Lipid a derivatives and uses thereof

Abstract

Provided herein are compounds of Formula (I), or salts thereof. Also disclosed are compositions, kits, and methods / uses. Exemplary uses include treating diseases (e.g., inflammation, autoimmune diseases) and as immunostimulatory compounds and compositions.

Description

LIPID A DERIVATIVES AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalPatent Application U.S.S.N. 63 / 598,030, filed November 10, 2023, the entire contents of which are incorporated herein by reference.GOVERNMENT SUPPORT

[0002] This invention was made with government support under HT9425-23- 1-0226 awarded by Defense Health Agency, Medical Research and Development Branch (DHA / MRDB). The government has certain rights in this invention.BACKGROUND

[0003] Molecular structure of commensal lipid A is highly diverse and complex because (Vatanen, T„ et al. (2016) Cell 165, 1551; Cullen, T.W., et al. (2015) Science 347, 170). A few studies have shown that structural diversity in lipid A affects the susceptibility of commensals to anti-microbial peptides and impacts on the immunomodulatory response they induce (Vatanen, T„ et al. (2016) Cell 165, 1551; Cullen, T.W., et al. (2015) Science 347, 170;Jacobson, A.N., et al. (2018) mBio, 9). However, how the molecular diversity in lipid A structure found in symbiotic microbes modulate host immunomodulatory response remains unclear.SUMMARY

[0004] Provided herein are structurally diverse lipid A derivatives and their corresponding activity.

[0005] In one aspect, provided herein are compounds of Formula (I):or salt thereof, wherein R1, R2, R3, R4, R5, R2, R3, and R4are as provided herein. In some embodiments, the compound is of the formula:or salt thereof.

[0006] In another aspect, provided herein are compositions comprising a compound as provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V)), or salt thereof, and optionally a pharmaceutically acceptable excipient.

[0007] In a further aspect, provided herein are methods of treating or preventing a disease in a subject, the method comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V)), or salt thereof, or composition provided herein. In some embodiments, the disease is inflammation or is characterized by inflammation including abnormal. In some embodiments, the disease is an autoimmune disease.

[0008] In one aspect, provided herein are methods of modulating an immune response such as an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V)), or salt thereof, or composition provided herein.

[0009] In another aspect, provided herein are methods of inducing an immune response to an antigen in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound as provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V)), or salt thereof, or composition provided herein and the antigen. The antigen may be a self-antigen, a microbial antigen such as but not limited to a bacterial antigen, a viral antigen, or a fungal antigen.

[0010] In a further aspect, provided herein are kits comprising a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V)), or salt thereof, or composition provided herein and instructions for using the compound or composition.

[0011] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows IFN-β response induced by linear and branched lipid A derivatives described herein.

[0013] FIG. 2 shows TNF-α response induced by linear and branched lipid A derivatives described herein.

[0014] FIG. 3 shows IFN-α inducing activity from mouse bone marrow-derived dendritic cells in response to lipid A derivative treatment. IFN-β activity was assessed at 24 h of posttreatment by using murine bone marrow-derived dendritic cells (BMDCs). X axis indicates the concentrations (ng / mL) of each individual lipid A treated to BMDCs.

[0015] FIGs. 4A-4C show therapeutic effect of branched lipid A derivatives in DSS- induced colitis compared to 4A-MPLA. FIG. 4A shows the dosing schedule of mice and thetimeline for monitoring weight changes. FIG. 4B shows the structures of the linear and branched lipid A derivatives. FIG. 4C shows the weight change of mice between 0 to 7 days post-treatment. Arrows indicate the datapoints when 4A-MPLA_B2 exerted more therapeutic effect compared to the effects from other lipid A analog treatments.

[0016] FIG. 5 shows the immunomodulatory response suppressing proinflammatory TNF- a response. Human PBMCs isolated from ulcerative colitis or Crohn’s Disease patients were stimulated with E. coli lipid A (6A-DPLA) in the presence or absence of 4A-MPLAs (4A- MPLA, 2258, C1P) or 5A-MPLA for 24 h. This experiment shows the effect of 4A-MPLAs or 5A-MPLA inhibiting proinflammatory TNF-a production induced by E. coli lipid A. TNF- a activity induced by 6A-DPLA alone calculated as 100%.

[0017] FIG. 6 shows a chiral HPLC analysis conditions and chromatograms of 58.

[0018] FIG. 7 shows a chiral HPLC analysis conditions and chromatograms of 59.DEFINITIONS

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0020] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen etal., Tetrahedron 33 :2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0021] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0022] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “C1-6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5.6alkyl.

[0023] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr),unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., -CF3, Bn).

[0024] In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0025] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCl2, -CF2Cl, and the like.

[0026] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within theparent chain (“heteroC1-20alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl.

[0027] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms6“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.double bond.

[0028] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“hetero C2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0029] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0030] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0031] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4),cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro [4.5] dec any 1 (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0032] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified,each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0033] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carboncarbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0034] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0035] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydro thiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl,1.4.5.7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl,4.5.6.7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1, 2,3,4- tetrahydro-l,6-naphthyridinyl, and the like.

[0036] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 > electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0037] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0038] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 > electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl,and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g.. 2-indolyl) or the ring that does not contain a heteroatom (e.g.. 5-indolyl).

[0039] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0040] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, pheno thiazinyl, phenoxazinyl, and phenazinyl.

[0041] “Hetero aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0042] The term “unsaturated bond” refers to a double or triple bond.

[0043] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0044] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0045] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0046] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” acyl, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0047] Exemplary substituents include, but are not limited to, halogen, -CN, -NO2, -N3,carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S,each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen,carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X- is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3,carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X- is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3- 10 membered heterocyclyl or 5- 10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; andalkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, aryl, 3-10heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X- is a counterion.

[0048] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0049] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than

[0050] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0051] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -( (

[0052] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected fromwherein R^, Rbb, and Rccare as defined herein, with the proviso thatthe nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0053] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected fromare as defined herein.

[0054] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen (i.e., -C(=O)-).

[0055] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0056] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ionssulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate,malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0057] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0058] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0059] As used herein, the term “tertiary carbon” refers to a carbon atom bound to three other carbon atoms.

[0060] As used herein, the term “quaternary carbon” refers to a carbon atom bound to four other carbon atoms.

[0061] As used herein, the term “acyl” refers to any group attached via -C(=O)- bond. In some embodiments, the acyl group is -C(=O)(substituted or unsubstituted alkyl). In some embodiments, the acyl group is -C(=O)(unsubstituted alkyl). In some embodiments, an amide (-NHC(=O)-) and ester (-OC(=O)-) may be considered an acyl group do to inclusion of the - C(=O)- moiety.

[0062] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0063] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0064] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature,solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0065] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0066] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0067] The terms “composition”, “formulation”, and “preparation” are used interchangeably.

[0068] A “subject” to which administration is contemplated refers to a human (i.e., independent of gender of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or nonhuman animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal.

[0069] The term “modulate,” “modulating,” “modulation,” or “modulator” refer to the ability of a compound to reduce / increase, slow / speed up, halt / initiate, inhibit / stimulate, or prevent / cause activity of a target or physiological reaction in a cell relative to vehicle. In some embodiments, “modulate,” “modulating,” “modulation,” or “modulator” refers to reducing or inhibiting. In some embodiments, “modulate,” “modulating,” “modulation,” or“modulator” refers to increasing or activating. In some embodiments, immune response is modulated. In some embodiments, proinflammatory immune response is modulated (i.e., decreased or down-regulated).

[0070] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into a biological system including a subject.

[0071] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0072] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0073] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form. In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0074] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0075] As used herein “immune response” is used to refer to a physiological reaction which occurs within an organism typically for the purpose of defending against antigens such as non-self antigens. Toxins, allergens, graft- versus-host disease, and microorganisms (e.g., viruses, bacteria, fungi, protozoa, and worms) are a few examples of agents that may elicit an immune response.

[0076] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Such conditions may also be referred to as characterized by inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated,exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus- graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis,angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0077] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, bums, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0078] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of a subject against substances and tissues normally present in the subject (e.g., self-antigens). In other words, the immune system mistakes some part of the subject as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, , psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0079] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, Figures, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0080] Provided herein are compounds, compositions, and methods / uses.Compounds

[0081] In one aspect, provided herein are compounds of Formula (I):or salt thereof, wherein:R1and R4are each independently hydrogen or -PO3H2;R2and R2are each independently substituted or unsubstituted alkyl comprising a terminal tertiary or quaternary carbon; andR3, R4, R5, and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl.

[0082] In certain embodiments, R2is substituted or unsubstituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is unsubstituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is substituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl). In some embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl). In some embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is hydrogen.

[0083] In certain embodiments, R2is substituted or unsubstituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is unsubstituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is substituted alkyl comprising a terminal tertiary carbon. In certain embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl). In some embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl). In some embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is hydrogen.

[0084] In certain embodiments, R2and R2are each independently substituted or unsubstituted alkyl comprising a terminal tertiary carbon. In some embodiments, R2and R2are each independently unsubstituted alkyl comprising a terminal tertiary carbon.

[0085] In some embodiments, at least one of R2and R2is substituted alkyl comprising a terminal tertiary carbon. In certain embodiments, at least one of R2and R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and - C(=O)(substituted or unsubstituted alkyl).

[0086] In some embodiments, each R2or R2are independently substituted alkyl comprising a terminal tertiary carbon. In certain embodiments, each R2or R2are independently substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl).

[0087] In some embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl); and R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is hydrogen.

[0088] In certain embodiments, R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl); and R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is - OR6and R6is hydrogen.

[0089] In some embodiments, R6is hydrogen, substituted or unsubstituted alkyl, or - C(=O)(substituted or unsubstituted alkyl). In some embodiments, R6is hydrogen. In some embodiments, R6is substituted or unsubstituted alkyl. In some embodiments, R6is substituted alkyl. In some embodiments, R6is unsubstituted alkyl. In some embodiments, R6is unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tertbutyl. In some embodiments, R6is -C(=O)(substituted or unsubstituted alkyl). In some embodiments, R6is -C(=O)(substituted or unsubstituted C10-20 alkyl). In some embodiments, R6is -C(=O)(substituted or unsubstituted C10-18 alkyl). In some embodiments, R6is - C(=O)(substituted or unsubstituted C14 alkyl). In some embodiments, R6is - C(=O)(substituted C14 alkyl). In some embodiments, R6is -C(=O)(unsubstituted C14 alkyl).

[0090] In some embodiments, the compound of Formula (I) is of Formula (II):or salt thereof, wherein: each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0091] In some embodiments, the compound of Formula (I) or (II) is of Formula (II-A):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0092] In some embodiments, the compound of Formula (I) or (II) is of Formula (II-B):(II-B), or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0093] In some embodiments, the compound of Formula (I) is of Formula (III):or salt thereof, wherein: each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0094] In some embodiments, the compound of Formula (I) or (III) is of Formula (III-A):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0095] In some embodiments, the compound of Formula (I) or (II) is of Formula (III-B):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

[0096] As provided herein, n is an integer from 0 to 20. In some embodiments, n is an integer from 2 to 18. In some embodiments, n is an integer from 4 to 16. In some embodiments, n is an integer from 6 to 14. In some embodiments, n is an integer from 8 to 14. In some embodiments, n is an integer from 10 to 12. In some embodiments, n is 11.

[0097] In some embodiments, R3is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is substituted or unsubstituted alkyl. In some embodiments, R3is unsubstituted alkyl. In some embodiments, R3is unsubstituted methyl. In some embodiments, R3is substituted alkyl. In some embodiments, R3is substituted methyl.

[0098] In some embodiments, R3is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is substituted or unsubstituted alkyl. In some embodiments, R3is unsubstituted alkyl. In some embodiments, R3is unsubstituted methyl. In some embodiments, R3is substituted alkyl. In some embodiments, R3is substituted methyl.

[0099] In some embodiments, R4is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is substituted or unsubstituted alkyl. In some embodiments, R4is unsubstituted alkyl. In some embodiments, R4is unsubstituted methyl. In some embodiments, R4is substituted alkyl. In some embodiments, R4is substituted methyl.

[0100] In some embodiments, R5is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R5is hydrogen. In some embodiments, R5is substituted or unsubstitutedalkyl. In some embodiments, R5is unsubstituted alkyl. In some embodiments, R5is unsubstituted methyl. In some embodiments, R5is substituted alkyl. In some embodiments, R5is substituted methyl.

[0101] In some embodiments, R3, R4, and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl; and R5is hydrogen. In certain embodiments, R3and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl; and R4and R5are hydrogen. In some embodiments, R3is substituted or unsubstituted alkyl; and R3, R4and R5are hydrogen. In some embodiments, R3is substituted or unsubstituted alkyl; and R3, R4and R5are hydrogen. In some embodiments, R3and R3are each independently substituted or unsubstituted alkyl; and R4and R5are hydrogen.

[0102] In certain embodiments, compound comprises two, three, four, or five acyl chains. For example, all of the comparative compounds (4A-MPLA, 4A-MPLA #1, 4A-MPLA #2, 4A-MPLA #3, and 4A-MPLA #4) are tetra-acylated compounds. In some embodiments, the compound comprises three or four acyl chains. In some embodiments, the compound comprises four acyl chains. In certain embodiments, the acyl chains comprise 14-17 carbons. In some embodiments, the acyl chains comprise from 15-17 carbons.

[0103] In some embodiments, R or R is:

[0104] In some embodiments, R i: y

[0105] In some embodiments, R

[0106] In some embodiments, R2or R2is:Thus, in some embodiments, the compound of Formula (I) is of Formula (IV) or (V):or salt thereof.

[0107] In some embodiments, R2is:

[0108] In some embodiments, the compound of Formula (I) is a compound of Formula (IV):(IV), or salt thereof.

[0109] In some embodiments, R2is:

[0110] In some embodiments, the compound of Formula (I) is a compound of Formula(V):or salt thereof.

[0111] As provided herein, R1is hydrogen or -PO3H2. In certain embodiments, R1is hydrogen. In some embodiments, R1is -PO3H2.

[0112] As provided herein, R4is hydrogen or -PO3H2. In certain embodiments, R4is hydrogen. In some embodiments, R4is - PO3H2.

[0113] In some embodiments, R1and R4are both hydrogen. In some embodiments, R1is - PO3H2and R4is hydrogen.

[0114] In some embodiments, the compound is of the formula:or salt thereof.

[0115] In certain embodiments, the compound is of the formula:or salt thereof.

[0116] In certain embodiments, the compound is of the formula:

[0117] In certain embodiments, the compound is of the formula:or salt thereof.

[0118] In certain embodiments, the compound is of the formula:, or salt thereof.

[0119] In some embodiments, the compound or composition is substantially free of constitutional isomers and stereoisomers. In some embodiments, the compound or composition is substantially free of constitutional isomers. In some embodiments, the compound or composition is substantially free of regioisomers and stereoisomers. In some embodiments, the compound or composition is substantially free of regioisomers.

[0120] In some embodiments, the compound or composition may be pure (i.e., it is free or substantially free of one other chemical compound or a combination of chemical compounds. In some embodiments, the compound is at least 70% pure, or at least 75% pure, or at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 95% pure, or at least 96% pure, or at least 97% pure, or at least 98% pure, or at least 99% pure, or at least 99.1% pure, or at least 99.2% pure, or at least 99.3% pure, or at least 99.4% pure, or at least 99.5% pure, or at least 99.6% pure, or at least 99.7% pure, or at least 99.8% pure, or at least 99.9% pure, or 100% pure. The compound may represent, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% (w / w) of the composition, or in other embodiments, it may represent 100% of the composition (w / w) indicating complete purity. In some embodiments, at least 95% (w / w) of the composition is comprised of a compound of Formula (I), and does not include anv other compound or any combination ofother compounds such as, but not limited to, bacterial cell membrane components, lipopolysaccharides (LPS), etc.

[0121] In various embodiments, the compound or composition is free or substantially free of components found in a B. fragilis capsule. In various embodiments, the compound or composition is substantially free of polysaccharides, including naturally occurring polysaccharides. In various embodiments, the compound or composition is substantially free of LPS. In various embodiments, the compound or composition is free of lipidated and / or non-lipidated polysaccharide A (PSA).

[0122] In various embodiments, the compound or composition is provided in a form that is free of B. fragilis membrane, and thus is not provided as a B. fragilis cell or as a B. fragilis outer membrane vesicle (OMV).

[0123] In various embodiments, the compound or composition is provided in or as a liposome or micelle form, and such liposome or micelle form may be non-naturally occurring (e.g., it may lack naturally occurring components and / or it may further comprise non- naturally occurring components such as non-naturally occurring lipids, surfactants, stabilizers, and the like). In various embodiments, the compound or composition is provided in or as a micelle form.

[0124] In some embodiments, the compound or composition is sterile.

[0125] In certain embodiments, the compound or composition is in lyophilized form. Lyophilized forms of the compound or composition are particularly suitable for long-term storage, ranging from days, weeks, months or even years.

[0126] In certain embodiments, the compound or composition is suitable for administration to a human. In some embodiments, the compound or composition is formulated for delivery to the gut. In some embodiments, the compound or composition is formulated for delivery to the lungs. In some embodiments, the compound or composition is formulated for delivery to the central nervous system.Compositions

[0127] Provided herein are compositions comprising the compounds disclose herein. In one aspect, provided herein are compositions comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, composition comprises a compound disclosed herein, or salt thereof. In certain embodiments, thecomposition comprises a compound disclosed herein, or salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, the composition comprises a compound disclosed herein, or salt thereof and a pharmaceutically acceptable excipient.

[0128] Compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0129] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0130] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0131] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0132] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0133] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation .

[0134] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0135] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0136] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered incombination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In some embodiments, the additional pharmaceutical agent is an immunomodulator. In certain embodiments, the immunomodulator is an immunosuppressant. In some embodiments, the immunomodulator is an immune activator.

[0137] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). In one aspect, provided herein are kits comprising a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein and instructions for using the compound or composition. The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0138] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.Methods and Uses

[0139] Provided herein are methods and uses comprising administration or utilization of the compounds and compositions disclosed herein.

[0140] In one aspect, provided herein are methods of treating or preventing a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein. In some embodiments, the disease is inflammation. In some embodiments, the disease is characterized by inflammation. In some embodiments, the disease is characterized by inflammation including abnormal. In certain embodiments, the disease is an autoimmune disease. In some embodiments, the inflammation or autoimmune disease is multiple sclerosis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, or type I diabetes. In certain embodiments, the disease is multiple sclerosis. In certain embodiments, the disease is Crohn’s disease. In certain embodiments, the disease is ulcerative colitis. In certain embodiments, the disease is rheumatoid arthritis. In certain embodiments, the disease is type I diabetes. In some embodiments, the disease is asthma.

[0141] In another embodiment, provided herein are methods of modulating an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein. In another embodiment, provided herein are methods of modulating an immune response such as an innate in a subject, the method comprising administering to the subject a therapeutically effective amount a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein. In another aspect, provided herein are methods of modulating an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein.

[0142] In one aspect, provided herein are methods of inducing an immune response to an antigen in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (II), (III), (IV), or (V), or a salt thereof), or salt thereof, or composition as provided herein and the antigen. The antigen may be a self-antigen, a microbial antigen such as but not limited to abacterial antigen, a viral antigen, or a fungal antigen. The antigen may be a self-antigen. The antigen may be a microbial antigen. In some embodiments, the microbial antigen is selected from, but not limited to, a bacterial antigen, a viral antigen, or a fungal antigen.EXAMPLES

[0143] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Synthetic schemesA. Acyl chain building blocks

[0144] The one-tailed acyl chain 85a-b was generally synthesized in 11 steps (Scheme 1). Starting from 3-buten-l-ol (56), the hydroxyl group was protected with the tertbutyldiphenylsilyl (TBDPS) group to afford 57 in excellent yield. Then, the alkene was transformed to racemic epoxide 58 in excellent yield. To generate chirally pure epoxide, kinetic resolution via-Jacobsen’s cobalt(II) catalyst ((.S\.S')-Co-salcn) gave 59 with >99% enantiomeric excess (ee) which was checked by chiral high-performance liquid chromatography (HPLC) analysis. (See FIGs. 6 and 7.)

