:15) to give (((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)methanetriyl)tribenzene (10 g, 85%) as an oil. LC / MS: C 51 H 63 Calculated mass for N3O3: 765.49, Measured: 788.50 [M+Na] + . Synthesis of (2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecan-1-ol [ka]

[0177] To a mixture of (((2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyloxy)methanetriyl)tribenzene (10 g, 13.1 mmol, 1.0 equiv) in toluene (60 mL) and MeOH (60 mL) was added concentrated aqueous HCl (2 mL; 12 M). The mixture was heated to 60° C. and stirred overnight. The pH value of the aqueous phase was adjusted to about 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; EtOAc / PE: 1:10) to give (2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecan-1-ol (5 g, 73%) as an oil. LC / MS: C 32 H 49 Calculated mass for N3O3: 523.38, Measured: 546.25 [M+Na] + . Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl acetate [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 AcO (120 mL) was stirred at room temperature overnight. The reaction was quenched with crushed ice, and the resulting mixture was extracted with DCM (3 × 300 mL). The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl acetate (20 g, 74%) as an oil. Synthesis of (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodo-tetrahydro-2H-pyran [ka]

[0178] To a mixture of (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 equiv) in DCM (150 mL) was added TMSI (6.9 g, 34.5 mmol, 1.0 equiv) under an atmosphere of N at 0° C. 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 give (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodo-tetrahydro-2H-pyran (19 g, 85%) as an oil.

[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)octadecan-1-ol (3.0 g, 5.7 mmol, 1.0 equiv.), TBAI (19.0 g, 51.4 mmol, 9.0 equiv.), DIPEA (2.2 g, 17.0 mmol, 3.0 equiv.), and 4Å-MS (2 g) in benzene (80 mL) was stirred at 65° C. for 20 minutes under a N atmosphere. To this mixture was added a solution of (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-iodo-tetrahydro-2H-pyran (18.6 g, 17.2 mmol, 3.0 equiv.) in benzene (30 mL). The mixture was stirred at 65° C. for an additional 2 hours, cooled to room temperature, and EtOAc (150 mL) was added. The mixture was filtered, and the filtrate was washed with saturated sodium thiosulfate solution (2×80 mL), brine (2×80 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (120 g; EtOAc / PE 1:5) to give (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 oil. LC / MS: C 66 H 83 Calculated mass for N3O8: 1045.62, Found: 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] To 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 equiv.) in THF (30 mL) was added 1 M PMe in THF (3.2 mL, 3.2 mmol, 1.1 equiv.) at room temperature. The mixture was stirred at room temperature for 5 hours, then HO (10 mL) was added, and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (MeOH / DCM 1:20) to give (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)octadecan-2-amine (2 g, 68%) as an oil. 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] To a mixture of (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)octadecan-2-amine (200 mg, 0.2 mmol, 1.0 equiv) in EtOH (10 mL) and DCM (3 mL) was added 20% Pd(OH) / C (0.2 g). The mixture was hydrogenated (1 atm) at room temperature for 16 h, then the catalyst was removed by filtration through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give (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 oil.

[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)octadecan-2-yl)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecaneamide Synthesis of 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde [ka] To a mixture of oxalyl chloride (164 mg, 1.29 mmol, 1.5 equiv) in DCM (5 mL) was added dropwise DMSO (202 mg, 2.58 mmol, 3.0 equiv) at −78° C. under an atmosphere of N 2 . The mixture was stirred for 15 min at −78° C., then (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (100 mg, 0.86 mmol, 1.0 equiv) in DCM (1 mL) was added dropwise. The mixture was stirred for 50 min at −78° C., then Et 3 N (1 mL) was added. Stirring was continued for an additional 5 min at −78° C., then the mixture was allowed to warm to room temperature. HO (10 mL) was added, and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with HO (20 mL) and brine (20 mL), then dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to give 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (70 mg, 71%) as an oil. The compound was used without further purification. f =0.3, PE / EtOAc 1:3. Synthesis of (10-carboxydecyl)triphenylphosphonium bromide

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

[0184] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (315 mg, 0.61 mmol, 1.0 equiv.) in THF (5 mL) at 0 °C under an atmosphere of N 2 , 2 M NaHMDS in THF (0.61 mL, 1.22 mmol, 2 equiv.) was slowly added. The mixture was stirred at 0 °C for 1 h, and then 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (70 mg, 0.61 mmol, 1.0 equiv.) in THF (1 mL) was added at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. Then HO (10 mL) was added and the pH was adjusted to 4-5 with 2 N HCl. The mixture was extracted with EtOAc (20 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (PE / EtOAc 2:1) to give (E)-11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undec-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)undec-10-enoic acid (60 mg, 0.22 mmol, 1.0 equiv.) and PtO (5 mg, 0.022 mmol, 0.1 equiv.) in EtOH (50 mL) was hydrogenated (1 atm) at room temperature for 1 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was rinsed with EtOH. The filtrate was concentrated under reduced pressure to give 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)octadecan-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 equiv.) in THF (5 mL) was added HBTU (154 mg, 0.41 mmol, 2.0 equiv.), EtN (41 mg, 0.41 mmol, 2.0 equiv.), and NMM (41 mg, 0.41 mmol, 2.0 equiv.) at room temperature under an atmosphere of N. The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica (DCM / MeOH 9:1) and preparative HPLC to give 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)octadecan-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] + ; 1H 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 equiv.) in CHCN (100 mL) under an atmosphere of N was added PPh (3.0 g, 11.31 mmol, 1.0 equiv.). The mixture was heated to 90 °C and stirred for 72 h, then concentrated under reduced pressure and the crude product crystallized from EtOAc to give (10-carboxydecyl)triphenylphosphonium bromide (5.8 g, 97%) as a solid. LC / MS: C 29 H 36 Calculated mass for BrO2P: 526, Measured mass: 447 [M-Br] + .

[0188] Synthesis of (E)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodec-11-enoic acid [ka] To a mixture of (10-carboxydecyl)triphenylphosphonium bromide (0.4 g, 0.76 mmol, 1.0 equiv.) in THF (10 mL) at 0 °C under an atmosphere of N was slowly added NaHMDS, 2 M in THF (0.8 mL, 1.6 mmol, 2.1 equiv.). The mixture was stirred at 0 °C for 1 h, and then 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (87 mg, 0.76 mmol, 1.0 equiv.) in THF (1 mL) was added at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. Then HO (10 mL) was added and the pH was adjusted to 4-5 with 2 N HCl. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give (E)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodec-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)dodec-11-enoic acid (0.11 g, 0.39 mmol, 1.0 equiv.) and PtO (10 mg, 0.04 mmol, 0.1 equiv.) in EtOH (70 mL) was hydrogenated at room temperature (1 atm) for 1 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give 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)octadecan-2-yl)-12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanamide [ka] To a mixture of 12-(3-fluorobicyclo[1.1.1]pentan-1-yl)dodecanoic acid (0.1 g, 0.35 mmol, 1.0 equiv.) 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 equiv.) in THF (6 mL) was added HBTU (267 mg, 0.70 mmol, 2.0 equiv.), EtN (71 mg, 0.70 mmol, 2.0 equiv.), and NMM (71 mg, 0.70 mmol, 2.0 equiv.) at room temperature under an atmosphere of N. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (DCM / MeOH 8:1) and preparative HPLC to give 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)octadecan-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] + ; 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)octadecan-2-yl)undecaneamide Synthesis of (E)-11-(bicyclo[2.2.2]octan-1-yl)undec-10-enoic acid [ka] To a mixture of 9-carboxynonyl(triphenyl)phosphonium bromide (371 mg, 0.72 mmol, 1.0 equiv.) in THF (5 mL) at 0 °C under an atmosphere of N2, NaHMDS, 2 M in THF (0.72 mL, 1.44 mmol, 2 equiv.) was slowly added. The mixture was stirred at 0 °C for 1 h, and then bicyclo[2.2.2]octane-1-carbaldehyde (0.1 g, 0.72 mmol, 1.0 equiv.) in THF (1 mL) was added at 0 °C. The mixture was warmed to room temperature and stirred for 16 h. HO was then added, and the pH was adjusted to approximately 4–5 with 2 N HCl. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 2:1) to give (E)-11-(bicyclo[2.2.2]octan-1-yl)undec-10-enoic acid (0.15 g, 71%) as a solid. LC / MS: C 19 H 32 Calculated mass for O2: 292, measured mass: 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)undec-10-enoic acid (0.15 g, 0.51 mmol, 1.0 equiv.) and 10% Pd / C (20 mg) in MeOH (10 mL) was hydrogenated at room temperature (1 atm) for 1 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 11-(bicyclo[2.2.2]octan-1-yl)undecanoic acid (130 mg, 86%) as a solid. LC / MS: C 19 H 34 Calculated mass for O2: 294, measured mass: 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)octadecan-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 equiv.) 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 equiv.) in DCM (5 mL) was added EDCI (127 mg, 0.66 mmol, 1.5 equiv.) and DMAP (11 mg, 0.09 mmol, 0.2 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc (10 mL) and washed with brine (5 mL). The aqueous layer was extracted with EtOAc (10 mL × 2), and the combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to give 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)octadecan-2-yl)undecaneamide (0.2 g, 35%) as a solid. LC / MS: C 85 H 117 Calculated mass for NO9: 1296, Measured mass: 1297 [M+H] + .

