Toll-like receptor ligand

Abstract

To provide compositions that are useful in treating, preventing, or reducing susceptibility to diseases or conditions mediated by Toll-like receptors (TLRs), such as cancer, infectious disease, allergy, autoimmune disease, sepsis, and ischemia reperfusion.SOLUTION: A pharmaceutical composition contains a pharmaceutically acceptable carrier, an antigen, and a TLR ligand with an allose-based core. The antigen is an allergen.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 629,513, filed on 12 February 2018, which is incorporated herein by reference in its entirety.

[0002] Statements concerning the interests of the government This invention was made with government support under grant number 1R43AI136081-01A1 granted by the National Institutes of Allergy and Infectious Diseases. The U.S. Government has certain rights to this invention.

[0003] The present invention relates to Toll-like receptor ligands useful for treating diseases or conditions mediated by Toll-like receptors. [Background technology]

[0004] Gram-negative bacteria have long been known to evoke immune responses via Toll-like receptors (TLRs). The unique components specific to these pathogens have been associated with strong innate and adaptive immune responses. Because pharmacological manipulation of the innate immune response could lead to more effective vaccines and novel therapeutic approaches against autoimmune diseases, allergic diseases, atopic diseases, malignant diseases, and infections, there is considerable interest in developing TLR agonists and antagonists.

[0005] The first microbial product discovered to be a Toll-like receptor agonist was lipid A, derived from LPS, a highly conserved glucosamine-based bacterial cell membrane component specific to Gram-negative bacteria that activates Toll-like receptor 4 (TLR-4). Lipid A is a potent immunomodulator, but its pharmaceutical applications are limited due to its extreme toxicity, including the induction of systemic inflammatory response syndromes. The toxic effects of lipid A can be mitigated by selective chemical modification of lipid A to produce monophosphoryl lipid A compounds (MPL immunostimulants; GlaxoSmithKline). MPL immunostimulants and related compounds possess adjuvant activity when used in vaccine formulations with protein and carbohydrate antigens to enhance humoral and / or cellular immunity against antigens. The heterogeneity, low potency, and poor stability of MPL and other natural or synthetic TLR4 ligands have hindered their use in many indications. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, improved TLR ligands with enhanced potency, stability, and / or purity are needed. [Means for solving the problem]

[0007] The present invention provides compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as methods, compositions and kits for treating or preventing diseases or conditions mediated by Toll-like receptors. The TLR ligands of the present invention have a novel allose-based skeleton with remarkable stability in aqueous formulations. In one embodiment, the present invention relates to formula (I) [ka] (In the formula, R 1 teeth, [ka] and; R2a , R 2b and R 2c are each independently C 4~22 alkyl, -X 1 -C 3~21 alkyl, -CH2-X 1 -C 2~20 alkyl or -CH(R 10 )(R 11 )); R 10 is, each time it appears, independently C 1~21 alkyl, -X 1 -C 2~20 alkyl or -CH2-X 1 -C 1~19 alkyl; R 11 is, each time it appears, independently C 3~17 alkyl, -X 2 -C 2~16 alkyl, -CH2-X 2 -C 1~15 alkyl, -X 2 -C(=Y 4 )C 1~15 alkyl, -CH2-C(=Y 4 )C 1~15 alkyl, -X 2 -C(=Y 4 )C 1~15 alkylene-Z 1 -C 1~15 alkyl, -CH2-C(=Y 4 )C 1~15 alkylene-Z 1 -C 1~15 alkyl, -C 3~17 alkylene-Z 1 -C 1~15 alkyl, -X 2 -C 2~16 alkylene-Z 1 -C 1~15 alkyl, -CH2-X 2 -C 1~15 alkylene-Z 1 -C 1~15 alkyl, -X 2 -C(=Y 4 )C 1~15 alkyl-Z 2 or -X 2-C 2~16 Alkilen-Z 2 and; R 3a , R 3b and R 3c These are, independently, CO2H, -OSO3H, -OP(O)(OH)2, and -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene -P(O)(OH)2, H or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of haloalkylene-P(O)(OH)2; R 3d is CO2H, -SO3H, -P(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene-P(O)(OH)2,H,C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6An ester of alkylene-P(O)(OH)2 or -C 1~6 haloalkylene-P(O)(OH)2; R 4a is CO2H, CH2OSO3H, CH2CO2H, CH2P(O)(OH)2, CH2OH, H or an ester of CO2H, CH2SO3H, CH2CO2H or CH2P(O)(OH)2; R 4b is, each time it occurs, independently CO2H, CH2OSO3H, CH2CO2H, CH2P(O)(OH)2, CH2OH, H or an ester of CO2H, CH2SO3H, CH2CO2H or CH2P(O)(OH)2; R 5 and R 6 are, each time they occur, independently H, C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 alkyl or -C 1~6 alkylene-OH; X 1 and X 2 are, each time they occur, independently O, S or NH; X 3 is O, S, NH or CH2; Y<![CDATA[ 1 ]]>Y 2 and Y 3 are independently O, S, NH or H2; Y 4 is, each time it occurs, independently O, S or NH; Z 1 is, each time it occurs, independently phenylene or 5- to 6-membered heteroarylene, and phenylene and heteroarylene are optionally substituted with 1 to 4 substituents independently selected from C 1~4 alkyl, C 1~4 haloalkyl, -OC 1~4 alkyl, -OC 1~4 haloalkyl, cyano and halogen; Z 2 is, each time it occurs, independently phenyl or 5- to 6-membered heteroaryl, where Z 2 is C1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 Optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen; and k and q are each independent integers between 0 and 4. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0008] Another aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to a disease or condition mediated by a Toll-like receptor, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0010] Another aspect of the present invention provides a method for inducing, enhancing, or modulating an immune response in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition to a subject in need thereof.

[0011] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0012] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to an infection in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0013] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to an allergy in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0014] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to an autoimmune disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0015] Another aspect of the present invention provides a method for treating, preventing, or reducing susceptibility to a bacterial, viral, prion infection, autoimmune, cancer, or allergy in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition to a subject in need thereof.

[0016] Another aspect of the present invention provides a method for treating or preventing autoimmunity, allergy, ischemia-reperfusion, or sepsis in a subject, or for reducing susceptibility thereto, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0017] In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating diseases or conditions mediated by Toll-like receptors.

[0018] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for the treatment of a disease or condition mediated by a Toll-like receptor.

[0019] The present invention also provides a kit containing a compound of formula (I). [Brief explanation of the drawing]

