Diaryltrehalose compounds and uses thereof

Abstract

To provide additional adjuvants with improved efficacy and safety attributes to advance new vaccines and therapeutics in the areas of infectious disease, as well as autoimmunity and cancer.SOLUTION: The present invention provides diaryl trehalose compounds UM1024, for example in the reaction formula below, and methods of use thereof, for example as vaccine adjuvants.SELECTED DRAWING: Figure 1-1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 633,375, filed February 21, 2018, which is hereby incorporated by reference in its entirety.

[0002] Government Interest Statement This invention was made with federal support under Contract No. HHSN272201400050C awarded by the National Institutes of Health. The federal government has certain rights in this invention.

[0003] The present disclosure relates to diaryltrehalose (DAT) compounds and methods of their use, for example, as vaccine adjuvants. [Background technology]

[0004] Globally, there are several disease-causing pathogens for which available preventive measures are limited or nonexistent. Many of these diseases fall into the bacterial and fungal pathogen classes, including Mycobacterium tuberculosis (Mtb), Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Candida albicans, and Aspergillus fumigatus, for which Th17-mediated immunity is implicated in disease prevention. While antigens are available for some of these pathogens, the development of Th17-inducing adjuvants has lagged behind. Currently, approved adjuvant systems available for human use primarily induce either Th2-type (aluminum salts) or Th1-type (MPL) responses.

[0005] Currently, the only adjuvant available for human use that promotes Th17-mediated immune responses is CAF01, a cationic liposome containing a synthetic Mincle receptor ligand (trehalose dibehenate) formulated with dimethyldioctadecylammonium bromide. However, this adjuvant has not progressed beyond phase I clinical trials. Summary of the Invention [Problem to be solved by the invention]

[0006] Additional adjuvants with improved efficacy and safety attributes are needed to advance novel vaccines and therapeutics in the areas of infectious diseases, as well as autoimmunity and cancer. [Means for solving the problem]

[0007] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: L 1 is -OH or -X(CR 1a R 1a’ ) m O p Ar 1 and; L 2 HA-Y(CR 2a R 2a’ ) n O q Ar 2 and; X and Y each independently represent -OC(O)-, -NR a C(O)-, -NR b C(S)-, -NR c -,-SO2NR c -, -O-, and -OC(O)CH=CH-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 1a , R 1a’ , R 2a and R 2a’ are, if present, each independently selected from hydrogen and C1-C4 alkyl; p is 0 or 1; q is 0 or 1; Ar 1 and Ar 2 are each independently selected from aryl or heteroaryl, where each aryl or heteroaryl is independently selected from hydrogen, C1-C 12 -Alkyl, hydroxy, C1-C 12 -Alkoxy, halo, C1-C4 haloalkyl, Ar 3 , C1-C8-alkoxy-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, hydroxy-C1-C8-alkyl, amino, nitro, -NH-Ar 4 , C1-C8-alkoxy-Ar 5 , C1-C8-alkylsulfonyl, and C1-C8-alkoxy-C1-C8-alkoxy-C1-C8-alkoxy, or these substituents, together with the atoms to which they are attached, may be optionally joined to form an aryl ring; wherein each heteroaryl may contain 1, 2, 3, 4, or 5 heteroatoms selected from O, S, or N; Ar 3 , Ar 4 and Ar 5 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; and Here, the compound is 6,6'-bis(2-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(benzoylamino)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-benzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-dichlorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,3-dibenzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-benzyloxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methyl-6-aminobenzoyl)-α,α-D-trehalose, 6,6'-bis(3-methoxy-4-fluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dimethoxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-heptyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(cinnamoylamino)-α,α-D-trehalose, 6,6'-bis(3,4-dimethoxycinnamoylamino)-α,α-D-trehalose, 6,6'-bis(isonicotinoylamino)-α,α-D-trehalose, or 6,6'-Bis(pyrazine-2-carbonylamino)-α,α-D-trehalose isn't it.

[0008] The present specification also includes compounds of formula (Ia) and (Ib), compounds of formula (II) and pharmaceutically acceptable salts thereof, adjuvant compositions containing such compounds, and compositions containing such compounds. Also disclosed are vaccine compositions containing such compounds and compositions, methods of using such compounds and compositions to induce an enhanced immune response in a subject, and methods of using such compounds and compositions to induce or enhance the immunogenicity of an antigen.

[0009] Other aspects and embodiments of the present disclosure will become apparent in light of the following description and drawings. [Brief explanation of the drawings]

[0010] [Figure 1-1] Cytokine responses from fresh peripheral blood mononuclear cells (PBMCs) cultured in the presence of various concentrations of a selection of DAT compounds were delivered either by dissolving in IPA and drying onto the bottom of tissue culture plates, or by dissolving in DMSO and diluting into culture medium. TNFα (Figure 1A) and IL-6 (Figure 1B) were measured 18–24 h after treatment. [Figure 1-2] Cytokine responses from fresh peripheral blood mononuclear cells (PBMCs) cultured in the presence of various concentrations of a selection of DAT compounds were delivered either by dissolving in IPA and drying onto the bottom of tissue culture plates, or by dissolving in DMSO and diluting into culture medium. TNFα (Figure 1A) and IL-6 (Figure 1B) were measured 18–24 h after treatment. [Figure 2] Cytokine responses in supernatants from freshly prepared PBMC stimulated with various concentrations of selected DAT compounds solubilized in DMSO and diluted in culture medium are shown. [Figure 3] IL-6 responses in supernatants from freshly prepared PBMC stimulated with various concentrations of selected DAT compounds solubilized in DMSO and diluted in culture medium are shown. [Figure 4-1] NF-κB secreted embryonic alkaline phosphatase (SEAP) production in the supernatant of HEK-Blue Mincle mouse or human reporter cells stimulated with various concentrations of selected DAT compounds (FIG. 4A) and TNFα cytokine production in a mouse macrophage cell line (FIG. 4B). [Figure 4-2]NF-κB secreted embryonic alkaline phosphatase (SEAP) production in the supernatant of HEK-Blue Mincle mouse or human reporter cells stimulated with various concentrations of selected DAT compounds (FIG. 4A) and TNFα cytokine production in a mouse macrophage cell line (FIG. 4B). [Figure 5-1] Anti-M72 antibody responses of mouse splenocytes (FIG. 5B) after two rounds of immunization (FIG. 5A) are shown. [Figure 5-2] Anti-M72 antibody responses of mouse splenocytes (FIG. 5B) after two rounds of immunization (FIG. 5A) are shown. [Figure 6-1] The frequencies of CD4 and CD8 T cells producing IL-17A (Figure 6A), IL-5 (Figure 6B), or IL-2 (Figure 6C) in restimulated mouse splenic erythrocytes after immunization with liposome formulations containing selected CLR adjuvant candidates are shown. [Figure 6-2] The frequencies of CD4 and CD8 T cells producing IL-17A (Figure 6A), IL-5 (Figure 6B), or IL-2 (Figure 6C) in restimulated mouse splenic erythrocytes after immunization with liposome formulations containing selected CLR adjuvant candidates are shown. [Figure 6-3] The frequencies of CD4 and CD8 T cells producing IL-17A (Figure 6A), IL-5 (Figure 6B), or IL-2 (Figure 6C) in restimulated mouse splenic erythrocytes after immunization with liposome formulations containing selected CLR adjuvant candidates are shown. [Figure 7] Substituted benzoic acids that have been used or are contemplated for use in the preparation of compounds of formula (I) or compounds of formula (II) are depicted. [Figure 8] Specific diaryl-substituted benzoic acids that have been used or are contemplated for use in the preparation of compounds of formula (I) or compounds of formula (II) are provided. [Figure 9] Certain trifluoromethyl-substituted benzoic acid derivatives have been used or are contemplated for use in the preparation of compounds of formula (I) or compounds of formula (II). [Figure 10]Further structures of compounds of formula (I) or compounds of formula (II) are shown. [Figure 11] Other acids that have been used or are contemplated for use in the preparation of compounds of formula (I) or compounds of formula (II) are listed. [Figure 12] The structures of further compounds of formula (I) are shown. [Figure 13] The structures of further compounds of formula (I) are shown. [Figure 14] The structures of further compounds of formula (I) are shown. [Figure 15] The structures of further compounds of formula (I) are shown. [Figure 16] The structures of further compounds of formula (I) are shown. [Figure 17] The structures of further compounds of formula (I) are shown. DETAILED DESCRIPTION OF THE INVENTION

[0011] This paper describes a class of compounds that can act as Th17-inducing adjuvants, which can be useful for targeting diseases with high medical burden for which effective vaccines are not available.These compounds can also be useful in the treatment of cancer.

[0012] The C-type lectin receptor (CLR) family contains numerous diverse members with different substrates, adaptor proteins, downstream signaling pathways, and cell-type expression profiles. While some members of this family are purely phagocyte receptors, the majority are known to activate intracellular signaling networks that induce functional changes within cells, such as transcriptional regulation, endocytosis / phagocytosis, and / or cell adhesion and migration. One of the best-characterized signaling cascade-inducing receptors is Mincle (CLEC4e).

[0013] Mincle must couple to the ITAM-containing adaptor molecule FcRγ to trigger downstream signaling, and ligand binding is required for Ca 2+However, the ligands for the Mincle receptor are distinct from those for other CLR receptors, such as dectin-1 and dectin-2, and include the mycobacterial glycolipid trehalose-6,6'-dimycolate (TDM), its synthetic analog trehalose dibehenate (TDB), and many α-mannose-containing lipids found in various fungi and Candida strains. These ligands are also found in many pathogenic organisms, including M. tuberculosis, S. mansoni, and T. rubrum. In addition, some preclinical vaccine models have shown that the Th1 / Th17 adjuvant properties require the use of TDB and subsequent Mincle-induced signaling.

[0014] Using the approach described herein to identify novel Th17-inducing CLR agonists as vaccine adjuvants, which can interrogate single CLRs on the surface of myeloid cells using specifically designed molecules and follow their effects through signaling pathways and subsequent downstream cytokine / biomarker induction, novel biologically active compounds have been identified that may serve as the basis for a new class of Th17-inducing adjuvants. Furthermore, mechanism of action (MOA) studies combining lead CLR agonists / antagonists with Toll-like receptor (TLR) agonists can be used to determine crosstalk between CLRs and TLRs through assessment of (1) intracellular signaling pathways, (2) biomarker upregulation, and (3) in vivo cytokine / biomarker induction.

[0015] The compounds described herein may represent a novel class of Th17-inducing adjuvants for vaccines targeting bacterial and fungal pathogens that cause a significant disease burden in humans, certain cancers, and autoimmune diseases.

[0016] 1.Definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below; however, methods and materials similar or equivalent to those described herein may be used in practice or testing. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0017] As used herein, the terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variations thereof are intended to be open-ended transitional phrases, terms, or phrases that do not exclude the possibility of additional actions or structures. The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprising," "consisting of," and "consisting essentially of" the embodiments or elements provided herein, whether explicitly stated or not.

[0018] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes at least the degree of error associated with measurement of the particular quantity). The modifier "about" should also be considered to disclose a range defined by the absolute values of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4." The term "about" can refer to ±10% of the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" may mean 0.9 to 1.1. Other meanings of "about" may be apparent from the context, such as rounding, so that, for example, "about 1" could also mean 0.5 to 1.4.

[0019] The term "immune response" includes any immune-related response, including, but not limited to, an increase or decrease in cytokine expression, production or secretion (e.g., IL-1, IL-6, IL-17, TNFα expression, production or secretion), cytotoxicity, immune cell migration, antibody production and / or immune cell responses.

[0020] The term "monotherapy," as used herein, means that only a single drug or therapeutic agent is administered.

[0021] The phrases "modulating an immune response" or "modulating an immune response" or "modulating an immune response" include upregulating, enhancing, stimulating, enhancing or increasing an immune response as defined herein.

[0022] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as those elements listed in the CAS Periodic Table of the Elements. Elements, CAS version), Handbook of Chemistry and Physics, 75 thIn addition, for general principles of organic chemistry and specific functional moieties and reactivity, see Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Laroc k, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0023] The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0024] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain containing 1 to 10 carbon atoms. The term "lower alkyl" or "C1-C6-alkyl" means a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. The term "C1-C3-alkyl" means a straight or branched hydrocarbon chain containing 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0025] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and from 1 to 10 carbon atoms.

[0026] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0027] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0028] The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example, 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, -CHCH-, -CHCHCH-, -CHCH(CH)CH-, -CHCHCHCHCH-, -CHCH(CH)CHCH-, and -CHCHCHCHCHCH-.

[0029] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.

[0030] The term "alkylsulfonyl," as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through a sulfonyl group, as defined herein.

[0031] The term "amide" as used herein means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0032] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0033] The term "amino" as used herein refers to -NR x R y (In the formula, R x and R y (which may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl). When an amino is an aminoalkyl group or any other moiety that is attached together to two other moieties, the amino is -NR x -(In the formula, R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl).

[0034] The term "aryl," as used herein, refers to a phenyl group, or a bicyclic or tricyclic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group attached to the parent molecular moiety and fused to a phenyl group, a cycloalkyl group, as defined herein, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Tricyclic fused ring systems are exemplified by a phenyl group attached to the parent molecular moiety and fused to a bicyclic fused ring system, as described herein. Representative examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, indolyl (e.g., 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, and 1H-indol-7-yl), benzodioxolyl (e.g., benzo[d][1,3]dioxol-4-yl and benzo[d][1,3]dioxol-5-yl), chromanyl (e.g., chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl), and tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4-tetrahydroquinolin-7-yl, and 1,2,3,4-tetrahydroquinolin-8-yl).

[0035] The term "arylamino," as used herein, means at least one aryl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0036] The term "cyanoalkyl," as used herein, means at least one --CN group appended to the parent molecular moiety through an alkylene group, as defined herein.

[0037] The term "cyanofluoroalkyl," as used herein, means at least one --CN group appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0038] The term "cycloalkoxy," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0039] The term "cycloalkyl," as used herein, refers to a carbocyclic ring system containing 3 to 10 carbon atoms, 0 heteroatoms, and 0 double bonds. Cycloalkyls may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl. "Cycloalkyl" also refers to a cycloalkyl group attached to a parent molecular moiety and substituted with an aryl group, as defined herein. (e.g., a phenyl group), a heteroaryl group as defined herein, or a carbocyclic ring system fused to a heterocycle as defined herein. Representative examples of such cycloalkyl groups include, but are not limited to, 2,3-dihydro-1H-indenyl (e.g., 2,3-dihydro-1H-inden-1-yl and 2,3-dihydro-1H-inden-2-yl), 6,7-dihydro-5H-cyclopenta[b]pyridinyl (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl), oxaspiro[3.3]heptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), and 5,6,7,8-tetrahydroquinolinyl (e.g., 5,6,7,8-tetrahydroquinolin-5-yl).

[0040] The term "cycloalkenyl," as used herein, refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Cycloalkenyls may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, cycloheptenyl, and bicyclo[2.2.1]heptenyl.

[0041] The term "fluoroalkyl" as used herein means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3,3-trifluoropropyl.