[0194] Synthesis of 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)octadecan-2-yl)undecaneamide [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)octadecan-2-yl)undecanamide (0.1 g, 0.08 mmol, 1.0 equiv.) and 20% Pd(OH) / C (0.2 g) in EtOH / DCM (10 mL / 3 mL) was hydrogenated at room temperature (1 atm) for 16 hours. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography on a silica gel column (DCM / MeOH) and preparative HPLC to give 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)octadecan-2-yl)undecanamide (8.9 mg, 15%) as a solid. LC / MS: C 43 H 81 Calculated mass for NO9: 755.59, Measured mass: 756.50 [M+H] + ; 1H 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, 12H), 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)octadecan-2-yl)-11-(2-methylcyclopropyl)undecaneamide Synthesis of (E)-11-(2-methylcyclopropyl)undec-10-enoic acid [ka] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (488 mg, 0.95 mmol, 1.0 equiv.) in THF (5 mL) at 0 °C under an atmosphere of N was slowly added NaHMDS, 2 M in THF (1.0 mL, 2.0 mmol, 2.0 equiv.). The mixture was stirred at 0 °C for 1 h, and then 2-methylcyclopropane-1-carbaldehyde (80 mg, 0.95 mmol, 1.0 equiv.) in THF (1 mL) was added at 0 °C. The mixture was warmed to room temperature and stirred for 16 h. Then HO (10 mL) was added, and the pH was adjusted to approximately 4-5 with 2 N HCl. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 2:1) to give (E)-11-(2-methylcyclopropyl)undec-10-enoic acid (120 mg, 53%) as a solid. LC / MS: C 15 H 26 Calculated mass for O2: 238, measured mass: 237 [MH]- .

[0196] Synthesis of 11-(2-methylcyclopropyl)undecanoic acid [ka] To a mixture of (E)-11-(2-methylcyclopropyl)undec-10-enoic acid (120 mg, 0.50 mmol, 1.0 equiv.) in THF (5 mL) and HO (5 mL) at room temperature was added p-MeCHSONHNH (938 mg, 5.0 mmol, 10 equiv.) and KOAc (642 mg, 6.6 mmol, 13 equiv.). The mixture was heated to reflux and stirred for 5 hours, cooled, and HO was added. The mixture was extracted with EtOAc (30 mL x 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (PE / EtOAc) to give 11-(2-methylcyclopropyl)undecanoic acid (90 mg, 74%) as an oil. LC / MS: C 15 H 28 Calculated mass for O2: 240, measured mass: 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)octadecan-2-yl)-11-(2-methylcyclopropyl)undecaneamide [ka] To a mixture of 11-(2-methylcyclopropyl)undecanoic acid (80 mg, 0.33 mmol, 1.0 equiv.) 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 equiv.) in THF (6 mL) was added HBTU (252 mg, 0.66 mmol, 2.0 equiv.), EtN (67 mg, 0.66 mmol, 2.0 equiv.), and NMM (67 mg, 0.66 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM / MeOH 8:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(2-methylcyclopropyl)undecanamide (20.7 mg, 9%) as a solid. LC / MS: C 39 H 75 Calculated mass for NO9: 701.54, measured mass: 702.45 [M+H] + ; 1 H 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-(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)octadecan-2-yl)undecaneamide Synthesis of (E)-11-(cuban-1-yl)undec-10-enoic acid [ka] To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (0.4 g, 0.8 mmol, 1.0 equiv.) in THF (6 mL) at 0 °C under an atmosphere of N 2 , NaHMDS, 2 M in THF (0.8 mL, 1.6 mmol, 2.0 equiv.) was slowly added. The mixture was stirred at 0 °C for 1 h, and then cubane-1-carbaldehyde (0.1 g, 0.8 mmol, 1.0 equiv.) in THF (1 mL) was added at 0 °C. The mixture was warmed to room temperature and stirred for 16 h. Then, HO (10 mL) was added, and the pH was adjusted to approximately 4-5 with 2 N HCl. The mixture was extracted with EtOAc (20 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (PE / EtOAc 2:1) to give (E)-11-(cuban-1-yl)undec-10-enoic acid (0.11 g, 49%) as a solid. LC / MS: C 19 H 26 Calculated mass for O2: 286, measured mass: 285 [MH] - .

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

[0200] Synthesis of 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)octadecan-2-yl)undecaneamide [ka] To a mixture of 11-(cuban-1-yl)undecanoic acid (80 mg, 0.3 mmol, 1.0 equiv.) 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, equiv.) in THF (6 mL) was added HBTU (210 mg, 0.55 mmol, 2.0 equiv.), EtN (56 mg, 0.55 mmol, 2.0 equiv.), and NMM (56 mg, 0.55 mmol, 2.0 equiv.) at room temperature under an atmosphere of N. The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH) and preparative HPLC to give 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)octadecan-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-(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)octadecan-2-yl)dodecanamide Synthesis of (E)-12-(cuban-1-yl)dodec-11-enoic acid [ka] To a mixture of (10-carboxydecyl)triphenylphosphonium bromide (319 mg, 0.6 mmol, 1.0 equiv.) in THF (6 mL) at 0 °C under an atmosphere of N2, NaHMDS, 2 M in THF (0.6 mL, 1.2 mmol, 2.0 equiv.) was slowly added. The mixture was stirred at 0 °C for 1 h, and then cubane-1-carbaldehyde (80 mg, 0.6 mmol, 1.0 equiv.) in THF (1 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. HO (10 mL) was then added, and the pH was adjusted to approximately 4-5 with 2 N HCl. The mixture was extracted with EtOAc (20 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica (PE / EtOAc 2:1) to give (E)-12-(cuban-1-yl)dodec-11-enoic acid (110 mg, 60%) as a solid. LC / MS: C 20 H 28 Calculated mass for O2: 300, measured mass: 299 [MH] - .

[0202] Synthesis of 12-(cuban-1-yl)dodecanoic acid [ka] A mixture of (E)-12-(cuban-1-yl)dodec-11-enoic acid (110 mg, 0.37 mmol, 1.0 equiv.) and PtO (8 mg, 0.04 mmol, 0.1 equiv.) in EtOH (70 mL) was hydrogenated (1 atm) at room temperature for 1 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give 12-(cuban-1-yl)dodecanoic acid (0.1 g, 90%) as a solid. LC / MS: C 20 H 30 Calculated mass for O2: 302, measured mass: 301 [MH] - .