[0020] [Figure 1A] Figures 1A, 1B, and 1C show hTLR4 activation by representative compounds. Hek hTLR4-expressing cells, which also contain an NF-κB-driven SEAP reporter, were stimulated with the indicated compounds at the indicated concentrations for 18 hours, and the cell supernatant was evaluated for SEAP. The results show average OD values ​​that exceed the average OD values ​​for vehicles treated with two technically replicated cycles (±SD). [Figure 1B] Figures 1A, 1B, and 1C show hTLR4 activation by representative compounds. Hek hTLR4-expressing cells, which also contain an NF-κB-driven SEAP reporter, were stimulated with the indicated compounds at the indicated concentrations for 18 hours, and the cell supernatant was evaluated for SEAP. The results show average OD values ​​that exceed the average OD values ​​for vehicles treated with two technically replicated cycles (±SD). [Figure 1C] Figures 1A, 1B, and 1C show hTLR4 activation by representative compounds. Hek hTLR4-expressing cells, which also contain an NF-κB-driven SEAP reporter, were stimulated with the indicated compounds at the indicated concentrations for 18 hours, and the cell supernatant was evaluated for SEAP. The results show average OD values ​​that exceed the average OD values ​​for vehicles treated with two technically replicated cycles (±SD). [Figure 2A] Figures 2A and 2B show the induction of MIP-1β cytokine from hMM6 cells in response to the compound. hMM6 cells and monocyte / macrophage cell lines were treated with the compound at increasing concentrations over 18 hours. The supernatant was collected and analyzed for MIP-1β production by ELISA. [Figure 2B] Figures 2A and 2B show the induction of MIP-1β cytokine from hMM6 cells in response to the compound. hMM6 cells and monocyte / macrophage cell lines were treated with the compound at increasing concentrations over 18 hours. The supernatant was collected and analyzed for MIP-1β production by ELISA. [Figure 3]Figure 3 shows the induction of the MIP-1β cytokine from mouse RAW264.7 cells in response to a compound. mRAW264.7 cells and macrophage cell lines were treated with the compound at increasing concentrations over 18 hours. The supernatant was collected and analyzed for MIP-1β production by ELISA. [Figure 4A] Figure 4A shows the induction of MIP-1β from primary hPBMCs in response to compounds 1-4 (average of 3 donors). [Figure 4B] Figure 4B shows the induction of MIP-1β from primary hPBMCs in response to compounds 1, 2, 4, 5, 6, and 7 (shown in one donor). [Figure 4C] Figure 4C shows the induction of MIP-1β from primary hPBMCs in response to compounds 8 and 9 (shown in one donor). Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compounds shown at increasing concentrations over 18 hours, and the supernatant was analyzed for MIP-1β production. [Figure 5A] Figures 5A (average of 3 donors), 5B (1 donor), and 5C (1 donor) show the induction of RANTES from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for RANTES production by ELISA. [Figure 5B] Figures 5A (average of 3 donors), 5B (1 donor), and 5C (1 donor) show the induction of RANTES from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for RANTES production by ELISA. [Figure 5C]Figures 5A (average of 3 donors), 5B (1 donor), and 5C (1 donor) show the induction of RANTES from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for RANTES production by ELISA. [Figure 6A] Figures 6A (average of 3 donors), 6B (1 donor), and 6C (1 donor) show the induction of TNFα cytokines from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for TNFα production by ELISA. [Figure 6B] Figures 6A (average of 3 donors), 6B (1 donor), and 6C (1 donor) show the induction of TNFα cytokines from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for TNFα production by ELISA. [Figure 6C] Figures 6A (average of 3 donors), 6B (1 donor), and 6C (1 donor) show the induction of TNFα cytokines from primary hPBMCs in response to the compound. Primary human peripheral blood mononuclear cells were isolated from the whole blood of three different donors using a Ficoll gradient. The cells were then treated with the compound at increasing concentrations over 18 hours, and the supernatant was analyzed for TNFα production by ELISA. [Figure 7] Figure 7 shows the influenza virus-specific IgG2a antibody titers measured 14 days after intramuscular immunization of BALB / c mice with or without the compound of the present invention using 0.2 μg of A / Victoria H3N2 influenza virus antigen. [Figure 8]Figure 8 shows the survival results of 12-14 week old mice (BALB / c) administered 10, 1, and 0.1 μg aqueous formulations of compound 4 intranasally (10 μL / nostril) on day 2. On day 0, the animals were challenged by intranasal inoculation with 1 LD50 of A / HK / 68 (mouse-adapted H3N2 human influenza virus). Compound 4 provided dose-dependent protection. [Figure 9] Figure 9 shows a stability graph of compound 1, formulated in 2.5% glycine, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 10A] Figures 10A and 10B show stability graphs of compound 2, formulated in 2.5% glycine and 2% glycerol, respectively, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 10B] Figures 10A and 10B show stability graphs of compound 2, formulated in 2.5% glycine and 2% glycerol, respectively, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 11] Figure 11 shows a stability graph of compound 3, formulated in 2.5% glycine, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 12] Figure 12 shows a stability graph of compound 4, formulated in 2.5% glycine, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 13] Figure 13 shows a stability graph of compound 5, formulated in 2% glycerol, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Figure 14] Figure 14 shows a stability graph of compound 6, formulated in 2% glycerol, stored at 2–8°C, 25°C, and 40°C, and monitored for degradation by reverse-phase HPLC. [Modes for carrying out the invention]

[0021] 1.Definition As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those generally shown above or exemplified by the specific classes, subclasses and species of the present invention. As described herein, the variables in Formula I include certain groups, such as alkyl and cycloalkyl groups. As those skilled in the art will recognize, the substituent combinations envisioned by the present invention are combinations that result in the formation of stable or chemically feasible compounds. As used herein, the term “stable” means a compound that does not substantially change when exposed to conditions that enable their formation, detection, and preferably their recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable or chemically feasible compound is one that does not substantially change when held at a temperature of 40°C or less for at least one week in the absence of moisture or other highly chemically reactive conditions.

[0022] As used herein, the term "alkyl" means a linear or branched saturated hydrocarbon. Representative examples of alkyls 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, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0023] As used herein, the term "alkylene" means a divalent group derived from a linear or branched saturated hydrocarbon. Examples of alkylenes are not limited to those specified herein. However, examples include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, and CH2CH(CH3)CH(CH3)CH2-.

[0024] As used herein, the term "aryl" means phenyl or bicyclic aryl. Bicyclic aryls are naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl. Phenyls and bicyclic aryls are bonded to the parent molecule via any carbon atoms contained in the phenyl or bicyclic aryl.

[0025] The term "halogen" refers to chlorine, bromine, iodine, or fluorine atoms.

[0026] As used herein, the term "haloalkyl" means an alkyl group in which one, two, three, four, five, six, or seven hydrogen atoms are substituted with halogens. Representative examples of haloalkyls include, but are not limited to, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1,1-dimethylethyl.

[0027] As used herein, the term “heteroaryl” means an aromatic heterocycle, i.e., an aromatic ring containing at least one heteroatom selected from O, N, or S. Heteroaryls may contain 5 to 12 ring atoms. Heteroaryls may be 5- to 6-membered monocyclic heteroaryls or 8- to 12-membered bicyclic heteroaryls. A 5-membered monocyclic heteroaryl ring contains two double bonds and 1, 2, 3, or 4 heteroatoms as ring atoms. Representative examples of 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl. A 6-membered heteroaryl ring contains three double bonds and 1, 2, 3, or 4 heteroatoms as ring atoms. Representative examples of six-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, and triazinyl. Bicyclic heteroaryls are eight- to twelve-membered ring systems having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring. Representative examples of bicyclic heteroaryls include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthilidinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[bJ-pyridinyl]. The heteroaryl group is bonded to the parent molecule via any substitutable carbon atom or any substitutable nitrogen atom contained in the group.

[0028] As used herein, the term "cycloalkyl" refers to a monocyclic whole-carbon ring containing a 0 heteroatom and a 0 double bond as ring atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyls described herein may be bonded to the parent molecule via any substitutable carbon atoms.

[0029] The term “heterocyclic” or “heterocyclic formula” generally refers to a ring system containing at least one heteroatom as a ring atom, where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, the nitrogen or sulfur atom of the heterocyclic ring is optionally substituted with an oxo. Heterocyclic rings can be monocyclic, fused bicyclic, or spirocyclic rings. Monocyclic heterocyclic rings are generally 4, 5, 6, 7, or 8-membered non-aromatic rings containing at least one heteroatom selected from O, N, or S. A 4-membered ring contains one heteroatom and optionally one double bond. A 5-membered ring contains zero or one double bond and one, two, or three It contains heteroatoms. The 6, 7, or 8-membered ring contains 0, 1 or 2 double bonds and 1, 2 or 3 heteroatoms. Representative examples of monocyclic heterocycles, but not limited to, include azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazole-5-yl, 3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadia Examples include zolinyl, oxadiazolidinyl, oxazolinyl, oxazolinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl, thiopyranyl, and trithianil. A condensed bicyclic heterocycle is a 7-12 membered system having a monocyclic heterocycle condensed to a phenyl, saturated or partially saturated carbocyclic, or another monocyclic heterocycle or monocyclic heteroaryl ring. Representative examples of fused bicyclic heterocycles include, but are not limited to, 1,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-1H-flo[3,4-c]pyrrolyl, 2,3-dihydro-1,4-benzodioxynyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyradinyl, and 1,2,3,4-tetrahydroquinolinyl. A spiroheterocycle refers to a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic heterocycle in which two substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8 constituent elements. Examples of spiroheterocycles, though not limited to them, include 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane.The monocyclic heterocyclic groups of the present invention may contain alkylene bridges of 1, 2, or 3 carbon atoms linking two non-adjacent atoms of the group. Examples of such bridged heterocyclic groups include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl. Monocyclic, fused bicyclic, and spiroheterocyclic groups are bonded to the parent molecule via any substitutable carbon or nitrogen atoms contained within the group.