[0042] The term "fluoroalkoxy," as used herein, means at least one fluoroalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0043] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0044] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by halogen.

[0045] The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.

[0046] The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms has been replaced with a halogen.

[0047] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced with a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyl include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0048] The term "heteroaryl," as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system. An aromatic monocyclic ring is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring attached to a parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, indolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl. Examples include benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0049] The term "heterocycle" or "heterocyclic" as used herein refers to a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 7- and 8-membered ring contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, Examples include oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocyclic group, or a bridged monocyclic heterocyclic ring system in which two non-adjacent atoms of the ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzothienyl. azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), oxabicyclo[2.2.1]heptanyl (including 7-oxabicyclo[2.2.1]heptan-3-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to a phenyl group, or bicyclic heterocycles fused to a monocyclic cycloalkyl, or bicyclic heterocycles fused to a monocyclic cycloalkenyl, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles where two non-adjacent atoms of the bicyclic ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, azaadamantane (1-azatricyclo[3.3.1.13,7]decane), and oxaadamantane (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocycles can be attached to the parent molecular moiety through any carbon atom or any nitrogen atom in the ring and can be unsubstituted or substituted.

[0050] The terms "hydroxyl" or "hydroxy" as used herein refer to an --OH group.

[0051] The term "hydroxyalkyl," as used herein, means at least one --OH group is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0052] The term "hydroxyfluoroalkyl," as used herein, means at least one --OH group is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0053] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by the prefix "C x ~C y where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C1-C3-alkyl" refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0054] The term "sulfonamide" as used herein refers to -S(O)NR d -or-NR d S(O)-(wherein, R d means that the aryl group may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0055] The term "sulfonyl" refers to the group -S(O)2R', where R' is alkoxy, alkyl, aryl, carbocyclic, heterocarbocyclic; heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0056] The term "substituent" refers to a group "substituted" on an aryl, heteroaryl, phenyl, or pyridinyl group at any atom of that group. Any atom may be substituted.

[0057] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents, including, but not limited to, halogen, ═O (oxo), ═S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, hydroxypropyl ... Examples of alkyl groups include oxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl. For example, if a group is described as "optionally substituted" (such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, or other group such as an R group), it can have 0, 1, 2, 3, 4, or 5 substituents independently selected from halogen, ═O (oxo), ═S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0058] term [ka] means a single bond (-) or a double bond (=).

[0059] For the compounds described herein, groups and substituents thereof may be selected according to the allowed valences of atoms and substituents that do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, etc., such that the selection and substitution gives rise to stable compounds.

[0060] When a substituent is specified by its conventional chemical formula written from left to right, such formula also encompasses the same substituent that may result by writing the structure from right to left. For example, -CHNH- is also intended to encompass -NHCH-.

[0061] For the recitation of numerical ranges herein, each intervening number therebetween is expressly contemplated with the same precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0062] 2.Compound In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: L 1 is -OH or -X(CR 1a R 1a’ ) m O p Ar 1 and; L 2 HA-Y(CR 2a R 2a’ ) n O q Ar 2 and; X and Y each independently represent -OC(O)-, -NR a C(O)-, -NR b C(S)-, -NR c -,-SO2NR c -, -O-, and -OC(O)CH=CH-; R a, R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 1a , R 1a’ , R 2a and R 2a’ are, if present, each independently selected from hydrogen and C1-C4 alkyl; p is 0 or 1; q is 0 or 1; Ar 1 and Ar 2 are each independently selected from aryl or heteroaryl, where each aryl or heteroaryl is independently selected from hydrogen, C1-C 12 Alkyl, hydroxy, C1-C 12 Alkoxy, halo, C1-C4 haloalkyl, Ar 3 , C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, -NH-Ar 4 , C1-C8 alkoxy-Ar 5 , C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or these substituents, together with the atoms to which they are attached, optionally join to form an aryl ring; wherein each heteroaryl optionally contains 1, 2, 3, 4, or 5 heteroatoms selected from O, S, or N; Ar 3 , Ar 4 and Ar 5 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; and Here, the compound is 6,6'-bis(2-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(benzoylamino)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-benzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-dichlorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,3-dibenzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-benzyloxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methyl-6-aminobenzoyl)-α,α-D-trehalose, 6,6'-bis(3-methoxy-4-fluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dimethoxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-heptyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(cinnamoylamino)-α,α-D-trehalose, 6,6'-bis(3,4-dimethoxycinnamoylamino)-α,α-D-trehalose, 6,6'-bis(isonicotinoylamino)-α,α-D-trehalose, or 6,6'-Bis(pyrazine-2-carbonylamino)-α,α-D-trehalose isn't it.

[0063] In some embodiments, p and q are 0.

[0064] In some embodiments, L 1 teeth, [ka] and; m is 0, 1 or 2; R 1a and R 1a’ are, if present, each independently selected from hydrogen and C1-C4 alkyl; and R 2a , R 3a , R 4a , R 5a , and R 6a are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12 and selected from alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, arylamino, C1-C8 alkoxy-aryl, C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or together with the atom to which they are attached, optionally joined to form an aryl ring.

[0065] In some embodiments, R 1a’ is hydrogen, if present.

[0066] In some embodiments, R 2a , R 3a , R 4a , R 5a , and R 6a are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12and selected from alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, arylamino, C1-C8 alkoxy-aryl, C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or together with the atom to which they are attached, optionally joined to form an aryl ring.

[0067] In some embodiments, L 2 teeth, [ka] and; n is 0, 1 or 2; R 1b and R 1b’ are, if present, each independently selected from hydrogen and C1-C4 alkyl; and R 2b , R 3b , R 4b , R 5b , and R 6b are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12 Alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, arylamino, C1-C8 alkoxy-aryl, C1-C8 alkylsulfonyl, and C1-C8 alkoxy. -C1-C8 alkoxy-C1-C8 alkoxy, or together with the atoms to which they are attached, optionally taken together to form an aryl ring.

[0068] In some embodiments, R 1b’ is hydrogen, if present.

[0069] In some embodiments, R 2b , R 3b , R4b , R 5b , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl. 3b and R 4b together with the carbon atoms to which they are attached are optionally joined to form an aryl ring.

[0070] In another embodiment, the compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof [wherein: X and Y each independently represent -OC(O)- and -NR a C(O)-; R a are independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 1a , R 1a’ , R 1b and R 1b’ are, if present, each hydrogen; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, and hydroxy.

[0071] In some embodiments, R 2a , R 3a , R 4a , R 5a , and R 6aAt least one of R is C1-C8 alkyl; 2b , R 3b , R 4b , R 5b , and R 6b At least one of R is C1-C8 alkyl. 3a , R 3b , R 5a , and R 5b Each of is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is isopropyl, tert-butyl, methyl, or ethyl. In an exemplary embodiment, the C1-C8 alkyl is tert-butyl.

[0072] In some embodiments, R 2a , R 2b , R 4a , R 4b , R 6a , R 6 are each independently hydroxy or hydrogen. 2a and R 2b are, respectively , hydroxy. In some embodiments, R 4a and R 4b are each hydroxy.

[0073] In some embodiments, R 2a , R 2b , R 6a , and R 6b is methyl. In some embodiments, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently hydrogen or C1-C8 alkyl. In some embodiments, C1-C8 alkyl is methyl or tert-butyl.

[0074] In some embodiments, m and n are 0.

[0075] In another embodiment, a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof [wherein: X and Y each independently represent -OC(O)- and -NR a C(O)-; R a are independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12 Alkoxy, C1-C4 haloalkyl, Ar 3 and -NH-Ar 4 or optionally taken together with the atom to which they are attached form an aryl ring; Ar 3 , Ar 4 and Ar 5 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0076] In some embodiments, R 3a , R 3b , R 5a , and R 5b are each C1-C5 alkoxy. 2a , R 2b , R 4a , R 4b , R 6a , and R 6b are each hydrogen. 4a and R4b are each C1-C5 alkoxy. 3a , R 3b , R 4a , R 4b , R 5a , and R 5b and each is ethoxy. 2a , R 2b , R 6a and R 6b are each hydrogen.

[0077] In some embodiments, R 2a and R 2b are each C1-C5 alkoxy or hydroxy. 3a , R 4a , R 5a , and R 6a Of At least one is C1-C8 alkyl, and R 3b , R 4b , R 5b , and R 6b At least one of is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is tert-butyl.

[0078] In some embodiments, R 2a , R 3a , R 4a , R 5a , and R 6a At least one of R is C1-C4 haloalkyl; 2b , R 3b , R 4b , R 5b , and R 6b At least one of R is C1-C4 haloalkyl. 2a and R 2b are each C1-C4 haloalkyl. 3a , R 3b , R 5a , and R 5b are each hydrogen. 6a and R6b are each hydrogen or C1-C4 haloalkyl. 4a and R 4b are each hydrogen or C1-C4 alkoxy. In some embodiments, C1-C4 alkoxy is methoxy.

[0079] In some embodiments, R 3a and R 3b are each C1-C4 haloalkyl. 5a and R 5b are each hydrogen or C1-C4 haloalkyl. 2a and R 2b are each hydrogen or hydroxy. 4a , R 4b , R 6a , and R 6b are each hydrogen.

[0080] In some embodiments, R 5a , and R 5b are each C1-C4 alkoxy. In some embodiments, the C1-C4 alkoxy is methoxy. In some embodiments, R 3a , R 3b , R 4a , R 4b , R 6a , and R 6b is hydrogen.

[0081] In some embodiments, the C1-C4 haloalkyl is trifluoromethyl.

[0082] In some embodiments, R 6a and R 6b are each hydrogen, and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently hydrogen, hydroxy, Ar3 and -NH-Ar 4 is selected from, where R 2a , R 3a , R 4a , and R 5a At least one of them is Ar 3 or -NH-Ar 4 and R 2b , R 3b , R 4b , and R 5b At least one of them is Ar 3 or -NH-Ar 4 and Ar 3 and Ar 4 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0083] In some embodiments, Ar 3 and Ar 4 is phenyl unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, alkoxy, C1-C4 alkyl, and hydroxy-C1-C4 alkyl. In some embodiments, phenyl is substituted with 1 substituent selected from methyl, hydroxy, and hydroxymethyl. In some embodiments, R 2a , R 3a , R 4a , and R 5a At least one of R is hydroxy; 2b , R 3b , R 4b , and R 5b At least one of the is hydroxy.

[0084] In some embodiments, R 3a , R 4a , and R 5a At least two of them are C5-C 12 is alkoxy, and R 3b , R4b , and R 5b At least two of them are C5-C 12 is alkoxy, and R 2a , R 2b , R 6a , and R 6b are each hydrogen. 3a , R 3b , R 5a , and R 5b are C5 to C respectively. 12 In some embodiments, R 4a and R 4b are C5 to C respectively. 12 It is an alkoxy.

[0085] A compound selected from the group consisting of 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, 6,6'-bis(3,5-dipentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-triethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoylamino)-α,α-D-trehalose, and 6,6'-bis(2,6-hydroxy-3,5-di-tert-butylbenzoylamino)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound is 6,6-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound is 6,6-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0, 1 or 2; n is 0, 1 or 2; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8-alkyl, hydroxy, C1-C8-alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8-alkoxy-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, and hydroxy-C1-C8-alkyl; where R 3a and R 4a together with the carbon atoms to which they are attached optionally together form an aryl ring; where R 3b and R 4b together with the carbon atoms to which they are attached optionally together form an aryl ring; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; and Here, the compound is 6,6'-bis(2-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-benzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-dichlorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dibenzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-benzyloxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methyl-6-aminobenzoyl)-α,α-D-trehalose, 6,6'-bis(3-methoxy-4-fluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dimethoxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-heptyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-n-pentyloxybenzoyl)-α,α-D-trehalose, or 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose isn't it.

[0089] In some embodiments, R 3a , R 3b , R 5a , and R 5b are each C2-C8 alkoxy. 3a , R 3b , R 5a , and R 5b are each ethoxy.

[0090] In some embodiments, R 2a , R 2b , R 4a , R 4b , R 6a , and R 6b is hydrogen. In some embodiments, R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , and R 6a and at least one of R 6b is tert-butyl. In some embodiments, R 3a , R 3b , R 5a , and R 5b are each tert-butyl. In some embodiments, R 2a and R 2bare each hydroxy. In some embodiments, R 4a , R 4b , R 6a , and R 6b are each hydrogen.

[0091] In some embodiments, m is 0 and n is 0.

[0092] In some embodiments, X and Y are each —C(O)O—.

[0093] In another embodiment, the compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0 or 1; n is 0 or 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 6a , and R 6b are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and C1-C4 alkoxy; R 4a and R 4b is hydrogen; R 3a , R 3b , R 5a , and R 5bare each independently selected from C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl; and wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0094] In some embodiments: each n is 0; R 2a and R 2b are each independently hydrogen or hydroxy; R 3a and R 3b are each independently selected from C1-C8 alkyl, hydroxy, C2-C8 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, and C1-C4 haloalkyl; R 5a and R 5b are each independently selected from C1-C8 alkyl, hydroxy, C2-C8 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, and C1-C4 haloalkyl; and R 6a and R 6b are each independently hydrogen or hydroxy.

[0095] In some embodiments, R 3a , R 3b , R 5a , and R 5b are each C2-C8 alkoxy. 3a , R 3b , R 5a , and R 5b are each ethoxy.

[0096] In some embodiments, R 2a , R 2b , R 6a , and R 6b are each hydrogen.

[0097] In some embodiments, R 3a , R 3b , R 5a , and R 5b At least one of R 3a , R 3b , R 5a , and R 5b are each tert-butyl.

[0098] In some embodiments, R 2a and R 2b are each hydroxy.

[0099] In some embodiments, R 6a and R 6b are each hydrogen.

[0100] In some embodiments, m is 0 and n is 0.

[0101] In some embodiments, X and Y are each —C(O)O—.

[0102] In another embodiment, the compound of formula (IIb): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0 or 1; n is 0 or 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 6a and R 6b are each hydrogen; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from hydrogen, hydroxy, and aryl, where R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b at least one of is aryl; or where R 3a and R 4a together with the carbon atoms to which they are attached optionally together form an aryl ring; or where R 3b and R 4b together with the carbon atoms to which they are attached optionally together form an aryl ring; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0103] In some embodiments, m is 0 and n is 0.

[0104] In some embodiments, R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5bis phenyl, and the phenyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, alkoxy, C1-C4 alkyl, and hydroxy-C1-C4 alkyl. In some embodiments, the phenyl is substituted with 1 substituent selected from methyl, hydroxy, and hydroxymethyl.

[0105] In some embodiments, X and Y are each —C(O)O—.

[0106] In another embodiment, a compound of formula (IIc): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0 or 1; n is 0 or 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, hydroxy, and C1-C4 alkoxy, and C1-C4 haloalkyl, where R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6bat least one of which is C1-C4 haloalkyl is disclosed.