[0203] Synthesis of 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)octadecan-2-yl)dodecanamide [ka] To a mixture of 12-(cuban-1-yl)dodecanoic acid (80 mg, 0.26 mmol, 1.0 equiv.) 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 equiv.) in THF (6 mL) was added HBTU (201 mg, 0.53 mmol, 2.0 equiv.), TEA (53 mg, 0.53 mmol, 2.0 equiv.), and NMM (53 mg, 0.53 mmol, 2.0 equiv.) at room temperature under a N atmosphere. The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH) and preparative HPLC to give 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)octadecan-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] + ; 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-diheptylhept-6-yn-1-amine [ka] To a mixture of hept-6-ynal (0.7 g, 6.4 mmol, 1.0 equiv.) in DCE (10 mL) was added diheptylamine (1.3 g, 6.4 mmol, 1.0 equiv.) at room temperature under an atmosphere of N2. The mixture was stirred at room temperature for 15 minutes, and then NaBH(OAc)3 (2.0 g, 9.5 mmol, 1.5 equiv.) and AcOH (0.1 mL) were added. The mixture was stirred at room temperature for 3 hours, and then HO (10 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (MeOH / DCM 1:8) to give N,N-diheptylhept-6-yn-1-amine (0.7 g, 36%) as an oil. LC / MS: C 21 H 41 Calculated mass for N: 307, Measured mass: 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)pentyl)-N-heptylheptan-1-amine [ka] N,N-diheptylhept-6-yn-1-amine (38 mg, 0.12 mmol, 1.3 equiv.) 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 equiv.) t To a mixture of BuOH (3 mL) and HO (3 mL) was added CuSO (5 mg, 0.03 mmol, 0.3 equiv) and sodium ascorbate (6 mg, 0.03 mmol, 0.3 equiv) at room temperature under an atmosphere of N. The mixture was stirred at room temperature for 16 h, then diluted with EtOAc (10 mL), washed with brine (5 mL), and the aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to give 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)pentyl)-N-heptylheptan-1-amine (0.1 g, 77%) as an oil. LC / MS: C 87 H 124 Calculated mass for 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)pentyl)-N-heptylheptan-1-amine (0.1 g, 0.07 mmol, 1.0 equiv) in EtOH (10 mL) and DCM (3 mL) and 20% Pd(OH) / C (0.2 g) was hydrogenated at room temperature (1 atm) for 16 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with EtOH / DCM (3:1). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM / MeOH 8:1) and preparative HPLC to give (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, Found: 813.70 [M+H] + ; 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-diheptyloct-7-yn-1-amine [ka] To a mixture of oct-7-ynal (0.7 g, 5.6 mmol, 1.0 equiv.) in DCE (10 mL) was added diheptylamine (1.2 g, 5.6 mmol, 1.0 equiv.) at room temperature under an atmosphere of N2. The mixture was stirred at room temperature for 15 minutes, and then NaBH(OAc)3 (1.8 g, 8.5 mmol, 1.5 equiv.) and AcOH (0.1 mL) were added. The mixture was stirred at room temperature for 3 hours, and then HO (10 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (MeOH / DCM 1:8) to give N,N-diheptyloct-7-yn-1-amine (0.6 g, 33%) as an oil. LC / MS: C 22 H 43 Calculated mass for N: 321, Measured mass: 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)hexyl)-N-heptylheptan-1-amine [ka] N,N-diheptyloct-7-yn-1-amine (40 mg, 0.12 mmol, 1.0 equiv.) 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 equiv.) t To a mixture of BuOH (3 mL) and HO (3 mL) was added CuSO (6 mg, 0.04 mmol, 0.3 equiv.) and sodium ascorbate (7 mg, 0.04 mmol, 0.3 equiv.) at room temperature. The mixture was stirred at room temperature for 1 day, then diluted with EtOAc (10 mL). The mixture was washed with brine, and the aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to give 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)hexyl)-N-heptylheptan-1-amine (0.1 g, 59%) as an oil. 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)octadecan-2-yl)-1H-1,2,3-triazol-4-yl)hexyl)-N-heptylheptan-1-amine (0.1 g, 0.07 mmol, 1.0 equiv) in EtOH (10 mL) and DCM (3 mL) and 20% Pd(OH) / C (0.2 g) was hydrogenated at room temperature (1 atm) for 16 h. The catalyst was removed by filtration through a pad of Celite, and the filter cake was washed with EtOH / CHCl (3:1). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM / MeOH) and preparative HPLC to give (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 (11.1 mg, 18%) as a solid. LC / MS: C 46 H 90 Calculated mass for N4O8: 826.68, Found: 827.95 [M+H] + .; 1H 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)octadecan-2-yl)dodecane-1-sulfinamide - a mixture of two diastereomers [ka] Synthesis of S-dodecylethanethioate To a mixture of 1-bromododecane (0.5 g, 2.0 mmol) in THF (10 mL) was added potassium ethanethioate (274 mg, 2.4 mmol) at room temperature. The mixture was heated to 80° C. and stirred for 3 hours, then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc) to give S-dodecylethanethioate (382 mg, 78%) as an oil.

[0211] Synthesis of dodecane-1-sulfine chloride To a mixture of S-dodecylethanethioate (0.3 g, 1.2 mmol) in DCM (5 mL) was slowly added AcO (126 mg, 1.2 mmol) and SOCl (332 mg, 2.5 mmol) at −20° C. The mixture was warmed to −5° C. and stirred for 2 h, then concentrated under reduced pressure to give dodecane-1-sulfine chloride (295 mg, 95%) as an oil.

[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)octadecan-2-yl)dodecane-1-sulfinamide - Synthesis of a mixture of two diastereomers To a mixture 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 (60 mg, 0.13 mmol) in DMA (3 mL) was added EtN (25 mg, 0.25 mmol) and dodecane-1-sulfine chloride (47 mg, 0.19 mmol) at room temperature under an atmosphere of N. The mixture was stirred at room temperature for 3 h, then HO was added and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified twice by column chromatography on silica gel (DCM / MeOH 9:1) to give 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)octadecan-2-yl)dodecane-1-sulfinamide (3.4 mg, 3.9%) as a solid. LC / MS: C 36 H 73 Calculated mass for NO9S: 695.50, Measured mass: 696.55 [M+H] + .

[0213] 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)octadecan-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide - a mixture of two diastereomers [ka] Synthesis of 9-(bromotriphenyl-lambda-5-phosphanyl)nonanoic acid A mixture of 9-bromononanoic acid (5.0 g, 21.1 mmol) and PhP (5.53 g, 21.1 mmol) in MeCN (50 mL) was heated to reflux and stirred for 3 days. The mixture was concentrated under reduced pressure, and the residue was triturated with EtO (200 mL) and filtered to give 9-(bromotriphenyl-lambda-5-phosphanyl)nonanoic acid (10.0 g, 95%) 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]dec-9-enoic acid To a mixture of 9-(bromotriphenyl-lambda-5-phosphanyl)nonanoic acid (2.95 g, 5.9 mmol) in THF (50 mL) was added 2 M NaHMDS (5.9 mL, 11.8 mmol) at -10 °C under an atmosphere of N2. The mixture was warmed to room temperature and stirred at room temperature for 1 hour, then a mixture of 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (450 mg, 3.9 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature overnight, then 2 M HCl (20 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give (9E)-10-[3-fluorobicyclo[1.1.1]pentan-1-yl]dec-9-enoic acid (500 mg, 50%) as an oil. 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 A mixture of (9E)-10-[3-fluorobicyclo[1.1.1]pentan-1-yl]dec-9-enoic acid (500 mg, 1.96 mmol) and PtO (50 mg, 0.22 mmol) in EtOH (300 mL) was stirred under an atmosphere of H (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 give 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}decan-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) was added dropwise 1 M BH in THF (5.9 mL, 5.9 mmol) under an atmosphere of N. The mixture was stirred at room temperature for 2 h, then quenched with MeOH (20 mL), concentrated under reduced pressure, and the residue was purified by column chromatography on silica (PE / EtOAc 3:1) to give 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decan-1-ol (430 mg, 91%) as an oil. 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}decan-1-ol (430 mg, 1.77 mmol) in DCM (30 mL) was added PhP (930 mg, 3.54 mmol) and CBr (1.18 g, 3.54 mmol) under a N atmosphere. The mixture was stirred at room temperature for 4 h, then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EtOAc 10:1) to give 1-(10-bromodecyl)-3-fluorobicyclo[1.1.1]pentane (480 mg, 89%) as an oil. 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. and stirred for 4 h, then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EtOAc 10:1) to give 1-[(10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decyl)sulfanyl]ethanone (450 mg, 95%) as an oil. 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] To 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) under a N atmosphere was added AcO (17 mg, 0.17 mmol) and SOCl (45 mg, 0.33 mmol) at −20° C. The mixture was stirred at −20° C. for 10 minutes and then concentrated under reduced pressure to give 10-{3-fluorobicyclo[1.1.1]pentan-1-yl}decane-1-sulfinyl chloride (50 mg, 97%) as an oil.