[0030] As used herein, the term "oxo" refers to an oxygen atom bonded to the parent molecule. The oxo may be bonded to a carbon or sulfur atom by a double bond. Alternatively, the oxo may be bonded to a nitrogen atom by a single bond, i.e., an N-oxide.

[0031] Terms such as "alkyl," "cycloalkyl," and "alkylene" may be preceded by an indication of the number of atoms present in the group in certain cases (for example, "C 1~4 "Alkyl", "C 3~6 Cycloalkyl, C 1~4 "Alkylene"). These designations are used in a manner that is generally understood by those skilled in the art. For example, the designation "C" followed by a subscript number indicates the number of carbon atoms present in the following group. Thus, "C3 alkyl" is an alkyl group having three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is indicated as "C", the constituent elements of the subsequent group may have any number of carbon atoms that fall within the specified range. 1~4 "Alkyl" refers to an alkyl group that, for example, is arranged (i.e., linear or branched) and has 1 to 4 carbon atoms.

[0032] The compounds of the present invention have a stereochemical configuration around a core sugar, as particularly shown in formula (I). Apart from the stereochemistry of the core sugar, the stereocenters located in any substituent bonded to the core sugar are all isomers of that structure (e.g., enantiomers, diastereomers and geometric isomers). (or conformational) forms; for example, R and S configurations for each chiral center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers, enantiomers, diastereomers, and geometric (or conformational) mixtures of the compound are within the scope of the present invention. Unless otherwise specified, all tautomers of the compound of the present invention are within the scope of the present invention. Thus, the scope of the present invention includes tautomers of the compound of formula I. This structure also includes, if necessary, the amphoteric form of the compound or salt of formula I.

[0033] 2.Compound A first aspect of the present invention is formula (I) (wherein R 1 , R 2a , R 2b , R 3a , R 4a , Y 1 and Y 2 The present invention provides compounds of (as defined herein) or pharmaceutically acceptable salts thereof.

[0034] R 2a , R 2b and R 2c Independently, C 4~22 Alkyl, -X 1 -C 3~21 Alkyl, -CH2-X 1 -C 2~20 Alkyl or -CH(R 10 )(R 11 ) could be. R 10 Each time it appears, C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 It is alkyl. 11 Each time it appears, C 3~17Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 X 1 and X 2 Each instance is independently O, S, or NH. 4 Each instance is O, S, or NH. 1 Each instance is independently phenylene or a 5- to 6-membered heteroarylene, and phenylene and heteroarylene are C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 It is optionally substituted with 1 to 4 substituents independently selected from haloalkyl, cyano, and halogen. 2Each instance is independently a phenyl or a 5- to 6-membered heteroaryl, where Z 2 C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 R is optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen. 2a , R 2b and R 2c X in 1 , X 2 , Y 4 , Z 1 , Z 2 , R 10 and R 11 The independent occurrences of R may be the same or different depending on the definition set forth herein. Similarly, R 2a , R 2b , R 2c , R 10 and R 11 Each alkyl and alkylene group in the compound may have the same or different number of carbon atoms. Therefore, the variable X 1 , X 2 , Y 4 , Z 1 , Z 2 , R 10 and R 11 The description of embodiments relating to refers to embodiments having one or more occurrences of the definitions of the variables described. However, each distinct occurrence may be the same or have different definitions.

[0035] In one embodiment, R 2a , R 2b and R 2c Each of them operates independently, -CH(R 10 )(R 11 )

[0036] In one embodiment, R 10 C 1~19 Alkyl or C 3~21 C such as alkyl 1~21 Alkyl (for example, linear C 11 C such as alkyl 11It is alkyl.

[0037] In one embodiment, R 10 Each time it appears, C 1~19 Alkyl or C 3~21 C such as alkyl 1~21 Alkyl (for example, C 8~14 Alkyl, C 10~12 Alkyl or linear C 11 C such as alkyl 11 It is alkyl. 1~21 Alkyls may be the same or different (e.g., different chain lengths and / or linear). (In contrast, it is branched and chain-like).

[0038] In one embodiment, R 11 Each time it appears, -X 2 -C(=Y 4 )C 1~15 Alkyl (for example, -OC(=O)C9 alkyl, etc.) 1~15 It is alkyl. Independent -X 2 -C(=Y 4 )C 1~15 Alkyls may be the same or different (for example, different chain lengths and / or linear versus branched and / or X). 2 and Y 4 O, S, or NH in R. 11 One example is -X 2 -C(=Y 4 )C9 alkyl, other examples include -X 2 -C(=Y 4 )C 10 It can be alkyl. Alternatively, R 11 All three examples can be different.

[0039] In one embodiment, R 11 Each time it appears, -X 2 -C 2~16 Alkyl (for example, -OC) 10 Alkyl and other -OC 2~16 It is alkyl. Independent -X 2 -C2~16 Alkyls may be the same or different (for example, different chain lengths and / or linear versus branched and / or X). 2 O, S, or NH in R. 11 One example is -X 2 -C 10 It can be alkyl, and another example is -X 2 -C 11 It can be alkyl. Alternatively, R 11 All three examples can be different.

[0040] In one embodiment, R 11 Each time it appears, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 (For example, -OC(=O)C7 alkylene-Z 2 -OC(=O)C 1~15 Alkilen-Z 2 ) is an independent -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 They may be the same or different (for example, different chain lengths and / or linear versus branched and / or X 2 and Y 4 O, S, or NH in R. 11 One example is -X 2 -C(=Y 4 )C7 Alkilen-Z 2 This is possible, and another example is -X 2 -C(=Y 4 )C8 Alkilen-Z 2 It is possible. Instead, R 11 All three examples can be different.

[0041] In one embodiment, R 11 This is when it appears once (for example, R 2b (in) -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 (For example, -OC(=O)C7 alkylene-Z2 -OC(=O)C 1~15 Alkilen-Z 2 ) and R 11 The other two occurrences of (for example, R 2a and R 2c In this case, independently, -X 2 -C(=Y 4 )C 1~15 Alkyl (for example, -OC(=O)C9 alkyl, etc.) 1~15 Alkyl) or R 11 This is another option.

[0042] In one embodiment, R 11 Each time it appears, -X 2 -C 2~16 Alkilen-Z 2 (For example, -OC 8~9 Alkilen-Z 2 -OC 2~16 Alkilen-Z 2 ) is an independent -X 2 -C 2~16 Alkilen-Z 2 They may be the same or different (for example, different chain lengths and / or linear versus branched and / or X 2 O, S, or NH in R. 11 One example is -X 2 -C8 Alkiren-Z 2 This is possible, and another example is -X 2 -C9Alkiren-Z 2 It is possible. Instead, R 11 All three examples can be different.

[0043] In one embodiment, R 11 This is when it appears once (for example, R 2b (in) -X 2 -C 2~16 Alkilen-Z 2 (For example, -OC 8~9 Alkilen-Z 2 -OC 2~16 Alkilen-Z 2 ) and R 11The other two occurrences of (for example, R 2a and R 2c In this case, independently, -X 2 -C 2~16 Alkyl (for example, -OC) 10 Alkyl and other -OC 2~16 Alkyl) or R 11 This is another option.

[0044] For example, -CH(R 10 )(R 11 In embodiments having at least one occurrence of R 10 and R 11 At least one occurrence of can be defined as follows: R 10 C 1~19 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. R 10 C 1~19 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. 10 C 1~19 It can be alkyl, R 11 C 3~17 It is alkyl. 10 C 1~19 It can be alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. 10 C 1~19 It can be alkyl, R 11 is X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~19 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10C 1~19 It can be alkyl, R 11 is X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~19 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 That is. R 10 C 1~19 It can be alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 2 That is the case.

[0045] R 10 C 11 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkyl (e.g., -OC(=O)C9 alkyl) or -X 2 -C 2~16 Alkyl (for example, -OC) 10 It is alkyl. For example, -CH(R 10 )(R 11 )but, [ka] It is possible.

[0046] R 10 C 11 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkyl (e.g., -OC(=O)C9 alkyl), -X 2 -C 2~16 Alkyl (for example, -OC) 10 Alkyl), -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2(For example, -OC(=O)C7 alkylene-Z 2 ) or -X 2 -C 2~16 Alkilen-Z 2 (For example, -OC 8~9 Alkilen-Z 2 ) For example, -CH(R 10 )(R 11 )but, [ka] It is possible.