[0107] In some embodiments: m is 0; n is 0; and R 2a and R 2b are each independently selected from hydrogen, hydroxy, C1-C4 alkoxy, and C1-C4 haloalkyl; R 3a , R 3b , R 5a , R 5b , R 6a and R 6b are each independently selected from hydrogen and C1-C4 haloalkyl; and R 4a and R 4b are each independently selected from hydrogen, hydroxy, and C1-C4 haloalkyl.

[0108] In some embodiments, R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b At least one of is trifluoromethyl.

[0109] In some embodiments, X and Y are each —C(O)O—.

[0110] In another embodiment, a compound of formula (IId): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 1; n is 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b, and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0111] In some embodiments, R 1a and R 1b are each hydrogen.

[0112] In some embodiments: 2a , R 2b , R 4a , R 4b , R 6a , and R 6b are each independently selected from hydrogen, hydroxy, and C1-C4 alkoxy; and R 3a , R 3b , R 5a , and R 5b are each independently selected from hydrogen and C1-C8 alkoxy.

[0113] In some embodiments, X and Y are each —C(O)O—.

[0114] In another embodiment, a compound of formula (IIe): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0 or 1; n is 0 or 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 5a , R 5b , R 6a , and R 6b are each hydrogen; and R 3a , R 3b , R 4a , and R 4b are each independently selected from C1-C8 alkyl, hydroxy, C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl.

[0115] In some embodiments, R 3a , R 3b , R 4a , and R 4b are each independently selected from hydroxy and C1-C8 alkoxy.

[0116] In some embodiments, m is 0 and n is 0.

[0117] In some embodiments, X and Y are each —C(O)O—.

[0118] In another embodiment, 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, and 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof is disclosed.

[0119] In another embodiment, a compound which is 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof, is disclosed.

[0120] In another embodiment, a compound which is 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof, is disclosed.

[0121] Other compounds according to the present disclosure are shown in FIG.

[0122] The present compounds may exist as stereoisomers where asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically encompassed within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the present compounds may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. Such resolution methods are exemplified by (1) coupling the enantiomeric mixture with a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and optionally liberating the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or its latest edition); (2) direct separation of the optically enantiomeric mixture on a chiral chromatographic column; or (3) fractional recrystallization methods.

[0123] It is to be understood that the compounds may have tautomeric forms, as well as geometric isomers, and that these also form embodiments of the present disclosure.

[0124] The present disclosure also includes isotopically labeled compounds, which have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in compounds of the present disclosure include, but are not limited to, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The elements are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. The compounds may also incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that may be incorporated into compounds of formula (I) are: 11 C. 13 N, 15 O, and 18 F. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying Examples, using the appropriate isotopically labeled reagent in place of the non-isotopically labeled reagent.

[0125] a. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt or zwitterion of a compound that is soluble or dispersible in water or oil, suitable for the treatment of disorders, free from undue toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit-risk ratio, and effective for its intended use. The salt may be prepared during the final isolation and purification of the compound, or separately by reacting the amino group of the compound with a suitable acid. For example, the compound may be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salt may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0126] Base addition salts may be prepared during the final isolation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0127] b. General synthesis The compounds of formula (I) may be prepared by synthetic methods or by metabolic methods. Preparation of compounds by metabolic methods includes those occurring in the human or animal body (in vivo). or in vitro methods.

[0128] Abbreviations used in the schemes and descriptions below include the following: DCC is N,N'-dicyclohexylcarbodiimide; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; TBTU is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; and TMS is tetramethylsilyl.

[0129] Compounds of formula (I) may be synthesized as shown in Scheme 1. [ka]

[0130] As shown in Scheme 1, the compound 2,3,4,2',3',4'-hexakis-O-trimethylsilyl-α,α-trehalose (prepared as described in Johnson et al. J. Carbohydr. Chem. 17(6), 969-974 (1998)) can be coupled with an appropriate aryl acid. This may be achieved using a coupling agent (e.g., DCC, EDC, TBTU, etc.). Alternatively, the aryl acid may be coupled under Mitsunobu conditions or by SN2 displacement of the corresponding 6,6'-triflate compound. For more specific exemplary syntheses, see the Examples.

[0131] Certain aryl acids, such as benzoic acid, may be commercially available. Others may be synthesized by known methods. Benzoic acids that have been used in the preparation of exemplary compounds or are contemplated for use in the preparation of future compounds include those illustrated in Figures 7-9.

[0132] The compounds and intermediates may be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds are found, for example, in "Vogel's These include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperatures, optionally with pretreatment with activated carbon, thin layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described in "Textbook of Practical Organic Chemistry," 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0133] The disclosed compounds may have at least one basic nitrogen, and therefore may be capable of forming a desired salt upon treatment of the compound with an acid. For example, the compound may be reacted with an acid at room temperature or above to provide the desired salt, which precipitates after cooling and is collected by filtration. Examples of acids suitable for the reaction of include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0134] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions may be worked up in conventional manner, for example by removing the solvent from the residue, and further purified according to methodologies generally known in the art, including, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared from commercially available materials by one skilled in the art using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or techniques similar to the schemes described above, or by procedures described in the Synthetic Examples section.

[0135] The scope of this disclosure includes routine experimentation, including the proper manipulation of reaction conditions, reagents, and synthetic sequences, the protection of any chemical functional groups that may be incompatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; for examples, see P. G. M. Wuts and T. W. Greene, in Greene's book titled "Protective Groups in Organic Synthesis" (4 th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of compounds of the present disclosure can be achieved by methods similar to those described in the synthetic schemes and specific examples set forth above.

[0136] If an optically active form of a disclosed compound is required, it may be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0137] Similarly, if a pure geometric isomer of a compound is required, it may be obtained by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolution of a geometric isomeric mixture of the compound or intermediate using standard procedures such as chromatographic separation.

[0138] It will be understood that the synthetic schemes and specific examples as described are illustrative and should not be read as limiting the scope of the present disclosure as defined by the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0139] c. Biological activity The compounds disclosed herein, including compounds of formula (I) (including compounds of formulas (I), (Ia), and (Ib)) and compounds of formula (II) (including compounds of formulas (II), (IIa), (IIb), (IIc), (IId), and (IIe)), can have biological activity that makes them useful as immunological adjuvants or immunomodulators. For example, the compounds disclosed herein can be used to treat or prevent the development of inflammatory bowel disorders. The combination may stimulate the immune system's response to a co-administered antigen. In some embodiments, the compound may modulate the immune response when administered as a monotherapy. In some embodiments, the compound may have activity as a Th-17 stimulating adjuvant.

[0140] In some embodiments, the compounds may stimulate cytokine production in a sample or upon administration to a subject. The compounds may stimulate the production of Th17-type cytokines. Exemplary cytokines include IL-6, IL-1β, IL-23, and TNFα. Such activity may be tested by established methods. For example, the levels of such cytokines may be measured in a sample of peripheral blood mononuclear cells (PBMCs) after exposure to the compounds.

[0141] The compounds disclosed herein, including compounds of Formula (I) (including compounds of Formulas (I), (Ia), and (Ib)) and compounds of Formula (II) (including compounds of Formulas (II), (IIa), (IIb), (IIc), (IId), and (IIe)), may also possess biological activity that makes them useful, for example, as cytotoxic compounds for the treatment of cancer. In some embodiments, the compounds may inhibit or reduce the growth or proliferation of cancer cells. Such activity can be determined by established methods.

[0142] 3. Composition The disclosed compounds may be incorporated into pharmaceutical, adjuvant, and vaccine compositions that may be suitable for administration to a subject (such as a patient, which may be human or non-human).

[0143] a. Pharmaceutical Composition The disclosed compounds may be incorporated into pharmaceutical compositions. The pharmaceutical composition may contain a "therapeutically effective amount" or a "prophylactically effective amount." A "therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result, at the dosage and for the period of time necessary. A therapeutically effective amount of a composition may be determined by one of skill in the art and may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of Formula (I)) are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective to achieve a desired prophylactic result, at the dosage and for the period of time necessary. Typically, because a prophylactic dose is used prior to or at an earlier stage of disease in a subject, the prophylactically effective amount will be less than the therapeutically effective amount.

[0144] For example, a therapeutically effective amount of a compound of formula (I) is about 0.001 mg / kg to about 1000 mg / kg, 0.01 mg / kg to about 1000 mg / kg, 0.1 mg / kg to about 1000 mg / kg, 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 6 It may be 50 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0145] Pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means any kind of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. Some examples of materials that can act as pharmaceutically acceptable carriers include, but are not limited to, lactose, glucose and sucrose. starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository wax; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; propylene glycol, etc.; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition, at the discretion of the formulator.

[0146] Thus, the compounds and their physiologically acceptable salts may be formulated, for example, for administration by solid administration, eye drops, topical oily formulations, injection, inhalation (either through the mouth or nose), implant, or oral, buccal, sublingual, parenteral, or rectal administration. For techniques and formulations, reference may be made generally to "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.

[0147] The type of carrier used will depend on the route of administration of the disclosed compounds and the form of the composition, which may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or local administration (e.g., transdermal, pulmonary, nasal, otic, ocular, liposome delivery system, or iontophoresis).

[0148] Carriers for systemic administration typically include at least one of a diluent, lubricant, binder, disintegrant, colorant, flavorant, sweetener, antioxidant, preservative, glidant, solvent, suspending agent, wetting agent, surfactant, combinations thereof, etc. All carriers are optional in the composition.

[0149] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of one or more diluents in a systemic or topical composition is typically about 50 to about 90%.

[0150] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate, and liquid lubricants such as polyethylene glycol and vegetable oils, e.g., peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter. The amount of one or more lubricants in a systemic or topical composition is typically about 5 to about 10%.

[0151] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of one or more binders in a systemic composition is typically about 5 to about 50%.

[0152] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of one or more disintegrants in a systemic or topical composition is typically from about 0.1 to about 10%.

[0153] Suitable coloring agents include coloring agents such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0154] Suitable flavorings include menthol, peppermint, and fruit flavors. The amount of one or more flavorings in a systemic or topical composition, if used, is typically about 0.1 to about 1.0%.

[0155] Suitable sweeteners include aspartame and saccharin. The amount of one or more sweeteners in a systemic or topical composition is typically from about 0.001 to about 1%.

[0156] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of one or more antioxidants in a systemic or topical composition is typically from about 0.1 to about 5%.

[0157] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of one or more preservatives in a systemic or topical composition is typically from about 0.01 to about 5%.

[0158] Suitable lubricants include silicon dioxide. The amount of one or more lubricants in a systemic or topical composition is typically about 1 to about 5%.

[0159] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer solution. The amount of one or more solvents in a systemic or topical composition is typically from about 0 to about 100%.

[0160] Suitable suspending agents include AVICEL RC-591 (supplied by FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of one or more suspending agents in a systemic or topical composition is typically about 1 to about 8%.

[0161] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, and TWEENS from Atlas Powder Company, Wilmington, Delaware. Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of one or more surfactants in a systemic or topical composition is typically from about 0.1% to about 5%.

[0162] The amount of each component in a systemic composition may vary depending on the type of systemic composition being prepared; generally, systemic compositions contain 0.01% to 50% of an active compound (e.g., a compound of Formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically contain 0.1% to 10% of the active ingredient and 90% to 99.9% of carriers, including diluents and solvents. nothing.

[0163] Compositions for oral administration can be in various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active ingredient, usually at least about 5%, and more specifically, about 25% to about 50%. Oral dosage compositions contain about 50% to about 95% of the carrier, and more specifically, about 50% to about 75%.

[0164] Tablets may be compressed, triturated, enteric-coated, sugar-coated, film-coated, or multi-layered. Tablets typically contain an active ingredient and a carrier containing a component selected from diluents, lubricants, binders, disintegrants, colorants, flavorants, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific coloring agents are FD&C dyes, which may be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavorings such as menthol, peppermint, or fruit flavors, or combinations thereof.

[0165] Capsules (including implants, time-release, and sustained-release formulations) typically contain an active compound (e.g., a compound of Formula (I)) in a gelatin-containing capsule and a carrier comprising one or more diluents as disclosed above. Granules typically contain a disclosed compound and preferably a lubricant, such as silicon dioxide, which improves flow properties. Implants may be biodegradable or non-biodegradable.

[0166] The selection of ingredients in a carrier for an oral composition depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for purposes of this invention.

[0167] The solid compositions may be coated by conventional methods, typically with a pH or time-dependent coating, to release the disclosed compounds in the gastrointestinal tract around the desired application or at various locations and times to prolong the desired effect. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industrie, Essen, Germany), wax, and shellac.

[0168] The composition for oral administration can be in liquid form.For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc.The liquid composition for oral administration typically comprises the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants.The oral liquid composition preferably comprises one or more components selected from colorants, flavorants, and sweeteners.

[0169] Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions typically contain soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions may further comprise a lubricant, a colorant, a flavorant, a sweetener, an antioxidant, and a glidant.

[0170] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansing liquids, moisturizers, sprays, skin patches, etc. The topical composition comprises the disclosed compounds (e.g., compounds of formula (I) of formula (II)) and a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the skin. The carrier may further comprise one or more optional ingredients.

[0171] The amount of carrier used in conjunction with the disclosed compounds is sufficient to provide a practical amount of the composition for administration of each unit dose of the compound. Techniques and compositions for producing dosage forms useful in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Co., 1999; Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0172] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier comprises a topical carrier. Suitable topical carriers include one or more components selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, etc. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0173] The carrier of the topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives, all of which are optional.

[0174] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and sebacic acid. Examples of suitable emollients include di-n-butyl ether, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohols, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin use include stearyl alcohol and polydimethylsiloxane. The amount of one or more emollients in a skin-based topical composition is typically about 5% to about 95%.

[0175] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant is typically from about 0% to about 95%.

[0176] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of one or more solvents in a topical composition is typically about 0% to about 95%.

[0177] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of one or more humectants in a topical composition is typically 0% to 95%.

[0178] The amount of one or more thickening agents in a topical composition is typically from about 0% to about 95%.

[0179] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectites, trialkylarylammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of one or more powders in a topical composition is typically 0% to 95%.

[0180] The amount of fragrance in a topical composition is typically from about 0% to about 0.5%, particularly from about 0.001% to about 0.1%.

[0181] Suitable pH-adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0182] b. Adjuvant and Vaccine Compositions The compounds may also be incorporated into adjuvant and vaccine compositions. Vaccine compositions may further comprise an antigen. Suitable antigens include microbial pathogens, bacteria, viruses, proteins, glycoproteins, lipoproteins, peptides, glycopeptides, lipopeptides, toxoids, carbohydrates, and tumor-specific antigens. Mixtures of two or more antigens may also be used.

[0183] Adjuvant and vaccine compositions can include an "effective amount" of the disclosed compounds. In the context of an adjuvant or vaccine composition, an "effective amount" refers to an amount effective, at the dosage and for the duration necessary, to achieve a desired result (e.g., enhancing an immune response to one or more antigens). The immune response may be measured, for example, by measuring antibody titers to the antigen, assessing the ability of a vaccine containing the compound to immunize a host in response to a disease or antigenic challenge, etc. For example, administration of an "effective amount" of a compound or composition to a subject can increase one or more antibody titers by 10% or more compared to a non-immunized control, 20% or more compared to a non-immunized control, 30% or more compared to a non-immunized control, 40% or more compared to a non-immunized control, 50% or more compared to a non-immunized control, 50% or more compared to a non-immunized control, 70% or more compared to a non-immunized control, 80% or more compared to a non-immunized control, 90% or more compared to a non-immunized control, or 100% or more compared to a non-immunized control.