[0220] 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)octadecan-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide - a mixture of two diastereomers To a mixture of (2S,3R,4S,5R,6R)-2-{[(2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol (50 mg, 0.10 mmol) in DMA (3 mL) and DCM (1 mL) was added EtN (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, and the residue was purified by preparative HPLC to give 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)octadecan-2-yl)-10-(3-fluorobicyclo[1.1.1]pentan-1-yl)decane-1-sulfinamide - a mixture of two diastereomers (5.1 mg, 7%) as a solid. LC / MS: C 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]octadecan-2-yl]-11-[3-fluorobicyclo[1.1.1]pentan-1-yl]undecaneamide [ka] To a mixture of (2S,3S)-4-[[(2S,3S,4R)-2-amino-3,4-dihydroxyoctadecyl]oxy]butane-1,2,3-triol [Diaz et al. Tetrahedron: 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) was added HBTU (90 mg, 0.24 mmol), EtN (24 mg, 0.24 mmol), and NMM (24 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature overnight and then purified by preparative HPLC to give N-[(2S,3S,4R)-3,4-dihydroxy-1-[(2S,3S)-2,3,4-trihydroxybutoxy]octadecan-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)undecanamido)-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 To a mixture 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)methanol [Org. Biomol. Chem. 2011, 9, 8413] (0.7 g, 0.7 mmol) and (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (0.5 g, 1.5 mmol) in THF (20 mL) was added 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 in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc 3:1) to give ((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, 86%) as an oil. LC / MS: C 79 H96 N4O 11 Calculated mass: 1277, Measured mass: 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 To a mixture 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 (0.8 g, 0.6 mmol) in DMF (15 mL) was added piperidine (0.3 g, 3.5 mmol). The mixture was stirred at room temperature for 0.5 h, then quenched with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (PE / EtOAc 2:1) to give ((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, 91%) as an oil. LC / MS: C 64 H 86 Calculated mass for 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]phenanthren-17-yl)pentanoyl)-L-valinate To a mixture 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 (0.6 g, 0.6 mmol) and chenodeoxycholic acid (268 mg, 0.68 mmol) in DMF (10 mL) was added HATU (324 mg, 0.85 mmol) and DIPEA (147 mg, 1.14 mmol) at room temperature. The mixture was stirred at room temperature for 6 hours, then HO was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc 3:1) to give ((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 oil. LC / MS: C 88 H 124 N4O 12 Calculated mass: 1429, Measured mass: 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 A mixture 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]phenanthren-17-yl)pentanoyl)-L-valinate (0.6 g, 0.4 mmol) and 20% Pd(OH) / C (0.6 g) in MeOH (15 mL) and DCM (15 mL) was hydrogenated (1 atm) at room temperature for 16 hours. The mixture was filtered through a pad of Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give ((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]phenanthren-17-yl)pentanoyl)-L-valinate (0.33 g, 83%) as a solid. LC / MS: C 53 H 96 N2O 12 Calculated mass: 953, Measured mass: 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)undecanamido)-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) To a mixture of 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 HBTU (119 mg, 0.32 mmol), EtN (0.1 mL), and NMM (0.1 mL) at room temperature under a N atmosphere. The mixture was stirred at room temperature for 16 h, then quenched with HO and extracted with EtOAc. The combined organic layer was washed with brine, dried over NaSO, and filtered. The filtrate was purified by silica gel column chromatography (DCM / MeOH) to give the crude product (50 mg), which was further purified by trituration with CHCN to give ((2R,3R,4S,5R,6S)-6-(((2S,3S,4R)-2-(11-(3-fluorobicyclo[1.1.1]pentan-1-yl)undecanamido)-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: C69 H 121 FN2O 13 Calculated mass: 1205, Measured mass: 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}octadecan-2-yl]-11-(oxetan-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(oxetan-3-yl)undec-10-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (565 mg, 1.1 mmol) in THF (20 mL) was added 2.0 M NaHMDS (1.1 mL, 2.2 mmol) at 0 °C under an atmosphere of N. The mixture was warmed to room temperature and stirred for 1 h, 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 pH ∼1 with 1 N HCl and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(oxetan-3-yl)undec-10-enoic acid (100 mg, 42%) as an oil. LC / MS: C 14 H 24 Calculated mass for O3: 240, measured mass: 239 [MH] - .

[0228] Step 2: Synthesis of 11-(oxetan-3-yl)undecanoic acid A mixture of 11-(oxetan-3-yl)undec-10-enoic acid (100 mg, 0.4 mmol), PtO (20 mg, 0.1 mmol), and EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(oxetan-3-yl)undecanoic acid (100 mg, 99%) as a solid. LC / MS: C 14 H 26 Calculated mass for O3: 242, measured mass: 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}octadecan-2-yl]-11-(oxetan-3-yl)undecaneamide To a mixture 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 (50 mg, 0.1 mmol) in DMF (2 mL) was added 11-(oxetan-3-yl)undecanoic acid (25 mg, 0.1 mmol), EtN (0.1 mL), NMM (0.1 mL), and HBTU (80 mg, 0.2 mmol) under an atmosphere of N. The mixture was stirred at room temperature for 16 h and then diluted with HO (10 mL). Extraction with EtOAc (30 mL × 3) was performed. The combined organic layer was washed with brine (30 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-(oxetan-3-yl)undecanamide (13.8 mg, 19%) as a solid. LC / MS: C 38 H 73 NO 10Calculated mass: 703.99, Measured mass: 704.50 [M+H] + . 1 H 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(3-methyloxetan-3-yl)undec-10-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (564 mg, 1.1 mmol) in THF (20 mL) was added 2 M NaHMDS (1.1 mL, 2.2 mmol) at 0 °C under an atmosphere of N. The mixture was warmed to room temperature and stirred for 1 h, followed by the addition of 100 mg of methyloxetane-3-carbaldehyde (1.0 mmol) in THF (2 mL). The mixture was stirred overnight at room temperature, then acidified to pH 1 with 1 N HCl and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA 1:1) to afford 11-(3-methyloxetan-3-yl)undec-10-enoic acid (110 mg, 43%) as an oil. LC / MS:C 15 H 26Calculated mass for O3: 254, measured mass: 253 [MH] - . Step 2: Synthesis of 11-(3-methyloxetan-3-yl)undecanoic acid

[0231] A mixture of 11-(3-methyloxetan-3-yl)undec-10-enoic acid (110 mg, 0.4 mmol) and PtO (20 mg, 0.1 mmol) in EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(3-methyloxetan-3-yl)undecanoic acid (110 mg, 99%) as a solid. LC / MS: C 15 H 28 Calculated mass for O3: 256, measured mass: 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide

[0232] To a mixture 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 (50 mg, 0.1 mmol) in DMF (2 mL) was added 11-(3-methyloxetan-3-yl)undecanoic acid (27 mg, 0.1 mmol), EtN (0.1 mL), NMM (0.1 mL), and HBTU (80 mg, 0.2 mmol) under an atmosphere of N. The mixture was stirred at room temperature for 16 h and then diluted with HO (10 mL). Extraction with EtOAc (30 mL × 3) was performed. The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide (10.2 mg, 13%) as a solid. LC / MS: C 39 H 75 NO 10 Calculated mass: 718.01, Measured mass: 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)octadecan-2-yl)undecaneamide [ka] Step 1: Synthesis of (11-((1s,3s)-adamantan-1-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give (11-((1s,3s)-adamantan-1-yl)undec-10-enoic acid (250 mg, 799%) as a solid. LC / MS: C 21 H 34 Calculated mass for O2: 318, measured mass: 317 [MH] - .

[0234] Step 2: Synthesis of 11-((1r,3s)-adamantan-1-yl)undecanoic acid A mixture of (11-((1s,3s)-adamantan-1-yl)undec-10-enoic acid (250 mg, 0.7 mmol) and PtO (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 11-((1r,3s)-adamantan-1-yl)undecanoic acid (250 mg, 99.4%) as a solid. LC / MS: C 21 H 36 Calculated mass for O2: 320, measured mass: 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)octadecan-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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography on silica gel (DCM / MeOH 5:1) and and purified by preparative HPLC to give 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)octadecan-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)octadecan-2-yl)-11-(tetrahydrofuran-3-yl)undecaneamide [ka] Step 1: Synthesis of 11-(tetrahydrofuran-3-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(tetrahydrofuran-3-yl)undec-10-enoic acid (250 mg, 79%) as a solid. LC / MS: C 15 H 26 Calculated mass for O3: 254, measured mass: 253 [MH] - .

[0237] Step 2: Synthesis of 11-(tetrahydrofuran-3-yl)undecanoic acid A mixture of 11-(tetrahydrofuran-3-yl)undec-10-enoic acid (200 mg, 0.7 mmol) and PtO (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h, then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(tetrahydrofuran-3-yl)undecanoic acid (200 mg, 99%) as a solid. LC / MS: C 15 H 28 Calculated mass for O3: 256, measured mass: 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)octadecan-2-yl)-11-(tetrahydrofuran-3-yl)undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(tetrahydrofuran-3-yl)undecanamide (9 mg, 8%) as a solid. LC / MS: C 39 H 75 NO 10 Calculated mass: 717.54, Measured mass: 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)octadecan-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecaneamide [ka] Step 1: Synthesis of 11-(tetrahydro-2H-pyran-4-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(tetrahydro-2H-pyran-4-yl)undec-10-enoic acid (200 mg, 85%) as a solid. LC / MS: C 16 H 28 Calculated mass for O3: 268, measured mass: 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)undec-10-enoic acid (200 mg, 0.7 mmol) and PtO (40 mg, 0.2 mmol) in EtOH (50 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(tetrahydro-2H-pyran-4-yl)undecanoic acid (200 mg, 99%) as a solid. LC / MS: C 16 H 30 Calculated mass for O3: 270, measured mass: 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)octadecan-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(tetrahydro-2H-pyran-4-yl)undecanamide (9.6 mg, 8.7%) as a solid. LC / MS:C 40 H 77 NO 10 Calculated mass: 731.55, Measured mass: 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)octadecan-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)piperidin-4-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(1-(tert-butoxycarbonyl)piperidin-4-yl)undec-10-enoic acid (280 mg, 76%) as a solid. LC / MS: C 21 H 37 Calculated mass for NO4: 367, measured mass: 366 [MH] - .