[0047] -CH(R 10 )(R 11 In a further embodiment having at least one appearance of R 10 and R 11 At least one occurrence of can be defined as follows: R 10 C 3~21 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It can be alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It can be alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~ 15 It is alkyl. In one embodiment, R10 C 3~21 It can be alkyl, R 11 C 3~17 It is alkyl. In one embodiment, R 10 C 3~21 It can be alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. In one embodiment, R 10 C 3~21 It can be alkyl, R 11 -CH2-X 2 -C 1~15 It is alkyl.

[0048] -CH(R 10 )(R 11 In a further embodiment having at least one appearance of R 10 and R 11 At least one occurrence of can be defined as follows: R 10 C 1~21 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11C 3~17 It is alkyl. 10 C 1~21 It can be alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. 10 C 1~21 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. 10 C 1~21 It can be alkyl, R 11 -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl.

[0049] In other embodiments, R 10 ga-X 1 -C 2~20 It can be alkyl. -CH(R 10 )(R 11 In a further embodiment having at least one appearance of R 10 and R 11 At least one occurrence of can be defined as follows: R 10 ga-X 1 -C 2~20 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 ga-X1 -C 2~20 It can be alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 C 3~17 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 -CH2-X 2 -C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. 10 ga-X 1 -C 2~20 It can be alkyl, R 11 -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl.

[0050] In other embodiments, R10 -CH2-X 1 -C 1~19 It can be alkyl. -CH(R 10 )(R 11 In a further embodiment having at least one appearance of R 10 and R 11 At least one occurrence of can be defined as follows: For example, R 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 C 3~17 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 -CH2-X 2 -C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 -CH2-C(=Y4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. 1 0 -CH2-X 1 -C 1~19 It can be alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. 10 -CH2-X 1 -C 1~19 It can be alkyl, R 11 -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl.

[0051] In one embodiment, R 10 C 1~19 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 C 3~17 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. In another embodiment, R 10 C1~19 It is alkyl, R 11 is X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 is X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 C 1~19 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 In another embodiment, R 10 C 1~19 It is alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 2 That is the case.

[0052] In a further embodiment, R 10 C 11 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkyl (e.g., -OC(=O)C9 alkyl) or -X 2 -C 2~16 Alkyl (for example, -OC) 10 It is alkyl. For example, -CH(R 10 )(R 11 )but, [ka] It is possible.

[0053] In a further embodiment, R 10 C 11 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkyl (e.g., -OC(=O)C9 alkyl), -X 2 -C 2~16 Alkyl (for example, -OC) 10 Alkyl), -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 (For example, -OC(=O)C7 alkylene-Z 2 ) or -X 2 -C 2~16 Alkilen-Z 2 (For example, -OC 8~9 Alkilen-Z 2 ) For example, -CH(R 10 )(R 11 )but, [ka] It is possible.

[0054] In one embodiment, R 10 C 3~21 It is alkyl, R 11 ga-X 2 -C(= Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 ga-X 2-C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 C 3~17 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. In one embodiment, R 10 C 3~21 It is alkyl, R 11 -CH2-X 2 -C 1~15 It is alkyl.

[0055] In one embodiment, R 10 C 1~21 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 C 3~17 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 ga-X 2 -C 2~16 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 -CH2-X 2 -C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 It is alkyl. In one embodiment, R 10 C 1~21 It is alkyl, R 11 -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl.

[0056] In other embodiments, R 10 ga-X 1 -C 2~20 It is alkyl. For example, in one embodiment, R 10 ga-X 1 -C 2~20 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -CH2-C(=Y 4 )C 1~15 is alkylene-Z 1 -C 1~15 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -X 2 -C 2~16 is alkylene-Z 1 -C 1~15 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -C 3~17 is alkylene-Z 1 -C 1~15 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is C 3~17 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -X 2 -C 2~16 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -CH2-X 2 -C 1~15 is alkyl.

[0057] In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -X 2 -C(=Y 4 )C 1~15 is alkyl. In certain embodiments, R 10 is -X1 -C 2~20 is alkyl, and R 11 is -CH2-C(=Y 4 )C 1~15 is alkyl. In certain embodiments, R 10 is -X 1 -C 2~20 is alkyl, and R 11 is -CH2-X 2 -C 1~15 is alkylene-Z 1 -C 1~15 is alkyl.

[0058] In other embodiments, R<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1~15 It is alkyl. In another embodiment, R 10 -CH2-X 1 -C 1~19 It is alkyl, R 11 ga-X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 -CH2-X 1 -C 1~19 It is alkyl, R 11 -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 -CH2-X 1 -C 1~19 It is alkyl, R 11 ga-C 3~17 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 -CH2-X 1 -C 1~19 It is alkyl, R 11 ga-X 2 -C 2~16 Alkilen-Z 1 -C 1~15 It is alkyl. In another embodiment, R 10 -CH2-X 1 -C 1~19 It is alkyl, R 11 -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl.

[0060] In one embodiment, Y 4 O(for example, -X 2 -C(=O)C 1~15 It is alkyl.

[0061] In one embodiment, X 2is O (for example, R 11 ga-OC 2~16 Alkyl, -OC(=O)C 1~15 (It is alkyl.)

[0062] In one embodiment, Y 1 , Y 2 and Y 3 The value is O.

[0063] In one embodiment, X 3 The value is O.

[0064] R 3a , R 3b and R 3c These are, independently, CO2H, -OSO3H, -OP(O)(OH)2, and -C 1~6 Alkylene -CO2H (e.g., CH2CO2H), -C 1~6 Alkylene-OSO3H (e.g., CH2OSO3H), -C 1~6 Alkylene -OP(O)(OH)2 (e.g., -CH2OP(O)(OH)2), -OC 1~6 Alkylene -P(O)(OH)2 (e.g., -OCH2P(O)(OH)2), -C 1~6 Alkylene-P(O)(OH)2 (e.g., CH2P(O)(OH)2), -C 1~6 Haloalkylene -P(O)(OH)2 (e.g., CF2P(O)(OH)2), H or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of the haloalkylene -P(O)(OH)2.

[0065] In one embodiment, R 3a This is -OP(O)(OH)2.

[0066] In one embodiment, R 3a This is -OSO3H.

[0067] In one embodiment, R 3a This is -OCH2P(O)(OH)2.

[0068] R 3d is CO2H, -SO3H, -P(O)(OH)2, -C 1~6 Alkylene -CO2H (e.g., -CH2CO2H), -C 1~6 Alkylene-OSO3H (e.g., -CH2OSO3H), -C 1~6 Alkylene -OP(O)(OH)2 (e.g., -CH2OP(O)(OH)2), -OC 1~6 Alkylene -P(O)(OH)2 (e.g., -OCH2P(O)(OH)2), -C 1~6 Alkylene-P(O)(OH)2 (e.g., CH2P(O)(OH)2), -C 1~6 Haloalkylene-P(O)(OH)2 (for example, CF2P(O)(OH)2), H, C 1~6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C 1~6 Haloalkyl (e.g., trifluoromethyl, trifluoroethyl), C 3~8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.) or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of the haloalkylene -P(O)(OH)2.

[0069] In one embodiment, R 4a This is CH2OH.

[0070] In one embodiment, R 1 but, [ka] In a further embodiment, k is 1; R 3b is hydrogen, COOH, or its ester; R 3d , R 5 and R 6 Each of them is hydrogen.

[0071] In one embodiment, R 1 but, [ka] For example, R 1 but, [ka] It is possible. 1 Specific examples include, [ka] This is an example. In the above example, a further embodiment is in which q is an integer from 1 to 4.

[0072] In other embodiments, R 1 but, [ka] In the equation, q1 and q2 are integers between 0 and 4, where q1 + q2 is an integer between 1 and 4.

[0073] In one embodiment, R 1 but, [ka] And; R 2a , R 2b and R 2c However, each operates independently, -CH(R 10 )(R 11 ) and; R 10 C 1~21 Alkyl; R11 However, each time it appears, independently, -X 2 -C 2~16 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 And; R 3a -OSO3H, -OP(O)(OH)2, or -OC 1~6 It is alkylene-P(O)(OH)2; R 3b is H, CO2H, or its ester; R 3d , R 5 and R 6 Each of them is hydrogen; Y 1 , Y 2 , Y 3 and Y 4 O is X 2 and X 3 O is R 4a The compound is CH2OH; and k is 1.