[0145] Next, 60 was added to 59 and produced 61 in excellent yield. The triple bond was reduced to provide 62 in very good yield. After reduction, benzylation of the secondary alcohol with benzyl 2,2,2-trichloroacetimidate catalyzed by trifluoromethanesulfonic acid (TfOH) generated 63 as a crude. Subsequently, the MOM group was deprotected with zirconium(IV) chloride (ZrCU) smoothly to afford 64 in good yield based on recovered 62 over 2 steps. The primary alcohol was tosylated to give 65 which is a common intermediate for acyl chain building blocks in excellent yield. As a key step, a copper-catalyzed crosscoupling with 77-butylmagncsium chloride (produced 89a without any byproducts observed by LC-MS in excellent yield. Similarly, a copper-catalyzed cross-coupling with z-pentylmagneisum bromide (z-PeMgBr) produced 89b. In succession, the TBDPS group was deprotected to provide 90a-b in excellent yield. Finally, Jones oxidation converted the primary alcohol to carboxylic acid 85a-b in good yield.

[0148] From 85a-b, debenzylation followed by p-bromophenacyl group protection of the carboxylic acid gave 94a-b in excellent yield over 2 steps (Scheme 2). This was a new approach to the 94a-b. The secondary alcohol was esterified with palmitoyl chloride and produced 95a-b in excellent yield. Finally, p-bromophenacyl group deprotection provided 86a-b in excellent yield.B. Glucosamine building blocks

[0149] Glucosamine building blocks 87 and 88 were synthesized in 6 and 7 steps, respectively (Scheme 3). Starting from D-(+)-glucosamine (96), diazo transfer with imidazole- 1- sulfonyl azide followed by acetylation produced 98 in excellent yield over 2 steps. After that, regioselective anomeric deacetylation with hydrazine acetate (N2H4 • AcOH) provided 99 in excellent yield. Subsequently, the anomeric hydroxyl group was protected with the tert-butyldimethylsilyl (TBDMS) group to afford 100 in excellent yield. Finally, deacetylation followed by protection of the C-4 and C-6 hydroxyl groups with a benzylidene acetal generated 87 in very good yield over 2 steps. In addition, benzylation of the C-3 hydroxyl group with silver(I) oxide gave 88 in excellent yield.

[0150] Scheme 3. Synthesis of glucosamine building blocks. Reagents and conditions: (i)Imidazole- 1 -sulfonyl azide pyridine, 0imidazole, DCM, r.t., 18hr; (v) NaOMe, MeOH, 0 °C to r.t., 15 min; (vi) PhCH(OMe)2, p-TsOH H2O, ACN, r.t., 15 hr; (vii) BnBr, Ag2O, 4 A molecular sieves, DCM, r.t., 24 hr.C. Donors and Acceptors

[0151] DO and AO were synthesized from glucosamine building block 88 (Scheme 4). To synthesize DO, the azide of 88 was reduced to an amine with zinc and acetic acid (AcOH), and the amine was protected with the Troc group to afford 103 in excellent yield over 2 steps. The TBDMS group was deprotected under HF-pyridine to generate 104 in excellent yield. The lactol was transformed to trichloroacetimidate using cesium carbonate (Cs2CO3) and gave DO in quantitative yield as a crude. To synthesize AO, reduction of the azide followed by Fmoc group protection produced 105 in excellent yield over 2 steps. Selective ring opening reaction of the 4,6-O-benzylidene acetal with dichlorophenylborane (PhBCl2) provided AO having a free C-6 hydroxyl group in good yield.

[0152] DI and Al were synthesized from glucosamine building block 87, similar to DO and A0 (Scheme 5). To synthesize DI, the azide of 87 was reduced to an amine, and the amine was protected with the Troc group to afford 107. In the Troc group protection, we first attempted with A,A-diisopropylethylamine (DIPEA) in DCM. However, di-protected 106 was detected by LC-MS as a considerable by-product (Data not shown). This observation suggests that the Troc group was attached to the C-3 hydroxyl group. Fortunately, sodium bicarbonate in water prevented Troc group protection of the C-3 hydroxyl groupand generated 107 in excellent yield over 2 steps. The C-3 hydroxyl group was esterified with 85a-b and gave 108 in excellent yield. The TBDMS group was deprotected under HF- pyridine to produce 109 in excellent yield. The lactol was transformed to trichloroacetimidate using l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) instead of Cs2COa to reduce undesirable saponification and provided DI in very good yield. To synthesize Al, reduction of the azide followed by Fmoc group protection generated 110 in excellent yield over 2 steps.Esterification of the C-3 hydroxyl group with 85a-b gave 111 in excellent yield. Selective ring opening reaction of the 4,6-O-benzylidene acetal produced Al having a free C-6 hydroxyl group in very good yield.

[0153] Scheme 4. Synthesis of DO and A0. Reagents and conditions: (i) Zn / AcOH, DCM, r.t., 4 hr; (ii) TrocCl, DIPEA, DCM, 0 °C to r.t., 3 hr; (iii) HF-Pyridine, pyridine, THF, -40 °C to r.t., 15 hr; (iv) ChCCN, Cs2CO3, DCM, r.t., 1 hr; (v) FmocCl, DIPEA, DCM, 0 °C to r.t., 3 hr; (vi) PhBCh, Et3SiH, DCM, -78 °C, 30 min.

[0154] Scheme 5. Synthesis of DI and Al. Reagents and conditions: (i) Zn / AcOH, DCM,CbCCN, DBU, DCM, r.t., 1 hr; (vi) FmocCl, DIPEA, DCM, 0 °C to r.t., 3 hr; (vii) PhBCh, EhSiH, DCM, -78 °C, 30 min.D. BfLAs

[0155] The BfLA library was constructed in 7 steps by assembling building blocks in a combinatorial manner (Scheme 6). Trimethylsilyl trifluoromethanesulfonate (TMSOTf)- mediated Schmidt glycosylation of Donors and Acceptors afforded 112 with trichloroacetamide as an impurity. Fortunately, zinc and AcOH condition for Troc group deprotection decomposed not only the Troc group but also trichloroacetamide, which was followed by first amide coupling mediated bydicyclohcxylcarbodi i midc (DCC) generated 114 in good yields over 3 steps. Next, Fmoc group deprotection with DBU followed by second amide coupling mediated by I -|bis(dimcthylamino)mcthylcnc|triazolo[4,5-Z?]pyridinium 3-oxid hexafluorophosphate (HATU) gave 115 in very good yields except when 86a-b was used. Optimization of the second amide coupling of two-tailed chains was achieved by column purification after Fmoc group deprotection followed by addition of DIPEA as a base additive. After the amide couplings, the TBDMS group was deprotected under HF-pyridine to produce 116 excellent yields. The lactol was phosphorylated with tetrabenzyl pyrophosphate and provided 117 as a crude. Finally, global debenzylation via catalytic hydrogenation under high pressure (1.0 MPa) using palladium black afforded the desired BfEA analogues. Global debenzylation of 116 afforded the dephosphorylated BfEA analogues (NP-BfEAs).

[0156] Scheme 6. General synthesis of BfLAs. Reagents and conditions: (i) TMSOTf, 4 A molecular sieves, DCM, -20 °C, 30 min; (ii) Zn / AcOH, THF, r.t., 2 hr; (iii) 85a-b or 86a-b,DCC, DCM, r.t., overnight; (iv) DBU, DCM, r.t., 30 min, then 85a-b or 86a-b, HATU, DMAP, DMF, r.t., overnight (For 115(1,1,0,2) and 115(1,1*, 0,2*), column purification was conducted after Fmoc deprotection and DIPEA was added as an additive in amide coupling step; (v) HF-Pyridine, pyridine, THF, r.t., 16 hr; (vi) Tetrabenzyl pyrophosphate, LHMDS, THF / toluene (5:1, v / v), -78 °C, 30 min, then 0 °C, 1 hr; (vii) H2(1.0 MPa), Pd black, THF, r.t.48-72 hr. (viii) H2(1.0 MPa), Pd black, DCM / MeOH (1:1, v / v), r.t. 48 hr.General Experimental Information

[0157] Materials: All commercially available reagents for organic synthesis were purchased from Sigma- Aldrich, Tokyo Chemical Industry Co., Ltd, or ThermoFisher Scientific and used without further purification unless otherwise specified. Solvents were purchased from commercial vendors and used without further purification unless otherwisementioned. Dry solvents were prepared using the ultimate solvent purification system CT- SPS-SA [Glass Contour]. 4 A molecular sieves used for reactions were activated with a microwave oven for 40 seconds, then stored in vacuo for 10 minutes three times before application. Dropwise addition with a syringe pump was performed using NE-300 [New Era Pump Systems, Inc.]. The progress of the reaction was monitored using thin-layer chromatography (TLC) (silica gel 60, F2540.25 mm) or liquid chromatography-mass spectrometry (LC-MS) LCMS-2020 [Shimadzu]. Components on TLC were visualized by UV light (254 nm) or by treating the TLC plates with p-anisaldehydeor phosphomolybdic acid followed by heating. Compounds were purified by medium-pressure liquid chromatography (MPLC) Isolera One [Biotage] or flash column chromatography on silica gel 60 (high-purity grade 9385, 230-400 mesh) [EMD Millipore]. Eluents used for purification are reported in parentheses.

[0158] Compound characterization: Optical rotations were measured by JP / P-1030 [JASCO] using a sodium lamp (D line, 589 nm).!H and13C NMR spectra were obtained on Bruker AVANCE III HD 500 MHz [Bruker] or Varian VNMRS 500 MHz [Varian, Inc.]. Chemical shifts were reported in parts per million (d, ppm).1H NMR spectra were calibrated using the residual solvent peak or tetramethylsilane (TMS, 0.00 ppm) asan internal standard.13C NMR spectra were calibrated using the residual solvent peak (77.00 ppm or . Multiplicity was noted as follows: s (singlet); d (doublet);t (triplet); q (quartet); quin (quintet); m (multiplet); br s (broad singlet), etc. Coupling constants were reported in Hz. Low-resolution mass spectrometry (LRMS) was obtained by LCMS-2020 [Shimadzu] using electron spray ionization (ESI). Mass spectrometry (MS) was confirmed by ultrafleXtreme [Bruker] using matrix-assisted laser desorption / ionization time- of-flight (MALDI-TOF). Chiral HPLC analysis was conducted by Chiral Technology Korea.Synthetic InformationA. Acyl chain building blocks

[0159] Compound 57

[0160] To a solution of 3-buten-l-ol (56) (14.42 g, 200.04 mmol, 1 equiv.) and imidazole (27.23 g, 400.07 mmol, 2 equiv.) in dichloromethane (DCM) (200 mL, 1 M for 56) at 0°C was added tert-butyldiphenylsilyl chloride (TBDPSC1) (57.72 g, 210.04 mmol, 54.45 mL, 1.05 equiv.), then stirred at room temperature (r.t.) for 4 hr. After completion of the reaction checked by TLC, the reaction mixture was filtered with DCM and quenched with brine. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (EtOAc) three times. The combined organic layer was dried over anhydrousand concentrated in vacuo after filtration. The resultant was filtered with hexane and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hexane) to afford 57 as a colorless oil. Yield: 98% (60.86 g, 196.00 mmol);1H NMR (500 MHz,Reference peak CDCl3at 7.26 ppm): 37.70-7.66 (m, 4H), 7.45- 7.41 (m, 2H), 7.41-7.37 (m, 4H), 5.84 (ddt, J= 17.1, 10.3, 6.9 Hz, 1H), 5.09-5.00 (m, 2H), 3.72 (t, J= 6.7 Hz, 2H), 2.33 (qt, J= 6.7, 1.3 Hz, 2H), 1.06 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 135.6, 135.4, 134.0, 129.5, 127.6, 116.3, 63.5, 37.2, 26.8, 19.2; LRMS (ESI)

[0161] Compound 58

[0162] To a solution of 57 (60.86 g, 196.00 mmol, 1 equiv.) in DCM (400 mL, 0.5 M for 57) at 0 °C was added 3-chloroperbenzoic acid (m-CPBA) (52.71 g, 235.21 mmol, 1.2 equiv.), then stirred at r.t. for 24 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with IN NaOH(aq) (400 mL, 2 equiv.). The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by flash column chromatography on silica gel (5% EtOAc in hexane) to afford 58 as a white solid. The 58 was used as a reference compound to check enantiomeric purity with chiral HPLC analysis (FIG. 6). Yield: 99% (63.06 g, 193.13 mmol); [a]D250.00 (c = 1.00, CHCh); ‘ H NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.70-7.66 (m, 4H), 7.46-7.41 (m, 2H), 7.41-7.37 (m, 4H), 3.88-3.78 (m, 2H), 3.11 (tdd, J = 5.7, 4.0, 2.7 Hz, 1H), 2.79 (dd, J= 5.1, 4.0 Hz, 1H), 2.52 (dd, J= 5.1, 2.7 Hz, 1H), 1.78 (dt, J= 7.0, 5.7 Hz, 2H), 1.06 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 135.53, 135.51, 133.7, 133.6, 129.7, 127.7, 60.9, 50.1, 47.2, 35.7, 26.8, 19.2; LRMS (ESI) m / z calcd for C2oH2702Si [M+H]+: 327.2, found: 327.2. See FIG. 6 showing chiral HPLC analysis conditions and chromatograms of 58

[0163] Compound 59

[0164] To a solution 58 (63.06 g, 193.13 mmol, 1 equiv.) in dry tetrahydrofuran (THF) (20 mL, 10 M for 58) at r.t. were added (S,S)-(+)-A^Af'-bis(3,5-di-tert-butylsalicylidene)-l,2- cyclohexanediaminocobalt(II) ((S^-Co-salen) (2.33 g, 3.86 mmol, 0.02 equiv.) and acetic acid (AcOH) (927.84 mg, 15.45 mmol, 884.50 z / L, 0.08 equiv.), then stirred at r.t. for 1 hr. To the reaction mixture at 0 °C was added (1.91 g, 106.22 mmol, 1.91 mL, 0.55equiv.) slowly, then stirred at r.t. for 48 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc in hexane) to afford 59 as a pale-yellow solid. The enantiomeric purity of 59 was determined by chiral HPLC analysis (FIG. 7). Yield: 44% (27.93 g, 85.54 mmol); Enantiomeric purity: >99% ee (230 nm); [a]D25-5.25 (c = 1.00, CHCI3);NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.70-7.66 (m, 4H), 7.46-7.42 (m, 2H), 7.42-7.37 (m, 4H), 3.89- 3.78 (m, 2H), 3.11 (tdd, J = 5.8, 4.0, 2.7 Hz, 1H), 2.79 (dd, J= 5.1, 4.0 Hz, 1H), 2.52 (dd, J =5.1, 2.8 Hz, 1H), 1.78 (dt, J = 7.0, 5.7 Hz, 2H), 1.07 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCI3 at 77.00 ppm): 3 135.53, 135.51, 133.7, 133.6, 129.7, 127.7, 60.9,50.1, 47.2, 35.7, 26.8, 19.2; LRMS (ESI) m / z calcd fo found:327.2. See FIG. 7 showing a chiral HPLC analysis conditions and chromatograms of 59

[0165] Compound 60

[0166] To a solution of 7-octyn-l-ol (4.80 g, 38.04 mmol, 1 equiv.) in dry DCM (90 mL, 0.4 M for 7-octyn-l-ol) at 0 °C were added dry Y.Y-diisopropylcthylaminc (DIPEA) (9.83 g, 76.08 mmol, 13.25 mL) and chloromethyl methyl ether (M0MC1) (4.59 g, 57.06 mmol, 4.33 mL, 1.5 equiv.) slowly under Ar(g), then stirred at r.t. for 20 hr. After completion of the reaction checked by TLC, the reaction mixture was concentrated in vacuo. The resultant was filtered with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 5%) to afford 60 as a colorless oil.ppm): 34.61 (s, 2H), 3.52 (t, J= 6.6 Hz, 2H), 3.35 (s, 3H), 2.19 (td, J= 7.1, 2.7 Hz, 2H), 1.93 (t, J = 2.1 Hz, 1H), 1.63-1.57 (m, 2H), 1.57-1.50 (m, 2H), 1.47-1.34 (m, 4H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 96.4, 84.6, 68.1, 67.8, 55.1, 29.6, 28.49, 28.48, 28.4, 25.7, 18.3; LRMS (ESI) m / z calcd for C10H19O2 [M+H]+: 171.1, found: 171.2.

[0167] Compound 61

[0168] To a solution of 60 (5.87 g, 34.49 mmol, 2 equiv.) in dry THF (40 mL) at -78 °C was added n-butyllithium (n-BuLi) solution (2.0 M in cyclohexane, 16.38 mL, 1.9 equiv.) dropwise with a syringe pump (rate: 1 mL / min) under Ar(g), then stirred at -78 °C for 20 min. To the reaction mixture at -78 °C was added boron trifluoride diethyl etherate (BF3 • 0Et2) (4.90 g, 34.49 mmol, 4.26 mL, 2 equiv.) dropwise with a syringe pump (rate: 1 mL / min), then stirred at -78 °C for 20 min. To the reaction mixture at -78 °C was added 59 (5.63 g, 17.24 mmol, 1 equiv.) in dry THF (20 mL + 5 mL rinse) dropwise with a syringe pump (rate: 1 mL / min), then stirred at -78 °C for 7 hr. The final concentration of the reaction mixture was 0.2 M for 59. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with saturated NH4Cl(aq) at -78 °C, then warmed to r.t. The resultant was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (10% EtOAc in hexane) to afford 61 as a pale-yellow oil. Yield: 97% (8.32 g, 16.747.26 ppm): 37.71-7.65 (m, 4H), 7.46-7.42 (m, 2H), 7.42-7.37 (m, 4H), 4.60 (s, 2H), 4.00 (dtt, J = 9.4, 6.3, 3.2 Hz, 1H), 3.90 (ddd, J = 10.4, 5.8, 4.6 Hz, 1H), 3.84 (ddd, J = 10.4, 7.8, 4.3 Hz, 1H), 3.51 (t, J= 6.6 Hz, 2H), 3.35 (s, 3H), 3.23 (d, J= 3.3 Hz, 1H), 2.44-2.34 (m, 2H), 2.16 (tt, J= 7.2, 2.4 Hz, 2H), 1.88-1.72 (m, 2H), 1.63-1.55 (m, 2H), 1.53-1.46 (m, 2H), 1.43-1.33 (m, 4H), 1.05 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 135.54, 135.52, 133.1, 133.0, 129.79, 129.78, 127.8, 96.4, 82.6, 76.4, 70.1, 67.7, 62.9, 55.1, 37.5, 29.6, 28.9, 28.6, 27.5, 26.8, 25.7, 19.0, 18.7; LRMS (ESI) m / z calcd for C3oH44Na04Si [M+Na]+: 519.3, found: 519.3.

[0169] Compound 62

[0170] To a solution of 61 (8.32 g, 16.74 mmol, 1 equiv.) in EtOAc (150 mL, 0.1 M for 61) at r.t. was added Pd / C (832 mg, 10 wt%), then stirred at r.t. for 2 hr under H2(g). After completion of the reaction checked by LC-MS, the reaction mixture was filtered through celite with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 10%) to afford 62 as a colorless oil. Yield: 84% (7.07 g, 14.11 mmol); [a]D25+7.44 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.70-7.66 (m, 4H), 7.46-7.42 (m, 2H), 7.42- 7.38 (m, 4H), 4.62 (s, 2H), 3.92-3.80 (m, 3H), 3.52 (t, J= 6.7 Hz, 2H), 3.36 (s, 3H), 3.25 (d, J= 2.6 Hz, 1H), 1.75-1.62 (m, 2H), 1.62-1.56 (m, 2H), 1.55-1.47 (m, 1H), 1.47-1.40 (m, 2H), 1.40-1.26 (m, 11H), 1.05 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 135.56, 135.54, 133.0, 132.9, 129.81, 129.79, 127.8, 96.4, 71.9, 67.9, 63.7, 55.1, 38.3, 37.5, 29.73, 29.68, 29.55, 29.53, 29.4, 26.8, 26.2, 25.6, 19.0; LRMS (ESI) m / z calcd for C3oH4sNa04Si [M+Na]+: 523.3, found: 523.3.