[0243] Step 2: Synthesis of 11-(1-(tert-butoxycarbonyl)piperidin-4-yl)undecanoic acid A mixture of 11-(1-(tert-butoxycarbonyl)piperidin-4-yl)undec-10-enoic acid (280 mg, 0.76 mmol) and PtO (40 mg, 0.2 mmol) in EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to give 11-(1-(tert-butoxycarbonyl)piperidin-4-yl)undecanoic acid (280 mg, 99%) as a solid. LC / MS: C 21 H 39 Calculated mass for NO4: 369, measured mass: 368 [MH] - .

[0244] Step 3: 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)octadecan-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and analyzed by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC. Purification by HPLC with HPLC-MS / MS yielded 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)octadecan-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate (13.6 mg, 6%) as a solid. LC / MS: C 45 H 86 N2O 11 Calculated mass: 830.62, Measured mass: 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)octadecan-2-yl)-11-(piperidin-4-yl)undecaneamide [ka] To 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)octadecan-2-yl)amino)-11-oxoundecyl)piperidine-1-carboxylate (100 mg, 0.14 mmol) in EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure and the residue was purified by preparative HPLC to give 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)octadecan-2-yl)-11-(piperidin-4-yl)undecanamide (10.2 mg, 12.2%) as a solid. LC / MS: C 40 H 78 Calculated mass for N2O9: 730.57, Found: 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)octadecan-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)azetidin-3-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(1-(tert-butoxycarbonyl)azetidin-3-yl)undec-10-enoic acid (180 mg, 33%) as a solid. LC / MS: C 19 H 33 Calculated mass for NO4: 339, measured mass: 338 [MH] - .

[0247] Step 2: Synthesis of 11-[1-(tert-butoxycarbonyl)azetidin-3-yl]undecanoic acid A mixture of 11-(1-(tert-butoxycarbonyl)azetidin-3-yl)undec-10-enoic acid (180 mg, 0.53 mmol) and PtO (40 mg, 0.2 mmol) in EtOH (50 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-[1-(tert-butoxycarbonyl)azetidin-3-yl]undecanoic acid (180 mg, 99%) as a solid. LC / MS: C 19 H 35 Calculated mass for NO4: 341, measured mass: 340 [MH] - .

[0248] Step 3: 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)octadecan-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC. to give 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)octadecan-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate (9.4 mg, 6.2%) as a solid. LC / MS: C 43 H 82 N2O 11 Calculated mass: 802.59, Measured mass: 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-(azetidin-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)octadecan-2-yl)undecaneamide [ka] To 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)octadecan-2-yl)amino)-11-oxoundecyl)azetidine-1-carboxylate (100 mg, 0.14 mmol) in EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 11-(azetidin-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)octadecan-2-yl)undecanamide (7.6 mg, 8.6%) as a solid. LC / MS: C 38 H 74 Calculated mass for N2O9: 702.54, Found: 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)octadecan-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecaneamide [ka] Step 1: Synthesis of 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undec-10-enoic acid (100 mg, 51%) as a solid. LC / MS: C 16 H 28 Calculated mass for O4S: 316, measured mass: 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)undec-10-enoic acid (80 mg, 0.3 mmol) and PtO (20 mg, 0.1 mmol) in EtOH (30 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanoic acid (80 mg, 80%) as a solid. LC / MS: C 16 H 30 Calculated mass for O4S: 318, measured mass: 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)octadecan-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPMC. Purification by LC gave 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)octadecan-2-yl)-11-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)undecanamide (20.7 mg, 21%) as a solid. LC / MS: C 40 H 77 NO 11 Calculated mass for S: 779.52, Measured mass: 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)octadecan-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate [ka] Step 1: Synthesis of 11-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)undec-10-enoic acid (150 mg, 42%) as a solid. LC / MS: C 20 H 35 Calculated mass for NO4: 353, measured mass: 352 [MH] - .

[0254] Step 2: Synthesis of 11-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)undecanoic acid A mixture of 11-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]undec-10-enoic acid (150 mg, 0.3 mmol) and PtO (20 mg, 0.1 mmol) in EtOH (50 mL) was stirred under an atmosphere of H (balloon) for 1 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 11-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)undecanoic acid (140 mg, 93%) as a solid. LC / MS: C 20 H 37 Calculated mass for NO4: 355, measured value: 354 [MH] - .

[0255] Step 3: 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)octadecan-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC. to give 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)octadecan-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate (6.1 mg, 3.6%) as a solid. LC / MS: C 44 H 84 N2O 11 Calculated mass: 816.61, Measured mass: 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)octadecan-2-yl)-11-(pyrrolidin-3-yl)undecaneamide [ka] To 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)octadecan-2-yl)amino)-11-oxoundecyl)pyrrolidine-1-carboxylate (60 mg, 0.07 mmol) in EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure and purified by preparative HPLC to give 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)octadecan-2-yl)-11-(pyrrolidin-3-yl)undecanamide (15.6 mg, 28%) as an oil. LC / MS: C 39 H 76 Calculated mass for N2O9: 716.56, Found: 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}octadecan-2-yl]-11-{2-oxa-6-azaspiro[3.3]heptan-6-yl}undecaneamide [ka] Step 1: Synthesis of tert-butyl 11-(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) was added tert-butyl 11-bromoundecanoate (642 mg, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol). The mixture was heated to 100 °C and stirred for 5 h, then diluted with HO (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were 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 on silica gel (PE / EtOAc 1:1) to give tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate (339 mg, 50%) as a solid. LC / MS: C 20 H 37 Calculated mass for 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 and then concentrated under reduced pressure to give 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}octadecan-2-yl]-11-{2-oxa-6-azaspiro[3.3]heptan-6-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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-{2-oxa-6-azaspiro[3.3]heptan-6-yl}undecanamide (8.5 mg, 6.8%) as a solid. LC / MS: C 40 H 76 N2O 10 Calculated mass: 744.55, Measured mass: 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)octadecan-2-yl)-11-morpholinoundecanamide [ka] Step 1: Synthesis of tert-butyl 11-morpholinoundecanoate Prepared in a similar manner to tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give tert-butyl 11-morpholinoundecanoate (450 mg, 88%) as a solid. LC / MS: C 19 H 37 Calculated mass for NO3: 327, Measured mass: 328 [M+H] + .

[0260] Step 2: Synthesis of 11-morpholinoundecanoic acid To a mixture of tert-butyl 11-(morpholin-4-yl)undecanoate (450 mg, 1.3 mmol) and EtOAc (5 mL) was added 2N HCl in EtOAc (5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 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)octadecan-2-yl)-11-morpholinoundecanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide. Purification by column chromatography on silica gel (PE / EtOAc 2:1) gave 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)octadecan-2-yl)-11-morpholinoundecanamide (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)octadecan-2-yl)-11-morpholinoundecanamide 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)octadecan-2-yl)-11-morpholinoundecanamide (70 mg, 0.055 mmol) and Pd(OH) / C (20 mg) in DCM (5 mL) and EtOH (5 mL) was stirred under an atmosphere of H (balloon) for 16 h. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 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)octadecan-2-yl)-11-morpholinoundecanamide (9.1 mg, 23%) as a solid. LC / MS: C 39 H 76 N2O 10 Calculated mass: 732.55, Measured mass: 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)octadecan-2-yl)-11-(piperidin-1-yl)undecaneamide [ka] Step 1: Synthesis of tert-butyl 11-(piperidin-1-yl)undecanoate Prepared in a similar manner as tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give tert-butyl 11-(piperidin-1-yl)undecanoate (240 mg, 47%) as a solid. LC / MS: C 20 H 39 Calculated mass for NO2: 325, Measured mass: 326 [M+H] + .

[0263] Step 2: Synthesis of 11-(piperidin-1-yl)undecanoic acid To a mixture of tert-butyl 11-(piperidin-1-yl)undecanoate (180 mg, 0.5 mmol) and EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 11-(piperidin-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)octadecan-2-yl)-11-(piperidin-1-yl)undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(piperidin-1-yl)undecanamide (32 mg, 26%) as an oil. LC / MS: C 40 H 78 Calculated mass for N2O9: 730.57, Found: 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)octadecan-2-yl)-11-(pyrrolidin-1-yl)undecaneamide [ka] Step 1: Synthesis of tert-butyl 11-(pyrrolidin-1-yl)undecanoate Prepared in a similar manner as tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give tert-butyl 11-(pyrrolidin-1-yl)undecanoate (310 mg, 64%) as a solid. LC / MS: C 19 H 37 Calculated mass for NO2: 311, Measured mass: 312 [M+H] + .