[0074] In one embodiment, R 1 but, [ka] And; R 2a , R 2b and R 2c However, each operates independently, -CH(R 10 )(R 11 ) and; R 10 C 1~21 Alkyl; R 11 However, each time it appears, independently, -X 2 -C 2~16 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkyl or -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 And; R3a -OSO3H, -OP(O)(OH)2, or -OC 1~6 It is alkylene-P(O)(OH)2; R 3b is H, CO2H, or its ester; R 3d , R 5 and R 6 Each of them is hydrogen; Y 1 , Y 2 , Y 3 and Y 4 O is X 2 and X 3 O is R 4a The compound is CH2OH; and k is 1.

[0075] In one embodiment, R 1 but, [ka] And; R 2a , R 2b and R 2c However, each operates independently, -CH(R 10 )(R 11 ) and; R 10 C 1~21 Alkyl; R 11 ga-X 2 -C 2~16 Alkyl or -X 2 -C(=Y 4 )C 1~15 Alkyl; R 3a is -OSO3H or -OP(O)(OH)2; R 3b is H, CO2H, or its ester; R 3d , R 5 and R 6 Each of them is hydrogen; Y 1 , Y 2 , Y 3 and Y 4 O is X 2 and X 3 O is R 4a The compound is CH2OH; and k is 1.

[0076] The compound of formula (I) is formula (Ia) [ka] (In the formula, R 2a , R 2b , R 2c , R 3a and R 3b In this specification, it is defined as (It is a cage) It can be represented as R 3a R can be -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2, where R 2a , R 2b , R 2c and R 3b R is defined as described herein. 3a R can be -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2, where R 3b is H, CO2H, or an ester of CO2H, and R 2a , R 2b and R 2c This is as defined herein. For example, R 2a , R 2b and R 2c is -CH(R 10 )(R 11 ) can be, and here, R 10 Each time it appears, C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 Alkyl; R 11 Each time it appears, C 3~17 Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 1 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 X 1 , X 2 , Y 4 , Z 1 and Z 2 R is defined as described herein. 2a , R 2b and R 2c is -CH(R 10 )(R 11 ) can be, and here, R 10 Each time it appears, C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 Alkyl; R 11 Each time it appears, C 3~17 Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 1 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15Alkilen-Z 1 -C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 Alkyl or -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 X 1 , X 2 , Y 4 , Z 1 and Z 2 This is defined herein.

[0077] The compound of formula (I) is the same as formula (II) [ka] (In the formula, R 10 Each time it appears, C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 Alkyl; R 11 Each time it appears, C 3~17 Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 1 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15Alkilen-Z 1 -C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 and R 3a , R 3b , X 1 , X 2 , Y 4 , Z 1 and Z 2 (as defined herein) It can be represented as R 10 C 1~21 Alkyl; R 11 Each time it appears, it is independently -OC(=O)C 1~15 Alkyl, -OC 2~16 Alkyl, -OC(=O)C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 And; R 3a These are -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2; R 3b is an ester of H, CO2H, or CO2H; Z 2 Each instance is independently a phenyl or a 5- to 6-membered heteroaryl, where Z 2 C1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 It is optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen. In one embodiment, R 10 C 1~21 Alkyl; R 11 Each time it appears, it is independently -OC(=O)C 1~15 Alkyl, -OC 2~16 Alkyl or -OC(=O)C 1~15 Alkilen-Z 2 And; R 3a These are -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2; R 3b is an ester of H, CO2H, or CO2H; Z 2 Each instance is independently a phenyl or a 5- to 6-membered heteroaryl, where Z 2 C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 It is optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen. In one embodiment, R 10 C 1~21 Alkyl; R 11 Each time it appears, it is independently -OC(=O)C 1~15 Alkyl, -OC 2~16 Alkyl or -OC(=O)C 1~15 Alkilen-Z 2 And; R 3a These are -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2; R 3b is an ester of H, CO2H, or CO2H; Z 2 Each time it appears, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4This is a phenyl molecule that is optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen groups.

[0078] In embodiments described herein, R 2a , R 2b and R 2c These are -CH(R 10 )(R 11 ) is a further embodiment, R 10 Each of these cases is the same (for example, C 11 C such as alkyl 1~21 Alkyl) and R 11 Each case is the same (for example, -OC(=O)C9 alkyl and -OC(=O)C 1~15 Alkyl, -OC 10 Alkyl and other -OC 2~16 Alkyl, -OC(=O)C7 alkylene-Z 2 -OC(=O)C 1~15 Alkilen-Z 2 ) In other embodiments, R 10 Each occurrence is the same (for example, C 11 C such as alkyl 1~21 Alkyl) and R 11 The same is not the same in all occurrences (for example, R 2b In R 11 -OC(=O)C7alkylene-Z 2 -OC(=O)C 1~15 Alkilen-Z 2 And R 2a and R 2c In R 11 -OC(=O)C9 alkyl and other -OC(=O)C 1~15 (It is alkyl.)

[0079] R 3a , R 3b , R 3c , R 3d , R 4a and R 4b Examples of esters in this context include alkyl esters (for example, C 1~6 Alkyl esters), haloalkyl esters (for example, C1~6 Examples include haloalkyl esters and aryl esters (for example, optionally substituted phenyl or naphthyl esters).

[0080] In one embodiment, the compound of formula (I) is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0081] In another embodiment, the compound includes an isotopically labeled form. The isotopically labeled form of the compound is identical to the compound, except that one or more atoms of the compound are substituted with one or more atoms having a different atomic mass or mass number than the atoms that normally exist in higher natural abundance. Examples of isotopes that are commercially readily available and can be incorporated into the compound by known methods include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F and 36 Cl isotopes are one example.

[0082] In one embodiment, the compound of formula (I) is a TLR agonist (e.g., TLR4).

[0083] In one embodiment, the compound of formula (I) is a TLR antagonist (e.g., TLR4).

[0084] In one embodiment, the compound of formula (I) is a TLR regulator.

[0085] 3. Usage and Method When an exogenous antigen confers an antigen to the immune system, it responds by triggering a defensive reaction characterized by the coordinated interaction of both the innate and adaptive immune systems. These two independent systems satisfy two mutually exclusive requirements: rate (contributed by the innate system) and specificity (contributed by the adaptive system).

[0086] The innate immune system acts as the first line of defense against invading pathogens, blocking them while the adaptive response matures. The innate immune system is triggered within minutes of infection, regardless of the antigen, depending on the widely conserved patterns of pathogens (however, it is not nonspecific and can distinguish between self and pathogen). Importantly, the innate immune system also creates an inflammatory and co-stimulatory environment (sometimes called a danger signal) that enhances the adaptive immune system and induces (or divides) the optimal cellular or humoral response to deal with the infectious agent. The development of TLR modulators for therapeutic targeting of the innate immune system has been outlined (see Nature Medicine, 2007, 13, 552-559; Drug Discovery Today: Therapeutic Strategies, 2006, 3, 343-352 and Journal of Immunology, 2005, 174, 1259-1268).

[0087] The adaptive response takes several days or weeks to become effective, but ultimately provides the good antigen specificity necessary for complete elimination of the pathogen and the formation of immunological memory. The adaptive response is primarily mediated by T and B cells that undergo germline gene rearrangement and are characterized by specificity and long-lasting memory. However, the adaptive response also involves the recruitment of elements of the innate immune system, including professional phagocytic cells (macrophages, neutrophils, etc.) and granulocytes (basophils, eosinophils, etc.) that engulf bacteria and even larger parasites. Once the adaptive immune response matures, subsequent exposure to pathogens leads to rapid elimination of the pathogen because highly specific memory cells are produced that are rapidly activated upon subsequent exposure to their alloantigens.

[0088] In certain embodiments, the compounds and compositions provided herein induce cell-mediated and / or humoral immune responses. In other embodiments, the immune response induces long-lasting (e.g., neutralizing) antibodies and cell-mediated immunity that respond rapidly upon exposure to infectious agents.