[0171] Compound 63

[0172] To a solution of 62 (2.41 g, 4.80 mmol, 1 equiv.) in dry DCM (2.5 mL) at 0 °C was added benzyl 2,2,2-trichloroacetimidate (1.82 g, 7.20 mmol, 1.34 mL, 1.5 equiv.) in hexane (25 mL) under Ar(g). To the reaction mixture at 0 °C was added trifluoromethanesulfonic acid (TfOH) (36.04 mg, 240.16 / / mol, 21.25 0.05 equiv.) dropwise, thenstirred at r.t. for 24 hr. The final concentration of the reaction mixture was 0.167 M for 62. When the reaction was checked by TLC and LC-MS, the reaction mixture was filtered with hexane to remove trichloroacetamide. The filtrate was quenched with saturated NaHCCh(aq) and extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 10%) to afford crude 63 (1.95 g, 3.30 mmol) as a colorless oil and recover 62 (526.9 mg, 1.05 mmol). Yield: 69% as a crude,88% as a crude based on recovered starting material (brsm); LRMS (ESI) m / z calcd for C37H54NaO4Si [M+Na]+: 613.4, found: 613.4.

[0173] Compound 64

[0174] To a solution of crude 63 (1.95 g, 3.30 mmol, 1 equiv.) in dry isopropyl alcohol (z- PrOH) (30 mL, 0.1 M for crude 63) at r.t. was added zirconium(IV) chloride (384.97 mg, 1.65 mmol, 0.5 equiv.), then stirred at 85 °C with reflux condenser for 2 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with brine and extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (5% EtOAc in hexane gradient to 17%) to afford 64 as a colorless oil. Yield: 87% (1.58 g, 2.88 mmol), 60% over 2 steps, 77% over 2 steps based on recovered 62; [«]D25-3.99 (c = 1.00, CHCh);JH NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.69-7.64 (m, 4H), 7.44-7.39 (m, 2H), 7.39-7.33 (m, 4H), 7.32-7.23 (m, 5H), 4.48 (d, J= 11.5 Hz, 1H), 4.44 (d, J = 11.5 Hz, 1H), 3.83 (dt, J= 10.3, 6.7 Hz, 1H), 3.75 (dt, J= 10.3, 5.9 Hz, 1H), 3.66-3.59 (m, 3H), 1.83-1.71 (m, 2H), 1.61-1.44 (m, 4H), 1.40-1.22 (m, 13H), 1.05 (s, 9H);p pp 129.5, 128.3, 127.7, 127.61, 127.60, 127.3, 76.0, 71.0, 63.1, 60.7, 37.1, 34.1, 32.8, 29.7, 29.6, 29.4, 26.9, 25.7, 25.3, 19.2; LRMS (ESI)found: 569.3.

[0175] Compound 65

[0176] To a solution of 64 (1.58 g, 2.88 mmol) and 4-(dimethylamino)pyridine (DMAP) (35.22 mg, 288.32 / / mol, 0.1 equiv.) in dry DCM (28 mL, 0.1 M for 64) at 0 °C were added dry triethylamine (TEA) (583.50 mg, 5.77 mmol, 804.28 / / L, 2 equiv.) and p- toluenesulfonyl chloride (TsCl) (659.61 mg, 3.46 mmol, 1.2 equiv.) under Ar(g), then stirred at r.t. for 14 hr. After completion of the reaction checked by TLC, the reaction mixture wasquenched with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (2% EtOAc in hexane gradient to 12%) to afford 65 as a colorless oil. Yield: 98% (1.98 g, 2.83 mmol); [a]D25-3.61 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.82-7.76 (m, 2H), 7.68-7.63 (m, 4H), 7.43-7.39 (m, 2H), 7.39-7.31 (m, 6H), 7.31-7.22 (m, 5H), 4.48 (d, J= 11.5 Hz, 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.82 (ddd, J= 10.2, 7.4, 6.0 Hz, 1H), 3.75 (dt, J= 10.2, 5.9 Hz, 1H), 3.66-3.57 (m, 1H), 2.44 (s, 3H), 1.84-1.70 (m, 2H), 1.63 (dt, J = 14.5, 6.6 Hz, 2H), 1.57-1.43 (m, 2H), 1.40-1.33 (m, 1H), 1.32-1.26 (m, 3H), 1.25-1.18 (m, 8H), 1.05 (s, 9H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 144.6, 139.0, 135.6, 133.9, 129.8, 129.5,128.3, 127.9, 127.7, 127.61, 127.60, 127.3, 76.0, 71.0, 70.7, 60.7, 37.1, 34.1, 29.7, 29.5, 29.3, 28.9, 28.8, 26.9, 25.3, 25.2, 21.6, 19.2; LRMS (ESI) m / z calcd fo723.4, found: 723.4.

[0177] Compound 89a

[0178] To a solution of 65 (1.33 g, 1.90 mmol) in dry THF (11 mL) at -78 °C were added 1 -phenyl- 1 -propyne (132.52 mg, 1.14 mmol, 142.81 / / L, 0.6 equiv.), dilithium tetrachlorocuprate(II) (Li2CuC14) solution (0.1 M in THF, 1.90 mL, 0.1 equiv.), and n- butylmagnesium chloride (n-BuMgCI) solution (2.0 M in THF, 5.70 mL, 6 equiv.) dropwise under Ar(g), then stirred at r.t. for 1 hr. The final concentration of the reaction mixture was 0.1 M for 65. After completion of the reaction checked by TLC, the reaction mixture was quenched with saturated NH4Cl(aq) at 0 °C and extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 3%) to afford 89a as a colorless oil. Yield: 97% (1.08 g, 1.84 mmol); [«]D25-4.77 (c = 1.00, CHCh);1H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.69-7.63 (m, 4H), 7.44-7.39 (m, 2H), 7.39-7.33 (m, 4H), 7.32-7.22 (m, 5H), 4.48 (d, J= 11.4 Hz, 1H), 4.44 (d, J= 11.5 Hz, 1H), 3.83 (ddd, J= 10.2, 7.4, 6.0 Hz, 1H), 3.75 (dt, J= 10.2, 5.9 Hz, 1H), 3.66-3.58 (m, 1H), 1.84-1.71 (m, 2H), 1.60-1.42 (m, 2H), 1.41-1.34 (m, 1H), 1.34-1.28 (m, 3H), 1.28-1.23 (m, 18H), 1.05 (s, 9H), 0.88 (t, J= 6.9 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 139.0, 135.6, 134.0, 129.54, 129.53, 128.3, 127.7, 127.61, 127.60, 127.3, 76.1, 71.0, 60.7, 37.1, 34.1, 31.9, 29.79, 29.70, 29.69, 29.68, 29.66, 29.4, 26.9, 25.3, 22.7, 19.2, 14.1; LRMS (ESI) m / z calcd for C39H58NaO2Si [M+Na]+: 609.4, found: 609.4.

[0179] Compound 89b

[0180] Following the synthetic procedure described in 89a, 65 (953.4 mg, 1.36 mmol) and z-pentylmagnesium bromide (z-PeMgBr) solution (2.0 M in diethyl ether, 4.08 mL) in dry THF (8 mL) provided 89b as colorless oil. Yield: 98% (804.8 mg, 1.34 mmol); [«]D25-4.79 (c = 1.00, CHCh);1H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.70- 7.62 (m, 4H), 7.45-7.39 (m, 2H), 7.39-7.33 (m, 4H), 7.32-7.22 (m, 5H), 4.48 (d, J= 11.5 Hz, 1H), 4.44 (d, J = 11.5 Hz, 1H), 3.83 (ddd, J = 10.2, 7.4, 6.0 Hz, 1H), 3.75 (dt, J= 10.1, 5.9 Hz, 1H), 3.66-3.58 (m, 1H), 1.84-1.71 (m, 2H), 1.58-1.44 (m, 3H), 1.39-1.29 (m, 2H), 1.29-1.22 (m, 16H), 1.19-1.13 (m, 2H), 1.05 (s, 9H), 0.86 (d, J = 6.6 Hz, 6H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 139.0, 135.6, 133.9, 129.5, 128.3, 127.7, 127.6, 127.3, 76.1, 71.0, 60.7, 39.1, 37.1, 34.1, 30.0, 29.8, 29.73, 29.70, 29.69, 29.65, 28.0, 27.4, 26.9, 25.3, 22.7, 19.2; LRMS (ESI) m / z calcd for C4oH6oNa02Si [M+Na]+: 623.4, found: 623.4.

[0181] Compound 90a

[0182] To a solution of 89a (1.06 g, 1.80 mmol, 1 equiv.) in dry THF (15 mL) at r.t. was added tetrabutylammonium fluoride (TBAF) solution (1.0 M in THF, 2.16 mL, 1.2 equiv.), then stirred at r.t. for 4 hr. The final concentration of the reaction mixture was 0.1 M for 89a. After completion of the reaction checked by TLC, the reaction mixture was quenched with brine and extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified byMPLC on silica gel (5% EtOAc in hexane gradient to 15%) to afford 90a as a colorless oil. Yield: 97% (611.7 mg, 1.75 mmol); [a]D25-30.79 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.37-7.31 (m, 4H), 7.31-7.26 (m, 1H), 4.60 (d, J = 11.4 Hz, 1H), 4.48 (d, J = 11.4 Hz, 1H), 3.80 (ddd, J = 11.3, 7.0, 4.4 Hz, 1H), 3.73 (ddd, J = 11.1, 6.8, 4.6 Hz, 1H), 3.64 (dddd, 7= 7.9, 6.6, 5.3, 3.9 Hz, 1H), 2.39 (br s, 1H), 1.86-1.79 (m, 1H), 1.79-1.71 (m, 1H), 1.71-1.63 (m, 1H), 1.58-1.49 (m, 1H), 1.37-1.22 (m, 22H), 0.88 (t, 7= 6.9 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3138.4, 128.5, 127.8, 127.7, 78.7, 70.9, 60.9, 35.8, 33.4, 31.9, 29.8, 29.68, 29.66, 29.64, 29.59,29.4, 25.1, 22.7, 14.1; LRMS (ESI) m / z calcd for found: 349.3.

[0183] Compound 90b

[0184] Following the synthetic procedure described in 90a, 89b (1.24 g, 2.06 mmol) in dry THF (8 mL) provided 90b as colorless oil. Yield: 99% (741.4 mg, 2.04 mmol); [«]D25- 28.79 (c = 1.00, CHCh);1H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 3 7.37-7.32 (m, 4H), 7.31-7.26 (m, 1H), 4.60 (d, 7 = 11.4 Hz, 1H), 4.48 (d, 7= 11.4 Hz, 1H), 3.83-3.77 (m, 1H), 3.77-3.69 (m, 1H), 3.68-3.60 (m, 1H), 2.43 (br s, 1H), 1.86-1.79 (m, 1H), 1.79-1.71 (m, 1H), 1.70-1.63 (m, 1H), 1.58-1.47 (m, 2H), 1.36-1.23 (m, 18H), 1.15 (q, 7= 6.8 Hz, 2H), 0.86 (d, 7 = 6.7 Hz, 6H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 138.4, 128.5, 127.8, 127.7, 78.7, 70.9, 60.9, 39.0, 35.8, 33.4, 29.9, 29.8, 29.71, 29.67, 29.65, 29.595, 29.588, 28.0, 27.4, 25.1, 22.7; LRMS (ESI) m / z calcd

[0185] Compound 85a

[0186] To a solution of 90a (597.4 mg, 1.71 mmol, 1 equiv.) in acetone (14 mL, 0.1 M for 90a) at 0 °C was added Jones reagent (1.25 M, 2.74 mL, 2 equiv.), then stirred at 0 °C for 2 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with H2O and extracted with EtOAc five times under IN HCl(aq). The combined organic layerwas dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (5% EtOAc in hexane gradient to 30%) to afford 85a as a pale-yellow oil. Yield: 68% (423.1 mg, 1.17 mmol); [«]D25-7.05 (c = 1.00, CHCh);!H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 3 11.20 (br s, 1H), 7.35-7.30 (m, 4H), 7.30-7.26 (m, 1H), 4.57 (s, 2H), 3.91-3.83 (m, 1H), 2.63 (dd, J = 15.4, 7.1 Hz, 1H), 2.56 (dd, J= 15.5, 5.1 Hz, 1H), 1.70-1.62 (m, 1H), 1.60-1.52 (m, 1H), 1.43-1.32 (m, 2H), 1.32-1.21 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 176.7, 138.1, 128.4, 127.8, 127.7, 75.7, 71.5, 39.4, 34.1, 31.9, 29.68, 29.66, 29.65, 29.64, 29.57, 29.5, 29.4, 25.1, 22.7, 14.1; LRMS (ESI) m / z calcd

[0187] Compound 85b

[0188] Following the synthetic procedure described above with 85a, 90b (474.8 mg, 1.31 mmol) in acetone (7 mL) provided 85b as colorless oil. Yield: 72% (354.75 mg, 0.942 mmol); [a]D25-6.34 (c = 1.00, ‘ H NMR (500 MHz, CDCl3, Reference peak TMS at0.00 ppm): 3 11.14 (br s, 1H), 7.36-7.30 (m, 4H), 7.30-7.26 (m, 1H), 4.57 (s, 2H), 3.91-3.83 (m, 1H), 2.63 (dd, J = 15.4, 7.1 Hz, 1H), 2.55 (dd, J= 15.5, 5.1 Hz, 1H), 1.70-1.61 (m, 1H), 1.60-1.47 (m, 2H), 1.42-1.32 (m, 2H), 1.29-1.24 (m, 16H), 1.15 (q, J = 6.9 Hz, 2H), 0.86 (d, J = 6.6 Hz, 6H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 176.7, 138.1, 128.4, 127.9, 127.7, 75.7, 71.6, 39.4, 39.1, 34.1, 30.0, 29.73, 29.69, 29.66, 29.594, 29.587, 29.56, 28.0, 27.4, 25.1, 22.7; LRMS (ESI) found: 377.3.

[0189] Compound 93a

[0190] To a solution of 85a (1.42 g, 3.91 mmol, 1 equiv.) in EtOAc (20 mL, 0.2 M for 85a) at r.t. was added Pd / C (142 mg, 10 wt%), then stirred at r.t. for 3 hr under H2(g). After completion of the reaction checked by LC-MS, the reaction mixture was filtered throughcelite with EtOAc. The filtrate was concentrated in vacuo to afford 93a as a crude. The crude93a was used in the next step without any further purification. LRMS (ESI) m / z calcd for C16H31O3 [M-H]’: 271.2, found: 271.2.

[0191] Compound 93b

[0192] To a solution of 85b (380.2 mg, 1.01 mmol, 1 equiv.) in EtOAc (5 mL, 0.2 M for85b) at r.t. was added Pd / C (38.02 mg, 10 wt%), then stirred at r.t. for 3 hr under H2(g). After completion of the reaction checked by LC-MS, the reaction mixture was filtered through celite with EtOAc. The filtrate was concentrated in vacuo to afford 93b as a crude. The crude93b was used in the next step without any further purification. LRMS (ESI) m / z calcd for C17H34O3 [M-H]’: 285.2, found: 285.2.

[0193] Compound 94a

[0194] To a solution of crude 93a (1 equiv.) in EtOAc (20 mL, 0.2 M for crude 93a) at 0 °C were added TEA (474.78 mg, 4.69 mmol, 654.42, 1.2 equiv.) and 2,4'- dibromoacetophenone (1.20 g, 4.30 mmol, 1.1 equiv.), then stirred at r.t. for 15 hr. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with brine. The organic layer was separated and the aqueous layer was extracted with DCM three times. The combined organic layer was dried over anhydrous and concentrated invacuo after filtration. The residue was purified by flash column chromatography on silica gel (DCM) to afford 94a as a white solid. Yield: 90% over 2 steps (1.66 g, 3.53 mmol); [a]D25-2.02 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.78 (d, J= 8.4 Hz, 2H), 7.65 (d, J= 8.3 Hz, 2H), 5.42 (d, J= 16.5 Hz, 1H), 5.31 (d, J= 16.5 Hz, 1H), 4.16-4.07 (m, 1H), 3.29 (d, J= 3.9 Hz, 1H), 2.68 (dd, J = 15.1, 3.0 Hz, 1H), 2.56 (dd, J= 15.1, 9.3 Hz, 1H), 1.64-1.54 (m, 1H), 1.54-1.43 (m, 2H), 1.42-1.35 (m, 1H), 1.35-1.22 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference

[0195] Compound 94b

[0196] To a solution of crude 93b (1 equiv.) in EtOAc (5 mL, 0.2 M for crude 93b) at 0 °C were added TEA (122.60 mg, 1.21 mmol, 168.98 z / L, 1.2 equiv.) and 2,4'- dibromoacetophenone (308.68 mg, 1.11 mmol, 1.1 equiv.), then stirred at r.t. for 16 hr. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with brine. The organic layer was separated and the aqueous layer was extracted with DCM three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by flash column chromatography on silica gel (DCM) to afford 94b as a white solid. Yield: 80% over 2 steps (391.4 mg, 0.810 mmol);

[0197] Compound 95a

[0198] To a solution of 94a (1.63 g, 3.47 mmol, 1 equiv.) and dry pyridine (1.92 g, 24.29 mmol, 1.96 mL, 7 equiv.) in dry DCM (34 mL, 0.1 M for 94a) at 0 °C was added palmitoyl chloride (1.14 g, 4.16 mmol, 1.26 mL, 1.2 equiv.) under Ar(g), then stirred at r.t. for 18.5 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with H2O, then stirred at r.t. for 30 min. The organic layer was separated and the aqueous layer was extracted with EtOAc three times under brine. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine. The residue was purified byMPLC on silica gel (0% DCM in hexane gradient to 100%) to afford 95a as a white solid. Yield: 99% (2.43 g, 3.44 mmol); [a]D25+0.21 (c = 1.00, CHCh);(500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.76 (d, J= 8.3 Hz, 2H), 7.63 (d, J= 8.3 Hz, 2H), 5.32-5.25 (m, 3H), 2.76 (dd, J = 15.4, 7.5 Hz, 1H), 2.71 (dd, J= 15.5, 5.4 Hz, 1H), 2.30 (t, J = 7.5 Hz, 2H), 1.70-1.56 (m, 4H), 1.34-1.22 (m, 46H), 0.88 (t, J = 6.8 Hz, 6H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 190.9, 173.3, 169.9, 132.8, 132.2, 129.2, 129.1, 70.1, 65.9, 38.9, 34.5, 34.0, 31.9, 29.69, 29.67, 29.65, 29.6, 29.54, 29.52, 29.48, 29.4, 29.33, 29.31, 29.2, 25.1, 25.0, 22.7, 14.1; LRMS (ESI

[0199] Compound 95b

[0200] To a solution of 94b (548.7 mg, 1.13 mmol, 1 equiv.) and dry pyridine (628.39 mg, 7.94 mmol, 0.640 mL, 7 equiv.) in dry DCM (11 mL, 0.1 M for 94b) at 0 °C was added 13- methyltetradecaonyl chloride (444.05 mg, 1.70 mmol, 1.5 equiv.) under Ar(g), then stirred at r.t. for 17 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with H2O, then stirred at r.t. for 30 min. The organic layer was separated and the aqueous layer was extracted with EtOAc three times under brine. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine. The residue was purified by MPLC on silica gel (0% DCM in hexane gradient to 100%) to afford 95b as a white solid. Yield: 96% (771.36 mg, 1.09 mmol); +0.33 (c = 1.00, CHCh); LRMS(ESI) calcd fo

[0201] Compound 86a

[0202] To a suspension of 95a (2.49 g, 3.52 mmol, 1 equiv.) in acetic acid (AcOH) (8.8 mL, 0.4 M for 95a) at r.t. was added zinc (dust, <10 / / m, 2.30 g, 35.16 mmol, 10 equiv.), then sonicated at r.t. for 1 min. The reaction mixture was stirred at 60 °C for 1 hr. After completion of the reaction checked by TLC, the reaction mixture was diluted and filtered through celite with DCM. The filtrate was concentrated in vacuo. The resultant was evaporated at 40 °C with toluene three times to remove AcOH. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 50%) to afford 86a as a white solid. Yield: 92% (1.65 g, 3.24 mmol); [a]D25-1.07 (c = 1.00, CHCh); ‘ H NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): d 10.60 (br s, 1H), 5.21 (quin, J= 6.3 Hz, 1H), 2.63 (dd, J= 15.8, 7.3 Hz, 1H), 2.58 (dd, J= 15.8, 5.4 Hz, 1H), 2.28 (t, J = 7.5 Hz, 2H), 1.68-1.56 (m, 4H), 1.36- 1.20 (m, 46H), 0.88 (t, J = 6.8 Hz, 6H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): <5 175.7, 173.3, 70.0, 38.8, 34.5, 34.0, 31.9, 29.70, 29.69, 29.67, 29.65, 29.6, 29.54, 29.49, 29.4, 29.34, 29.28, 29.1, 25.1, 25.0, 22.7, 14.1; LRMS (ESI) m / z calcd for C32H61O4 [M-H]’: 509.5, found: 509.5.