[0184] Vaccine preparation is a well-developed art, and general guidance on vaccine preparation and formulation is readily available from any of a variety of sources. One such example is *New Trends and Developments in Vaccines*, edited by Voller et al., University Park Press, Baltimore, Md., USA 1978.

[0185] The vaccine compositions of the present disclosure may also contain other compounds, which may be biologically active or inactive. For example, one or more immunogenic portions of other tumor antigens may be present in the vaccine composition, either incorporated into a fusion polypeptide or as separate compounds. The polypeptides may, but need not, be conjugated to other macromolecules, as described, for example, in U.S. Patent Nos. 4,372,945 and 4,474,757. Vaccine compositions may generally be used for prophylactic and therapeutic purposes.

[0186] In one embodiment, the antigen in the vaccine composition is a peptide, polypeptide, or immunogenic portion thereof. An "immunogenic portion," as used herein, is a portion of a protein that is recognized by (i.e., specifically binds to) a B-cell and / or T-cell surface antigen receptor. Such an immunogenic portion generally comprises at least 5 amino acid residues, more preferably at least 10, and even more preferably at least 20 amino acid residues of an antigenic protein or variant thereof.

[0187] Immunogenic portions of an antigenic polypeptide may generally be identified using well-known techniques, such as those summarized in Paul, Fundamental Immunology, 3rd ed., pp. 243-247 (Raven Press, 1993) and the references cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, antisera, and / or T-cell lines or clones. As used herein, antisera and antibodies are "antigen-specific" if they specifically bind to the antigen (i.e., they react with the protein in an ELISA or other immunoassay and do not show detectable reactivity with unrelated proteins). Such antisera and antibodies may be prepared as described herein and using well-known techniques. An immunogenic portion of a protein is one that reacts with such antisera and / or T-cells (e.g., in an ELISA and / or T-cell reactivity assay) at a level not substantially below the reactivity of the full-length polypeptide. Such immunogenic portions may react in such assays at a level similar to or greater than the reactivity of the full-length polypeptide. Such screening may generally be performed using methods well known to those skilled in the art, such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. For example, a polypeptide may be immobilized on a solid support and contacted with patient serum, allowing antibodies in the serum to bind to the immobilized polypeptide. Unbound serum may then be removed, and the bound antibodies may be isolated, e.g., by immunoblotting. 125 It can be detected using I-labeled protein A.

[0188] Peptide and polypeptide antigens may be prepared using any of a variety of well-known techniques. Recombinant polypeptides encoded by DNA sequences can be readily prepared from isolated DNA sequences using any of a variety of expression vectors known to those skilled in the art. Expression can be achieved in any appropriate host cell transformed or transfected with an expression vector containing a DNA molecule encoding the recombinant polypeptide. Suitable host cells include prokaryotes, yeast, and higher eukaryotic cells such as mammalian cells and plant cells. Preferably, the host cells used are Escherichia coli (E. coli), yeast, or mammalian cell lines such as COS or CHO.

[0189] Portions and other variants of protein antigens having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may also be made by synthetic means, using techniques well known to those of skill in the art. For example, such polypeptides may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, in which amino acids are added sequentially to a growing amino acid chain. See Merrifield, J. Am. Chem. Soc. 85:2149-2146, 1963. Automated polypeptide synthesizers are commercially available from suppliers such as Perkin Elmer / Applied BioSystems Division (Foster City, Calif.) and may be operated according to the manufacturer's instructions.

[0190] Fusion proteins may generally be prepared using standard techniques, including chemical conjugation. Preferably, fusion proteins are expressed as recombinant proteins, allowing for higher levels of production in expression systems compared to non-fused proteins. Briefly, DNA sequences encoding the polypeptide components may be assembled separately and ligated into an appropriate expression vector. The 3' end of the DNA sequence encoding one polypeptide component is ligated, with or without a peptide linker, to the 5' end of the DNA sequence encoding the second polypeptide component, such that the reading frames of the sequences are in phase. This allows for translation into a single fusion protein that retains the biological activity of both component polypeptides.

[0191] A peptide linker sequence may be used to separate the first and second polypeptide components by a distance sufficient to ensure folding of each polypeptide into its secondary and tertiary structure. Such peptide linker sequences are incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be selected based on the following factors: (1) the ability to adopt a flexible, extended conformation; (2) the inability to adopt secondary structures that may interact with functional epitopes on the first and second polypeptides; and (3) the absence of hydrophobic or charged residues that may react with the polypeptide functional epitopes. Preferred peptide linker sequences contain Gly, Asn, and Ser residues. Other near-neutral amino acids, such as Thr and Ala, may also be used in the linker sequence. Amino acid sequences that can be usefully used as linkers include those disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci. USA 83:8258-8262, 1986; U.S. Pat. Nos. 4,935,233 and 4,751,180. Linker sequences may generally be from 1 to about 50 amino acids in length. A linker sequence is not necessary when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.

[0192] In another embodiment, the compounds or adjuvant compositions described herein may be used in the preparation of DNA-based vaccine compositions. An exemplary vaccine of this type contains DNA encoding one or more polypeptide antigens such that the antigens are produced in situ. The DNA may be present in any of a variety of delivery systems known to those skilled in the art, including nucleic acid expression systems, bacterial, and viral expression systems. Numerous gene delivery techniques are well known in the art, such as those described by Rolland, Crit. Rev. Therap. Drug Carrier Systems 15:143-198, 1998, and references cited therein. A suitable nucleic acid expression system contains the necessary DNA sequences for expression in the patient, including a suitable promoter and termination signal. Bacterial delivery systems involve the administration of bacteria (e.g., Bacillus Calmette-Guerrin) that express an immunogenic portion of a polypeptide on its cell surface or secrete such an epitope. In a preferred embodiment, the DNA is delivered via viral expression. The virus is introduced using a system (eg, vaccinia or other poxvirus, retrovirus, or adenovirus), which typically involves the use of a non-pathogenic (defective), replication-competent virus. For exemplary systems, see, e.g., Fisher-Hoch et al., Proc. Natl. Acad. Sci. USA 86:317-321, 1989; Flexner et al., Ann. NY Acad. Sci. 569:86-103, 1989; Flexner et al., Vaccine 8:17-21, 1990; U.S. Pat. Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89 / 01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berkner, Biotechniques 6:616-627, 1988; Rosenfeld et al., Science 252:431-434, 1991; Kolls et al., Proc. Natl. Acad. Sci. USA 91:215-219, 1994; Kass-Eisler et al., Proc. Natl. Acad. Sci. USA 90:11498-11502, 1993; Guzman et al., Circulation 88:2838-2848, 1993; and Guzman et al., Cir. Res. 73:1202-1207, 1993. Techniques for incorporating DNA into such expression systems are well known to those skilled in the art.

[0193] Alternatively, the DNA may be "naked," as described, for example, in Ulmer et al., Science 259:1745-1749, 1993, and reviewed by Cohen, Science 259:1691-1692, 1993. Uptake of naked DNA may be increased by coating the DNA onto biodegradable beads that are efficiently transported into cells. It will be apparent that vaccines may contain both polynucleotide and polypeptide components, if desired.

[0194] It will further be apparent that the vaccines may contain pharmaceutically acceptable salts of the desired polynucleotide, polypeptide and / or carbohydrate antigens. For example, such salts may be prepared from pharmaceutically acceptable non-toxic bases, including organic bases (e.g., salts of primary, secondary and tertiary amines and basic amino acids) and inorganic bases (e.g., sodium, potassium, lithium, ammonium, calcium and magnesium salts).

[0195] Adjuvant systems can exhibit potent adjuvant effects when administered over a wide range of dosages and ratios.

[0196] The amount of antigen in each vaccine dose will generally be selected to induce a protective immune response without significant adverse side effects associated with typical vaccines. Such amounts will vary depending on the specific immunogen used and its format. Generally, it is expected that each dose will contain about 1-1000 μg of protein, most typically about 2-100 μg, and preferably about 5-50 μg. Of course, the dosage administered will depend on age, weight, type of concomitant treatment, if any, and the nature of the antigen being administered.

[0197] The immunogenic activity of a given amount of vaccine composition can be readily determined, for example, by monitoring the increase in antibody titer against the antigen used in the vaccine composition (Dalsgaard, K. Acta Veterinia Scandinavica 69:1-40 (1978)). Another common method involves intradermal injection of various amounts of the vaccine composition into CD-1 mice, after which serum is collected from the mice and tested for anti-immunogen antibodies, for example, by ELISA. These and other similar techniques will be apparent to those skilled in the art.

[0198] The antigen may be an antigen specific to an infectious disease, autoimmune disease, condition, or pathogenic variant that is to be treated with a given vaccine composition. Antigens can be derived from and / or isolated from essentially any desired source depending on the cancer, pathogen, or disease. By way of example, antigens can be derived from viral sources such as influenza virus, feline leukemia virus, feline immunodeficiency virus, human HIV-1, HIV-2, herpes simplex virus type 2, human cytomegalovirus, hepatitis A, B, C, or E, respiratory syncytial virus, human papillomavirus, rabies, measles, or foot-and-mouth disease virus. Exemplary antigens can also be derived from bacterial sources such as anthrax, diphtheria, Lyme disease, malaria, tuberculosis, leishmaniasis, T. cruzi, Ehrlichia, Candida, or protozoa such as Babesia bovis or Plasmodium. The one or more antigens will typically comprise natural or synthetic amino acids, for example, in the form of peptides, polypeptides, or proteins, and may also comprise polysaccharides, or mixtures thereof. Exemplary antigens may be isolated from natural sources, synthesized using solid phase synthesis, or obtained by recombinant DNA techniques.

[0199] In another embodiment, tumor antigens may be used in vaccine compositions for the prevention and / or treatment of cancer. Tumor antigens are surface molecules that are differentially expressed on tumor cells compared to non-tumor tissues. Tumor antigens allow tumor cells to be immunologically distinguishable from normal cells and provide diagnostic and therapeutic targets for human cancers. Tumor antigens are characterized as either membrane proteins or altered carbohydrate molecules of glycoproteins or glycolipids on the cell surface. Cancer cells often express a variety of antigens, including truncated epidermal growth factor, folate-binding protein, epithelial mucin, melanoferrin, carcinoembryonic antigen, prostate-specific membrane antigen, HER2, and HER2. 2Tumor cells, such as IgG1-neu (which are candidates for use in therapeutic cancer vaccines), have unique tumor antigens on their surface. Because tumor antigens are normal or related to normal components of the body, the immune system often cannot mount an effective immune response against them to destroy the tumor cells. To achieve such a response, the adjuvant systems described herein can be utilized. As a result, exogenous proteins can enter the processing pathway of endogenous antigens, leading to the production of cytolytic or cytotoxic T cells (CTLs). This adjuvant effect promotes the production of antigen-specific CTLs, which seek out and destroy tumor cells bearing on their surface one or more tumor antigens used for immunization. Exemplary cancer types for which this approach can be used include prostate cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer, head and neck cancer, melanoma, leukemia, lymphoma, and the like.

[0200] In one embodiment, the antigen present in the vaccine composition is an autoantigen rather than a foreign antigen, i.e., the vaccine composition is directed against an autoimmune disease. Examples of autoimmune diseases include type 1 diabetes, conventional organ-specific autoimmunity, neurological diseases, rheumatic / connective tissue diseases, autoimmune cytopenias, and related autoimmune diseases. Such conventional organ-specific autoimmunity may include thyroiditis (Graves' disease + Hashimoto's disease), gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, hypogonadism, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, anti-receptor antibody disease, and vitiligo. Such neurological diseases may include schizophrenia, Alzheimer's disease, depression, hypopituitarism, diabetes insipidus, sicca syndrome, and multiple sclerosis. Such rheumatic / connective tissue diseases may include rheumatoid arthritis, systemic lupus erythematous (SLE) or lupus, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren's syndrome. Other autoimmune-related diseases may include autoimmune uvoretinitis, glomerulonephritis, post-myocardial infarction syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, and other immune-related diseases as provided herein and known in the relevant arts.

[0201] In one embodiment, an antigen may be covalently linked to an adjuvant, such as a compound of Formula I, to create a separate molecule that can exhibit enhanced adjuvant effect to the antigen, which may be greater than the adjuvant effect achievable in the absence of such covalent linkage, as in a mixture of the components (i.e., a mixture of the antigen and a compound of Formula (I)). Covalent linkage may be achieved by reaction through a functional group; for example, in the case of a compound of Formula I, reaction through a carboxylic acid group, a hydroxyl group, or an aldehyde functional group. For such covalently linked antigens, further enhanced adjuvant effect may be achieved by incorporating an inorganic salt adjuvant with the compound. The inorganic salt adjuvant preferably comprises aluminum hydroxide or aluminum phosphate, although other known inorganic salt adjuvants, such as calcium phosphate, zinc hydroxide, or calcium hydroxide, may also be used.

[0202] Adjuvants may include other polynucleotides and / or polypeptides. It will be apparent that the vaccines may contain pharmaceutically acceptable salts of the polynucleotides and polypeptides provided herein. Such salts may be prepared from pharmaceutically acceptable non-toxic bases, including organic bases (e.g., salts of primary, secondary, and tertiary amines and basic amino acids) and inorganic bases (e.g., sodium, potassium, lithium, ammonium, calcium, and magnesium salts).

[0203] The vaccine compositions may be formulated for and administered in any suitable manner, including, for example, topical, oral, nasal, intravenous, intravaginal, epicutaneous, sublingual, intracranial, intradermal, intraperitoneal, subcutaneous, intramuscular, or by inhalation. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a fat, a wax, or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate, may be used.

[0204] In one exemplary embodiment, the vaccine formulation is administered to a mucosa, particularly to the oral cavity, and preferably to a sublingual site, to elicit an immune response. Oral administration may often be preferred over traditional parenteral delivery due to the ease and convenience offered by non-invasive administration techniques. Furthermore, this approach also provides a means to elicit mucosal immunity, which can often be difficult to achieve with traditional parenteral delivery and may confer protection from airborne pathogens and / or allergens. A further advantage of oral administration is that sublingual vaccine delivery may improve patient compliance, particularly for pediatric applications or for applications that traditionally require multiple injections over a long period of time, such as with allergy desensitization therapy.

[0205] The vaccine composition may also contain a buffer (e.g., neutral buffered saline or phosphate buffered saline), a carbohydrate (e.g., glucose, mannose, sucrose, or dextran), mannitol, a protein, polypeptide, or an amino acid such as glycine, an antioxidant, a bacteriostatic agent, a chelating agent such as EDTA or glutathione, an adjuvant (e.g., aluminum hydroxide), a solute that renders the formulation isotonic, hypotonic, or slightly hypotonic with the blood of the recipient, a suspending agent, a thickening agent, and / or a preservative. Alternatively, the vaccine composition may be formulated as a lyophilizate. The compound may also be encapsulated in liposomes using well-known technology.