[0089] Two types of T cells, CD4 and CD8 cells, are generally considered necessary for initiating and / or enhancing cell-mediated and humoral immunity. CD8 T cells can express the CD8 coreceptor and are commonly called cytotoxic T lymphocytes (CTLs). CD8 T cells can be recognized by or interact with antigens presented on MHC class I molecules.

[0090] CD4 T cells can express the CD4 coreceptor and are commonly called T helper cells. CD4 T cells can recognize antigen peptides bound to MHC class II molecules. After interacting with MHC class II molecules, CD4 cells can secrete factors such as cytokines. These secreted cytokines can activate B cells, cytotoxic T cells, macrophages, and other cells involved in the immune response. Helper T cells, or CD4+ cells, can be further classified into two functionally distinct subsets: the TH1 phenotype and the TH2 phenotype, which differ in cytokine and effector functions. .

[0091] Activated TH1 cells enhance cellular immunity (including increased antigen-specific CTL production) and are therefore particularly useful in responding to intracellular infections. Activated TH1 cells may secrete one or more of IL-2, IFN-γ, and TNF-β. The TH1 immune response can lead to a local inflammatory response by activating macrophages, NK (natural killer) cells, and CD8 cytotoxic T cells (CTLs). The TH1 immune response may also act to amplify the immune response by stimulating B and T cell growth with IL-12. TH1-stimulated B cells may secrete IgG2a.

[0092] Activated TH2 cells enhance antibody production and are therefore useful in responding to extracellular infections. Activated TH2 cells may secrete one or more IL-4, IL-5, IL-6, and IL-10. The TH2 immune response may result in the production of IgG1, IgE, IgA, and memory B cells for future protection.

[0093] An enhanced immune response may include one or more enhanced TH1, TH2, and TH17 immune responses.

[0094] The TH1 immune response may include one or more of the following: an increase in CTLs, an increase in one or more cytokines associated with the TH1 immune response (such as IL-2, IFN-γ, and TNF-β), an increase in activated macrophages, an increase in NK activity, or an increase in IgG2a production. Preferably, an enhanced TH1 immune response would include an increase in IgG2a production.

[0095] The TH2 immune response may include an increase in one or more cytokines associated with the TH2 immune response (such as IL-4, IL-5, IL-6, and IL-10) or an increase in the production of one or more IgG1, IgE, IgA, and memory B cells. Preferably, an enhanced TH2 immune response would include an increase in IgG1 and IgE production.

[0096] The Th17 immune response may include an increase in one or more cytokines associated with the Th17 immune response (such as IL-17, IL-22, IL-23, TGF-β, and IL-6) or an increase in humoral immunity and memory B cells.

[0097] In certain embodiments, the immune response is one or more of the TH1 immune response, TH2 response, and TH17 response. In other embodiments, the immune response provides an enhanced TH1 response, TH2 response, and / or TH17 response. In some embodiments, the compounds or compositions disclosed herein may function as adjuvants (e.g., in vaccines).

[0098] In certain embodiments, the enhanced immune response is either or both a systemic and / or mucosal immune response. In other embodiments, the immune response provides either or both an enhanced systemic immune response and / or an enhanced mucosal immune response. In certain embodiments, the mucosal immune response is a TH1, TH2, or TH17 immune response. In certain embodiments, the mucosal immune response includes an increase in IgA production.

[0099] In certain embodiments, the immunogenic compositions provided herein are used as vaccines, wherein such compositions comprise an immunologically effective amount of one or more antigens.

[0100] Autoimmune diseases are (i) humoral antibodies or autoantibody responses to autoantigens (for example, Graves' primary hyperthyroidism caused by antibodies to TSH receptors), or (ii) cellular responses in which immune cells destroy non-immune cells from which autoantigens originate (for example, thyroid cells). Autoimmune diseases are defined by Hashimoto's thyroiditis or pancreatic β-islet cells (type 1 diabetes). Many autoimmune diseases are a combination of both phenomena, and for example, Hashimoto's disease and type 1 diabetes also have autoantibodies, anti-thyroid peroxidase (TPO) or anti-glutamate decarboxylase (GAD) / islet cells. Autoimmune diseases often have inflammatory elements, including, but are not limited to, increased adhesion molecules (for example, increased vascular cell adhesion molecule-1 (VCAM-1) and altered leukocyte adhesion to the vascular system), for example, colitis, systemic lupus, systemic sclerosis, and vascular complications of diabetes.

[0101] Toll-like receptors (TLRs) are type I transmembrane proteins characterized by an extracellular N-terminal leucine-rich repeat (LRR) domain, followed by an intracellular (cytoplasmic) tail containing a cysteine-rich region, a transmembrane (TM) domain, and a conserved region called the Toll / IL-1 receptor (TIR) ​​domain. TLRs are pattern recognition receptors (PRRs) primarily expressed in immune cells, including, but not limited to, dendritic cells, T lymphocytes, macrophages, monocytes, and natural killer cells. The LRR domain is crucial for ligand binding and associated signaling and is a common feature of PRRs. The TIR domain is important in protein-protein interactions and is associated with the innate immune system. The TIR domain also integrates the larger IL-1 R / TLR superfamily, which consists of three subgroups. The first group includes members with immunoglobulin domains in their extracellular regions, as well as IL-1 and IL-18 receptors and accessory proteins, and ST2. The second group encompasses TLRs. The third group includes intracellular adapter proteins that are important for signaling.

[0102] TLRs are a group of pattern recognition receptors that bind to pathogen-associated molecular patterns (PAMPS) derived from bacteria, fungi, protozoa, and viruses, and function as the first line of defense against invading pathogens. TLRs are essential for inducing the expression of genes involved in inflammatory responses, and TLRs and the innate immune system are crucial processes in the development of antigen-specific adaptive immunity.

[0103] Adaptive (humoral or cellular) immunity is related to the TLR signaling mechanisms of the innate immune system. The innate immune system is a protective immune cell response that functions rapidly to deal with external stimuli, including, but not limited to, bacterial or viral factors. Adaptive immunity is a slower response and involves the differentiation and activation of naive T lymphocytes into T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), or other T cell types. Th1 cells primarily promote cellular immunity, while Th2 cells primarily promote humoral immunity. Pathological expression of innate immune system signals originating from the TLR pathway, despite the host defense system's influence, is involved in causing autoimmune-inflammatory diseases.

[0104] All TLRs appear to function as either homodimers or heterodimers in the recognition of specific or sets of specific molecular determinants present in pathogens, including bacterial cell surface lipopolysaccharides, lipoproteins, bacterial flagellins, and DNA and viral RNA derived from both bacteria and viruses. The cellular response to TLR activation involves the activation of one or more transcription factors, resulting in the production and secretion of cytokines and costimulatory molecules such as interferons, TNF-α, interleukins, MIP-1, and MCP-1, which contribute to the killing and removal of pathogenic invaders. TLR spatial expression is consistent with the host's environmental interface. While a few other Toll-like proteins have been cloned in the genus Drosophila, the human TLR family consists of at least 11 members, TLR1–TLR11, which, due to differences in the cellular expression and signaling pathways they initiate, elicit overlapping but distinct biological responses. Each TLR is expressed on different subsets of leukocytes, and each TLR is specific in its expression pattern and PAMP sensitivity, enabling the detection of various subsets of pathogens and careful monitoring by the immune system. Make it Noh.

[0105] TLRs are distributed throughout the cell. TLR1, TLR2, TLR3, and TLR4 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are expressed in intracellular compartments such as endosomes. TLR3-, TLR7-, or TLR9-mediated recognition of their ligands requires endosome maturation and processing. When macrophages, monocytes, dendritic cells, or non-immune cells that become antigen-presenting cells phagocytose bacteria, the bacteria are degraded, and CpG DNA is released into phagosome-lysosomes or endosome-lysosomes, where it can interact with TLR9 recruited from the endoplasmic reticulum after nonspecific uptake of CpG DNA. Furthermore, when viruses enter cells via receptor-mediated endocytosis, viral components are exposed to the cytoplasm through fusion of the viral membrane with the endosomal membrane. This results in an explosion of TLR ligands such as dsRNA, ssRNA, and CpG DNA to TLR9 in phagosome / lysosome or endosome / lysosomal compartments.