[0266] Step 2: Synthesis of 11-(pyrrolidin-1-yl)undecanoic acid To a mixture of tert-butyl 11-(pyrrolidin-1-yl)undecanoate (310 mg, 0.99 mmol) and EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 11-(pyrrolidin-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)octadecan-2-yl)-11-(pyrrolidin-1-yl)undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(pyrrolidin-1-yl)undecanamide (15 mg, 12.4%) as an oil. LC / MS:C 39 H 76 Calculated mass for N2O9: 716.56, Found: 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)octadecan-2-yl)-11-thiomorpholinoundecanamide [ka] Step 1: Synthesis of tert-butyl 11-thiomorpholinoundecanoate Prepared in a similar manner to tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give tert-butyl 11-thiomorpholinoundecanoate (340 mg, 64%) as a solid. LC / MS: C 19 H 37 Calculated mass for NO2S: 343, Measured mass: 344 [M+H] + .

[0269] Step 2: Synthesis of 11-thiomorpholinoundecanoic acid To a mixture of tert-butyl 11-thiomorpholinoundecanoate (400 mg, 1.2 mmol) and EtOAc (5 mL) was added 2N HCl in EtOAc (5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 11-thiomorpholinoundecanoic 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)octadecan-2-yl)-11-thiomorpholinoundecanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-thiomorpholinoundecanamide (17.1 mg, 13.6%) as an oil. LC / MS: C 39 H76 N2O9S: 748.53, Measured: 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}octadecan-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]hept-2-en-2-yl)undec-10-enoic acid Prepared in a similar manner to 11-(3-methyloxetan-3-yl)undec-10-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 11-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)undec-10-enoic acid (110 mg, 54%) as a solid. LC / MS: C 20 H 32 Calculated mass for O2: 304, measured mass: 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]hept-2-en-2-yl)undec-10-enoic acid (100 mg, 0.3 mmol) and PtO (20 mg, 0.1 mmol) in EtOH (50 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 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 for O2: 308, measured mass: 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}octadecan-2-yl]-11-[(1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give N-[(2S,3S,4R)-3,4-dihydroxy-1-{[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-[(1S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]undecanamide (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)octadecan-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 in a similar manner as tert-butyl 11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)undecanoate and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give tert-butyl 11-(1,1-dioxidethiomorpholino)undecanoate (320 mg, 55%) as a solid. LC / MS: C 19 H 37 Calculated mass for NO4S: 375, Measured mass: 376 [M+H] + .

[0275] Step 2: Synthesis of 11-(1,1-dioxidethiomorpholino)undecanoic acid To a mixture of tert-butyl 11-(1,1-dioxidothiomorpholino)undecanoate (300 mg, 0.79 mmol) and EtOAc (3 mL) was added 2N HCl in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 11-(1,1-dioxidothiomorpholino)undecanoic acid (200 mg, 78%) as a solid. LC / MS: C 15 H 29 Calculated mass for NO4S: 319, measured mass: 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)octadecan-2-yl)-11-(1,1-dioxidethiomorpholino)undecaneamide Prepared in a similar manner as N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(1,1-dioxidethiomorpholino)undecanamide (17.3 mg, 16.2%) as a solid. LC / MS:C 39 H 76 N2O 11 Calculated mass for S: 780.52, Measured mass: 704.50 [M+H] + ; 1H 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)octadecan-2-yl)-11-(isopropylsulfonyl)undecaneamide [ka] Step 1: Synthesis of tert-butyl 11-(isopropylthio)undecanoate To a mixture of 2-propanethiol (3.5 g, 46.6 mmol) and DMF (30 mL) was added tert-butyl 11-bromoundecanoate (1.0 g, 3.1 mmol) and CsCO (2.5 g, 7.7 mmol). The mixture was stirred at room temperature for 5 hours, then diluted with HO (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 2:1) to give 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) was added m-CPBA (870 mg, 5.0 mmol). The mixture was stirred at room temperature overnight and then diluted with HO (50 mL). Extraction was performed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 2:1) to give 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 and then concentrated under reduced pressure to give 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)octadecan-2-yl)-11-(isopropylsulfonyl)undecaneamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-11-(isopropylsulfonyl)undecanamide (31.3 mg, 28%) as a solid. LC / MS: C 38 H 75 NO 11 Calculated mass for S: 753.51, Measured mass: 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)octadecan-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) was added 2 M NaHMDS (0.65 mL, 1.3 mmol) at 0 °C under an atmosphere of N2. The mixture was warmed to room temperature and stirred for 1 h, 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 HO (20 mL) and extracted with EtOAc (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 on silica gel (PE / EtOAc 1:1) to give 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 To a mixture of methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate (200 mg, 0.6 mmol) in MeOH (5 mL), THF (5 mL), and HO (5 mL) was added LiOH (42 mg, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, then acidified to pH ∼3 with 1N HCl and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH 10:1) to give 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid (66 mg, 53%) as a solid. LC / MS: C 15 H 28 Calculated mass for O5S: 320, measured mass: 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)octadecan-2-yl)-10-((1,1-dioxidetetrahydro-2H-thiopyran-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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC. Purification gave 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)octadecan-2-yl)-10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanamide (22.2 mg, 14.5%) as an oil. LC / MS: C 39 H 75 NO 12 Calculated mass for S: 781.50, Measured mass: 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)octadecan-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decanamide [ka] Step 1: Synthesis of methyl 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoate Prepared in a similar manner to methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give methyl 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoate (95 mg, 37%) as an oil.

[0285] Step 2: Synthesis of 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoic acid Prepared in a similar manner to 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid and purified by column chromatography on silica gel (DCM / MeOH 10:1) to give 10-((tetrahydro-2H-pyran-4-yl)oxy)decanoic acid (65 mg, 80%) as a solid. LC / MS: C 15 H 28 Calculated mass for O4: 272, measured mass: 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)octadecan-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPLC to give 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)octadecan-2-yl)-10-((tetrahydro-2H-pyran-4-yl)oxy)decanamide (12 mg, 13%) as an oil. LC / MS:C 39 H 75 NO 11 Calculated mass: 733.53, Measured mass: 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)octadecan-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide [ka] Step 1: Synthesis of ethyl 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoate Prepared in a similar manner to methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give ethyl 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoate (94 mg, 29%) as an oil.

[0288] Step 2: Synthesis of 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoic acid Prepared in a similar manner to the acidification of 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid and purified by column chromatography on silica gel (DCM / MeOH 10:1) to give 9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanoic acid (57 mg, 70%) as a solid. LC / MS: C 15 H 28 Calculated mass for O4: 272, measured mass: 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)octadecan-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecanamide and purified by column chromatography on silica gel (PE / EtOAc 5:1) to give 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)octadecan-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide as a solid. LC / MS:C 81 H 111 NO 11 Calculated mass: 1273.82, Measured mass: 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)octadecan-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)octadecan-2-yl)-9-((tetrahydro-2H-pyran-4-yl)methoxy)nonanamide (20 mg, 0.013 mmol) and Pd(OH) (40 mg) in EtOH (3 mL) and DCM (3 mL) was stirred under an atmosphere of H (balloon) for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 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)octadecan-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: 733.53, Measured mass: 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)octadecan-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 Prepared in a similar manner to methyl 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoate and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give ethyl 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoate (62 mg, 23%) as an oil.