[0206] The vaccine composition may also include other adjuvants or immunoeffectors. Suitable adjuvants include, for example, Freund's incomplete and complete adjuvants (Difco Laboratories, Detroit, Mich.); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ); AS-2 (SmithKline Beecham); inorganic salts (e.g., aluminum, silica, kaolin, and carbon); aluminum hydroxide gel (alum), Aluminum salts such as AlK(SO4)2, AlNa(SO4)2, AlNH4(SO4), and Al(OH)3; calcium salts (e.g., Ca3(PO4)2), iron, or zinc; insoluble suspensions of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polynucleotides (e.g., polyIC and polyAU acid); polyphosphazenes; cyanoacrylates; polymerase-(DL-lactide-co-glycoside); biodegradable microspheres; liposomes; lipid A and its derivatives; monophosphoryl lipid A; wax D from Mycobacterium tuberculosis, as well as polysaccharides derived from Corynebacterium parvum, Bordetella pertussis, and other bacteria. pertussis, and substances found in members of the Brucella genus; bovine serum albumin; diphtheria toxoid; tetanus toxoid; edestin; keyhole limpet hemocyanin; Pseudomonas aeruginosa toxin A; choleragenoids; cholera toxin; pertussis toxin; viral proteins; and Quil A. Aminoalkyl glucosamine phosphate compounds can also be used (see, e.g., WO 98 / 50399, U.S. Pat. No. 6,113,918 (granted from U.S. patent application Ser. No. 08 / 853,826), and U.S. patent application Ser. No. 09 / 074,720). In addition, adjuvants such as cytokines (e.g., GM-CSF or interleukin-2, -7, or -12), interferons, or tumor necrosis factors may also be used as adjuvants. Protein and polypeptide adjuvants may be obtained from natural or recombinant sources by methods well known to those skilled in the art. When obtained from recombinant sources, the adjuvant may comprise a protein fragment that includes at least the immunostimulatory portion of the molecule.Other known immunostimulatory macromolecules that can be used include, but are not limited to, polysaccharides, tRNA, non-metabolizable synthetic polymers such as polyvinylamine, polymethacrylic acid, polyvinylpyrrolidone, mixed polycondensates of 4',4-diaminodiphenylmethane-3,3'-dicarboxylic acid and 4-nitro-2-aminobenzoic acid (having relatively high molecular weight) (see Sela, M., Science 166:1365-1374 (1969)), or glycolipids, lipids, or carbohydrates.

[0207] Within the vaccine compositions provided herein, the adjuvant composition is preferably designed to induce a predominantly Th17-type immune response. High levels of Th17-type cytokines (e.g., IL-6, IL-1β, IL-23, and TNFα) can favor the induction of a cell-mediated immune response to an administered antigen. After administration of a vaccine as provided herein, a patient can support an immune response that includes a Th17-type response. In some embodiments where the response is predominantly Th17-type, the levels of Th17-type cytokines can increase more than the levels of other cytokines. The levels of these cytokines can be readily assessed using standard assays. For a review of cytokine families, see Mosmann and Coffman, Ann. Rev. Immunol. 1989, 7:145-173.

[0208] The compositions described herein may be administered as part of a sustained-release formulation (i.e., a formulation such as a capsule, sponge, or gel (e.g., made of a polysaccharide) that provides for a sustained release of the compound after administration). Such formulations are generally prepared using well-known technology (see, e.g., Coombes et al., Vaccine 14:1429-1438, 1996) and may be administered, for example, by oral, rectal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the polypeptide, polynucleotide, or antibody dispersed in a carrier matrix and / or encased in a reservoir surrounded by a rate-limiting membrane. Carriers used in such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. Such carriers include microparticles of poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose, dextran, and the like. Other sustained-release formulations may be used. Extended-release carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysaccharide or oligosaccharide) and, optionally, an outer layer comprising an amphiphilic compound such as a phospholipid (see, e.g., U.S. Pat. No. 5,151,254 and WO 94 / 20078, WO 94 / 23701, and WO 96 / 06638). The amount of active compound contained in a sustained-release formulation will vary depending upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented.

[0209] Any of a variety of known delivery vehicles may be used in pharmaceutical compositions and vaccines to promote the generation of cell-targeted, antigen-specific immune responses. Delivery vehicles include antigen-presenting cells (APCs), such as dendritic cells, macrophages, B cells, monocytes, and other cells that may be engineered to be efficient APCs. Such cells may, but need not, be genetically modified to enhance antigen presentation, enhance activation and / or maintenance of T cell responses, have anti-targeting effects themselves, and / or be immunologically compatible with the recipient (i.e., matched HLA haplotypes). APCs may generally be isolated from any of a variety of biological fluids and organs, including tumor and peritumoral tissue, and may be autologous, allogeneic, syngeneic, or xenogeneic cells.

[0210] Certain embodiments may use dendritic cells or their precursors as antigen-presenting cells. Dendritic cells are extremely potent APCs (Banchereau and Steinman, Nature 392:245-251, 1998) and have been shown to be effective as physiological adjuvants for eliciting prophylactic or therapeutic antitumor immunity (see Timmerman and Levy, Ann. Rev. Med. 50:507-529, 1999). Dendritic cells can generally be identified based on their typical shape (stellate in situ, with prominent cytoplasmic processes (dendrites) visible in vitro), their ability to efficiently uptake, process, and present antigens, and their ability to activate naive T cell responses. Of course, dendritic cells may be engineered to express specific cell surface receptors or ligands not typically found on dendritic cells in vivo or ex vivo, and such modified dendritic cells are contemplated. As an alternative to dendritic cells, secretory vesicles, called exosomes, loaded with antigen may be used in vaccines (see Zitvogel et al., Nature Med. 4:594-600, 1998).

[0211] Dendritic cells and precursors may be obtained from peripheral blood, bone marrow, tumor-infiltrating cells, peritumor tissue-infiltrating cells, lymph nodes, spleen, skin, umbilical cord blood, or any other suitable tissue or body fluid. For example, dendritic cells may be differentiated ex vivo by adding a combination of cytokines, such as GM-CSF, IL-4, IL-13, and / or TNFα, to a culture of monocytes collected from peripheral blood. Alternatively, CD34-positive cells collected from peripheral blood, umbilical cord blood, or bone marrow may be differentiated into dendritic cells by adding to the culture medium a combination of GM-CSF, IL-3, TNFα, CD40 ligand, LPS, flt3 ligand, and / or one or more other compounds that induce dendritic cell differentiation, maturation, and proliferation.

[0212] Dendritic cells are conveniently classified as "immature" and "mature" cells, allowing for a convenient method of distinguishing between two well-characterized phenotypes. However, this nomenclature should not be interpreted as excluding all possible intermediate differentiation stages. Immature dendritic cells are characterized as APCs with high antigen uptake and processing capacity, which correlates with high expression of Fcγ receptors and mannose receptors. The mature phenotype is typically characterized by low expression of these markers but high expression of cell surface molecules involved in T cell activation, such as class I and class II MHC, adhesion molecules (e.g., CD54 and CD11), and costimulatory molecules (e.g., CD40, CD80, CD86, and 4-1BB).

[0213] APCs can generally be transfected with a polynucleotide encoding an antigenic polypeptide (or a portion or other variant thereof) so as to express the antigenic polypeptide, or an immunogenic portion thereof, on the cell surface. Such transfection can be performed ex vivo, and compositions or vaccines comprising such transfected cells and adjuvants described herein can then be used for therapeutic purposes. Alternatively, a gene delivery vehicle targeted to dendritic cells or other antigen-presenting cells can be administered to a patient, resulting in transfection occurring in vivo. For example, in vivo and ex vivo transfection of dendritic cells can be generally as described in WO 97 / 24447 or in Mahvi et al., Immunology and Cell This may be performed using any method known in the art, such as the gene gun technique described by [Biology 75:456-460, 1997]. Antigen loading of dendritic cells can be achieved by incubating dendritic cells or precursor cells with antigen polypeptides, DNA (naked or in a plasmid vector), or RNA; or with antigen-expressing recombinant bacteria or viruses (e.g., vaccinia, fowlpox, adenovirus, or lentivirus vectors). Prior to loading, the polypeptide may be covalently conjugated to an immunological partner (e.g., a carrier molecule) that provides T cell help. Alternatively, dendritic cells may be pulsed with an unconjugated immunological partner separately or in the presence of the polypeptide.

[0214] In one embodiment, a vaccine composition may contain liposomal vesicles containing a compound of Formula I. Liposomes are generally made of phospholipids or other lipid substances. Procedures for preparing liposomes are well known to those skilled in the art. Any lipid capable of forming vesicles containing a compound of Formula I can be used. For clinical applications, it is desirable that the lipid be non-toxic, physiologically acceptable, and metabolizable. Commonly used bilayer-forming lipids with clinical potential are phospholipids, fatty acids, sphingolipids, glycosphingolipids, and steroids. Glycerol-containing phospholipids are the most frequently used components of clinically useful liposome formulations. One commonly used example is phosphatidylcholine or lecithin. Steroid cholesterol and its derivatives are often included as components of the liposomal membrane. The aggregation and fusion tendencies of liposomes can be controlled by including small amounts of acidic or basic lipids in the formulation. The properties of phospholipid-containing liposomes depend on the chemistry of the phospholipid. Important considerations are the hydrocarbon chain length, the degree of unsaturation of the hydrocarbon chain, the degree of branching of the hydrocarbon chain, and the temperature of the system.

[0215] Multilamellar liposomes can be prepared by depositing a lipid mixture as a thin film by evaporation under reduced pressure, followed by dispersion in an excess amount of an aqueous buffer containing the antigen, with or without an organic solvent. Another method is to mix the antigen-containing aqueous phase with small unilamellar liposomes, followed by freeze-drying. The freeze-dried product is rehydrated, usually with a small amount of distilled water, to form multilamellar liposomes. Small unilamellar liposomes used in this method are prepared by dispersing lipids in an aqueous medium followed by mechanical dispersion means such as sonication, the use of a high-pressure device, or solvent injection. Large and intermediate-sized unilamellar liposomes can also be prepared by conventional techniques, including detergent dialysis, extrusion under high pressure through small-pore membranes, freeze-thawing followed by slow swelling, dehydration followed by rehydration and dilution, or dialysis of lipids in the presence of chaotropic ions. Liposome size can be made more uniform by fractionation procedures such as centrifugation or size exclusion chromatography, homogenization, or capillary pore membrane extrusion.

[0216] 4.How to use The disclosed compounds and compositions may be used in a variety of methods, including methods for modulating an immune response in a subject, methods for inducing or enhancing the immunogenicity of an antigen in a subject, and related methods. The disclosed compounds and compositions also find use in methods for treating cancer and related methods. The disclosed compounds and compositions may also be used in methods for the treatment and prevention of autoimmune disorders or infectious diseases.

[0217] Regulation of immune responses The disclosed compounds and compositions may be used in a method of modulating an immune response in a subject, the method comprising administering to the subject an effective amount of a compound described herein, an adjuvant composition described herein, or an immunomodulatory composition described herein.

[0218] In some embodiments, the disclosed compounds and compositions may be used in methods for inducing an enhanced immune response in a subject. In some embodiments, the enhanced immune response is a Th17-type immune response. In some embodiments, administration of the compounds or compositions may induce a Th17-type immune response, rather than a Th1-type or Th2-type immune response.

[0219] Enhanced immune responses may be induced by co-administering the compound or composition with an antigen. Suitable antigens include microbial pathogens, bacteria, viruses, proteins, glycoproteins, lipoproteins, peptides, glycopeptides, lipopeptides, toxoids, carbohydrates, and tumor-specific antigens. Mixtures of two or more antigens may also be used.

[0220] In some embodiments, the disclosed compounds and compositions may be administered as a monotherapy.

[0221] b. Induce or enhance the immunogenicity of an antigen The disclosed compounds and compositions may be used in a method of inducing or enhancing the immunogenicity of an antigen in a subject, the method comprising administering to the subject a vaccine composition comprising the antigen and an adjuvant composition comprising an effective amount of a compound or composition described herein.

[0222] Suitable antigens include microbial pathogens, bacteria, viruses, proteins, glycoproteins, lipoproteins, peptides, glycopeptides, lipopeptides, toxoids, carbohydrates, and tumor-specific antigens. Mixtures of two or more antigens may also be used.

[0223] c. Cancer treatment and related methods The disclosed compounds and compositions may be used in a method for treating cancer or reducing or inhibiting the proliferation of cancer cells, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein.

[0224] The method can be used on any cancer cells or in subjects with any type of cancer, such as those described by the National Cancer Institute. Exemplary cancers can include:

[0225] Digestive / gastrointestinal cancers, such as anal cancer; bile duct cancer; extrahepatic bile duct cancer; appendix cancer; carcinoid tumors, gastrointestinal cancer; colon cancer; colorectal cancer, including pediatric colorectal cancer; esophageal cancer, including pediatric esophageal cancer; gallbladder cancer; gastric cancer, including pediatric gastric cancer (stomach cancer); hepatocellular carcinoma, including adult (primary) hepatocellular carcinoma (liver cancer) and pediatric (primary) hepatocellular carcinoma (liver cancer); pancreatic cancer, including pediatric pancreatic cancer; sarcoma, rhabdomyosarcoma; islet cell pancreatic cancer; rectal cancer; and small intestine cancer, etc.;

[0226] Endocrine cancers, such as pancreatic islet cell carcinoma (endocrine pancreas); adrenocortical carcinoma, including pediatric adrenocortical carcinoma; gastrointestinal carcinoid tumors; parathyroid carcinoma; pheochromocytoma; pituitary tumors; thyroid carcinoma, including pediatric thyroid carcinoma Adenocarcinoma; childhood multiple endocrine neoplasia syndrome; and childhood carcinoid tumors;

[0227] Eye cancers, such as intraocular melanoma and retinoblastoma;

[0228] Musculoskeletal cancers, such as Ewing's family of tumors; osteosarcoma / malignant fibrous histiocytoma of bone; pediatric rhabdomyosarcoma; soft tissue sarcomas, including adult and pediatric soft tissue sarcomas; clear cell sarcoma of the tendon sheath; and uterine sarcoma;

[0229] Breast cancer, including childhood and male breast cancer and breast cancer during pregnancy;

[0230] Neurological cancers, such as pediatric brain stem glioma; brain tumor; pediatric cerebellar astrocytoma; pediatric cerebral astrocytoma / malignant glioma; pediatric ependymoma; pediatric medulloblastoma; pediatric pineal and supratentorial primitive neuroectodermal tumor; pediatric visual pathway and hypothalamic glioma; other pediatric brain cancer; adrenocortical carcinoma; central nervous system lymphoma, primary; pediatric cerebellar astrocytoma; neuroblastoma; craniopharyngioma; spinal cord tumor; central nervous system atypical teratoid / rhabdoid tumor; central nervous system embryonal tumor; and pediatric supratentorial primitive neuroectodermal tumor and pituitary tumor;

[0231] Genitourinary cancers, such as bladder cancer, including pediatric bladder cancer; renal cell carcinoma (kidney cancer); ovarian cancer, including pediatric ovarian cancer; ovarian epithelial cancer; ovarian low malignant potential tumor; penile cancer; prostate cancer; renal cell carcinoma, including pediatric renal cell carcinoma; renal pelvis and ureter, transitional cell carcinoma; testicular cancer; urethral cancer; vaginal cancer; vulvar cancer; cervical cancer; Wilms' tumor and other pediatric kidney tumors; endometrial cancer; and gestational trophoblastic tumor; germ cell cancers, such as pediatric extracranial germ cell tumors; extragonadal germ cell tumors; ovarian germ cell tumors;

[0232] Head and neck cancers, such as lip and oral cavity cancer; oral cavity cancer, including pediatric oral cavity cancer; hypopharyngeal cancer; laryngeal cancer, including pediatric laryngeal cancer; metastatic squamous cell carcinoma of the neck of unknown primary; oral cavity cancer; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer, including pediatric nasopharyngeal cancer; oropharyngeal cancer; parathyroid cancer; pharyngeal cancer; salivary gland cancer, including pediatric salivary gland cancer; throat cancer; and thyroid cancer;

[0233] blood cancers / blood cell cancers, such as leukemias (e.g., acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia; acute myeloid leukemia, including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia; chronic myelocytic leukemia; and hairy cell leukemia); lymphomas (e.g., AIDS-related lymphoma; cutaneous T-cell lymphoma; Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy; non-Hodgkin's lymphoma, including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma in pregnancy; mycosis fungoides; Sézary syndrome; Waldenstrom's macroglobulinemia; and primary central nervous system lymphoma); and other blood cancers (e.g., chronic myeloproliferative disorders; multiple myeloma / plasma cell neoplasms; myelodysplastic syndromes; and myelodysplastic / myeloproliferative disorders).