[0203] Compound 86b

[0204] To a suspension of 95b (757.8 mg, 1.07 mmol, 1 equiv.) in acetic acid (AcOH) (2.68 mL, 0.4 M for 95b) at r.t. was added zinc (dust, <10 z / m, 700.03 mg, 10.71 mmol, 10 equiv.), then sonicated at r.t. for 1 min. The reaction mixture was stirred at 60 °C for 1 hr. After completion of the reaction checked by TLC, the reaction mixture was diluted and filtered through celite with DCM. The filtrate was concentrated in vacuo. The resultant was evaporated at 40 °C with toluene three times to remove AcOH. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 50%) to afford 86b as a white solid. Yield: 87% (476.98 mg, 0.934 mmol);calcd foB. Glucosamine building blocks

[0205] Compound 97

[0206] To a solution of D-(+)-glucosamine hydrochloride (96) (5.39 g, 25.00 mmol, 1 equiv.), copper(II) sulfate pentahydrate mg, 249.96 / / mol, 0.01 equiv.), and potassium carbonate( ) ( g, 37.49 mmol, 1.5 equiv.) in methanol (MeOH) (125 mL, 0.2 M for 96) at r.t. was added imidazole- 1- sulfonyl azide30(5.19 g, 30.00 mmol, 1.2 equiv.), then stirred at r.t. for 2 hr. After completion of the reaction checked by LC- MS, the reaction mixture was filtered through celite with MeOH. The filtrate was concentrated in vacuo and evaporated at 40 °C with toluene three times to remove MeOH and H2O. Afforded crude 97 was used in the next step without any further purification. LRMS (ESI) m / z calcd for

[0207] Compound 98

[0208] To a solution of crude 97 (1 equiv.) in dry pyridine (125 mL, 0.2 M for crude 97) at 0 °C was added acetic anhydride (AC2O) (20.42 g, 200.03 mmol, 18.91 mL, 8 equiv.) dropwise with a syringe pump for 30 min under Ar(g), then stirred at r.t. for 14 hr. After completion of the reaction checked by LC-MS, the reaction mixture was concentrated in vacuo. The resultant was diluted with H2O and extracted with EtOAc five times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine and AcOH. The residue was purified by flash column chromatography on silica gel (10% EtOAc in hexane gradient to 33.33%) to afford 98 as a colorless syrup. Yield: 92% over 2 steps (8.60 g, 23.03 mmol)9.6, 4.5, 2.1 Hz, 1H), 3.70-3.63 (m, 2H), 2.19 (s, 6H), 2.11 (s, 3H), 2.09 (s, 3H), 2.08 (s, 6H), 2.04 (s, 3H), 2.02 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 170.5, 170.0, 169.8, 169.6, 169.5, 168.53, 168.49, 92.6, 89.9, 72.72, 72.67, 70.7, 69.7, 67.9, 67.7, 62.5, 61.38, 61.36, 60.3, 20.91, 20.86, 20.67, 20.65, 20.6, 20.5; LRMS (ESI)

[0209] Compound 99

[0210] To a solution of 98 (16.22 g, 43.46 mmol, 1 equiv.) in dry DMF (43.5 mL, 1 M for 98) at r.t. was added hydrazine acetate (4.80 g, 52.15 mmol, 1.2 equiv.) under Ar(g), then stirred at r.t. for 1 hr under Ar(g). After completion of the reaction checked by TLC, the reaction mixture was diluted withand extracted with EtOAc four times under brine. The combined organic layer was dried over anhydrous Na3SO4(s) and concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove DMF. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexane gradient to 50%) to afford 99 as a colorless syrup. Yield: 97% (13.93 g,5.53 (dd, J= 10.4, 9.4 Hz, 1H), 5.40 (t, J= 3.1 Hz, 1H), 5.05 (t, J= 9.6 Hz, 1H), 5.03-5.00 (m, 2H), 4.74 (d, J= 8.0 Hz, 1H), 4.30-4.20 (m, 3H), 4.17-4.07 (m, 2H), 3.94 (br s, 1H), 3.76- 3.68 (m, 1H), 3.51-3.45 (m, 2H), 3.43 (dd, J = 10.5, 3.4 Hz, 1H), 2.09 (s, 12H), 2.04 (s, 3H), 2.02 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 170.81, 170.77, 170.10, 170.05, 169.8, 169.7, 96.2, 92.1, 72.5, 71.9, 70.4, 68.5, 68.3, 67.6, 64.8, 62.0, 61.9, 61.4, 20.72, 20.71, 20.68, 20.65, 20.60, 20.55; LRMS (ESI) m / z calcd

[0211] Compound 100

[0212] To a solution of 99 (13.93 g, 42.06 mmol, 1 equiv.) and imidazole (8.59 g, 126.19 mmol, 3 equiv.) in dry DCM (140 mL, 0.3 M for 99) at r.t. was added tert-butyldimethylsilyl chloride (TBDMSC1) (12.68 g, 84.13 mmol, 2 equiv.), then stirred at r.t. for 18 hr under Ar(g). After completion of the reaction checked by TLC, the reaction mixture was quenched with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by flash column chromatography on silica gel (10% EtOAc in hexane gradient to 20%) to afford 100 as a colorless syrup. Yield: 96% (17.97 g, 40.33 mmol); [«]D25-2.44(500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 34.99-4.91 (m, 2H), 4.62 (d, J = 7.7 Hz, 1H), 4.18 (dd, J = 12.1, 6.1 Hz, 1H), 4.10 (dd, J = 12.1, 2.5 Hz, 1H), 3.70-3.62 (m, 1H), 3.45-3.38 (m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 0.93 (s, 9H), 0.16 (s, 3H), 0.16 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 170.5, 170.0, 169.6, 97.1, 72.2, 71.8, 68.8, 66.0, 62.3, 25.5, 20.68, 20.66, 20.6, 17.9, -4.5, -5.3; LRMS

[0213] Compound 101

[0214] To a solution of 100 (17.97 g, 40.33 mmol, 1 equiv.) in MeOH (110 mL) at 0 °C was added sodium methoxide (NaOMe) solution (0.5 M in MeOH, 24.20 mL, 0.3 equiv.) slowly, then stirred at r.t. for 15 min. The final concentration of the reaction mixture was 0.3 M for 100. After completion of the reaction checked by TLC, the reaction mixture was quenched with Dowex® 50WX4 hydrogen form at 0 °C until pH <7 checked by pH paper. The resultant was concentrated in vacuo after filtration. The residue was evaporated at 40 °C with toluene three times to remove MeOH and H2O. Afforded crude 101 was used in the next step without any further purification.

[0215] Compound 87

[0216] To a solution of crude 101 (1 equiv.) in dry acetonitrile (ACN) (150 mL, 0.25 M for crude 101) at r.t. were added benzaldehyde dimethyl acetal (12.28 g, 80.66 mmol, 12.11 mL, 2 equiv.) and p-toluenesulfonic acid monohydrate (p-TsOH • H2O) (191.79 mg, 1.01 mmol, 0.025 equiv.) under Ar(g), then stirred at r.t. for 15 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with TEA (1.41 mL, 0.25 equiv.) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc in hexane gradient to 12.5%) to afford 87 as a white solid. Yield: 88% (14.48 g, 35.53 mmol); [a]D25-34.58 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.50-7.46 (m, 2H), 7.41-7.35 (m, 3H), 5.53 (s, 1H), 4.65 (d, J= 7.6 Hz, 1H), 4.29 (dd, J = 10.5, 5.0 Hz, 1H), 3.78 (t, J = 10.3 Hz, 1H), 3.62 (td, J = 9.3, 2.6 Hz, 1H), 3.56 (t, J= 9.2 Hz, 1H), 3.41 (ddd, J= 10.0, 9.1, 5.0 Hz, 1H), 3.33 (dd, J= 9.4, 7.6 Hz, 1H), 2.69 (d, J = 2.6 Hz, 1H), 0.95 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 136.8, 129.4, 128.4, 126.3, 102.0, 97.5, 80.7, 71.8, 69.0, 68.5, 66.3, 25.5, 17.9, -4.4, -5.2; LRMS (ESI) m / z calcd

[0217] Compound 88

[0218] To a solution of 87 (14.48 g, 35.53 mmol, 1 equiv.) in dry DCM (120 mL, 0.3 M for 87) at r.t. were added 4 A molecular sieves (14.48 g, 100 wt%) and benzyl bromide (15.19 g, 88.82 mmol, 10.56 mL, 2.5 equiv.), then stirred at r.t. for 30 min. To the reaction mixture at r.t. was added silver(I) oxide (32.93 g, 142.12 mmol, 4 equiv.), then stirredat r.t. for 24 hr under dark condition covered with aluminum foil. After completion of the reaction checked by TLC, the reaction mixture was filtered through celite with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 4%) to afford 88 as a white solid. Yield: 93% (16.40 g, 32.960.00 ppm): δ 7.50-7.46 (m, 2H), 7.42-7.36 (m, 5H), 7.36-7.31 (m, 2H), 7.31-7.27 (m, 1H), 5.57 (s, 1H), 4.91 (d, J = 11.4 Hz, 1H), 4.79 (d, J= 11.4 Hz, 1H), 4.59 (d, J= 7.7 Hz, 1H), 4.30 (dd, J= 10.5, 5.0 Hz, 1H), 3.80 (t, J= 10.3 Hz, 1H), 3.72 (t, J= 9.3 Hz, 1H), 3.52 (t, J = 9.4 Hz, 1H), 3.43-3.34 (m, 2H), 0.94 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): δ 137.9, 137.2, 129.0, 128.34, 128.26, 128.1, 127.8, 126.0, 101.3, 97.5, 81.6, 78.8, 74.8, 68.7, 68.6, 66.3, 25.5, 17.9, -4.4, -5.2; LRMS (ESI) m / z calcd for C26H36N3O5Si [M+H]+: 498.2, found: 498.2.C. Donors and Acceptors a. DO and AO

[0219] Compound 102

[0220] To a suspension of 88 (4.15 g, 8.35 mmol, 1 equiv.) and zinc (dust, <10 / / m, 5.46 g, 83.46 mmol, 10 equiv.) in DCM (40 mL, 0.2 M for 88) at r.t. was added AcOH (1.50 g, 25.04 mmol, 1.43 mL, 3 equiv.) slowly, then stirred at r.t. for 4 hr. After completion of the reaction checked by LC-MS, the reaction mixture was diluted with EtOAc and filtered. The filtrate was extracted with EtOAc three times under saturated NaHCO3(aq). The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration to afford 102 as a crude. The crude 102 was used in the next step without any further purification. LRMS (ESI) m / z calcd for C26H38NO5Si [M+H]+: 472.3, found: 472.3.

[0221] Compound 103

[0222] To a solution of crude 102 (1 equiv.) in dry DCM (40 mL, 0.2 M for 88) at 0 °C were added dry DIPEA (1.19 g, 9.19 mmol, 1.60 mL, 1.1 equiv.) and 2,2,2- trichloroethoxycarbonyl chloride (TrocCl) (1.86 g, 8.77 mmol, 1.21 mL, 1.05 equiv.) under Ar(g), then stirred at r.t. for 3 hr. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with brine. The organic layer was separated and the aqueouslayer was extracted with EtOAc three times. The combined organic layer was dried over anhydrou and concentrated in vacuo after filtration. The residue was purified byMPLC (0% EtOAc in hexane gradient to 10%) to afford 103 as a white solid. Yield: 95% over 2 steps (5.12 g, 7.92 mmol); +4.70 (c = 1.00, CHCh); ‘ H NMR (500 MHz,CDCl3, Reference peak TMS at 0.00 ppm)7.26 (m, 5H), 5.58 (s, 1H), 5.03 (d, J= 8.3 Hz, 1H), 4.95-4.87 (m, 2H), 4.72-4.61 (m, 3H), 4.30 (dd, J= 10.5, 5.0 Hz, 1H), 3.98 (t, J= 9.7 Hz, 1H), 3.80 (t, J= 10.3 Hz, 1H), 3.74 (t, J = 9.2 Hz, 1H), 3.46 (td, J= 9.7, 4.8 Hz, 1H), 3.32 (q, J= 9.9, 9.2 Hz, 1H), 0.88 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 153.8, 138.1, 137.3, 129.0, 128.4, 128.3, 128.2, 127.8, 126.0, 101.2, 96.0, 95.3, 82.6, 76.2, 74.5, 74.2, 68.7, 66.0, 60.1, 25.5, 17.9, -4.2, -5.4; LRMS (ESI) m / z calcd

[0223] Compound 104

[0224] To a solution of 103 (1.00 g, 1.55 mmol, 1 equiv.) in THF (12.49 mL, 1 volume of pyridine) and pyridine (12.26 g, 155.00 mmol, 12.49 mL, 100 equiv.) at -40 °C was added hydrogen fluoride pyridine (HF-Pyridine) (-70% HF, 2.22 g, 77.50 mmol, 2.01 mL, 50 equiv.) slowly, then stirred at r.t. for 15 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with NaHCCh(aq) (100 mL, 50 volumes of HF-Pyridine) at 0 °C and extracted with EtOAc three times. The combined organic layer was dried over anhydrousand concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine. The residue was purified by MPLC on silica gel (5% EtOAc in hexane gradient to 35%) to afford 104 as a white solid. Yield:99% (821.4 mg, 1.46 mmol) Reference peak TMS at0.00 ppm): 37.53-7 AS (m, 2H), 7.43-7.35 (m, 3H), 7.35-7.25 (m, 5H), 5.60 (s, 1H), 5.27 (t, J= 3.7 Hz, 1H), 5.16 (d, J= 9.5 Hz, 1H), 4.93 (d, J= 11.9 Hz, 1H), 4.78 (d, J= 12.0 Hz, 1H), 4.69 (t, J= 12.3 Hz, 2H), 4.27 (dd, J = 10.3, 4.9 Hz, 1H), 4.06 (td, J= 9.7, 4.8 Hz, 1H), 3.97 (tdd, J= 9.6, 3.8, 1.5 Hz, 1H), 3.85-3.72 (m, 3H), 3.04-2.99 (m, 1H);13C NMR (125128.3, 128.0, 127.8, 126.0, 101.3, 95.4, 92.7, 82.8, 75.4, 74.7, 74.4, 68.9, 62.8, 55.1; LRMS (ESI) m / z calcd for C23H24ChNNaO7[M+Na]+: 554.1, found: 554.1.

[0225] Compound DO

[0226] To a solution of 104 (821.4 mg, 1.54 mmol, 1 equiv.) in dry DCM (15 mL, 0.1 M for 104) at r.t. were added trichloroacetonitrile (2.23 g, 15.42 mmol, 1.55 mL, 10 equiv.) and cesium carbonate (CS2CO3) (552.54 mg, 1.70 mmol, 1.1 equiv.) under Ar(g), then stirred at r.t. for 1 hr. After completion of the reaction checked by TLC, the reaction mixture was filtered through celite with DCM. The filtrate was concentrated in vacuo. The resultant was evaporated at 40 °C with toluene three times to remove H2O. Afforded DO as an off- white solid was used in the next step without any further purification. Yield: quantitative (1.07 g, 1.57 mmol) as a crude; α / β = 8 / 1;!H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): δ 8.68 (s, 1H), 7.55-7.48 (m, 2H), 7.43-7.38 (m, 3H), 7.38-7.28 (m, 5H), 6.35 (d, J = 3.7 Hz, 1H), 5.64 (s, 1H), 5.00 (d, J = 11.8 Hz, 1H), 4.78-4.65 (m, 4H), 4.35 (dd, J = 10.5, 4.8 Hz, 1H), 4.16 (td, J = 9.3, 3.6 Hz, 1H), 3.98 (td, J = 9.6, 4.8 Hz, 1H), 3.91-3.84 (m, 2H), 3.81 (t, J = 10.3 Hz, 1H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): δ 160.5, 154.2, 137.6, 136.9, 129.1, 128.6, 128.4, 128.3, 128.1, 125.9, 101.3, 95.6, 95.3, 90.7, 82.1, 74.7, 74.5, 74.4, 68.6, 65.4, 54.4; LRMS (ESI) m / z calcd for C25H24CI6N2O7 [M+Na]+697.0, found: 697.0.

[0227] Compound 102

[0228] To a suspension of 88 (5.42 g, 10.89 mmol, 1 equiv.) and zinc (dust, <10 / / m, 7.12 g, 108.91 mmol, 10 equiv.) in DCM (50 mL, 0.2 M for 88) at r.t. was added AcOH (1.96 g, 32.67 mmol, 1.87 mL, 3 equiv.) slowly, then stirred at r.t. for 4 hr. After completion of the reaction checked by LC-MS, the reaction mixture was diluted with EtOAc and filtered. The filtrate was extracted with EtOAc three times under saturated NaHCO3(aq). The combinedorganic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration to afford 102 as a crude. The crude 102 was used in the next step without any further purification. LRMS (ESI) m / z calcd for C26H38NO5Si [M+H]+: 472.3, found: 472.3.

[0229] Compound 105

[0230] To a solution of crude 102 (1 equiv.) in dry DCM (50 mL, 0.2 M for 88) at 0 °C were added dry DIPEA (1.55 g, 11.98 mmol, 2.09 mL, 1.1 equiv.) and 9- fluorenylmethoxycarbonyl chloride (FmocCl) (2.96 g, 11.43 mmol, 1.05 equiv.) under Ar(g), then stirred at r.t. for 3 hr. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPEG on silica gel (0% EtOAc in hexane gradient to 15%) to afford 105 as a white solid. Yield: 97% (7.32 g, 3.22 mmol); [α]D25+0.37 (c = 1.00, CHCl3); NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): δ 7.75 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H), 7.57-7.34 (m, 7H), 7.34-7.17 (m, 7H), 5.54 (s, 1H), 5.18-4.45 (m, 4H), 4.44-3.93 (m, 5H), 3.92-3.59 (m, 2H), 3.59-3.33 (m, 1H), 3.28-3.00 (m, 1H), 0.86 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): δ 155.6, 143.8, 141.33, 141.27, 138.3, 137.5, 128.9, 128.3, 128.2, 127.74, 127.66, 127.6, 127.1, 126.1, 125.0, 120.0,101.2, 95.7, 82.7, 76.1, 74.4, 68.7, 66.5, 66.0, 60.3, 47.1, 25.6, 17.9, -4.4, -5.3; LRMS (ESI) m / z calcd for C41H47NNaO7Si [M+Na]+: 716.3, found: 716.3.