[0106] In the signaling pathways downstream of the TIR domain, TIR domain-containing adapters, MyD88 and / or TRIF, are essential for the induction of cytokines such as TNF-α and IL-12 via all TLRs. While TIR domain-containing adapter molecules are common to all TLRs, individual TLR signaling pathways differ, and activation of a particular TLR results in slightly different patterns of gene expression profiles. For example, activation of the TLR3 and TLR4 signaling pathways leads to the induction of type I interferon (IFN), while activation of the TLR2 and TLR5-mediated pathways does not. However, activation of the TLR7, TLR8, and TLR9 signaling pathways also leads to the induction of type I IFN, but this occurs through a different mechanism than TLR3 / 4-mediated induction.

[0107] Upon association, TLRs initiate a signaling cascade, leading to the activation of NFκB or IRF via adapter molecules containing a TIR domain that induces the adapter protein myeloid differentiation primary response gene 88 (MyD88) or interferon-β (TRIF). The MyD88-dependent pathway is similar to IL-1 receptor signaling, and it is thought that MyD88, which has a C-terminal TIR domain and an N-terminal cell death domain, binds to the TIR domain of the TLR. Upon stimulation, MyD88 recruits IRAK-4 to the TLR through the interaction of the cell death domains of both molecules, promoting IRAK-4-mediated phosphorylation of IRAK-1. Subsequently, phosphorylation of IRAK-1 leads to the recruitment of TNF receptor-associated factor 6 (TRAF6), resulting in the activation of two distinct signaling pathways. One pathway leads to the activation of the AP-1 transcription factor by activating MAP kinase. The other pathway activates the TAK1 / TAB complex, thereby enhancing the activity of the IκB kinase (IKK) complex. When activated, the IKK complex induces phosphorylation and subsequent degradation of the NFκB inhibitor IκB, thereby leading to nuclear translocation of the transcription factor NFκB and initiation of transcription of genes containing NFκB binding sites, such as cytokines, through their promoters. The MyD88-dependent pathway plays a crucial role and is essential for all TLR-mediated inflammatory cytokine production.

[0108] TLR-mediated TRIF-dependent signaling requires the sequential or simultaneous binding of TIR domain-containing adapter proteins, TRAM / TICAM-2 and TRIF / TICAM-1, to the TLR4-TIR domain. Signaling via the TRIF-dependent pathway induces a lower, slower, but more sustained activation of NF-κB via an alternative pathway requiring receptor-interacting protein 1 (RIP1). TRIF-dependent signaling also triggers the activation and nuclear translocation of interferon regulators (IRF)-3 and IRF-7, thereby driving the transcription and subsequent extracellular release of IFNβ. Next, Autocrine or paracrine binding of IFNβ to IFN-α / β receptors activates the JAK / STAT pathway, increasing the expression of IFNα and IFNβ, as well as IFN-inducible chemokines such as interferon-inducible protein-10 (IP-10), regulated expression in activated normal T cells (RANTES), and macrophage chemoattractant protein-1 (MCP-1). Monophosphoryl lipid A (MPLA) and CRX-547 (both TLR4 ligands) exhibit similar TRIF signaling activity, but with reduced MyD88 signaling activity compared to LPS. This TRIF bias response may be responsible for increased therapeutic index, reduced toxicity, and sustained adjuvant activity.

[0109] The compounds and compositions provided herein may be useful in inducing, enhancing, modulating, or suppressing at least one immune response in a host (e.g., TH1 T lymphocyte response, TH2 T lymphocyte response, TH17 T lymphocyte response, cytotoxic T lymphocyte (CTL) response, antibody response, cytokine response, lymphokine response, chemokine response, and inflammatory response). In certain embodiments, the immune response may include the production of at least one or more cytokines (where the cytokines are selected from interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)), the production of one or more interleukins (where the interleukins are selected from IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18, and IL-23), the production of one or more chemokines (where the chemokines are selected from MIP-1α, MIP-1β, RANTES, IP-10, CCL4, and CCL5), and a lymphocyte response selected from memory T cell responses, memory B cell responses, effector T cell responses, cytotoxic T cell responses, and effector B cell responses.

[0110] Cancer immunotherapy generally focuses on inducing innate or adaptive immune responses. Adaptive immune responses can consist of humoral, cellular, or both. Furthermore, the induction of CD4+ T helper cells is well established as necessary for the secondary induction of either antibodies or cytotoxic CD8+ T cells. Antigens that are selective or ideally specific to cancer cells (e.g., polypeptide antigens) provide a potent method for inducing an immune response against cancer.

[0111] The compounds and compositions of the present invention may be used to stimulate an immune response against cancer. The compounds and compositions of the present invention may be used to treat, prevent, or reduce susceptibility to cancers, including, but are not limited to, prostate, breast, lung, ovarian, pancreatic, colorectal and colon, stomach, skin and brain tumors, as well as malignant tumors affecting the bone marrow (including leukemia) and lymphocyte proliferative systems, such as Hodgkin lymphoma and non-Hodgkin lymphoma (including the prevention and treatment of metastatic disease, tumor recurrence, and paraneoplastic syndromes). In certain embodiments, the compounds and compositions are useful as modulators of Toll-like receptor activity and may be used to treat neoplasms, including, but are not limited to, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, carcinoma, sarcoma, leukemia, renal cell carcinoma, Kaposi's sarcoma, myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma.

[0112] The compounds and compositions of the present invention may also be useful in treating, preventing, or reducing susceptibility to food allergies, allergic rhinitis, allergic asthma, allergic skin diseases, seasonal allergies, and related allergic conditions. Other allergies include allergic conjunctivitis, atopic dermatitis, and psoriasis.

[0113] The compounds and compositions of the present invention are, but are not limited to, tuberculosis and mycobacterium avium, leprosy; pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis It may also be useful in treating, preventing, or reducing susceptibility to bacterial, fungal, and protozoan infections, including infections caused by bacteria such as Escherichia, Enterobacter, Salmonella, Staphylococcus, Klebsiella, Proteus, Pseudomonas, Streptococcus, and Chlamydia, as well as fungal infections such as candidiasis, aspergillosis, histoplasmosis, and cryptococcal meningitis.

[0114] The compounds and compositions of the present invention are effective against genital warts, common warts, plantar warts, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, dengue virus, herpes simplex virus (as merely an example, HSV-I, HSV-II, CMV or VZV), molluscum contagiosum, cowpox, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus (CMV), varicella-zoster virus (VZV), rhinovirus, enterovirus, adenovirus, and coronavirus. It may be used to treat, prevent, or reduce susceptibility to viral diseases such as viruses (e.g., SARS), influenza, parainfluenza, mumps virus, measles virus, papovavirus, hepadnavirus, flavivirus, retrovirus, arenavirus (just examples being LCM, Junin virus, Machupovirus, Guanalitovirus, and Lassa fever) and filovirus (just examples being Ebola virus or Marburg virus).

[0115] The compounds and compositions of the present invention may be used to treat, prevent, or reduce susceptibility to prion diseases or transmissible spongiform encephalopathy (TSE), such as Creutzfeldt-Jakob disease or chronic wasting disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and Kuru disease.

[0116] The compounds and compositions of the present invention may be used to treat, prevent, or reduce susceptibility to progressive neurodegenerative diseases (e.g., Alzheimer's disease).

[0117] The compounds and compositions of the present invention may be used to treat, prevent, or reduce the severity of epileptic seizures.

[0118] The compounds and compositions of the present invention can be used to treat, prevent, or reduce susceptibility to, and reduce the severity of, sepsis caused by bacterial, viral, or fungal infections, including wound infections, pneumonia, abdominal infections, renal infections, or bloodstream infections (bacteria), by antagonizing LPS (endotoxin) activation of the TLR4 receptor system.

[0119] The compounds and compositions of the present invention may be used to treat or prevent eye diseases such as macular degeneration, ocular hypertension, and eye infections, or to reduce susceptibility to them.

[0120] The compounds and compositions of the present invention may be used to treat, prevent, or reduce the severity of ischemic events such as ischemia-reperfusion injury (in which tissue damage is caused as a result of ischemic stroke), myocardial ischemia, acute kidney injury, or other ischemic events when blood supply returns to the tissue after a period of time, by releasing inflammatory cytokines via the TLR4 receptor and reducing ischemia or oxygen deficiency.