[0234] Lung cancer, such as non-small cell lung cancer and small cell lung cancer;

[0235] Respiratory cancers, such as adult malignant mesothelioma; pediatric malignant mesothelioma; malignant thymoma; pediatric thymoma; thymic carcinoma; bronchial adenoma / carcinoid, including pediatric bronchial adenoma / carcinoid; pleuropulmonary blastoma; non-small cell lung carcinoma; and small cell lung carcinoma;

[0236] Skin cancers, such as Kaposi's sarcoma; Merkel cell carcinoma; melanoma; and childhood skin cancers;

[0237] AIDS-related malignancies;

[0238] Other childhood cancers, rare childhood cancers, and cancers of unknown primary site; and

[0239] The aforementioned metastasis of cancer.

[0240] 5. Kit In one aspect, the disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof; (a) at least one antigen; and (b) instructions for administering the compound or composition; and one or more of:

[0241] In some embodiments, at least one disclosed compound and at least one antigen are co-formulated. In some embodiments, at least one disclosed compound and at least one antigen are co-packaged. The kits can also include compounds and / or products that are packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, doctor, pharmacy, or pharmacist can provide a kit that includes a disclosed compound and / or product and another component for delivery to a patient.

[0242] The disclosed kits can be used in conjunction with the disclosed methods of use.

[0243] The kits may further include information, instructions, or both, that use of the kit will result in increased immunity to a particular pathogen in a mammal (especially a human). The information and instructions may be in the form of words, pictures, or both. Additionally or alternatively, the kits may include the compound, composition, or both; and information, instructions, or both regarding how to administer the compound or composition, preferably with benefit in treating or preventing a medical condition in a mammal (e.g., a human).

[0244] The compounds and methods of the present disclosure may be better understood by reference to the following examples, which are intended to be illustrative, but not limiting, of the scope of the disclosure. [Example]

[0245] 6. Working Example Abbreviations used in the following schemes and examples are as follows: Ar is aryl; Bu is butyl; DBU is 1,8-diazabicyclo(5.4.0)undec-7-ene; DCC is N,N'-dicyclohexylcarbodiimide; DIAD is diisopropyl azodicarboxylate; DMSO is dimethyl sulfoxide; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et is ethyl; EtOH is ethanol; IPA is isopropyl alcohol; i-Pro is isopropyl; Me is methyl; MeOH is methanol; MTBE is methyl tert-butyl ether; PP h3 is triphenylphosphine; PPTS is pyridinium p-toluenesulfonate; TBAF is tetra-n-butylammonium fluoride; TBS is tert-butyldimethylsilyl or tert-butyldimethylsilane; TBSCl is tert-butyldimethylsilyl chloride; TBTU is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; tBu is tert-butyl; tBuOH is tert-butanol; THF is tetrahydrofuran; TLC is thin layer chromatography; and TMS is tetramethylsilyl or tetramethylsilane.

[0246] Example 1. Exemplary Benzoic Acid Synthesis Certain benzoic acids are commercially available, while others require esterification, acetalization, etc., as shown below. It may be synthesized using tertiarylation and deprotection procedures. [ka]

[0247] [Table 1]

[0248] Another highly functionalized benzoic acid was prepared through the acid-catalyzed dehydrative alkylation of t-butanol with 2,6-dihydroxybenzoic acid as shown below. [ka]

[0249] Example 2. Synthesis of compound UM1024 under Mitsunobu conditions [ka] 2,3,4,2',3',4'-Hexakis-O-trimethylsilyl-α,α-trehalose (prepared as described by Johnson et al. J. Carbohydr. Chem. 17(6), 969-974 (1998)) (230 mg, 0.39 mmol) and triphenylphosphine (276 mg, 1.05 mmol) were dissolved in methylene chloride (10 mL) with magnetic stirring under a nitrogen atmosphere, and the solution was cooled to 0-5°C in an ice bath. Diisopropyl azodicarboxylate (0.19 mL, 0.947 mmol) was added, and the reaction was stirred for 10 minutes. 3,5-Di-tert-butylsalicylic acid (167 mg, 0.648 mmol) was added, and the reaction was monitored by TLC. After 2 hours, the reaction The reaction mixture was quenched with cold water and extracted with methylene chloride. The combined organics were dried over sodium sulfate, filtered, concentrated, and the product was separated by silica gel chromatography using a heptane to ethyl acetate gradient to yield 33.9 g (9%) of 2,3,4,2',3',4'-hexakis-O-trimethylsilyl-6,6'-bis-(3,5-di-tert-butylsalisate)-α,α-trehalose. H NMR spectral data were recorded on an Agilent 400 MHz instrument, and high-resolution mass spectra were obtained on either an Agilent 6220 time-of-flight mass spectrometer (TOF-MS) or an Agilent 6520 time-of-flight quadrupole mass spectrometer (QTOF-MS).

[0250] 2,3,4,2',3',4'-Hexakis-O-trimethylsilyl-6,6'-bis-(3,5-di-tert-butylsalisate)-α,α-trehalose was dissolved in methylene chloride (10 mL) and methanol (10 mL) and treated with Dowex 50w X8 resin for 20 minutes with magnetic stirring. The resin was removed by filtration, the filtrate was concentrated, and the product was separated by silica gel chromatography using a chloroform to methanol gradient to yield 146 mg (48%) of 6,6'-bis-(3,5-di-tert-butylsalisate)-α,α-trehalose (UM1024).

[0251] The compound 6,6'-bis-(3,5-di-isopropylsalisate)-α,α-trehalose (UM1023) was prepared similarly (coupling yield 74.3 mg, 16).

[0252] Example 3. Synthesis of UM1024 by SN2 substitution [ka] 2,3,4,2',3',4'-Hexakis-O-trimethylsilyl-α,α-trehalose (prepared as described by Johnson et al. J. Carbohydr. Chem. 17(6), 969-974 (1998)) (385 mg, 0.50 mmol) was dissolved in methylene chloride (10 mL). Pyridine (0.25 mL, 3.1 mmol) was added with magnetic stirring under a nitrogen atmosphere, and the solution was cooled to 0-5°C in an ice bath. Trifluoromethanesulfonic anhydride was added, and the reaction was stirred for 1.5 hours. The reaction was washed with dilute hydrochloric acid, aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. 3,5-Di-tert-butylsalicylic acid (363 mg, 1.26 mmol) was treated with potassium trimethylsilanolate, and the potassium salt was precipitated with ether and dried. The crude trehalose intermediate was dissolved in toluene (15 mL) and combined with the aryl potassium salt, 18-crown-6 (132 mg, 0.50 mmol). The reaction was heated to 80° C. and monitored by TLC until the starting trehalose intermediate was consumed. The reaction was washed with aqueous sodium bicarbonate, dried over sodium sulfate, concentrated, and the product was isolated by silica gel chromatography using a heptane to ethyl acetate gradient to give 524 mg (85%) of 2,3,4,2',3',4'-hexakis-O -trimethylsilyl-6,6'-bis-(3,5-di-tert-butylsalisate)-α,α-trehalose was obtained. This product was deprotected as described in Example 2 to give 6,6'-bis-(3,5-di-tert-butylsalisate)-α,α-trehalose (UM1024).

[0253] Example 4. Synthesis of UM1015 by coupling reaction [ka] 2,3,4,2',3',4'-Hexakis-O-trimethylsilyl-α,α-trehalose (prepared as described by Johnson et al. J. Carbohydr. Chem. 17(6), 969-974 (1998)) (412 mg, 0.53 mmol), 3,5-diethoxybenzoic acid (276 mg, 1.31 mmol), and 4-(dimethylamino)pyridinium 4-toluenesulfonate (77 mg, 0.26 mmol) were dissolved in THF (10 mL) with magnetic stirring, and the solution was cooled to 0-5°C in an ice bath. DCC was added, and the reaction was allowed to warm to ambient temperature and stirred until the starting trehalose intermediate was consumed, as determined by TLC. The crude reaction mixture was purified by silica gel chromatography with a heptane to ethyl acetate gradient to yield 366 mg (60%) of 2,3,4,2',3',4'-hexakis-O-trimethylsilyl-6,6'-bis-(3,5-dimethoxybenzoate)-α,α-trehalose, which was deprotected similarly to the deprotection described in Example 2 to give 6,6'-bis-(3,5-dimethoxybenzoate)-α,α-trehalose (compound UM1015).

[0254] The compounds in Table 1 were prepared similarly to UM1015 using the appropriate phenol for the coupling reaction.

[0255] [Table 2]

[0256] Example 5. Synthesis of compounds containing lipidated benzoic acid Similar to that described in Example 1, lipidated benzoic acids may be synthesized using esterification, etherification, and deprotection procedures as shown below. [ka]

[0257] A solution of silylated trehalose (1 mmol, 1 equiv.) in dichloromethane was added to the solution of acid (3 m mol, 3 equiv.), EDCI-MeI (4 mmol, 4 equiv.), and DMAP (0.15 mmol, 0.15 equiv.) were added. The reaction was stirred overnight at room temperature and filtered. The filtrate was washed with cold dichloromethane. The combined layers were then washed with water and then brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (eluent: heptane: EtOAc 2:8 to 3:7).

[0258] Other coupling reactants were also used for the esterification: DCC (3.5 equivalents) / PPTS (0.4 equivalents) and DCC (3 equivalents) / DMAP (0.4 equivalents). These were optimized, and it was found that increasing the DMAP significantly increased the reaction yield. The product was deprotected in a manner similar to the deprotection described in Example 2.

[0259] [Table 3]

[0260] Example 6. Synthesis of amide-linked aryl and alkyl trehalose compounds [ka] i)TrCl,Py,40℃,16hr;ii)PhCOCl,0℃~rt,10hr;iii)TsOH-H2O,CH2Cl2 / MeOH(1:1),rt,12h r;iv)MsCl,Et3N,CH2Cl2,0℃,2hr;v)NaN3,DMF,65℃,14hr;vi)H2,Pd-C,EtOH / AcOH(1 / 2),1 M HCl,rt,28hr;vii);Acid,HATU,Et3N,CH2Cl2;0℃,4hr;viii)30% MeONa / MeOH,rt,5hr. 2,3,4,2',3',4'-Hexakis-O-benzoyl-α,α-trehalose (prepared as described in Chem Biol Drug Des 2015, 86(5), 1017-29) was combined with the acid (3 equivalents), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3 equivalents) and triethylamine (3 equivalents) in anhydrous dichloromethane at 0°C. The reaction was stirred at 0°C for 2 hours and then diluted with dichloromethane. The organic layer was washed with water and then brine and dried over magnesium sulfate. The crude product was purified by column chromatography (heptane: EtOAc 2:8 → 1:1).

[0261] Example 7. Synthesis of amide-linked aryl and alkyl trehalose compounds [ka] Solid sodium bicarbonate (2 equivalents) was added to a solution of trehaloseamine dihydrochloride (1 equivalent) in methanol. After stirring for 5 minutes, dichloromethane was added and the mixture was evaporated at room temperature. The addition and evaporation of dichloromethane aided in the complete removal of methanol. A solution of the residue in dry dichloromethane was treated with triethylamine (3.0 equivalents), followed by a substituted sulfonyl chloride (2.4 equivalents) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and then water again. The organic layer was concentrated in vacuo and purified by chromatography eluting with (99:1) dichloromethane-methanol to give the desired product.

[0262] Example 8. Biological activity A. Cytokine responses of compound-treated peripheral blood mononuclear cells (PBMCs). Tumor necrosis factor α (TNFα) and IL-6 production in peripheral blood mononuclear cells (PBMCs) were measured after exposure to various concentrations of DAT compounds synthesized as described above. Initial studies focused on two different methods of delivering DAT compounds to PBMC cultures. In the first delivery method, the indicated derivative compounds were dissolved in isopropanol, serially diluted, and then allowed to dry on the bottom of tissue culture plates. In the second delivery method, the indicated derivative compounds were dissolved in DMSO and serially diluted in tissue culture medium. For each method, compounds were added to PBMCs and incubated at 37°C. TNFα (Figure 1A) and IL-6 (Figure 1B) were measured by ELISA assay 18–24 h after treatment.

[0263] B. Cytokine analysis of supernatants of freshly prepared PBMCs after stimulation Supernatants from freshly prepared PBMCs stimulated with DMSO-solubilized DAT compounds (Example 5A) were analyzed for cytokines that help drive Th1 or Th17 adaptive immune responses: IFNγ, IL-12 p70, IL-6, IL-1β, and IL-23. Immunoassay results for IL-6, IL-1β, IL-23, and TNFα are shown in Figure 2. Minimal amounts of IL-12p70 were detected, and IFNγ was undetectable; therefore, neither is reported. The TNFα response from Example 5A was confirmed for the higher-responding compounds (UM1009, UM1015, UM1017, UM1019, UM1020, UM1021, UM1022, UM1023, and UM1024).

[0264] C. IL-6 induction in fresh human PBMCs The most active compounds were screened for IL-6 levels in fresh PBMCs from multiple donors as indicated in Figure 3. Isolated PBMCs were exposed to increasing concentrations of the indicated compounds, resuspended in DMSO and serially diluted in culture medium. IL-6 levels were determined from the supernatant 18 hours after treatment (Figure 3).