[0231] Compound A0

[0232] To a mixture of 105 (2.23 g, 3.22 mmol, 1 equiv.) and 4 A molecular sieves (2.23 g, 100 wt%) at r.t. was added dry DCM (32 mL, 0.1 M for 105) under Ar(g), then stirred at r.t.for 30 min. To the reaction mixture at -78 °C were added triethylsilane (1.50 g, 12.86 mmol, 2.05 mL, 4 equiv.) slowly and dichlorophenylborane (1.53 g, 9.65 mmol, 1.25 mL, 3 equiv.) dropwise for 5 min, then stirred at -78 °C for 30 min. After completion of the reaction checked by TLC, the reaction mixture was quenched with dropwise addition of MeOH (6.28 mL, 2 volumes of TEA) and TEA (3.14 mL, 7 equiv.) using a syringe pump (rate: 1 mL / min) at -78 °C, then warmed to r.t.. The resultant was filtered with DCM and the filtrate was washed with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 30%) to afford A0 as a white solid. Yield: 76% (1.71 g, 2.46 mmol); [α]D25+17.56 (c = 1.00, CHCh); NMR (500 MHz, CDCh, Reference peak TMS at 0.00 ppm): d 7.72 (d, J= 7.6 Hz, 2H), 7.57 (d, J= 7.6 Hz, 2H), 7.45-7.29 (m, 7H), 7.29-7.19 (m, 7H), 5.10-4.51 (m, 6H), 4.51-4.23 (m, 2H), 4.17 (t, J = 6.4 Hz, 1H), 4.10-3.92 (m, 1H), 3.88-3.75 (m, 1H), 3.74-3.62 (m, 1H), 3.62-3.49 (m, 1H), 3.49-3.34 (m, 1H), 3.28- 3.05 (m, 1H), 1.85 (br s, 1H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): δ 155.7, 143.82, 143.79, 141.3, 138.2, 138.0, 128.4, 128.3, 128.0, 127.92, 127.86, 127.70, 127.66, 127.1, 124.9, 120.0, 95.2, 80.4, 78.6,75.0, 74.7, 66.5, 62.2, 60.1, 47.1, 25.6, 17.9, -4.2, -5.2; LRMS (ESI) m / z calcd for C4iH49NNaO7Si [M+Na]+: 718.3, found: 718.3. b. DI and Al

[0233] Compound 106

[0234] To a suspension of 87 (1.78 g, 4.36 mmol, 1 equiv.) and zinc (dust, <10 μm, 2.85 g, 43.60 mmol, 10 equiv.) in DCM (21 mL, 0.2 M for 87) at r.t. was added AcOH (523.71 mg, 8.72 mmol, 499.25 μL, 2 equiv.) slowly, then stirred at r.t. for 4 hr. After completion of the reaction checked by LC-MS, the reaction mixture was diluted with EtOAc and filtered. The filtrate was extracted with EtOAc three times under saturated NaHCO3(aq). The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration to afford 106 as a crude. The crude 106 was used in the next step without any further purification. LRMS (ESI) m / z calcd for C19H32NO5Si [M+H]+: 382.2, found: 382.2.

[0235] Compound 107

[0236] To a suspension of crude 106 (1 equiv.) and sodium bicarbonate (NaHCCh) (1.83 g, 21.75 mmol, 5 equiv.) in H2O (20 mL) and THF (20 mL) at 0 °C was added TrocCl (1.20 g, 5.66 mmol, 778.61 / / L, 1.3 equiv.), then stirred at r.t. for 30 min. The final concentration of the reaction mixture was 0.1 M for 87. After completion of the reaction checked by LC-MS, the reaction mixture was diluted with EtOAc and extracted with EtOAc three times under brine. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (5% EtOAc in hexane gradient to 20%) to afford 107 as a white solid. Yield: 98% over 2 steps (2.38 g, 4.28 mmol); [a]D25-25.85 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 37.52-7.47 (m, 2H), 7.42-7.35 (m, 3H), 5.53 (s, 1H), 5.11 (d, J = 8.2 Hz, 1H), 4.81 (d, J= 7.9 Hz, 1H), 4.73 (d, J= 11.9 Hz, 1H), 4.66 (d, J= 11.9 Hz, 1H), 4.29 (dd, J = 10.5, 5.0 Hz, 1H), 4.03-3.95 (m, 1H), 3.77 (t, J= 10.3 Hz, 1H), 3.55 (t, J= 9.2 Hz, 1H), 3.45 (td, J= 9.7, 4.9 Hz, 1H), 3.37 (q, J= 8.7 Hz, 1H), 3.00 (br s, 1H), 0.89 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 154.4, 137.0, 129.4, 128.4, 126.4, 101.9, 96.2, 95.2, 81.5, 74.8, 70.6, 68.6, 66.2, 60.7, 25.6, 17.9, - 4.2, -5.3; LRMS (ESI) m / z calcd for C22H33ChNO7Si [M+H]+: 556.1, found: 556.1.

[0237] Compound 108

[0238] To a solution of 107 (2.08 g, 3.73 mmol, 1 equiv.), 85 (1.62 g, 4.48 mmol, 1.2 equiv.), and DMAP (91.16 mg, 746.21 / / mol, 0.2 equiv.) in dry DCM (19 mL, 0.2 M for 107) at O °C was added l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride(EDC • HC1) (1.07 g, 5.60 mmol, 1.5 equiv.) under Ar(g), then stirred at r.t. for 4 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with NaHCO3(aq). The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 10%) to afford 108 as a colorless syrup. Yield: 96% (3.23 g, 3.58 mmol); [a]D25-16.06 (c = 1.00 ‘ H NMR (500 MHz, CDC13, Reference peakTMS at 0.00 ppm): 37.43-7.36 (m, 2H), 7.33-7.21 (m, 8H), 5.45 (s, 1H), 5.37 (t, J= 10.0 Hz, 1H), 5.03 (d, J= 9.1 Hz, 1H), 4.88 (d, J= 7.8 Hz, 1H), 4.63 (q, J= 12.0 Hz, 2H), 4.50 (d, J = 11.6 Hz, 1H), 4.41 (d, J= 11.6 Hz, 1H), 4.30 (dd, J= 10.5, 5.0 Hz, 1H), 3.83-3.76 (m, 2H), 3.70 (t, J= 9.4 Hz, 1H), 3.60-3.47 (m, 2H), 2.64 (dd, J= 15.0, 6.1 Hz, 1H), 2.50 (dd, J = 15.0, 5.8 Hz, 1H), 1.59-1.42 (m, 2H), 1.37-1.12 (m, 22H), 0.91-0.85 (m, 12H), 0.11 (s, 3H), 0.09 (s, 3H);13C NMR (125 MHz, CDCI3, Reference peak CDCI3 at 77.00 ppm): 3171.4, 154.0, 138.4, 136.8, 129.1, 128.3, 128.2, 127.7, 127.5, 126.2, 101.5, 96.8, 95.3, 78.8, 75.5, 74.6, 71.1, 70.9, 68.6, 66.5, 59.1, 39.4, 34.3, 31.9, 29.68, 29.65, 29.61, 29.59, 29.55,29.4, 25.5, 25.2, 22.7, 17.9, 14.1, -4.2, -5.3; LRMS (ESI) m / z calcd

[0239] Compound 109

[0240] To a solution of 108 (2.29 g, 2.54 mmol) in THF (20.48 mL, 1 volume of pyridine) and pyridine (20.11 g, 254.20 mmol, 20.48 mL, 100 equiv.) at -40 °C was added HF-Pyridine (-70% HF, 3.63 g, 127.10 mmol, 3.30 mL, 50 equiv.) slowly, then stirred at r.t. for 16 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with (165 mL, 50 volumes of HF-Pyridine) at 0 °C and extracted with EtOAc threetimes. The combined organic layer was dried over anhydrousand concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine. The residue was purified by MPLC on silica gel (0% EtOAc in hexanegradient to 30%) to afford 109 as a sticky white solid. Yield: 97% (1.94 g, 2.46 mmol); < / .![> = 5 / 1; ’ H NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): d 7.44-7.38 (m, 2H), 7.33-7.21 (m, 8H), 5.54 (d, J= 9.8 Hz, 1H), 5.51-5.42 (m, 2H), 5.31 (t, J = 3.7 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.1 Hz, 1H), 4.50 (d, J= 11.6 Hz, 1H), 4.39 (d, J= 11.6 Hz, 1H), 4.28 (dd, J = 10.3, 4.9 Hz, 1H), 4.24-4.13 (m, 1H), 4.05 (td, J = 10.2, 3.6 Hz, 1H), 3.84-3.78 (m, 1H), 3.73 (dt, J = 21.8, 10.0 Hz, 2H), 3.24-3.19 (m, 1H), 2.68 (dd, J= 15.2, 6.4 Hz, 1H), 2.44 (dd, J = 15.3, 5.9 Hz, 1H), 1.57-1.40 (m, 2H), 1.36-1.11 (m, 22H), 0.88 (t, J = 6.8 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 171.8, 154.4, 138.4, 136.8, 129.1, 128.3, 128.2, 127.7, 127.5, 126.1, 101.6, 95.3, 92.5, 79.2, 75.4, 74.6, 71.1, 69.6, 68.8, 62.9, 54.8, 39.6, 34.5, 31.9, 29.69, 29.65, 29.6, 29.5, 29.4, 25.2, 22.7, 14.1; LRMS (ESI) m / z calcd

[0241] Compound DI

[0242] To a solution of 109 (1.29 g, 1.64 mmol, 1 equiv.) in dry DCM (16 mL, 0.1 M for 109) at r.t. were added trichloroacetonitrile (2.36 g, 16.35 mmol, 1.64 mL, 10 equiv.) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (49.79 mg, 327.06 / / mol, 48.81 / / L, 0.2 equiv.) under Ar(g), then stirred at r.t. for 1 hr. After completion of the reaction checked by TLC, the reaction mixture was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 15%) to afford DI as a colorless syrup. Yield: 83% (1.26 g, 1.35 mmol);Reference peak CDCl3at 7.26 ppm): d 8.75 (s, 1H), 7.45-7.39 (m, 2H), 7.34-7.22 (m, 8H), 6.41 (d, J= 3.7 Hz, 1H), 5.54-5.46 (m, 2H), 5.32 (d, J= 9.2 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.51 (dd, J = 13.7, 11.8 Hz, 2H), 4.43 (d, J= 11.6 Hz, 1H), 4.36 (dd, J = 10.5, 5.0 Hz, 1H), 4.27 (td, J= 9.9, 3.8 Hz, 1H), 4.07 (td, J= 9.9, 4.9 Hz, 1H), 3.87-3.76 (m, 3H), 2.70 (dd, J= 15.2, 6.3 Hz, 1H), 2.52 (dd, J = 15.2, 5.8 Hz, 1H), 1.60-1.43 (m, 2H), 1.39-1.12 (m, 22H), 0.88 (t, J= 6.8 Hz, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 172.0, 160.7, 154.2, 138.4, 136.5, 129.2, 128.3, 128.2, 127.6, 127.5, 126.0, 101.6, 95.2, 95.0, 90.6, 78.4, 75.4, 74.6, 71.2, 69.1, 68.4, 65.3, 54.6, 39.5, 34.4, 31.9,29.68, 29.65, 29.59, 29.55, 29.4, 25.2, 22.7, 14.1; LRMS (ESI) m / z calcd for C41H54Cl6N2NaO9[M+Na]+: 951.2, found: 951.1.

[0243] Compound 106

[0244] To a suspension of 87 (5.18 g, 12.70 mmol, 1 equiv.) and zinc (dust, <10 μm, 8.30 g, 126.99 mmol, 10 equiv.) in DCM (60 mL, 0.2 M for 87) at r.t. was added AcOH (1.53 g, 25.40 mmol, 1.45 mL, 2 equiv.) slowly, then stirred at r.t. for 4 hr. After completion of the reaction checked by LC-MS, the reaction mixture was diluted with EtOAc and filtered. The filtrate was extracted with EtOAc three times under saturated NaHCO3(aq). The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration to afford 106 as a crude. The crude 106 was used in the next step without any further purification. LRMS (ESI) m / z calcd for C19H32NO5Si [M+H]+: 382.2, found: 382.2.

[0245] Compound 110

[0246] To a solution of crude 106 (4.84 g, 12.69 mmol, 1 equiv.) in dry DCM (60 mL, 0.2 M for 87) at 0 °C were added dry DIPEA (1.80 g, 13.95 mmol, 2.43 mL, 1.1 equiv.) and FmocCl (3.45 g, 13.32 mmol, 1.05 equiv.) under Ar(g), then stirred at r.t. for 3 hr. After completion of the reaction checked by LC-MS, the reaction mixture was quenched with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 30%) to afford 110 as a white solid. Yield: 88% over 2 steps (6.71 g, 11.12 mmol); [α]D25-25.72 (c = 1.00, CHCl3); NMR (500 MHz, CDCl3, Reference peak CDCl3at 7.26 ppm): 87.77 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 6.2 Hz, 2H), 7.52-7.43 (m, 2H), 7.43-7.29 (m, 7H), 5.48 (s, 1H), 5.06-4.91 (m, 1H), 4.89-4.74 (m, 1H), 4.53-4.35 (m, 2H), 4.30-4.24 (m, 1H), 4.24-4.17 (m, 1H), 4.02 (br s, 1H), 3.75 (t, J = 10.2 Hz, 1H), 3.58-3.38 (m, 2H), 3.35-3.17 (m, 2H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 156.4, 143.8, 141.30, 141.25, 137.1, 129.2, 128.3, 127.71, 127.68, 127.1, 126.4, 125.0, 120.0, 101.8, 96.2, 81.5, 70.7, 68.6, 66.9, 66.2, 60.9, 47.1, 25.5, 17.9, -4.2, -5.3; LRMS (ESI)

[0247] Compound 111

[0248] To a solution of 110 (1.92 g, 3.17 mmol, 1 equiv.), 85 (1.38 g, 3.81 mmol, 1.2 equiv.), and DMAP (77.57 mg, 634.96 / / mol, 0.2 equiv.) in dry DCM (16 mL, 0.2 M for 110) at 0 °C was added EDC • HC1 (912.91 mg, 4.76 mmol, 1.5 equiv.), then stirred at r.t. for 4 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with NaHCO3(aq). The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 15%) to afford 111 as a colorless syrup. Yield: 93% (2.79 g, 2.94 mmol); [a]D25-13.60 (c = 1.00, CHCh);(500 MHz,, Reference peak TMS at 0.00 ppm): 37.75 (d, J= 7.5 Hz, 2H), 7.55 (d, J= 7.6 Hz, 2H), 7.47-7.36 (m, 4H), 7.34-7.27 (m, 5H), 7.27-7.19 (m, 5H), 5.49-5.38 (m, 2H), 4.91 (d, J = 8.4 Hz, 2H), 4.48 (d, J = 11.5 Hz, 1H), 4.39 (d, J= 11.5 Hz, 1H), 4.34-4.21 (m, 3H), 4.19-4.12 (m, 1H), 3.85-3.76 (m, 2H), 3.73 (t, J= 9.5 Hz, 1H), 3.63-3.52 (m, 2H), 2.65 (dd, J= 15.0, 6.3 Hz, 1H), 2.48 (dd, J = 15.0, 5.8 Hz, 1H), 1.55-1.46 (m, 1H), 1.46-1.38 (m, 1H), 1.34-1.03 (m, 22H), 0.90- 0.81 (m, 12H), 0.10 (s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peakat 77.00 ppm): 3 171.6, 155.7, 143.9, 143.8, 141.2, 138.4, 136.9, 129.0, 128.3, 128.2, 127.6, 127.5, 127.0, 126.2, 125.19, 125.15, 119.9, 101.5, 97.0, 78.9, 75.6, 71.2, 71.1, 68.7, 67.1, 66.5, 59.0, 47.0, 39.6, 34.3, 31.9, 29.67, 29.66, 29.65, 29.64, 29.58, 29.57, 29.5, 29.4,25.5, 25.1, 22.7, 17.8, 14.1, -4.2, -5.4; LRMS (ESI970.5, found: 970.5.

[0249] Compound Al

[0250] To a mixture of 111 (1.79 g, 1.89 mmol, 1 equiv.) and 4 A molecular sieves (1.79 g, 100 wt%) at r.t. was added dry DCM (19 mL, 0.1 M for 111) under Ar(g), then stirred at r.t. for 30 min. To the reaction mixture at -78 °C was added triethylsilane (879.77 mg, 7.57 mmol, 1.21 mL, 4 equiv.) slowly and dichlorophenylborane (901.21 mg, 5.67 mmol, 736.29 z / L, 3 equiv.) dropwise for 5 min, then stirred at -78 °C for 30 min. After completion of the reaction checked by TLC, the reaction mixture was quenched with dropwise addition of MeOH (3.7 mL, 2 volumes of TEA) and TEA (1.85 mL, 7 equiv.) using a syringe pump (rate: 1 mL / min) at -78 °C, then warmed to r.t. The resultant was filtered with DCM and washed with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrouconcentrated in vacuo after filtration. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 20%) to afford Al as a colorless syrup. Yield: 85% (1.53 g, 1.61 mmol); [a]D25+1.26 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.75 (d, J= 7.5 Hz, 2H), 7.55 (d, J= 7.4 Hz, 2H), 7.38 (t, J= 7.5 Hz, 2H), 7.32-7.18 (m, 12H), 5.28 (t, J= 10.0 Hz, 1H), 4.88 (d, J= 9.3 Hz, 1H), 4.79 (d, J= 7.9 Hz, 1H), 4.63 (d, J= 11.4 Hz, 1H), 4.57 (d, J= 11.4 Hz, 1H), 4.50 (d, J= 11.5 Hz, 1H), 4.45 (d, J= 11.4 Hz, 1H), 4.30-4.20 (m, 2H), 4.17-4.10 (m, 1H), 3.87-3.77 (m, 2H), 3.74-3.66 (m, 2H), 3.55 (q, J= 9.4 Hz, 1H), 3.49-3.43 (m, 1H), 2.55 (dd, J= 15.7, 7.0 Hz, 1H), 2.42 (dd, J = 15.6, 5.3 Hz, 1H), 1.86 (t, J= 6.9 Hz, 1H), 1.57-1.48 (m, 1H), 1.48-1.39 (m, 1H), 1.33-1.09 (m, 22H), 0.92-0.81 (m, 12H), 0.10 (s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 171.9, 155.8, 143.88, 143.82, 141.22, 141.20, 138.5, 137.6, 128.5, 128.3, 128.0, 127.9, 127.69, 127.65, 127.5, 127.0, 125.2, 119.9, 96.6,75.6, 75.5, 75.2, 74.5, 71.4, 67.2, 61.9, 58.5, 47.0, 39.7, 34.1, 31.9, 29.7, 29.64, 29.62, 29.58,29.55, 29.4, 25.5, 25.1, 22.7, 17.8, 14.1, -4.1, -5.3; LRMS (ESI) m / z calcd foD. BfLAsa. General synthetic procedure for compounds 112

[0251] To a mixture of Donor (DO or DI) (1.2 equiv.), Acceptor (AO or Al) (1 equiv.), and 4 A molecular sieves (100 wt%) at r.t. was added dry DCM (8 mL) under Ar(g), then stirred at r.t. for 30 min. To the reaction mixture at -20 °C was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.1 equiv.) in dry DCM (2 mL) dropwise with a syringe pump for 30 min, then stirred at -20 °C for 30 min. The final concentration of the reaction mixture was 0.1 M for Acceptors. After completion of the reaction checked by LC- MS, the reaction mixture was quenched with TEA (0.15 equiv.) at -20 °C. The resultant was filtered and the filtrate was washed with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc three times. The combined organic layer was dried over anhydrous and concentrated in vacuo after filtration. The residue waspurified by MPLC on silica gel (0% EtOAc in hexane gradient to 25%) to afford 112 with trichloroacetamide as an impurity. The crude 112 was used in the next step without any further purification.

[0252] Compound 112(0,0)

[0253] 112(0,0) was synthesized from DO (819.34 mg, 1.21 mmol) and AO (701.67 mg,1.01 mmol) with the general procedure a and obtained as a white solid. Yield: 91% as a crude (1.11 g, 919.47 LRMS (ESI) m / z calcdfound: 1231.4.

[0254] Compound 112(0,1)

[0255] 112(0,1) was synthesized from DO (813.20 mg, 1.20 mmol) and Al (950.9 mg,1.00 mmol) with the general procedure a and obtained as a white solid. Yield: 94% as a crude (1.38 g, 943.48 / / mol); LRMS (ESI) m / zfound: 1485.6.

[0256] Compound 112(1,0)

[0257] 112(1,0) was synthesized from DI (1.12 g, 1.21 mmol) and AO (699.74 mg, 1.01 mmol) with the general procedure a and obtained as a white solid. Yield: 94% as a crude (1.39 g, 945.74 MS (ESI) m / z calcd fofound: 1485.6.