[0292] Step 2: Synthesis of 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoic acid Prepared in a similar manner to 10-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)decanoic acid and purified by column chromatography on silica gel (DCM / MeOH 10:1) to give 8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanoic acid (47 mg, 86%) as a solid. LC / MS: C 15 H 28 Calculated mass for O4: 272, measured mass: 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)octadecan-2-yl)-8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanamide N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide was prepared in a similar manner and purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative H Purification by PLC gave 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)octadecan-2-yl)-8-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)octanamide (7.4 mg, 8.4%) as an oil. LC / MS: C 39 H 75 NO 11 Calculated mass: 733.53, Measured mass: 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)octadecan-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 To a mixture of 3-(tetrahydro-2H-pyran-4-yl)propan-1-ol (1.0 g, 6.9 mmol) and DMSO (20 mL) was added KOH (320 mg, 5.7 mmol) under an atmosphere of N. The mixture was heated to 80 °C and stirred for 1 h. Then 7-bromo-heptanoic acid (300 mg, 1.4 mmol) was added, and the mixture was stirred at 80 °C for an additional 2 h. After cooling, the mixture was acidified to pH 1 using 1 N HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH 10:1) to give 7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanoic acid (50 mg, 13%) as an oil. LC / MS:C 15 H 28 Calculated mass for O4: 272, measured mass: 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)octadecan-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except using THF as the solvent. Purification by column chromatography on silica gel (PE / EtOAc 3:1) gave 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)octadecan-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: 1273.82, Measured mass: 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)octadecan-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)octadecan-2-yl)-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanamide (24 mg, 0.019 mmol), Pd(OH) (40 mg), EtOH (3 mL), and DCM (3 mL) was stirred under an atmosphere of H (balloon) for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 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)octadecan-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: 733.53, Measured mass: 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)octadecan-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 Prepared in a similar manner to 7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)heptanoic acid and purified by column chromatography on silica gel (PE / EtOAc 2:1) to give 6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanoic acid (42 mg, 15%) as an oil. LC / MS: C 15 H 28 Calculated mass for O4: 272, measured mass: 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)octadecan-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except using THF as the solvent. Purification by column chromatography on silica gel (PE / EtOAc 3:1) gave 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)octadecan-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide (20 mg, 10%) as a solid. LC / MS: C 81 H 111 NO 11 Calculated mass: 1273.82, Measured mass: 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)octadecan-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)octadecan-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide (26 mg, 0.02 mmol), Pd(OH) (40 mg), EtOH (3 mL), and DCM (3 mL) was stirred under an atmosphere of H (balloon) for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 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)octadecan-2-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)butoxy)hexanamide (1.3 mg, 8.5%) as an oil. LC / MS: C 39 H 75 NO 11 Calculated mass: 733.53, Measured mass: 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)octadecan-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide [ka] Step 1: Synthesis of (15-carboxypentadecyl)triphenylphosphonium bromide To a mixture of 16-bromohexadecanoic acid (2.0 g, 5.9 mmol) and CHCN (30 mL) was added PhP (1.56 g, 5.9 mmol). The mixture was heated to 90 °C and stirred for 2 days, then filtered and washed with THF to give (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)heptadec-16-enoic acid To a mixture of (9-carboxynonyl)triphenylphosphonium bromide (800 mg, 1.3 mmol) in THF (15 mL) was added 2 M NaHMDS (1.65 mL, 3.3 mmol) at 0 °C under an atmosphere of N2. The mixture was warmed to room temperature and stirred for 1 h, then 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (152 mg, 1.3 mmol) in THF (1 mL) was added. The mixture was stirred overnight at room temperature and then acidified to pH ∼1 with 1 N HCl and extracted with EtOAc (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 on silica gel (PE / EtOAc 2:1) to give 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadec-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)heptadecano-16-enoic acid (140 mg, 0.39 mmol), PtO (20 mg, 0.1 mmol), and EtOH (50 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 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)octadecan-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, the amide was purified by column chromatography on silica gel (DCM / MeOH 5:1) and preparative HPMC. Purification by LC gave 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)octadecan-2-yl)-17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadecanamide (18.8 mg, 15.7%) as a solid. 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)octadecan-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanamide [ka] Step 1: Synthesis of (21-carboxyhenicosyl)triphenylphosphonium bromide To a mixture of 22-bromodocosanoic acid (1.4 g, 3.4 mmol) and CHCN (30 mL) under an atmosphere of N was added PhP (0.91 g, 3.4 mmol). The mixture was heated to 90 °C and stirred for 2 days, then concentrated under reduced pressure to give (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)tricos-22-enoic acid To a mixture of (21-carboxyhenicosyl)triphenylphosphonium bromide (300 mg, 0.4 mmol) in 1,4-dioxane (10 mL) was added 4A molecular sieves (0.5 g), K2CO3 (245 mg, 1.7 mmol), and 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde (75 mg, 0.7 mmol) at room temperature under a N2 atmosphere. The mixture was heated to 100 °C and stirred for 16 h. It was then diluted with HO, adjusted to pH 4-5 with 2N HCl, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EtOAc 2:1) to give 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)tricos-22-enoic acid (50 mg, 0.11 mmol) and PtO (5 mg) in EtOH (20 mL) was stirred at room temperature under an atmosphere of H (1 atm) for 1 h. The mixture was filtered through a pad of Celite, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give 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)octadecan-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except DMF / THF was used as the solvent. Purification by column chromatography on silica gel (DCM / MeOH) and washing with CH3CN gave 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)octadecan-2-yl)-23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanamide (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)octadecan-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanamide [ka] Step 1: Synthesis of 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)heneicosa-20-enoic acid 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid was prepared in a similar manner and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)heneicosa-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 Prepared in a similar manner to 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid to give 21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanoic acid (60 mg, 92%) 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)octadecan-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except DMF / THF was used as the solvent. Purification by column chromatography on silica gel (DCM / MeOH 9:1) and washing with CH3CN gave 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)octadecan-2-yl)-21-(3-fluorobicyclo[1.1.1]pentan-1-yl)henicosanamide (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] + ; 1H 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}octadecan-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosanamide [ka] Step 1: Synthesis of 21-(bromotriphenyl-lambda 5-phosphanyl)henicosanoic acid To a mixture of 21-bromohenicosanoic acid (1.16 g, 2.86 mmol) and CHCN (20 mL) was added PhP (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 C reverse-phase HPLC (HO, 5% HCl) / CHOH 5% to 100%) to give 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 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosa-22-enoic acid was prepared in a similar manner and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give (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 47 Calculated 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 Prepared in a similar manner to 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid to give 22-(3-fluorobicyclo[1.1.1]pentan-1-yl)docosanoic acid (40 mg, 99%) 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}octadecan-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except DMF / THF was used as the solvent. Purification by column chromatography on silica gel (DCM / MeOH 9:1) and washing with CH3CN gave N-[(2S,3S,4R)-3,4-dihydroxy-1-{[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}octadecan-2-yl]-22-{3-fluorobicyclo[1.1.1]pentan-1-yl}docosanamide (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] + ; 1 H 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)octadecan-2-yl)-24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosanamide [ka] Step 1: Synthesis of 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)oct-7-enoic acid Prepared in a similar manner to 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadec-16-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)oct-7-enoic acid (500 mg, 50%) as a solid. LC / MS: C 13 H 19 Calculated mass for FO2: 226, measured mass: 225 [MH] - .

[0316] Step 2: Synthesis of 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octanoic acid A mixture of 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)oct-7-enoic acid (500 mg, 2.21 mmol) and PtO (30 mg) in EtOH (100 mL) was stirred under an atmosphere of H (balloon) for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octanoic acid (500 mg, 99%) as a solid. LC / MS: C 13 H 21 Calculated mass for FO2: 228, measured mass: 227 [MH] - .

[0317] Step 3: Synthesis of 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octan-1-ol To a mixture of 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octanoic acid (500 mg, 2.19 mmol) and THF (10 mL) was added LiAlH (332 mg, 8.76 mmol) at 0 °C under an atmosphere of N. The mixture was stirred at 0 °C for 3 h, then diluted with aqueous NaSO and filtered. The filtrate was washed with EtOAc, the organic layer was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octan-1-ol (320 mg, 68%) as a solid.

[0318] Step 4: Synthesis of 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)octanal To a mixture of oxalyl chloride (284 mg, 2.24 mmol) and DCM (10 mL) was added dropwise DMSO (349 mg, 4.47 mmol) at −78° C. under an atmosphere of N2. The mixture was stirred at −78° C. for 15 min, then 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octan-1-ol (320 mg, 1.49 mmol) in DCM (2 mL) was added dropwise. The mixture was stirred at −78° C. for 50 min, then EtN (3 mL) was added. Stirring was continued at −78° C. for 5 min, then the mixture was warmed to room temperature, diluted with HO (10 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were washed with HO (20 mL), brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)octanal (300 mg, 95%) as an oil, which was used without further purification. f =0.4 (PE / EtOAc = 1:2).

[0319] Step 5: Synthesis of 24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracos-16-enoic acid To a mixture of (15-carboxypentadecyl)triphenylphosphonium bromide (844 mg, 1.41 mmol) and THF (20 mL) was added NaHMDS (1.5 mL, 9.6 mmol) at 0 °C under an atmosphere of N. The mixture was warmed to room temperature and stirred for 1 h. Then 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octanal (300 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 using 1 N HCl and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracos-16-enoic acid (400 mg, 63%) as a solid. LC / MS: C 29 H 51 Calculated mass for FO2: 450, measured mass: 449 [MH] - .

[0320] Step 6: Synthesis of 24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosanoic acid Prepared in a similar manner to 23-(3-fluorobicyclo[1.1.1]pentan-1-yl)tricosanoic acid to give 24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosanoic acid (180 mg, 90%) as a solid. LC / MS: C 29 H 53 Calculated mass for FO2: 452, measured mass: 451 [MH] - .