[0265] Compound UM1024 was the most potent compound for cytokine induction from human PBMCs, demonstrating a >1000-fold higher potency (EC50) than the other compounds. Compound 1023, which possesses an isopropyl group, exhibited lower activity, suggesting that the tert-butyl side chain of the aryl group is largely responsible for UM1024's potency. Compound UM1015 demonstrated potent and robust activity in only three of five donors (1, 20, and 15), suggesting high donor-to-donor variability for this compound. Similar structures, such as the 1014 dimethyl aryl ether, were inactive. These data indicate that the length or number of carbons and the aryl substitution pattern at that position are important for biological activity.

[0266] Compound UM1022, a dimethoxy derivative, reproducibly induced potent and robust IL-6 production. Compound UM1021, which contained a linker between the trehalose and aryl groups, induced some cytokine production, although at significantly reduced absolute levels. This suggests that π-π interactions of essential phenylalanines proximal to the proposed binding site may be important for the observed activity.

[0267] D. Signaling response of HEK-Blue™ Mincle reporter cells to compounds Compounds were also tested in the commercially available reporter Hek-Blue™ cell line. Hek-Blue™ cells were treated with increasing concentrations of the indicated compounds for 18 to 24 hours. Separated supernatants were measured for NF-κB secreted embryonic alkaline phosphatase (SEAP) production using QUANTI-Blue™ reagent (Figure 4A). SEAP production was robust in both mouse and human reporter lines (Figure 4A), indicating strong signaling through the Mincle receptor in both human and mouse systems.

[0268] In mouse reporter cell lines, UM1024 exhibited a characteristically high peak at low compound concentrations (Fig. 4A). Unlike the cytokine profile observed in PBMCs, UM1024 did not exhibit a significant leftward potency shift compared to the other compounds.

[0269] E. TNFα induction in mouse macrophage cells The compounds were also tested in a mouse macrophage cell line (Figure 4B). RAW264.7 cells were exposed to increasing concentrations of the compounds and evaluated for cytokine TNFα production. Many compounds were able to stimulate cytokine production from mouse cells, suggesting they are active in this species, although the overall levels and potency were significantly reduced compared to human cells.

[0270] [Table 4]

[0271] [Table 5]

[0272] [Table 6]

[0273] [Table 7]

[0274] F. Formulations and Immune Responses Liposomal formulations were prepared for in vitro and in vivo evaluation of the compounds. In these formulations, the lipid-to-adjuvant molar ratio was kept constant at 89:11, respectively, resulting in a lipid concentration of 11.174 μmol / mL. The lipid film was rehydrated in 10 mM Tris buffer at pH 7.4. The liposome formulations were prepared with 1 mole percent of a fluorescent lipid dye, N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE). This dye is incorporated into the lipid bilayer of the liposomes, allowing visualization of cell types by flow cell cytometry. The final formulations were sterile filtered using a two-stage 0.8 / 0.2 μm PES syringe filter.

[0275] Formulations were characterized by dynamic light scattering (DLS) for particle size analysis, and adjuvant concentration was quantified by ultraviolet absorbance for UM1024. Liposome formulations containing DDA required brief sonication for 10–15 min at 50°C to achieve a uniform suspension. No significant effect on particle size, zeta potential, or PDI values was observed in adjuvant-containing formulations compared with their blank formulations at neutral pH.

[0276] A second set of liposome formulations was made to compare UM1024 and TDB at a DDA:DSPC:adjuvant molar ratio of 22:67:11. The lipid concentration in these formulations was 8.38 mg / mL, while the adjuvant concentration varied proportionally to its molecular weight.

[0277] The compound UM1024 in a liposomal formulation was tested in vivo to determine its ability to promote humoral and cell-mediated immune responses to the Mycobacteria tuberculosis (Mtb) vaccine antigen M72. M72 is a recombinant protein that combines sequences from two mycobacterial proteins, Mtb32a and Mtb39a, expressed in BCG and M. tuberculosis strains; these sequences are expressed in human CD4 + and CD8 +It contains T cell epitopes and is highly conserved across 45 Mycobacterial strains, including multidrug-resistant and extensively multidrug-resistant strains, and covering every lineage tested to date.

[0278] Balb / c mice were immunized intramuscularly (i.m.) with 0.125 μg M72 and various doses of different CLR adjuvant candidates (Table 3) in liposomal formulations. The vaccination timeline was shown in Figure 5A. On day 19 (5 days after the secondary immunization), three mice per group were euthanized. T cell restimulation assays using spleens and intracellular cytokine staining were used to visualize antigen-specific CD4 and CD8 effector T cells, as defined by their production of IFNγ (Th1), IL-5 (Th2), or IL-17 (Th17).

[0279] [Table 8]

[0280] In a follow-up mouse study, animals were intramuscularly injected twice, 14 days apart, with a higher dose of 1 μg of M72 antigen combined with a single dose of 10 nmol of adjuvant. 14 days after the second injection, blood was collected, serum was separated, and anti-M72 antibody (subtypes IgG1 and IgG2a) levels were determined (Figure 5B). Responses were compared to naive mice, M72 antigen alone, and blank liposomes (no CLR compound added) containing M72 antigen.

[0281] Splenocytes from harvested spleens were restimulated with M72 antigen to determine CD4+ and CD8+ T cell responses to the various vaccines. Responses were compared to naive mice, M72 antigen alone, and M72 antigen in empty liposomes (no CLR compound added). UM1024 in liposomes elicited high levels of antigen-specific CD4+ and CD8+ T cell responses by intracellular cytokine staining. TDB induced CD4+ and CD8+ IL17A-producing cells, indicating a Th17 response (Figure 6A). Restimulation of splenocytes from mice vaccinated with the highest dose of TDB induced some IL-17A. The induction of antigen-specific Th17 cells, as indicated by increased IL17A responses, was important because Th17 cells confer protection against Mtb in mice after immunization.

[0282] IL-5 production, an indicator of a Th2 response, was observed in restimulated cells from mice that received the UM-1024-adjuvanted vaccine (Fig. 6B). However, because the Balb / c mouse strain is known to be Th2-biased, it is difficult to say whether this reflects further Th2 polarization in response to the UM-1024 adjuvant or whether it is a by-product of increased immune activation in a Th2-biased mouse strain.

[0283] IFNγ production was not increased above the level in naive mice in any of the vaccinated groups, suggesting that a Th1 response was not induced. TNFα production was increased in the groups adjuvanted with higher doses of UM-1024 compared with controls, and IL-2 production was modestly increased in most adjuvanted groups, except for the 10 nmol UM-1024 group, where IL-2 production was substantially increased compared with controls (Fig. 6C).

[0284] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limitations on the scope of the present disclosure, which is defined solely by the appended claims and their equivalents.

[0285] For reasons of completeness, the various aspects of the invention are set out in the following numbered clauses.

[0286] Clause 1. A compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof [wherein: L 1 is -OH or -X(CR 1a R 1a’ ) m O p Ar 1 and; L 2 HA-Y(CR 2a R 2a’ ) n O q Ar 2 and; X and Y each independently represent -OC(O)-, -NR a C(O)-, -NR b C(S)-, -NR c -,-SO2NR c -, -O-, and -OC(O)CH=CH-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 1a , R 1a’ , R 2a and R 2a’ are, if present, each independently selected from hydrogen and C1-C4 alkyl; p is 0 or 1; q is 0 or 1; Ar 1 and Ar 2 are each independently selected from aryl or heteroaryl, where each aryl or heteroaryl is independently selected from hydrogen, C1-C 12 Alkyl, hydroxy, C1-C 12 Alkoxy, halo, C1-C4 haloalkyl, Ar 3 , C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, -NH-Ar 4 , C1-C8 alkoxy-Ar 5, C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or these substituents, together with the atoms to which they are attached, optionally join to form an aryl ring; wherein each heteroaryl optionally contains 1, 2, 3, 4, or 5 heteroatoms selected from O, S, or N; Ar 3 , Ar 4 and Ar 5 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; and where 6,6'-bis(2-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(benzoylamino)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(4-benzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-dichlorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,3-dibenzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-benzyloxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methyl-6-aminobenzoyl)-α,α-D-trehalose, 6,6'-bis(3-methoxy-4-fluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dimethoxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-heptyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(cinnamoylamino)-α,α-D-trehalose, 6,6'-bis(3,4-dimethoxycinnamoylamino)-α,α-D-trehalose, 6,6'-bis(isonicotinoylamino)-α,α-D-trehalose, or 6,6'-Bis(pyrazine-2-carbonylamino)-α,α-D-trehalose Not a compound.

[0287] Clause 2. A compound of clause 1, or a pharmaceutical salt thereof, wherein p and q are 0.

[0288] Close 3. L 1 but, [ka] and; m is 0, 1 or 2; R 1a and R 1a’ are, if present, independently selected from hydrogen and C1-C4 alkyl; and R 2a , R 3a , R 4a , R 5a , and R 6a are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12A compound of clause 1 or 2 selected from alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, arylamino, C1-C8 alkoxy-aryl, C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or together with the atoms to which they are attached, optionally joined to form an aryl ring, or a pharmaceutical salt thereof.

[0289] Crows 4. R 1a’ A compound of any of clauses 1 to 3, or a pharmaceutical salt thereof, wherein, if present, is hydrogen.

[0290] Close 5. R 2a , R 3a , R 4a , R 5a , and R 6a are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl; where R 3a and R 4a optionally taken together with the carbon atom to which they are attached form an aryl ring, or a pharmaceutical salt thereof.

[0291] Close 6. L 2 but, [ka] and; n is 0, 1 or 2; R 1b and R 1b’ are, if present, independently selected from hydrogen and C1-C4 alkyl; and R 2b , R 3b , R 4b , R5b , and R 6b are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12 A compound of any of clauses 1-5 selected from alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, hydroxy-C1-C8 alkyl, amino, nitro, arylamino, C1-C8 alkoxy-aryl, C1-C8 alkylsulfonyl, and C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkoxy, or together with the atoms to which they are attached, optionally joined to form an aryl ring, or a pharmaceutical salt thereof.

[0292] Crows 7. R 1b’ A compound of any of clauses 1 to 6, or a pharmaceutical salt thereof, wherein, if present, is hydrogen.

[0293] Crows 8. R 2b , R 3b , R 4b , R 5b , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl; where R 3b and R 4b optionally taken together with the carbon atom to which they are attached form an aryl ring, or a pharmaceutical salt thereof.

[0294] Close 9. Compounds of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof [wherein: X and Y each independently represent -OC(O)- and -NR a C(O)-; Ra are independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 1a , R 1a’ , R 1b and R 1b’ are, if present, each hydrogen; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, and hydroxy.

[0295] Crows 10. R 2a , R 3a , R 4a , R 5a , and R 6a At least one of R is C1-C8 alkyl, 2b , R 3b , R 4b , R 5b , and R 6b or a pharmaceutically acceptable salt thereof.

[0296] Close 11. R 3a , R 3b , R 5a , and R 5b or a pharmaceutically acceptable salt thereof.

[0297] Clause 12. The compound of clause 11, or a pharmaceutically acceptable salt thereof, wherein C1-C8 alkyl is isopropyl, tert-butyl, methyl, or ethyl.

[0298] Clause 13. The compound of clause 12, or a pharmaceutically acceptable salt thereof, wherein C1-C8 alkyl is tert-butyl.

[0299] Close 14. R 2a , R 2b , R 4a , R 4b , R 6a , R 6b is each independently hydroxy or hydrogen, or a pharmaceutically acceptable salt thereof.

[0300] Close 15. R 2a and R 2b and R are each hydroxy, or a pharmaceutically acceptable salt thereof.

[0301] Close 16. R 4a and R 4b and R are each hydroxy, or a pharmaceutically acceptable salt thereof.

[0302] Close 17. R 2a , R 2b , R 6a , and R 6b is methyl, or a pharmaceutically acceptable salt thereof.

[0303] Close 18. R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b is each independently hydrogen or C1-C8 alkyl, or a pharmaceutically acceptable salt thereof.

[0304] Clause 19. The compound of clause 18, or a pharmaceutically acceptable salt thereof, wherein C1-C8 alkyl is methyl or tert-butyl.

[0305] Clause 20. A compound of any one of clauses 9 to 19, or a pharmaceutically acceptable salt thereof, wherein m and n are 0.

[0306] Close 21. Compounds of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof [wherein: X and Y each independently represent -OC(O)- and -NR a C(O)-; R a are independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently hydrogen, C1 to C 12 Alkyl, hydroxy, C1-C 12 Alkoxy, C1-C4 haloalkyl, Ar 3 and -NH-Ar 4 or optionally taken together with the atom to which they are attached form an aryl ring; Ar 3 , Ar 4 and Ar 5 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0307] Crows 22. R 3a , R 3b , R 5a , and R 5b and each is C1-C5 alkoxy, or a pharmaceutically acceptable salt thereof.

[0308] Crows 23. R 2a , R2b , R 4a , R 4b , R 6a , and R 6b and each are hydrogen, or a pharmaceutically acceptable salt thereof.

[0309] Crows 24. R 4a and R 4b and each is C1-C5 alkoxy, or a pharmaceutically acceptable salt thereof.

[0310] Crows 25. R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b and each is ethoxy, or a pharmaceutically acceptable salt thereof.

[0311] Crows 26. R 2a , R 2b , R 6a and R 6b A compound of claimuse 24, or a pharmaceutically acceptable salt thereof, wherein each of is hydrogen.

[0312] Crows 27. R 2a and R 2b or a pharmaceutically acceptable salt thereof.

[0313] Crows 28. R 3a , R 4a , R 5a , and R 6a At least one of R is C1-C8 alkyl, 3b , R 4b , R 5b , and R 6b or a pharmaceutically acceptable salt thereof.

[0314] Clause 29. The compound of clause 28, or a pharmaceutically acceptable salt thereof, wherein C1-C8 alkyl is tert-butyl.

[0315] Crows 30. R 2a , R 3a , R 4a , R 5a , and R 6a At least one of R is C1-C4 haloalkyl; 2b , R 3b , R 4b , R 5b , and R 6b or a pharmaceutically acceptable salt thereof.

[0316] Crows 31. R 2a and R 2b and each is C1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0317] Crows 32. R 3a , R 3b , R 5a , and R 5b A compound of clause 31, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

[0318] Crows 33. R 6a and R 6b and R are each hydrogen or C1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0319] Crows 34. R 4a and R 4b and each are hydrogen or C1-C4 alkoxy, or a pharmaceutically acceptable salt thereof.

[0320] Clause 35. The compound of clause 34, or a pharmaceutically acceptable salt thereof, wherein C1-C4 alkoxy is methoxy.

[0321] Clasue 36. R 3a and R 3b and each is C1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0322] Close 37. R 5a and R 5b and R are each hydrogen or C1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0323] Close 38. R 2a , and R 2b and R are each hydrogen or hydroxy, or a pharmaceutically acceptable salt thereof.

[0324] Clasue 39. R 4a , R 4b , R 6a , and R 6b However, each 2. The compound of clause 38, or a pharmaceutically acceptable salt thereof.