[0258] Compound 112(1,1)

[0259] 112(1,1) was synthesized from DI (1.12 g, 1.20 mmol) and Al (953.6 mg, 1.00 mmol) with the general procedure a and obtained as a colorless syrup. Yield: 99% as a crude (1.70 g, 989.82 / / mol); LRMS (ESI 1739.8,found: 1739.8. b. General synthetic procedure for compounds 113

[0260] To a suspension of crude 112 (1 equiv.) and zinc (dust, <10 / / m, 60 equiv.) in dry THF (4 volumes of AcOH) at r.t. was added AcOH (30 equiv.), then stirred at r.t. for 2 hr. After completion of the reaction checked by TLC, the reaction mixture was sonicated and filtered through celite with EtOAc. The filtrate was quenched with saturatedextracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration to afford 113 as a crude. The crude 113 was used in the next step without any further purification.c. General synthetic procedure for compounds 114

[0261] To a mixture of 85a-b or 86a-b (2 equiv.) any y (DCC) (3 equiv.) at r.t. was added dry DCM (1 mL), then stirred at r.t. for 30 min. To the reaction mixture at r.t. was added crude 113 (1 equiv.) in dry DCM (2 mL + 3 mL rinse), then stirred at r.t. for overnight (12-24 hr). The final concentration of the reaction mixture was 0.05 M for crude 113. After completion of the reaction checked by TLC, the reaction mixture was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 25% or 0% EtOAc in DCM gradient to 10%) to afford 114.

[0262] Compound 114(0,2,0)

[0263] 114(0,2,0) was synthesized from crude 112(0,0) (367.10 mg, 303.21 and 86a(309.78 mg, 606.42 / / mol) with the general procedure b and c (21.5 hr, 0% EtOAc in DCM gradient to 10%), and obtained as a sticky white solid. Yield: 74% over 3 steps (375.76 mg, 245.90 / / mol); [a]D25+0.24 (c = 1. NMR (500 MHz, Reference peakTMS at 0.00 ppm): 37.72 (d, J= 7.8 Hz, 2H), 7.57 (d, J= 7.5 Hz, 2H), 7.48-7.43 (m, 2H), 7.42-7.18 (m, 22H), 5.93 (d, J= 7.4 Hz, 1H), 5.54 (s, 1H), 5.13-5.05 (m, 2H), 5.01-4.83 (m,3H), 4.83-4.70 (m, 2H), 4.68-4.54 (m, 3H), 4.40 (t, J= 9.3 Hz, 2H), 4.32 (dd, J= 10.6, 5.0Hz, 2H), 4.17 (t, J= 6.5 Hz, 1H), 4.08-3.88 (m, 2H), 3.79-3.70 (m, 2H), 3.67 (t, J= 9.1 Hz,1H), 3.61-3.41 (m, 3H), 3.28 (dt, J= 9.7, 7.7 Hz, 1H), 3.22 (br s, 1H), 2.37 (dd, J= 15.0, 6.5 Hz, 1H), 2.30-2.21 (m, 1H), 2.16 (t, J= 6.9 Hz, 2H), 1.58-1.48 (m, 4H), 1.33-1.15 (m, 46H), 0.91-0.83 (m, 15H), 0.08 (s, 3H), 0.06 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.4, 170.0, 155.6, 143.8, 141.3, 138.5, 138.3, 138.1, 137.4, 128.9,128.4, 128.31, 128.27, 128.2, 127.9, 127.84, 127.79, 127.64, 127.58, 127.0, 126.0, 125.0, 120.0, 101.2, 99.6, 95.2, 82.5, 80.5, 78.8, 74.7, 74.5, 74.44, 74.35, 70.9, 68.8, 67.7, 66.5, 65.9, 59.8, 57.8, 47.2, 41.6, 34.5, 34.1, 31.9, 29.69, 29.66, 29.65, 29.62, 29.58, 29.56, 29.5, 29.41, 29.35, 29.3, 29.1, 25.6, 25.2, 25.0, 22.67, 17.89, 14.1, -4.0, -5.2; MS (MALDI-TOF) m / z calcd f

[0264] Compound 114(0,2,1)

[0265] 114(0,2,1) was synthesized from crude 112(0,1) (441.7 mg, 301.48 / / mol) and 86a(308.01 mg, 602.96 / / mol) with the general procedure b and c (16 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 75% over 3 steps (426.76 mg, 239.41 / / mol); [a]D25-2.78 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.75 (d, J= 7.5 Hz, 2H), 7.54 (d, J= 7.4 Hz, 2H), 7.50-7.44 (m, 2H), 7.41-7.34 (m, 5H), 7.33-7.18 (m, 17H), 5.92 (d, J = 7.4 Hz, 1H), 5.55 (s, 1H), 5.24 (t, J= 9.8 Hz, 1H), 5.15-5.06 (m, 2H), 4.91-4.85 (m, 2H), 4.74 (d, J= 7.7 Hz, 1H), 4.65-4.58 (m, 2H), 4.54 (d, J= 11.3 Hz, 1H), 4.49 (d, J= 11.6 Hz, 1H), 4.43 (d, J= 11.5 Hz, 1H), 4.41-4.30 (m, 2H), 4.23 (d, J = 7.5 Hz, 2H), 4.13 (t, J= 7.5 Hz, 1H), 3.98 (d, J = 11.1 Hz, 1H), 3.85-3.73 (m, 3H), 3.68 (t, J= 9.2 Hz, 1H), 3.66-3.49 (m, 4H), 3.29 (q, J= 8.4 Hz, 1H), 2.54 (dd, J = 15.7, 7.0 Hz, 1H), 2.46-2.34 (m, 2H), 2.29 (dd, J= 15.3, 5.6 Hz, 1H), 2.18 (t, J= 6.6 Hz, 2H), 1.61-1.46 (m, 5H), 1.46-1.38 (m, 1H), 1.34-1.08 (m, 68H), 0.91-0.83 (m, 18H), 0.11 (s, 3H), 0.08 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3173.4, 171.8, 170.0, 155.7, 143.9, 143.8, 141.22, 141.19, 138.5, 138.4, 137.7, 137.4, 128.9,128.4, 128.30, 128.27, 128.2, 127.9, 127.8, 127.7, 127.64, 127.61, 127.5, 127.0, 126.1, 125.2,119.9, 101.2, 99.8, 96.4, 82.5, 76.2, 75.5, 74.6, 74.5, 74.35, 74.34, 71.4, 70.9, 68.8, 67.9,67.1, 65.9, 58.3, 57.8, 47.0, 41.7, 39.7, 34.5, 34.2, 34.1, 31.9, 29.69, 29.68, 29.66, 29.65, 29.63, 29.59, 29.59, 29.57, 29.5, 29.44, 29.35, 29.3, 29.1, 25.6, 25.2, 25.1, 25.0, 22.7, 17.8,14.1, -3.9, -5.3; MS (MALDI-TOF) m / z calcd f found: 1804.086.

[0266] Compound 114(1,1,0)

[0267] 114(1,1,0) was synthesized from crude 112(1,0) (441.2 mg, 301.14 / / mol) and 85a(218.35 mg, 602.28 / / mol) with the general procedure b and c (16 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 72% over 3 steps (377.89 mg, 231.23 / / mol); [a]D25-10.42 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.72 (d, J= 7.6 Hz, 2H), 7.57 (d, J= 7.5 Hz, 2H), 7.46-7.13 (m, 29H), 6.27 (d, J = 8.9 Hz, 1H), 5.39 (s, 1H), 5.34 (t, J= 9.8 Hz, 1H), 4.99-4.64 (m, 4H), 4.64-4.54 (m, 2H), 4.53-4.49 (m, 2H), 4.49-4.29 (m, 5H), 4.25 (dd, J = 10.5, 5.0 Hz, 1H), 4.17 (t, J = 6.2 Hz, 1H), 3.97-3.81 (m, 3H), 3.78 (quin, J = 6.1 Hz, 1H), 3.74-3.66 (m, 3H), 3.63 (t, J = 9.4 Hz, 1H), 3.56-3.35 (m, 3H), 3.22 (br s, 1H), 2.64 (dd, J= 15.0, 6.4 Hz, 1H), 2.40 (dd, J = 15.0, 5.8 Hz, 1H), 2.30 (dd, J= 15.3, 7.0 Hz, 1H), 2.24 (dd, J = 15.3, 4.1 Hz, 1H), 1.54-1.37 (m, 4H), 1.35-1.07 (m, 44H), 0.91-0.83 (m, 15H), 0.10 (s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 171.2, 171.1, 155.6, 143.9, 143.8, 141.3, 138.5, 138.4, 138.3, 136.9, 129.0, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.71, 127.67, 127.65, 127.6, 127.4, 127.0, 126.1, 124.9, 120.0, 101.3, 101.1, 95.2, 80.5, 78.9, 78.5, 76.1, 75.5, 74.53, 74.46, 74.4, 71.6, 71.1, 70.8, 68.6, 67.9, 66.5, 66.3, 59.6, 54.5,47.1, 41.2, 39.7, 34.5, 33.7, 31.9, 29.68, 29.66, 29.64, 29.62, 29.56, 29.3, 25.6, 25.1, 25.0, 22.7, 17.9, 14.1, -4.0, -5.2; MS (MALDI-TOF) m / z calcd for 1655.960, found: 1656.040.

[0268] Compound 114(1,2,0)

[0269] 114(1,2,0) was synthesized from crude 112(1,0) (440.70 mg, 300.80 and 86a(307.32 mg, 601.60 / / mol) with the general procedure b and c (22 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 71% over 3 steps (402.5 mg, 225.80 / / mol); [a]D25-6.13 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.72 (d, J= 7.1 Hz, 2H), 7.58 (d, J= 7.5 Hz, 2H), 7.43-7.17 (m, 24H), 5.77 (d, J = 8.4 Hz, 1H), 5.46-5.39 (m, 2H), 5.07-4.84 (m, 4H), 4.83-4.69 (m, 2H), 4.68- 4.53 (m, 2H), 4.49 (d, J= 11.4 Hz, 1H), 4.45-4.25 (m, 4H), 4.18 (t, J = 6.0 Hz, 1H), 4.07- 3.86 (m, 2H), 3.83-3.69 (m, 4H), 3.65 (t, J= 9.4 Hz, 1H), 3.61-3.41 (m, 3H), 3.27 (br s, 1H), 2.64 (dd, J = 15.0, 6.2 Hz, 1H), 2.48 (dd, J = 15.0, 5.8 Hz, 1H), 2.36-2.21 (m, 3H), 2.18-2.01 (m, 1H), 1.63-1.51 (m, 3H), 1.51-1.41 (m, 3H), 1.34-1.12 (m, 68H), 0.91-0.84 (m, 18H), 0.11 (s, 3H), 0.08 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.8, 171.1, 169.6, 155.7, 143.8, 141.3, 139.4, 138.4, 138.3, 138.1, 136.9, 129.0,128.4, 128.30, 128.29, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.0, 126.1, 125.0, 120.0,101.4, 100.8, 95.3, 80.6, 78.9, 78.4, 75.6, 74.6, 74.5, 71.3, 71.1, 70.7, 68.6, 68.1, 66.5, 66.3, 59.7, 55.5, 47.2, 41.6, 39.5, 34.5, 34.4, 34.2, 31.9, 29.71, 29.66, 29.65, 29.63, 29.61, 29.59, 29.56, 29.5, 29.38, 29.36, 29.2, 25.6, 25.24, 25.22, 25.0, 22.7, 17.9, 14.1, -4.0, -5.2; MS (MALDI-TOF) m / z calcd f

[0270] Compound 114(1,1,1)

[0271] 114(1,1,1) was synthesized from crude 112(1,1) (521.27 mg, 303.15 / / mol) and 85a(219.81 mg, 606.30 / / mol) with the general procedure b and c (16 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 72% over 3 steps (473.16 mg, 250.53 / / mol); [a]D25-12.44 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): d 7.75 (d, J= 7.5 Hz, 2H), 7.55 (d, J= 7.4 Hz, 2H), 7.42-7.32 (m, 8H),7.32-7.17 (m, 21H), 6.30 (d, J= 8.9 Hz, 1H), 5.40 (s, 1H), 5.31 (t, J = 9.8 Hz, 1H), 5.19 (t, J = 9.8 Hz, 1H), 4.81 (d, J = 9.4 Hz, 1H), 4.66 (d, J = 7.8 Hz, 1H), 4.59 (d, J = 11.4 Hz, 1H), 4.56-4.50 (m, 2H), 4.50-4.45 (m, 3H), 4.43 (d, J = 11.7 Hz, 2H), 4.37 (d, J = 11.6 Hz, 1H),4.32-4.26 (m, 1H), 4.23 (d, J= 7.5 Hz, 2H), 4.13 (t, J= 7.5 Hz, 1H), 3.96 (q, J= 9.3 Hz, 1H), 3.87 (d, J = 11.0 Hz, 1H), 3.79 (quin, 7= 6.1 Hz, 2H), 3.76-3.67 (m, 3H), 3.66-3.51 (m, 3H), 3.51-3.44 (m, 1H), 3.40 (td, J = 9.7, 4.9 Hz, 1H), 2.65 (dd, J= 15.0, 6.4 Hz, 1H), 2.53 (dd, J= 15.7, 7.0 Hz, 1H), 2.45-2.36 (m, 2H), 2.35-2.24 (m, 2H), 1.55-1.39 (m, 6H), 1.35- 1.08 (m, 66H), 0.91-0.83 (m, 18H), 0.12 (s, 3H), 0.08 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): <5 171.8, 171.3, 171.2, 155.7, 143.9, 143.8, 141.21, 141.19, 138.5, 138.4, 137.9, 136.9, 129.0, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4, 127.00, 126.99, 126.1, 125.2, 119.9, 101.4, 101.3, 96.4, 78.8, 76.1, 76.0,75.5, 74.54, 74.48, 74.2, 71.6, 71.4, 71.1, 70.8, 68.6, 67.9, 67.1, 66.4, 58.2, 54.4, 47.0, 41.2,39.7, 39.6, 34.5, 34.1, 33.7, 31.9, 29.70, 29.67, 29.65, 29.63, 29.58, 29.57, 29.4, 25.6, 25.13, 25.08, 25.06, 22.7, 17.8, 14.1, -3.9, -5.3; MS (MALDI-TOF) m / z calcd fo 1910.185, found: 1910.220.

[0272] Compound 114(1,2,1)

[0273] 114(1,2,1) was synthesized from crude 112(1,1) (519.30 mg, 302.00 / / mol) and 86a(308.55 mg, 604.00 / / mol) with the general procedure b and c (22 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 75% over 3 steps (468.7 mg, 230.10 / / mol); [a]D25-8.41 (c = 1.00, CHCh);NMR (500 MHz,, Reference peak TMS at 0.00 ppm): 37.75 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 7.5 Hz, 2H), 7.41-7.35 (m, 4H), 7.32-7.17 (m, 20H), 5.83 (d, J= 8.4 Hz, 1H), 5.47-5.37 (m, 2H), 5.24 (t, J = 9.8 Hz, 1H), 5.01 (quin, J= 6.4 Hz, 1H), 4.90 (dd, J = 22.4, 8.8 Hz, 2H), 4.76 (d, J= 7.8 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 4.53 (d, J= 11.2 Hz, 1H), 4.49 (d, J= 11.5 Hz, 2H), 4.44 (d, J= 11.4 Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 4.36-4.30 (m, 1H), 4.23 (d, J= 7.5 Hz, 2H), 4.13 (t, J= 7.6 Hz, 1H), 3.98 (d, J= 11.2 Hz, 1H), 3.87-3.71 (m, 5H), 3.69-3.47 (m, 5H), 2.65 (dd, J= 15.0, 6.2 Hz, 1H), 2.55 (dd, J = 15.8, 7.0 Hz, 1H), 2.48 (dd, J = 15.1, 5.8 Hz, 1H), 2.41 (dd, J =15.8, 5.3 Hz, 1H), 2.38-2.25 (m, 3H), 2.18 (dd, J = 15.0, 5.7 Hz, 1H), 1.63-1.56 (m, 2H), 1.56-1.40 (m, 6H), 1.36-1.05 (m, 92H), 0.91-0.83 (m, 21H), 0.13 (s, 3H), 0.09 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.8, 171.8, 171.2, 169.6,155.8, 143.89, 143.85, 141.22, 141.19, 138.5, 138.4, 137.7, 136.9, 129.0, 128.4, 128.28, 128.27, 128.1, 127.84, 127.78, 127.7, 127.6, 127.50, 127.48, 127.0, 126.1, 125.2, 119.9, 101.4, 101.1, 96.5, 78.9, 75.9, 75.6, 75.5, 74.7, 74.5, 74.3, 71.4, 71.3, 71.1, 70.8, 68.6, 68.2, 67.1, 66.3, 58.2, 55.5, 47.0, 41.7, 39.7, 39.5, 34.5, 34.4, 34.2, 31.9, 29.71, 29.67, 29.65, 29.64, 29.60, 29.59, 29.57, 29.5, 29.38, 29.36, 29.35, 29.2, 25.6, 25.3, 25.2, 25.1, 25.0, 22.7, 17.9, 14.1, -3.9, -5.3; MS (MALDI-TOF) m / z calcd for2058.368, found: 2058.408.

[0274] Compound 114(0, 2*, 1)

[0275] 114(0, 2*, 1)wassynthesized from crude 112(0,1) (146.26 mg, 99.83and 86b(80.85 mg, 158.27 with the general procedure b and c (16 hr, 0% EtOAc in hexanegradient to 25%), and obtained as a sticky white solid. Yield: 78% over 3 steps (139.23 mg, 78.11 / / mol); [a]D25-2.86 (c = 1.00, CHCh); MS (MALDI-TOF) m / z calcd

[0276] Compound 114(1, l*,0)

[0277] 114(1, l*,0) was synthesized from crude 112(1,0) (248.22 mg, 169.42 / / mol) and85b (127.60 mg, 338.84 / / mol) with the general procedure b and c (16 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 74% over 3 steps (205.38 mg, 124.60 / / mol); [a]D25-12.19 (c = 1.00, CHCh); MS (MALDI-TOF) m / z calcd fo : 1669.976, found: 1670.025.

[0279] Compound 114(1, 2*, 0)

[0280] 114(1, 2*, 0) was synthesized from crude 112(1,0) (118.68 mg, 81.00) and 86b(82.76 mg, 162.01 / / mol) with the general procedure b and c (22 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 82% over 3 steps (118.93 mg, 66.72 / / mol); [a]D25-6.16 (c = 1.00, CHCh); MS (MALDI-TOF) m / z calcd

[0281] Compound 114(1, 2*, 1)

[0282] 114(1, 2*, 1) was synthesized from crude 112(1,1) (171.57 mg, 99.78 / / mol) and 86b(79.81 mg, 156.24 / / mol) with the general procedure b and c (20 hr, 0% EtOAc in hexane gradient to 25%), and obtained as a sticky white solid. Yield: 75% over 3 steps (151.65 mg, 74.45 / / mol); [a]D25-8.09 (c = 1.00, CHCh); MS (MALDI-TOF) m / z calcdd. General synthetic procedure of compounds 115

[0284] To a solution of 114 (1 equiv.) in dry DCM (2 mL, 0.05 M for 114) was added DBU (2 equiv.), then stirred at r.t. for 30 min. After completion of the reaction checked by TLC, the reaction mixture was added and rinsed with dry DMF (2 mL, 1 volume of DCM) to a mixture of 85a-b or 86a-b (1.5 equiv.), l-[bis(dimethylamino)methylene]-l / / -l,2,3- triazolo[4,5-Z?]pyridinium 3-oxid hexafluorophosphate (HATU) (2 equiv.), and DMAP (0.1 equiv.), then stirred at r.t. for overnight (12-24 hr). The final concentration of the reaction mixture was 0.025 M for 114. In the case of 115(0 ,2*, 1,1*), silica gel column chromatography (0% EtOAc in hexane gradient to 25%) was conducted after Fmoc deprotection to afford crude amine mixture, then the residue was dissolved in DCM / DMF (1:1, v / v) with HATU, DMAP and 85b. In the case of 115(1,1,0,2) and 115(1,1*, 0,2*), silica gel column chromatography (0% EtOAc in hexane gradient to 25%) was conducted after Fmoc deprotection to afford crude amine mixture, then the residue was dissolved in DCM / DMF (1:1, v / v) with HATU, DMAP and 86a-b using DIPEA (3 equiv.) as a base additive. After completion of the reaction checked by TLC, the reaction mixture was quenched with saturated and extracted with EtOAc three times. The combinedorganic layer was dried over anhydrous and concentrated in vacuo afterfiltration. The resultant was evaporated at 40 °C with toluene three times to remove DMF. The residue was purified by MPLC on silica gel (0% EtOAc in hexane gradient to 20%) to afford 115.