[0321] Step 7: 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)octadecan-2-yl)-24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, except DMF / THF was used as the solvent. Purification by column chromatography on silica gel (DCM / MeOH 9:1) and washing with CH3CN gave 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)octadecan-2-yl)-24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracosanamide (12.0 mg, 9.4%). LC / MS: C 53 H 100 Calculated mass for FNO9: 913.74, Measured mass: 936.80 [M+Na] + ; 1 H NMR (400 MHz, CD3OD) δ 4.20 (d, J = 6.4 Hz, 1H), 3.53-3.93 (m, 10H), 2.09-2.36 (m, 2H), 1.88 (d, J = 2.7 Hz, 6H), 1.56-1.67 (m, 6H), 0.92 (t, J = 6.6 Hz, 4H); 19 F NMR (376 MHz, CD3OD) δ -146.5.

[0322] 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)octadecan-2-yl)-25-(3-fluorobicyclo[1.1.1]pentan-1-yl)pentacosanamide [ka] Step 1: Synthesis of 9-(3-fluorobicyclo[1.1.1]pentan-1-yl)non-8-enoic acid Prepared in a similar manner to 17-(3-fluorobicyclo[1.1.1]pentan-1-yl)heptadec-16-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 9-(3-fluorobicyclo[1.1.1]pentan-1-yl)non-8-enoic acid (650 mg, 62%) as a solid. LC / MS: C 14 H 21 Calculated mass for FO2: 240, measured mass: 239 [MH] - .

[0323] Step 2: Synthesis of 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonanoic acid Prepared in a similar manner to 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octanoic acid to give 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonanoic acid (650 mg, 99%) as a solid. LC / MS: C 14 H 23 Calculated mass for FO2: 242, measured mass: 240 [MH] - .

[0324] Step 3: Synthesis of 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonan-1-ol Prepared in a similar manner to 8-{3-fluorobicyclo[1.1.1]pentan-1-yl}octan-1-ol and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonan-1-ol (400 mg, 65%) as a solid.

[0325] Step 4: Synthesis of 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonanal Prepared in a similar manner to 8-(3-fluorobicyclo[1.1.1]pentan-1-yl)octanal to give 9-{3-fluorobicyclo[1.1.1]pentan-1-yl}nonanal (280 mg, 94%). f =0.4, PE / EA=1:3.

[0326] Step 5: Synthesis of 25-(3-fluorobicyclo[1.1.1]pentan-1-yl)pentacos-16-enoic acid Prepared in a similar manner to 24-(3-fluorobicyclo[1.1.1]pentan-1-yl)tetracos-16-enoic acid and purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 25-(3-fluorobicyclo[1.1.1]pentan-1-yl)pentacos-16-enoic acid (200 mg, 35%) as a solid. LC / MS: C 30 H 53 Calculated mass for FO2: 464, measured mass: 463 [MH] - .

[0327] Step 6: Synthesis of 25-{3-fluorobicyclo[1.1.1]pentan-1-yl}pentacosanoic acid A mixture of 25-{3-fluorobicyclo[1.1.1]pentan-1-yl}pentacos-16-enoic acid (200 mg, 0.43 mmol) and PtO (30 mg) in EtOH (100 mL) was stirred under an atmosphere of H (balloon) for 1 h. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to give 25-{3-fluorobicyclo[1.1.1]pentan-1-yl}pentacosanoic acid (200 mg, 99.6%) as a white solid. LC / MS: C 30 H 55 Calculated mass for FO2: 466, measured mass: 465 [MH] - .

[0328] Step 7: 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)octadecan-2-yl)-25-(3-fluorobicyclo[1.1.1]pentan-1-yl)pentacosanamide 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}octadecan-2-yl]-11-(3-methyloxetan-3-yl)undecaneamide, exc...

Claims

1. Compound of formula DCD-(I): 【Chemical 266】 [In the formula, Z is, 【Chemical 267】 is selected from 【Chemical 268】 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; X １ and X ２ are each independently -C, -NR ｊ , -O, -SR ｋ , —Si; 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 hydrogen, oxygen, fluorine, -CF ３ or X ２ together to form cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 【Chemical 269】 indicates 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; when Y is nitrogen, R ｄ does not exist or R ｃ and R ｄ together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; R ｅ is alkyl or substituted alkyl; or a salt, solvate or hydrate thereof.

2. X １ The compound of claim 1, or a salt, solvate or hydrate thereof, wherein is -NH.

3. 1) R ａ is O, X ２ is C, 【Chemistry 270】 is carbonyl, or 2) R ａ is O, X ２ Ga-SR ｋ and R ｋ is methyl, 【Chemical 271】 are sulfur oxides, or 3) R ａ is CF ３ and X ２ is C, or 4) R ａ is F, X １ is C, X ２ is C, 【Chemical 272】 The compound of claim 2, or a salt, solvate or hydrate thereof, wherein is a double bond.

4. R ａ But, X ２ 4. The compound of claim 3, or a salt, solvate or hydrate thereof, which is combined with

5. R ｅ The compound according to any one of claims 1 to 4, or a salt, solvate or hydrate thereof, wherein is C8 to C20 alkyl or substituted C8 to C20 alkyl.

6. R ｄ is a C5-C25 alkyl group or a C5-C25 alkyl group 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; R ｂ is hydrogen, methyl, ethyl, propyl, butyl and 【Chemical 273】 is selected from the group consisting of 【Chemical 274】 indicates a bond to Y, and R ｚ 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, and optionally R ｚ is alkyl, for example, C1-C16 alkyl or C1-C16 substituted alkyl; R ｃ The compound according to any one of claims 1 to 5, or a salt, solvate or hydrate thereof, wherein is C1 to C10 alkyl. 【Request 7】 【Chemical 283】 【Chemical 284】 2. The compound of claim 1, selected from the group consisting of:

8. Compound of formula DCD-(II): 【Chemistry 275】 [In the formula, Z is, ​ is selected from 【Chemical 277】 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; X １ , X ２ , X ３ , X ４ and X ５ are each independently selected from carbon, nitrogen, oxygen, or sulfur; R ａ is optionally absent or, when present, selected from hydrogen or oxygen; 【Chemical 278】 indicates 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; when Y is nitrogen, R ｄ does not exist or R ｃ and R ｄ together with Y form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; R ｅ is alkyl or substituted alkyl; or a salt, solvate or hydrate thereof.

9. X １ , X ２ , X ３ , X ４ and X ５ together to form a pyrazole, or X １ , X ２ , X ３ , X ４ and X ５ together to form an imidazole, or X １ , X ２ , X ３ , X ４ and X ５ 9. The compound of claim 8, or a salt, solvate or hydrate thereof, wherein:

10. R ｅ is a C8-C20 alkyl or substituted C8-C20 alkyl; R ｄ is a C5-C25 alkyl group or a C5-C25 alkyl group 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; R ｂ is hydrogen, methyl, ethyl, propyl, butyl and 【Chemical 279】 is selected from the group consisting of 【Chemistry 280】 indicates a bond to Y, and R ｚ 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, and optionally R ｚ is alkyl, for example, C1-C16 alkyl or C1-C16 substituted alkyl; R ｃ The compound according to any one of claims 8 to 9, or a salt, solvate or hydrate thereof, wherein is C1 to C10 alkyl.

11. The compound of claim 1, wherein: 【Chemistry 285】 9. The compound of claim 8, or a salt, solvate or hydrate thereof, selected from:

12. 【Chemical 286】 【Chemistry 287】 【Chemistry 288】 2. The compound of claim 1, selected from the group consisting of:

13. A compound according to any one of claims 1 to 12, or a salt, solvate or hydrate thereof; and At least one pharma- ceutically acceptable carrier 13. A pharmaceutical composition comprising:

14. A composition comprising a compound described in any one of claims 1 to 12, or a salt, solvate or hydrate thereof, or a pharmaceutical composition described in claim 13, characterized in that the compound, or a salt, solvate or hydrate thereof, comes into contact with invariant natural killer T (iNKT) cells.

15. A composition comprising a compound described in any one of claims 1 to 12, or a salt, solvate or hydrate thereof, or a pharmaceutical composition described in claim 13, characterized in that the composition or pharmaceutical composition is administered to a subject in need thereof.

16. A composition or pharmaceutical composition for selectively reducing the presence of or eliminating senescent cells in a subject, comprising a compound according to any one of claims 1 to 12, or a salt, solvate or hydrate thereof, or the pharmaceutical composition according to claim 13.

17. A composition comprising a compound according to any one of claims 1 to 12, or a salt, solvate or hydrate thereof, for treating a disease, disorder, or condition by activating iNKT cells in a subject in need of such treatment.

18. The composition described in claim 17, wherein the disease, disorder, or condition is metabolic syndrome.

19. The composition described in claim 17, wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF).

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