[0325] Crows 40. R 5a and R 5b and each is C1-C4 alkoxy, or a pharmaceutically acceptable salt thereof.

[0326] Clause 41. The compound of clause 40, or a pharmaceutically acceptable salt thereof, wherein C1-C4 alkoxy is methoxy.

[0327] Close 42. R 3a , R 3b , R 4a , R 4b , R 6a , and R 6b is hydrogen, or a pharmaceutically acceptable salt thereof.

[0328] Clause 43. The compound of clauses 30 to 42, or a pharmaceutically acceptable salt thereof, wherein C1-C4 haloalkyl is trifluoromethyl.

[0329] Close 44. R 6a and R 6b are each hydrogen; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently hydrogen, hydroxy, Ar 3 and -NH-Ar 4 is selected from, where R 2a , R 3a , R 4a , and R 5a At least one of them is Ar 3 or -NH-Ar 4 and R 2b , R 3b , R 4b , and R 5b At least one of them is Ar 3 or -NH-Ar 4 and Ar 3 and Ar 4 are each independently selected from aryl or heteroaryl that are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0330] Crows 45. Ar 3 and Ar 4 is phenyl unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, alkoxy, C1-C4 alkyl, and hydroxy-C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0331] Clause 46. The compound of clause 45, or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with one substituent selected from methyl, hydroxy, and hydroxymethyl.

[0332] Crows 47. R 2a , R 3a , R 4a , and R 5a At least one of R is hydroxy; 2b , R 3b , R 4b , and R 5b or a pharmaceutically acceptable salt thereof.

[0333] Crows 48. R 3a , R 4a , and R 5a At least two of them are C5-C 12 is alkoxy, and R 3b , R 4b , and R 5b At least two of them are C5-C 12 is alkoxy, and R 2a , R 2b , R 6a , and R 6b and each are hydrogen, or a pharmaceutically acceptable salt thereof.

[0334] Close 49. R 3a , R 3b , R 5a , and R 5b However, each is C5~C 12 The compound of clause 48, or a pharmaceutically acceptable salt thereof, wherein:

[0335] Crows 50. R 4a and R 4b However, each is C5~C 12 A compound of clause 49, or a pharmaceutically acceptable salt thereof, wherein:

[0336] Clause 51. 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, 6,6'-bis(3,5-dipentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-triethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoylamino)-α,α-D-trehalose, 6,6'-bis(2,6-hydroxy-3,5-di-tert-butylbenzoylamino)-α,α-D-trehalose, a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0337] Close 52. A compound which is 6,6-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0338] Close 53. A compound which is 6,6-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0339] Clause 54. An adjuvant composition comprising an effective amount of any one of the compounds of clauses 1 to 53, or a pharmaceutically acceptable salt thereof.

[0340] Clause 55. A method for inducing an enhanced immune response in a subject, comprising administering to the subject the adjuvant composition of clause 54.

[0341] Clause 56. A vaccine composition comprising: (a) an antigen; and (b) an adjuvant composition comprising an effective amount of any one of the compounds of Clauses 1 to 53, or a pharmaceutically acceptable salt thereof.

[0342] Clause 57. A method for inducing or enhancing the immunogenicity of an antigen in a subject, comprising administering to the subject a vaccine composition comprising the antigen and an adjuvant composition containing an effective amount of any one of the compounds of Clauses 1 to 53, or a pharmaceutically acceptable salt thereof.

[0343] Clause 58. An immunomodulatory composition comprising an effective amount of any one of the compounds of clauses 1 to 53, or a pharmaceutically acceptable salt thereof.

[0344] Clause 59. A method for modulating an immune response in a subject, comprising administering to the subject the immunomodulatory composition of clause 58.

[0345] Clause 60. The method of clause 59, wherein the immunomodulatory composition is administered as monotherapy.

[0346] Clause 61. The method of clause 59 or clause 60, wherein the subject's immune response is increased.

[0347] Clause 62. Any one of the methods of clauses 59 to 61, wherein the subject is suffering from cancer, an autoimmune disorder, or an infectious disease.

[0348] Close 63. Compound of formula (II) [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0, 1 or 2; n is 0, 1 or 2; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1bare, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl; where R 3a and R 4a together with the carbon atoms to which they are attached optionally together form an aryl ring; where R 3b and R 4b together with the carbon atoms to which they are attached optionally together form an aryl ring; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; and where 6,6'-bis(2-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-hydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-benzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-difluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,6-dichlorobenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,3-dibenzyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-benzyloxy-3-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-methyl-6-aminobenzoyl)-α,α-D-trehalose, 6,6'-bis(3-methoxy-4-fluorobenzoyl)-α,α-D-trehalose, 6,6'-bis(3,4,5-trimethoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2,4-dimethoxy-6-methylbenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-heptyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-n-pentyloxybenzoyl)-α,α-D-trehalose, 6,6'-bis(2-hydroxy-4-methoxybenzoyl)-α,α-D-trehalose, 6,6'-bis(4-n-pentyloxybenzoyl)-α,α-D-trehalose, or 6,6'-bis(2,4-dihydroxy-6-methylbenzoyl)-α,α-D-trehalose Not a compound.

[0349] Crows 64. R 3a , R3b , R 5a , and R 5b and each is C2-C8 alkoxy.

[0350] Clause 65. The compound of clause 64, in which the C2-C8 alkoxy is ethoxy.

[0351] Crows 66. R 2a , R 2b , R 4a , R 4b , R 6a , and R 6b Compounds of clause 63 or clause 64, wherein is hydrogen.

[0352] Crows 67. R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , and R 6a and at least one of R 6b The compound of clause 63 is tert-butyl.

[0353] Crows 68. R 3a , R 3b , R 5a , and R 5b The compound of clause 67, in which each is tert-butyl.

[0354] Crows 69. R 2a and R 2b The compound of clause 68, in which each is hydroxy.

[0355] Crows 70. R 4a , R 4b , R 6a , and R 6b A compound of any one of clauses 67 to 69, wherein each of is hydrogen.

[0356] Clause 71. A compound of any one of clauses 63 to 70, wherein m is 0 and n is 0.

[0357] Clause 72. The compound of any one of clauses 63 to 71, wherein X and Y are each —C(O)O—.

[0358] Close 73. Compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0, 1 or 2; n is 0, 1 or 2; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 6a and R 6b are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and C1-C4 alkoxy; R 4a and R 4b is hydrogen; and R 3a , R 3b , R 5a , and R 5b are each independently selected from C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0359] Clause 74. Each n is 0; R 2a and R 2b are each independently hydrogen or hydroxy; R 3a and R 3b are each independently selected from C1-C8 alkyl, hydroxy, C2-C8 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, and C1-C4 haloalkyl; R 5a and R 5b are each independently selected from C1-C8 alkyl, hydroxy, C2-C8 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, and C1-C4 haloalkyl; and R 6a and R 6b Compounds of clause 73, wherein each independently is hydrogen or hydroxy.

[0360] Crows 75. R 3a , R 3b , R 5a , and R 5b Compounds of clause 73 or clause 74, wherein each is C2-C8 alkoxy.

[0361] Clause 76. The compound of clause 75, in which the C2-C8 alkoxy is ethoxy.

[0362] Crows 77. R 2a , R 2b , R 6a , and R 6b Compounds of clause 75 or clause 76, wherein each is hydrogen.

[0363] Crows 78. R 3a , R 3b , R 5a , and R 5bA compound of clause 73 or clause 74, wherein at least one of the groups is tert-butyl.

[0364] Crows 79. R 3a , R 3b , R 5a , and R 5b The compound of clause 78, in which each is tert-butyl.

[0365] Crows 80. R 2a and R 2b Compounds of clause 78 or clause 79, wherein each is hydroxy.

[0366] Crows 81. R 6a and R 6b Any one of compounds of clauses 78 to 80, wherein each of is hydrogen.

[0367] Clause 82. A compound of any one of clauses 73 to 83, wherein m is 0 and n is 0.

[0368] Clause 83. The compound of any one of clauses 73 to 82, wherein X and Y are each —C(O)O—.

[0369] Close 84. Compound of formula (IIb): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0, 1 or 2; n is 0, 1 or 2; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1bare, if present, each independently selected from hydrogen and C1-C4 alkyl; R 6a and R 6b are each hydrogen; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from hydrogen, hydroxy, and aryl, where R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b at least one of is aryl; or where R 3a and R 4a together with the carbon atoms to which they are attached optionally together form an aryl ring; or where R 3b and R 4b together with the carbon atoms to which they are attached optionally together form an aryl ring; wherein each aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0370] Clause 85. The compound of clause 84, wherein m is 0 and n is 0.

[0371] Crows 86. R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5band one of the groups is phenyl, and the phenyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of hydroxy, alkoxy, C1-C4 alkyl, and hydroxy-C1-C4 alkyl.

[0372] Clause 87. The compound of clause 86, wherein the phenyl is substituted with one substituent selected from methyl, hydroxy, and hydroxymethyl.

[0373] Clause 88. The compound of any one of clauses 84 to 87, wherein X and Y are each —C(O)O—.

[0374] Close 89. Compound of formula (IIc): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0, 1 or 2; n is 0, 1 or 2; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, hydroxy, and C1-C4 alkoxy, and C1-C4 haloalkyl, where R 2a , R 2b , R 3a , R 3b , R 4a, R 4b , R 5a , R 5b , R 6a , and R 6b at least one of which is C1-C4 haloalkyl].

[0375] Close 90. m is 0; n is 0; R 2a and R 2b are each independently selected from hydrogen, hydroxy, C1-C4 alkoxy, and C1-C4 haloalkyl; R 3a , R 3b , R 5a , R 5b , R 6a and R 6b are each independently selected from hydrogen and C1-C4 haloalkyl; and R 4a and R 4b are each independently selected from hydrogen, hydroxy, and C1-C4 haloalkyl.

[0376] Crows 91. R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b A compound of clause 89 or clause 90, wherein at least one of the groups is trifluoromethyl.

[0377] Clause 92. The compound of any one of clauses 89 to 91, wherein X and Y are each —C(O)O—.

[0378] Close 93. Compound of formula (IId): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 1; n is 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, halo, C1-C4 haloalkyl, aryl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl.

[0379] Crows 94. R 1a and R 1b Compounds of Clause 93, where each is hydrogen.

[0380] Crows 95. R 2a , R 2b , R 4a , R 4b , R 6a , and R 6b are each independently selected from hydrogen, hydroxy, and C1-C4 alkoxy; and R 3a , R 3b , R 5a , and R 5b are each independently selected from hydrogen and C1-C8 alkoxy.

[0381] Clause 96. The compound of any one of clauses 93 to 95, wherein X and Y are each —C(O)O—.

[0382] Close 97. Compounds of formula (IIe): [ka] or a pharmaceutically acceptable salt thereof [wherein: m is 0 or 1; n is 0 or 1; X and Y each independently represent -C(O)O- or -C(O)NR a -, -C(S)NR b -, -NR c -, and -O-; R a , R b , and R c are each independently selected from hydrogen and C1-C4 alkyl; R 1a and R 1b are, if present, each independently selected from hydrogen and C1-C4 alkyl; R 2a , R 2b , R 5a , R 5b , R 6a , and R 6b are each hydrogen; and R 3a , R 3b , R 4a , and R 4b are each independently selected from C1-C8 alkyl, hydroxy, C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl, and hydroxy-C1-C8 alkyl.

[0383] Crows 98. R 3a , R 3b , R 4a , and R 4b are each independently selected from hydroxy and C1-C8 alkoxy.

[0384] Clause 99. The compound of clause 97 or clause 98, wherein m is 0 and n is 0.

[0385] Clause 100. The compound of any one of clauses 97 to 99, wherein X and Y are each —C(O)O—.

[0386] Clause 101. 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, and 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0387] Close 102. A compound which is 6,6'-bis(3,5-dimethoxybenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0388] Close 103. A compound which is 6,6'-bis(2-hydroxy-3,5-di-tert-butylbenzoyl)-α,α-D-trehalose, or a pharmaceutically acceptable salt thereof.

[0389] Clause 104. An adjuvant composition comprising an effective amount of any one of the compounds of clauses 63 to 103, or a pharmaceutically acceptable salt thereof.

[0390] Clause 105. A method for inducing an enhanced immune response in a subject, comprising administering to the subject the adjuvant composition of clause 104.

[0391] Clause 106. A vaccine composition comprising: (a) an antigen; and (b) an adjuvant composition comprising an effective amount of any one of the compounds of clauses 63 to 103, or a pharmaceutically acceptable salt thereof.

[0392] Clause 107. A method for inducing or enhancing the immunogenicity of an antigen in a subject, comprising administering to the subject a vaccine composition comprising the antigen and an adjuvant composition containing an effective amount of any one of the compounds of Clauses 63 to 103, or a pharmaceutically acceptable salt thereof.

[0393] Clause 108. An immunomodulatory composition comprising an effective amount of any one of the compounds of clauses 63 to 103, or a pharmaceutically acceptable salt thereof.

[0394] Clause 109. A method for modulating an immune response in a subject, comprising administering to the subject the immunomodulatory composition of clause 108.

[0395] Clause 110. The method of clause 109, wherein the immunomodulatory composition is administered as monotherapy.

[0396] Clause 111. The method of clause 109 or clause 110, wherein the subject's immune response is increased.

[0397] Clause 112. Any one of the methods of clauses 109-111, wherein the subject is suffering from cancer, an autoimmune disorder, or an infectious disease.

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof [wherein: L １ teeth 【Chemistry 2】 and L ２ teeth 【Chemistry 3】 and X and Y each independently represent —OC(O)— and —NR ａ C(O)—; Each R ａ are independently hydrogen and C １ ~C ４ alkyl; m is 0; n is 0; R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ６ａ , and R ６ｂ are each hydrogen; and R ３ａ , R ３ｂ , R ５ａ , and R ５ｂ are each independently C １ ~C １２ Alkyl and C １ ~C ４ haloalkyl].

2. The compound is a compound of formula (Ia): 【Chemistry 4】 [In the formula, R ３ａ , R ３ｂ , R ５ａ , and R ５ｂ are each independently C １ ~C ８ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

3. Said C １ ~C ８ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein alkyl is isopropyl, tert-butyl, methyl or ethyl.

4. Said C １ ~C ８ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein alkyl is tert-butyl.

5. The compound is a compound of formula (Ib): 【Chemistry 5】 [In the formula, R ３ａ , R ３ｂ , R ５ａ , and R ５ｂ are respectively C １ ~C ４ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof;

6. Said C １ ~C ４ 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein haloalkyl is trifluoromethyl. 【Request 7】 【Chemical 6-1】 【Chemistry 6-2】 【Chemistry 6-3】 10. The compound of claim 1, selected from the group consisting of:

8. An adjuvant composition comprising an effective amount of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. A vaccine composition comprising: (a) an antigen; and (b) an adjuvant composition comprising an effective amount of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for inducing or enhancing the immunogenicity of an antigen in a subject, comprising an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for modulating an immune response in a subject, comprising an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

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