[0285] Compound 115(0,2,0,1)

[0286] 115(0,2,0,1) was synthesized from 114(0,2,0) (157.40 mg, 103.00 and 85a(56.01 mg, 154.50 with the general procedure d (14.5 hr), and obtained as a stickywhite solid. Yield: 80% (135.76 mg, 82.26 / / mol); [«]D25-5.76 (c = 1.00, CHCh);!H NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.49-7.44 (m, 2H), 7.40-7.34 (m, 3H), 7.34-7.21 (m, 20H), 6.51 (d, J= 8.3 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 5.54 (s, 1H), 5.12-5.05 (m, 2H), 4.89-4.83 (m, 2H), 4.75-4.68 (m, 2H), 4.65-4.59 (m, 2H), 4.56 (d, J = 11.0 Hz, 1H), 4.51 (d, J= 11.3 Hz, 1H), 4.43-4.36 (m, 2H), 4.30 (dd, J = 10.5, 5.0 Hz, 1H), 4.01 (d, J= 10.5 Hz, 1H), 3.89 (t, J= 8.4 Hz, 1H), 3.77-3.69 (m, 3H), 3.66 (t, J= 9.1 Hz, 1H), 3.55-3.47 (m, 3H), 3.44 (q, J= 8.4 Hz, 1H), 3.27 (q, J= 8.3 Hz, 1H), 2.41-2.33 (m, 3H), 2.25 (dd, J= 15.1, 5.7 Hz, 1H), 2.16 (t, J= 7.2 Hz, 2H), 1.62-1.57 (m, 1H), 1.57-1.46 (m, 5H), 1.34-1.15 (m, 68H), 0.93-0.84 (m, 18H), 0.10 (s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm):173.4, 171.1, 170.0, 138.53, 138.48, 138.07, 138.06, 137.4, 128.9, 128.5, 128.4, 128.28, 128.27, 128.2, 127.82, 127.78, 127.7, 127.6, 127.5, 127.4, 126.1, 101.2, 99.7, 95.3, 82.5, 80.8, 78.5, 76.4, 74.4, 74.3, 74.2, 71.0,70.9, 68.8, 68.1, 65.8, 58.4, 58.0, 41.6, 41.2, 34.5, 34.1, 33.5, 31.9, 29.70, 29.67, 29.65, 29.63, 29.59, 29.57, 29.56, 29.53, 29.51, 29.40, 29.35, 29.3, 29.1, 25.8, 25.2, 25.1, 25.0, 22.7,17.9, 14.1, -3.9, -5.0; MS (MALDI-TOF) m / 1672.122, found: 1672.082.

[0287] Compound 115(0,2,1,1)( , , , )

[0288] 115(0,2,1,1)wassynthesized from 114(0,2,1) (212.76 mg, 119.36 and 85a(64.89 mg, 179.04 / with the general procedure d (14 hr), and obtained as a sticky whitesolid. Yield: 83% (189.49 mg, 99.48 / / mol); [a]D25-5.37 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.49-7.44 (m, 2H), 7.40-7.33 (m, 7H), 7.33-7.17 (m, 16H), 6.21 (d, J= 9.3 Hz, 1H), 5.90 (d, J= 7.3 Hz, 1H), 5.54 (s, 1H), 5.16- 5.04 (m, 3H), 4.87 (d, J = 11.4 Hz, 1H), 4.61 (d, J = 11.4 Hz, 1H), 4.57 (dd, J = 11.5, 4.1 Hz, 2H), 4.52-4.41 (m, 5H), 4.38 (t, J= 9.3 Hz, 1H), 4.32 (dd, J= 10.4, 5.0 Hz, 1H), 3.96 (dd, J = 11.2, 1.9 Hz, 1H), 3.88-3.79 (m, 2H), 3.76-3.68 (m, 3H), 3.65 (t, J= 9.2 Hz, 1H), 3.56 (t, J = 9.1 Hz, 1H), 3.54-3.45 (m, 2H), 3.24 (q, J = 8.2 Hz, 1H), 2.55 (dd, J= 15.9, 7.2 Hz, 1H), 2.44-2.32 (m, 3H), 2.32-2.24 (m, 2H), 2.16 (t, J= 7.2 Hz, 2H), 1.61-1.41 (m, 8H), 1.34-1.17 (m, 90H), 0.92-0.81 (m, 21H), 0.07 (s, 3H), 0.03 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.4, 171.4, 170.8, 170.0, 138.6, 138.4, 138.3, 137.7, 137.4, 128.9, 128.5, 128.4, 128.30, 128.25, 128.2, 127.82, 127.78, 127.70, 127.69, 127.6, 127.5, 126.1, 101.2, 99.8, 96.2, 82.5, 76.2, 75.8, 75.5, 74.5, 74.4, 74.3, 74.2, 71.3, 70.9, 70.6, 68.8, 68.2, 65.9, 58.1, 55.9, 41.6, 41.1, 39.7, 34.5, 34.3, 34.1, 33.7, 31.9, 29.71, 29.70, 29.66, 29.65, 29.63, 29.59, 29.57, 29.5, 29.41, 29.36, 29.3, 29.1, 25.7, 25.22, 25.16, 25.0, 22.7, 17.8, 14.1, -3.8, -5.1; MS (MALDI-TOF) m / z calcd for

[0289] Compound 115(1,1,0,2)

[0290] 115(1,1,0,2) was synthesized from 114(1,1,0) (168.81 mg, 103.30 d 86a(79.15 mg, 154.94 / / mol) with the general procedure d (20 hr), and obtained as a sticky white solid. Yield: 38% (74.97 mg, 39.36 / / mol); [a]D25-13.97 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.39-7.36 (m, 2H), 7.36-7.31 (m, 5H), 7.31-7.19 (m, 18H), 6.29 (d, J= 8.9 Hz, 1H), 5.96 (d, J= 8.2 Hz, 1H), 5.39 (s, 1H), 5.31 (t, J = 9.8 Hz, 1H), 5.07 (quin, J= 6.1 Hz, 1H), 4.95 (d, J= 7.1 Hz, 1H), 4.74-4.69 (m, 2H), 4.62 (d, J= 11.4 Hz, 1H), 4.57 (d, J= 11.2 Hz, 1H), 4.52 (d, J= 11.7 Hz, 1H), 4.49-4.44 (m, 2H), 4.40 (d, J= 11.7 Hz, 1H), 4.36 (d, J= 11.6 Hz, 1H), 4.23 (dd, J= 10.5, 5.0 Hz, 1H), 3.99- 3.88 (m, 3H), 3.78 (quin, J= 6.2 Hz, 1H), 3.72-3.64 (m, 3H), 3.62 (t, J= 9.4 Hz, 1H), 3.57- 3.51 (m, 2H), 3.47 (q, J= 8.1 Hz, 1H), 3.39 (td, J= 9.7, 5.0 Hz, 1H), 2.64 (dd, J= 15.0, 6.4 Hz, 1H), 2.43-2.35 (m, 2H), 2.33-2.27 (m, 2H), 2.23 (dd, J= 15.4, 4.1 Hz, 1H), 2.18 (td, J = 7.5, 2.2 Hz, 2H), 1.61-1.51 (m, 4H), 1.51-1.39 (m, 4H), 1.34-1.08 (m, 90H), 0.92-0.84 (m, 21H), 0.12 (s, 3H), 0.09 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.5, 171.20, 171.17, 169.5, 138.5, 138.4, 138.3, 138.2, 136.9, 129.0, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8, 127.72, 127.67, 127.61, 127.59, 127.55, 127.4, 126.1, 101.34, 101.29, 94.9, 80.3, 78.9, 77.9, 76.1, 75.5, 74.3, 74.04, 73.97, 71.6, 71.2, 71.1, 70.9, 68.6, 68.3, 66.3, 58.0, 54.5, 41.9, 41.2, 39.7, 34.50, 34.47, 34.1, 33.7, 31.9, 29.70, 29.66, 29.65, 29.63, 29.58, 29.54, 29.53, 29.49, 29.4, 29.33, 29.28, 29.1, 25.7, 25.3, 25.1, 25.03, 24.96, 22.7, 17.9, 14.1, -3.9, -5.1; MS (MALDI-TOF

[0291] Compound 115(1,2,0,1)

[0292] 115(1,2,0,1) was synthesized from 114(1,2,0) (191.06 mg, 107.19 and 85a(58.29 mg, 160.78 / / mol) with the general procedure d (15 hr), and obtained as a sticky white solid. Yield: 68% (138.78 mg, 72.86 [a]D25-11.07 (c = 1.00, CHCh);(500MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.41-7.36 (m, 2H), 7.34-7.21 (m, 23H), 6.53 (d, J= 8.4 Hz, 1H), 5.80 (d, J= 8.4 Hz, 1H), 5.46-5.40 (m, 2H), 4.99 (quin, J= 6.3 Hz, 1H), 4.89 (d, J= 8.2 Hz, 1H), 4.85 (d, J= 7.3 Hz, 1H), 4.73-4.68 (m, 2H), 4.63 (d, J= 11.5 Hz, 1H), 4.52 (t, J = 10.1 Hz, 2H), 4.49 (d, J= 8.9 Hz, 1H), 4.39 (d, J= 11.4 Hz, 2H), 4.28 (dd, J= 10.5, 4.9 Hz, 1H), 4.05-3.99 (m, 1H), 3.87 (t, J= 8.4 Hz, 1H), 3.82-3.75 (m, 2H), 3.75-3.68 (m, 3H), 3.64 (t, J= 9.4 Hz, 1H), 3.55-3.44 (m, 4H), 2.64 (dd, J= 14.9, 6.2 Hz, 1H), 2.49 (dd, J= 15.0, 5.7 Hz, 1H), 2.36 (d, J = 5.5 Hz, 2H), 2.34-2.22 (m, 3H), 2.11 (dd, J = 15.1, 5.5 Hz, 1H), 1.63-1.56 (m, 3H), 1.54-1.48 (m, 2H), 1.48-1.41 (m, 3H), 1.33-1.13 (m, 90H), 0.91-0.85 (m, 21H), 0.11 (s, 3H), 0.09 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.8, 171.08, 171.06, 169.6, 138.6, 138.4, 138.09, 138.08, 136.9, 129.0, 128.5, 128.4, 128.30, 128.26, 128.1, 127.83, 127.80, 127.72, 127.67, 127.6, 127.5, 127.4, 126.1, 101.4, 100.8, 95.3, 80.8, 78.9, 78.1, 76.4, 75.6, 74.4, 74.3, 74.2, 71.3, 71.2, 71.0, 70.7, 68.6, 68.4, 66.2, 58.2, 55.6, 41.6, 41.2, 39.5, 34.5, 34.4, 34.2, 33.6, 31.9, 29.71, 29.68, 29.67, 29.65, 29.63, 29.61, 29.60, 29.57, 29.54, 29.46, 29.39, 29.36, 29.36, 29.2, 25.8, 25.24, 25.21, 25.1, 25.0, 22.7, 17.9, 14.1, -3.8, -4.9; MS (MALDI-TOF) m / z calcd for

[0294] Compound 115(1,1,1,1)115(1,1,1,1)

[0295] 115(1,1,1,1) was synthesized from 114(1,1,1) (203.86 mg, 107.94 and 85a(58.70 mg, 161.91 with the general procedure d (15 hr), and obtained as a sticky whitesolid. Yield: 85% (185.14 mg, 92.07 / / mol); [a]D25-15.81 (c = 1.00NMR (500MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.40-7.31 (m, 10H), 7.31-7.17 (m, 20H), 6.30 (d, 7= 9.0 Hz, 1H), 6.16 (d, J= 9.2 Hz, 1H), 5.39 (s, 1H), 5.30 (t, 7 = 9.8 Hz, 1H), 5.14- 5.06 (m, 1H), 4.58-4.51 (m, 3H), 4.51-4.43 (m, 6H), 4.43-4.35 (m, 3H), 4.26 (dd, 7= 10.5, 5.0 Hz, 1H), 3.92 (q, 7= 9.2 Hz, 1H), 3.88-3.76 (m, 4H), 3.76-3.64 (m, 4H), 3.61 (t, 7= 9.4 Hz, 1H), 3.54 (t, 7= 9.1 Hz, 1H), 3.44-3.35 (m, 2H), 2.64 (dd, 7 = 15.0, 6.4 Hz, 1H), 2.53 (dd, 7= 15.9, 7.1 Hz, 1H), 2.45-2.33 (m, 3H), 2.33-2.22 (m, 3H), 1.60-1.39 (m, 8H), 1.35- 1.10 (m, 88H), 0.91-0.82 (m, 21H), 0.09 (s, 3H), 0.03 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 171.4, 171.2, 171.1, 170.8, 138.6, 138.5, 138.30, 138.27, 137.9, 136.9, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.8, 127.70, 127.69, 127.67, 127.66, 127.44, 127.41, 126.1, 101.3, 96.2, 78.9, 76.1, 75.9, 75.8, 75.5, 75.4, 74.5, 74.3, 74.1, 71.6, 71.3, 71.1, 70.8, 70.6, 68.6, 68.1, 66.3, 55.9, 54.5, 41.2, 41.1, 39.70, 39.68, 34.5, 34.3, 33.7, 31.9, 29.70, 29.66, 29.63, 29.58, 29.4, 25.7, 25.23, 25.15, 25.1, 25.0, 22.7, 17.8, 14.1, -3.7, -5.1; MS (MALDI-TOF) m / z calcd for 2032.388, found: 2032.360.

[0296] Compound 115(1,2,1,1)

[0297] 115(1,2,1,1) was synthesized from 114(1,2,1) (226.78 mg, 111.33 ) and 85a(60.55 mg, 167.00 with the general procedure d (15 hr), and obtained as a sticky whitesolid. Yield: 87% (208.18 mg, 96.41 / / mol); [a]D25-10.09 (c = 1.00, CHCh);NMR (500 MHz, CDCl3, Reference peak TMS at 0.00 ppm): 37.40-7.32 (m, 6H), 7.32-7.17 (m, 19H), 6.22 (d, J= 9.3 Hz, 1H), 5.81 (d, J = 8.4 Hz, 1H), 5.45-5.37 (m, 2H), 5.12 (dd, J = 10.2, 9.0 Hz, 1H), 5.00 (quin, J= 6.1 Hz, 1H), 4.84 (d, J= 8.2 Hz, 1H), 4.59-4.54 (m, 2H), 4.53-4.42 (m, 6H), 4.40 (d, J = 11.6 Hz, 1H), 4.31 (dd, J = 10.5, 4.9 Hz, 1H), 3.95 (dd, J = 11.1, 2.2 Hz, 1H), 3.88-3.69 (m, 7H), 3.63 (t, J= 9.4 Hz, 1H), 3.58 (t, J= 9.1 Hz, 1H), 3.53-3.44 (m, 2H), 2.65 (dd, J = 15.0, 6.3 Hz, 1H), 2.56 (dd, J = 16.0, 7.1 Hz, 1H), 2.48 (dd, J = 15.0, 5.7 Hz, 1H), 2.44-2.22 (m, 6H), 2.15 (dd, J= 15.1, 5.6 Hz, 1H), 1.62-1.43 (m, 10H), 1.37-1.11 (m, 112H), 0.91-0.83 (m, 24H), 0.09 (s, 3H), 0.04 (s, 3H);13C NMR (125 MHz, CDCl3, Reference peak CDCl3at 77.00 ppm): 3 173.8, 171.4, 171.1, 170.8, 169.6, 138.6, 138.4, 138.3, 137.8, 136.9, 129.0, 128.5, 128.4, 128.29, 128.26, 128.1, 127.8, 127.71, 127.70, 127.68, 127.52, 127.45, 126.1, 101.4, 101.0, 96.2, 78.9, 75.88, 75.85, 75.6, 75.5, 74.5, 74.4, 74.2, 71.4, 71.3, 71.2, 70.8, 70.6, 68.6, 68.3, 66.3, 55.9, 55.6, 41.7, 41.1, 39.7, 39.5, 34.5, 34.4, 34.3, 34.2, 33.7, 31.9, 29.71, 29.67, 29.64, 29.62, 29.61, 29.57, 29.5, 29.39, 29.37, 29.2, 25.7, 25.3, 25.23, 25.16, 25.0, 22.7, 17.8, 14.1, -3.7, -5.0; MS (MALDI-TOF) m / z calcd for : 2180.571, found: 2180.597.

[0298] Compound 115(0, 2*, 1,1*)

[0299] 115(0, 2*, 1,1*) was synthesized from 114(0, 2*, 1) (99.25 mg, 55.68 / / mol) and 85b(31.45 mg, 83.52 / / mol) with the general procedure d (14 hr), and obtained as a sticky white solid. Yield: 67% (71.58 mg, 37.30 / / mol); [a]D25-5.53 (c = 1.00, CHCh); MS (MALDI-TOF) m / z calcd fo : 1940.362, found: 1940.372.

[0300] Compound 115(1,1*, 0,2*)

[0301] 115(1,1*, 0,2*) was synthesized from 114(1, l*,0) (205.38 mg, 124.60 / / mol) and86b (82.75 mg, 161.99 / / mol) with the general procedure d (20 hr), and obtained as a sticky white solid. Yield: 78% (185.92 mg, 96.89 / / mol); [a]D25-13.92 (c = 1.00, CHCh); MS (MALDI-TOF)

[0303] Compound 115(1, 2*, 0,1*)

[0304] 115(1, 2*, 0,1*) was synthesized from 114(1, 2*, 0) (58.45 mg, 32.79 ) and 85b(47.01 mg, 24.50 with the general procedure d (17 hr), and obtained as a sticky whitesolid. Yield: 75% (47.01 mg, 24.50 / / mol); [a]D25-10.93 (c = 1.00, CHCh); MS (MALDI- TOF) m / z calcd for1940.362, found: 1940.399.

[0305] Compound 115(1, 2*, 1,1*)

[0306] 115(1, 2*, 1,1*) was synthesized from 114(1, 2*, 1) (68.25 mg, 33.51 and 85b(15.13 mg, 40.18 / / mol) with the general procedure d (14 hr), and obtained as a sticky white solid. Yield: 68% (49.29 mg, 22.68 / / mol); [a]D25-10.17 (c = 1.00, CHCh); MS (MALDI- TOF) m / z. calcd for 2194.587, found: 2194.611.

[0307] e. General synthetic procedure for compounds 116

[0308] To a solution 115 (1 equiv.) in THF (1 volume of pyridine) and pyridine (500 equiv.) at -40 °C was added HF-Pyridine (-70% HF, 250 equiv.) slowly, then stirred at r.t. for 16 hr. After completion of the reaction checked by TLC, the reaction mixture was quenched with NaHCO3(aq) (50 volumes of HF-Pyridine) at 0 °C and extracted with DCM three times. The combined organic layer was dried over anhydrous Na2SO4(s) and concentrated in vacuo after filtration. The resultant was evaporated at 40 °C with toluene three times to remove pyridine. The residue was purified by MPLC on silica gel (0% MeOH in DCM gradient to 4%) to afford 116.

[0309] Compound116(0,2,0,1)

[0310] 116(0,2,0,1) was synthesized from 115(0,2,0,1) (42.11 mg, 25.51 / / mol) with the general procedure e and obtained as a sticky white solid. Yield: 93% (36.62 mg, 23.84 / / mol);MS (MALDI-TOF) m / z calcd for1558.035, found: 1558.012.

[0311] Compound 116(0,2,1,1)

[0312] 116(0,2,1,1) was synthesized from 115(0,2,1,1) (47.92 mg, 25.16 / / mol) with the general procedure e and obtained as a sticky white solid. Yield: 92% (41.64 mg, 23.26 / / mol);MS (MALDI-TOF) m / z calcd fo 812.260, found: 1812.273.

[0313] Compound 116(1,1,0,2)

[0314] 116(1,1,0,2) was synthesized from 115(1,1,0,2) (48.18 mg, 25.27 / / mol) with the general procedure e and obtained as a sticky white solid. Yield: 93% (41.96 mg, 23.43 / / mol);MS (MALDI-TOF) m / z calcd for 1812.260, found: 1812.320.

[0315] Compound 116(1,2,0,1)

[0316] 116(1,2,0,1) was synthesized from 115(1,2,0,1) (48.14 mg, 25.27 μmol) with the general procedure e and obtained as a sticky white solid. Yield: 93% (42.19 mg, 23.56 μmol);MS (MALDI-TOF) m / z calcd for C111H172N2NaO16[M+Na]+: 1812.260, found: 1812.274.

[0317] Compound 116(1,1,1,1)

[0318] 116(1,1,1,1) was synthesized from 115(1,1,1,1) (50.97 mg, 25.35 μmol) with the general procedure e and obtained as a sticky white solid. Yield: 92% (44.07 mg, 23.24 μmol); MS (MALDI-TOF) m / z calcd for C118H178N2NaO17[M+Na]+: 1918.302, found: 1918.347.

[0319] Compound 116(1,2,1,1)

[0320] 116(1,2,1,1) was synthesized from 115(1,2,1,1) (54.30 mg, 25.15 / ) with the general procedure e and obtained as a sticky white solid. Yield: 92% (47.44 mg, 23.2MS (MALDI-TOF) m / z calcd for 066.484, found: 2066.459.

[0321] Compound 116(0, 2*, 1,1*)116(0, 2*, 1,1*)

[0322] 116(0, 2*, 1,1*) was synthesized from 115(0, 2*, 1,1*) (71.58 mg, 37.30with the general procedure e and obtained as a sticky white solid. Yield: 92% (62.01 mg, 34.36 / / mol); MS (MALDI-TOF) m / z calcd for 1826.276, found:1826.322.

[0323] Compound 116(1,1*, 0,2*)116(1,1*, 0,2*)

[0324] 116(1,1*, 0,2*) was synthesized from 115(1,1*, 0,2*) (28.78 mg, 15.00 withthe general procedure e and obtained as a sticky white solid. Yield: 90% (24.40 mg, 13.52 / / mol); MS (MALDI-TOF) m / z calcd for 1826.276, found:1826.294.

[0325] Compound 116(1, 2*, 0,1*)

[0326] 116(1, 2*, 0,1*) was synthesized from 115(1, 2*, 0,1*) (19.33 mg, 10.07) with the general procedure e and obtained as a sticky white solid. Yield: 86% (15.68 mg, 8.69 / / mol); MS (MALDI-TOF) m / z calcd for1826.325.

[0327] Compound 116(1, 2*, 1,1*)116(1, 2*, 1,1*)

[0328] 116(1, 2*, 1,1*) was synthesized from 115(1, 2*, 1,1*) (20.10 mg, 9.25 / withthe general procedure e and obtained as a sticky white solid. Yield: 99% (18.76 mg, 9.11 / / mol); MS (MALDI-TOF) m / z calcd fo2080.527. f. General synthetic procedure for compounds 117

[0329] To a solution of 116 (1 equiv.) and tetrabenzyl pyrophosphate (5 equiv.) in dry THF (5 mL) and dry toluene (1 mL) at -78 °C was added lithium bis(trimethylsilyl)amide (LHMDS) solution (1.0 M in THF, 3 equiv.) under Ar(g), then stirred at -78 °C for 30 min. The reaction mixture was warmed to 0 °C, then stirred at 0 °C for 1 hr. After completionof the reaction checked by TLC, the reaction mixture was quenched witht 0 °C and extracted with DCM three times. The combined organic layer was dried overanhydrousnd concentrated in vacuo after filtration. The resultant was evaporated with acetone three times to remove toluene. The residue was filtered through a syringe filter (PTFE, 0.45 / / m) with cold MeOH (3 mL x 3) to remove impurities. The residue was dissolved with DCM (10 mL) and concentrated in vacuo to afford 117 as a crude.

[0330] Compound 117(0,2,0,1)

[0331] 117(0,2,0,1) was synthesized from 116(0,2,0,1) (16.99 mg, 11.06 / / mol) with the general procedure f and obtained as a sticky white solid. Yield: 72% (14.30 mg, 7.96 asa crude.

[0332] Compound 117(0,2,1,1)117(0,2,1,1)

[0333] 117(0,2,1,1) was synthesized from 116(0,2,1,1) (19.42 mg, 10.85 with thegeneral procedure f and obtained as a sticky white solid. Yield: 69% (15.45 mg, 7.53 / / mol) as a crude.

[0334] Compound 117(1,1,0,2)

[0335] 117(1,1,0,2) was synthesized from 116(1,1,0,2) (20.33 mg, 11.35 with thegeneral procedure f and obtained as a sticky white solid. Yield: 85% (19.72 mg, 9.61 asa crude.

[0336] Compound 117(1,2,0,1)117(1,2,0,1)

[0337] 117(1,2,0,1) was synthesized from 116(1,2,0,1) (20.88 mg, 11.66 with the general procedure f and obtained as a white solid. Yield: 76% (18.24 mg, 8.89 / as acrude.

[0338] Compound 117(1,1,1,1)117(1,1,1,1)

[0339] 117(1,1,1,1) was synthesized from 116(1,1,1,1) (21.78 mg, 11.4 ith thegeneral procedure f and obtained as a sticky white solid. Yield: 85% (21.14 mg, 9.80 a crude.

[0340] Compound 117(1,2,1,1)

[0341] 117(1,2,1,1) was synthesized from 116(1,2,1,1) (21.94 mg, 10.73 with thegeneral procedure f and obtained as a sticky white solid. Yield: 91% (22.52 mg, 9.77 sa crude.

[0342] Compound 117(0, 2*, 1,1*)

[0343] 117(0, 2*, 1,1*) was synthesized from 116(0, 2*, 1,1*) (23.32 mg, 12.9 withthe general procedure f and obtained as a sticky white solid. Yield: 55% (14.56 mg, 7.05 / / mol) as a crude.

[0344] Compound 117(1,1*, 0,2*)

[0345] 117(1,1*, 0,2*) was synthesized from 116(1,1*, 0,2*) (24.40 mg, 13.52 / / mol) with the general procedure f and obtained as a sticky white solid. Yield: 72% (20.21 mg, 9.79 / / mol) as a crude.

[0346] Compound 117(1, 2*, 0,1*)

[0347] 117(1, 2*, 0,1*) was synthesized from 116(1, 2*, 0,1*) (7.84 mg, 4.34 with thegeneral procedure f and obtained as a white solid. Yield: 64% (5.77 mg, 2.79 / / mol) as a crude.

[0348] Compound 117(1, 2*, 1,1*)117(1, 2*, 1,1*)

[0349] 117(1, 2*, 1,1*) was synthesized from 116(1, 2*, 1,1*) (8.21 mg, 3.99with the general procedure f and obtained as a sticky white solid. Yield: 53% (4.93 mg, 2.13 / / mol) as a crude. g. General synthetic procedure for BfLAs

[0350] To a solution of 117 (1 equiv.) in dry THF (3 mL) was added palladium black (100 wt%), then stirred at r.t. for 48 hr under H2(g) (1.0 MPa). After completion of the reaction, the reaction mixture was sonicated for 1 min, then quenched with TEA (20 equiv.). The resultant was filtered through a syringe filter (PTFE, 0.45 / / m) with dry THF (10 mL) to remove palladium black. The filtrate was concentrated in vacuo to afford BfLAs as a crude.

[0351] 3A-BfLA(0,2,0,l)

[0352] 3A-BfLA(0,2,0,l) was synthesized from 117(0,2,0,1) (13.23 mg, 7.36with the general procedure g and obtained as a white solid. Yield: 85% (7.93 mg, 6.25as a crude; MS (MALDI-TOF) m / z calcd fo

[0353] 4A-BfLA(0,2,l,l)

[0354] 4A-BfLA(0,2,l,l) was synthesized from 117(0,2,1,1) (8.25 mg, 4.02 withthe general procedure g and obtained as a white solid. Yield: Quanti. (6.75 mg, 4.43 / / mol) as a crude; MS (MALDI-TOF) m / z calcd fo 1419.989.

[0355] 4A-BfLA(l,l,0,2)

[0356] 4A-BfLA(l, 1,0,2) was synthesized from 117(1,1,0,2) (11.18 mg, 5.45 ) withthe general procedure g and obtained as a white solid. Yield: Quanti. (8.52 mg, 5.59a crude; MS (MALDI-TOF) m / z calcd for found:1419.995.

[0357] 4A-BfLA(l,2,0,l)

[0358] 4A-BfLA(l,2,0,l) was synthesized from 117(1,2,0,1) (8.89 mg, 4.43 withthe general procedure g and obtained as a white solid. Yield: 87% (5.73 mg, 3.76 / / mol) as a crude; MS (MALDI-TOF) m / z calcd fo : 1420.011, found: 1420.025.

[0359] 4A-BfLA(l, 1,1,1)4A-BfLA(1 , 1 ,1 ,1)

[0360] 4A-BfLA(l, 1,1,1) was synthesized from 117(1,1,1,1) (8.55 mg, 3.96 / / mol) with the general procedure g and obtained as a white solid. Yield: Quanti. (6.47 mg, 4.20 / / mol) as a crude; MS (MALDI-TOF) m / z calcd for1436.001.

[0361] 5A-BfLA(l,2,l,l)5A-BfLA(1,2,1,1)

[0362] 5A-BfLA(l,2,l,l) was synthesized from 117(1,2,1,1) (10.41 mg, 4.52 withthe general procedure g and obtained as a white solid. Yield: Quanti. (8.70 mg, 4.89 / / mol) as a crude; MS (MALDI-TOF) m / z calcd for1674.227.

[0363] 4A-BfLA(0,2*,l,l*)

[0364] 4A-BfLA(0,2*,l,l*) was synthesized from 117(0, 2*, 1,1*) (14.56 mg, 7.0with the general procedure g and obtained as a white solid. Yield: Quanti. (12.08 mg, 7.86 / / mol) as a crude; MS (MALDI-TOF) m / z calcd fo1434.079.

[0365] 4A-BfLA(l,l*,0,2*)4A-BfLA(1,1*,0,2*)

[0366] 4A-BfLA(l,l*,0,2*) was synthesized from 117(1,1*, 0,2*) (20.21 mg, 9.79 / with the general procedure g and obtained as a white solid. Yield: Quanti. (17.79 mg, 11.57 / / mol) as a crude; MS (MALDI-TOF) m / z calcd fo 1434.026, found:1434.048.

[0367] 4A-BfLA(l,2*,0,l*)

[0368] 4A-BfLA(l,2*,0,l*) was synthesized from 117(1, 2*, 0,1*) (5.77 mg, 2.79with the general procedure g and obtained as a white solid. Yield: Quanti. (5.13 mg, 3.34 / / mol) as a crude; MS (MALDI-TOF) m / z calcd fo 1434.026, found:1434.041.

[0369] 5A-BfLA(l,2*,l,l*)

[0370] 5A-BfLA(l,2*,l,l*) was synthesized from 117(1, 2*, 1,1*) (4.93 mg, 2.13with the general procedure g and obtained as a white solid. Yield: Quanti. (4.69 mg, 2.62 / / mol) as a crude; MS (MALDI-TOF) m / z calcd for1688.301. h. General synthetic procedure for NP-BfLAs

[0371] To a solution of 116 (1 equiv.) in DCM / MeOH (1:1, v / v) (2 mL) was added palladium black (100 wt%), then stirred at r.t. for 48 hr under H2(g) (1.0 MPa). After completion of the reaction, the resultant was filtered through a syringe filter (PTFE, 0.45with DCM / MeOH (1:1, v / v) (10 mL) to remove palladium black. The filtrate was concentrated in vacuo to afford NP-BfLAs as a crude.

[0372] NP-4A-BfLA(0,2*,l,l*)

[0373] NP-4A-BfLA(0,2*,l,l*) was synthesized from 116(0, 2*, 1,1*) (2.36 mg, 1.31 / / mol) with the general procedure g and obtained as a white solid. Yield: Quanti. (2.51 mg, 1.85 ) as a crude; MS (MALDI-TOF) m / z calcd for 1378.056, found: 1378.051.

[0374] NP-4A-BfLA(l,l*,0,2*)

[0375] NP-4A-BfLA(l,l*,0,2*) was synthesized from 117(1,1*, 0,2*) (0.51 mg, 0.28 / / mol) with the general procedure g and obtained as a white solid. Yield: Quanti. (0.94 mg, 0.69 / ) as a crude; MS (MALDI-TOF) m / z calcd for 1378.056, found: 1378.094.

[0376]

[0377] NP-4A-BfLA(l,2*,0,l*)

[0378] NP-4A-BfLA(l,2*,0,l*) was synthesized from 117(1, 2*, 0,1*) (2.26 mg, 1.25 / / mol) with the general procedure g and obtained as a white solid. Yield: Quanti. (2.37 mg, 1.75 as a crude; MS (MALDI-TOF) m / z calcd for1378.056, found: 1378.057.

[0379] NP-5A-BfLA(l,2*,l,l*)

[0380] NP-5A-BfLA(l,2*,l,l*) was synthesized from 117(1, 2*, 1,1*) (2.57 mg, 1.25with the general procedure g and obtained as a white solid. Yield: Quanti. (2.69 mg, 1.67 / / mol) as a crude; MS (MALDI-TOF) m / z calcd for1632.281, found: 1632.334.Compounds used in the Drawings

[0381] The compounds used in the Drawings appear below:BfLA(0,2*,l,l*) and SB2261),NP-4A-BfLA(l,l*,0,2*)),4A-MPLA B3 (also referred to as SB2259 and 4A-BfLA(l,2*,0,l*)),4A-MPLA BNP3 (also referred to as SB2263 and NP-4A-BfLA(l,2*,0,l*)),5A-MPLA B 1 (also referred to as SB2260 and 5A-BfLA(l,2*,l,l*)), and5A-MPLA BNP1 (also referred to as SB2264 and NP-5A-BfLA(l,2*,l,l*)).

[0382] Six comparative compounds were used in the studies carried out herein:Biological Studies

[0383] Mouse Studies: Mice were bred and housed under SPF conditions at the HMS Animal Facility. Mice were gender- and age-matched (typically 6 to 10 weeks). All performed experiments were in accordance with the guideline approved by the Harvard Medical Area Standing Committee on Animals.

[0384] Cytokine Profile Analysis: Cultured supernatant from bone marrow-derived dendritic cells (BMDCs) or peripheral blood mononuclear cells (PBMCs) isolated from ulcerative colitis or Crohn’s Disease patients incubated with different lipid A analogs were harvested at different time points, and the production of various cytokines were examined by the Mouse TNF-a and IFN-β according to the manufacturer's instruction (Mouse IFN-beta Quantikine ELISA Kit, R&D Systems, MIFNBO; and Mouse TNF-alpha Quantikine ELISA Kit, R&D Systems, MTA00B)

[0385] Lipid A Analog Oral Administration and DSS-induced Colitis: Various lipid A analogs were orally administered daily from day -3 to day 0 (20 pg x 4 times, total 80 pg / mouse) prior to the treatment with 3.0% DSS-dissolved water for 7 days. Weight changes were monitored daily.EQUIVALENTS AND SCOPE

[0386] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0387] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0388] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, theymay be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0389] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or salt thereof, wherein:R1and R4are each independently hydrogen or -PO3H2;R2and R2are each independently substituted or unsubstituted alkyl comprising a terminal tertiary or quaternary carbon; andR3, R4, R5, and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl.

2. The compound of claim 1, or salt thereof, wherein R2and R2are each independently substituted or unsubstituted alkyl comprising a terminal tertiary carbon.

3. The compound of claim 1 or 2, or salt thereof, wherein R2and R2are each independently unsubstituted alkyl comprising a terminal tertiary carbon.

4. The compound of claim 1 or 2, or salt thereof, wherein at least one of R2and R2is substituted alkyl comprising a terminal tertiary carbon.

5. The compound of any one of claims 1, 3, and 4, or salt thereof, wherein at least one of R2and R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl).

6. The compound of claim 1 or 2, or salt thereof, wherein each R2or R2are independently substituted alkyl comprising a terminal tertiary carbon.

7. The compound of claim any one of claims 1, 2, and 6, or salt thereof, wherein each R2or R2are independently substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl).

8. The compound of any one of claims, 1, 2, and 6-7, or salt thereof, wherein:R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl); andR2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is hydrogen.

9. The compound of any one of claims, 1, 2, and 6-7, or salt thereof, wherein:R2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is -C(=O)(substituted or unsubstituted alkyl); andR2is substituted alkyl comprising a terminal tertiary carbon, wherein the substituent is -OR6and R6is hydrogen.

10. The compound of claim 1, wherein the compound is of Formula (II):or salt thereof, wherein: each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

11. The compound of claim 10, wherein the compound is of Formula (II-A):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

12. The compound of claim 10, wherein the compound is of Formula (II-B):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

13. The compound of claim 1, wherein the compound is of Formula (III):or salt thereof, wherein: each R6is independently selected from hydrogen, substituted or unsubstituted alkyl, and -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

14. The compound of claim 13, wherein the compound is of Formula (III-A):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

15. The compound of claim 13, wherein the compound is of Formula (III-B):or salt thereof, wherein:R6is -C(=O)(substituted or unsubstituted alkyl); and each instance of n is independently an integer from 0 to 20.

16. The compound of any one of claims 1-15, or salt thereof, wherein:R3, R4, and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl; andR5is hydrogen.

17. The compound of any one of claims 1-16, or salt thereof, wherein:R3and R3are each independently selected from hydrogen and substituted or unsubstituted alkyl; andR4and R5are hydrogen.

18. The compound of any one of claims 1-17, or salt thereof, wherein:R3is substituted or unsubstituted alkyl; andR3, R4and R5are hydrogen.

19. The compound of any one of claims 1-17, or salt thereof, wherein:R3is substituted or unsubstituted alkyl; andR3, R4and R5are hydrogen.

20. The compound of any one of claims 1-17, or salt thereof, wherein:R3and R3' are each independently substituted or unsubstituted alkyl; andR4and R5are hydrogen.

21. The compound of any one of claims 1-20, or salt thereof, wherein the compound comprises two, three, four, or five acyl chains.

22. The compound of any one of claims 1-21, wherein the compound comprises three or four acyl chains.

23. The compound of any one of claims 1-22, or salt thereof, wherein the compound comprises four acyl chains.

24. The compound of any one of claims 21-23, or salt thereof, wherein the acyl chains comprise 14-17 carbons.

25. The compound of any one of claims 24-24, or salt thereof, wherein the acyl chains comprise from 15-17 carbons.

26. The compound of claim 1, or salt thereof, wherein R2is:

27. The compound of any one of claims 1-26, or salt thereof, wherein R1and R4are both hydrogen.

28. The compound of any one of claims 1-26, or salt thereof, wherein R1is -PO3H2and R4is hydrogen.

29. The compound of claim 1, wherein the compound is of the formula:salt thereof.

30. The compound of claim 1, wherein the compound is of the formula:or salt thereof.

31. A composition comprising the compound of any one of claims 1-30, or salt thereof, and optionally a pharmaceutically acceptable excipient.

32. A method of treating or preventing a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-30, or salt thereof, or composition of claim 31.

33. The method of claim 33, wherein the disease is inflammation or is characterized by inflammation including abnormal inflammation.

34. The method of claim 33, wherein the disease is an autoimmune disease.

35. The method of claim 33 or 34, wherein the inflammation or autoimmune disease is multiple sclerosis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, or type I diabetes.

36. The method of claim 33, wherein the disease is asthma.

37. A method of modulating an immune response such as an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-30, or salt thereof, or composition of claim 31.

38. A method of inducing an immune response to an antigen in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-30, or salt thereof, or composition of claim 31 and the antigen.

39. The method of claim 38, wherein the antigen is a self-antigen or a microbial antigen such as but not limited to a bacterial antigen, a viral antigen, or a fungal antigen.

40. A kit comprising a compound of any one of claims 1-30, or salt thereof, or composition of claim 32 and instructions for using the compound or composition.

Images