[0121] The compounds and compositions of the present invention are used by the host or target immune system to target its own tissues, cells, and biomolecules (e.g., peptides, polypeptides, proteins, glycoproteins, lipoproteins, etc.). It may be used to treat, prevent, or reduce susceptibility to autoimmune diseases, including diseases, conditions, or disorders that adversely mediate an immune response to an immune response against (such as roteolipids, lipids, glycolipids, nucleic acids like RNA and DNA, oligosaccharides, polysaccharides, proteoglycans, glycosaminoglycans, and other molecular components of target cells and tissues) or epitopes (specific immunologically defined recognition structures, such as those recognized by antibody variable region complementarity-determining regions (CDRs) or T cell receptors).

[0122] Therefore, autoimmune diseases are characterized by abnormal immune responses involving either cells or antibodies, and in either case, such abnormal immune responses are against normal, autologous tissues. Autoimmune diseases in mammals can generally be classified into one of two distinct categories: cell-mediated diseases (i.e., T-cell diseases) or antibody-mediated diseases. Non-exclusive examples of cell-mediated autoimmune diseases include multiple sclerosis, rheumatoid arthritis, Hashimoto's thyroiditis, type 1 diabetes mellitus (juvenile diabetes mellitus), and autoimmune uveoretinitis. Non-exclusive examples of antibody-mediated autoimmune diseases include myasthenia gravis, systemic lupus erythematosus (or SLE), Graves' disease, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune asthma, cryoglobulinemia, thrombotic thrombocytopenic purpura, primary biliary cirrhosis, and pernicious anemia.

[0123] 4. Pharmaceutical composition and administration In another embodiment of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds described herein and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more further therapeutic agents. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0124] The pharmaceutical compositions of the present invention can be produced by methods well known in the art, for example, by conventional mixing, dissolving, granulation, sugar coating, polishing, emulsification, encapsulation, capture, or freeze-drying processes.

[0125] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, and pectinate. Examples include phosphates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfonates, undecanoates, and valersates. Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N(C) salts. 1~4 Examples include alkyl) tetra salts. The present invention also envisions the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble, oil-soluble, or dispersible products can be obtained by such quaternization. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, amine cations formed using counterions such as non-toxic ammonium, quaternary ammonium and halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl (e.g., phenyl / substituted phenyl) sulfonates.

[0126] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, when used herein, may include any solvent, diluent, or other liquid vehicle, dispersion or suspension aid, surfactant, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, etc., to suit a desired specific dosage form. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. Any conventional carrier medium is considered to be within the scope of the present invention unless it is incompatible with the compounds of the present invention, for example, by producing some undesirable biological effect or by adversely interacting with any other component of the pharmaceutically acceptable composition.Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene-block polymers, lanolin, sugars, e.g., lactose, glucose and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose Examples of ingredients include methylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenic substances removed distilled water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solution; and other non-toxic synthetic lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants may also be present in the composition at the discretion of the compounder.

[0127] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intrasacral, intradermally, intranasally, vaginally, intraperitoneally, intramuscularly, intravenously, intratumorally, topically (as powders, ointments, or intravenous drips), orally, sublingually, or as oral or nasal sprays, depending on the severity of the disease being treated.

[0128] Pharmaceutical compositions for parenteral injection, pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, The product comprises a suspension or emulsion and a sterile powder for reconstitution into a sterile injection solution or dispersion immediately before use. Suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), vegetable oils (such as olive oil), injection organic acid esters (such as ethyl oleate), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of a coating material such as lecithin, and in the case of a dispersion, by maintaining the required particle size and by the use of a surfactant.

[0129] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be achieved by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride. Sustained absorption of injectable drug forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0130] In some cases, it is desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of crystalline or amorphous material having low water solubility. Then, the absorption rate of the drug depends on its dissolution rate, which may therefore depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered dosage forms is achieved by dissolving or suspending the drug in an oil vehicle.

[0131] Liquid dosage forms for oral or nasal administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, for example, water or other solvents, solubilizers and emulsifiers, and inert diluents commonly used in the art, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0132] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, cements, putties, thin films, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0133] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifiers and may have compositions that selectively release only the active ingredient, or preferentially in a delayed manner, in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules with excipients such as lactose and high molecular weight polyethylene glycol.

[0134] The active compound may also be microencapsulated using one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also include, as in common practice, further substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include buffers. These may optionally contain opacifiers and may have compositions that selectively release only the active ingredient, or preferentially in a delayed manner, in a specific part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0135] The compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound.

[0136] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if necessary. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present invention. Furthermore, the present invention envisions the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compounds to the body. Such dosage forms are prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers may also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0137] In preferred embodiments, the compounds of the present invention described herein may be formulated as either pharmaceutically acceptable salts or free acids. The compounds may be formulated with a pharmaceutically acceptable vehicle for injection, inhalation, ingestion, or other suitable forms of administration. The pharmaceutically acceptable vehicle is a medium, solution, or matrix that does not interfere with the immunomodulatory activity of the compound, is not harmful to the patient, and preferably provides considerable physical and chemical stability to the API. Examples of pharmaceutically acceptable vehicles include aqueous solutions, liposomes, oil-in-water or water-in-oil emulsions, polymer particles, block copolymers, aqueous dispersions, microparticles, protein solutions, or biodegradable particles for sustained release. For example, the vehicle may be microspheres, nanoparticles, or fine particles having the compounds of the present invention in or adsorbed on the matrix of the particles. The vehicle may also be an aqueous solution, buffer, or micelle dispersion containing monoethanolamine, triethylamine, triethanolamine, or other chemicals that make the formulation alkaline. The vehicle may be a suspension containing aluminum hydroxide, aluminum phosphate, calcium hydroxide, or calcium phosphate, where the compound may be adsorbed onto a metal surface. The vehicle can be any solvent, buffer, dispersion medium, vehicle, coating, diluent. This may also include antimicrobial and antifungal agents, mucosal adhesives, mucosal penetrating agents, absorption retarders, fillers, suspensions, colloids, etc. The use of such vehicles for APIs is well known to those skilled in the art. Except for vehicles or agents that are incompatible with APIs, their use in prophylactic or therapeutic compositions is conceivable.

[0138] In one embodiment, the compounds of the present invention are formulated in 2% glycerol or 2% glycine as an isotonic nanodispersion having a pH in the range of 5 to 7.4. In another embodiment, the compounds of the present invention are formulated in the lipid bilayer of liposomes. These liposomes may also contain other compounds having immunomodulatory activity to achieve co-formulation with the compounds of the present invention. More generally, the compounds of the present invention may be encapsulated in nanoparticles or microparticles, emulsions or other suitable vehicles described above, which may also contain other immunomodulatory compounds or excipients to enhance biological activity, improve stability, or modify the pharmacokinetics of the formulation in a preferred manner.

[0139] The compounds described herein may be administered as pharmaceutical compositions containing the compound of interest, in combination with one or more pharmaceutically acceptable carriers. The term “therapeutic dose” of the compound means a sufficient amount of the compound to treat a disorder with a reasonable benefit-risk ratio applicable to any medical treatment. However, it is understood that the total daily dose of the compound and composition may be determined by the attending physician within reasonable medical judgment. A specific therapeutically effective dose level for any particular patient may depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient’s age, weight, overall health and medical history, sex and dietary habits; the timing of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. For example, it is within the scope of the skills of the art to start administration of the compound at a lower level than required to obtain the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. The actual dose levels of the active ingredient in a pharmaceutical composition may be varied to obtain an amount of the active compound effective in obtaining the desired therapeutic response for a particular patient and a particular method of administration. In the treatment of certain medical conditions, repeated or long-term administration of the compound may be required to obtain the desired therapeutic response. "Repeated or long-term administration" refers to the administration of the compound daily (i.e., every day) or intermittently (i.e., not daily) over a period of several days, weeks, months, or longer.

[0140] In adults, the dosage is generally about 0.00001 to 100 mg / kg, preferably about 0.0001 to 100 mg / kg body weight / day, by inhalation, intranasal, intratumoral, sublingual, intradermal, or intraperitoneal administration; about 0.00001 to 100 mg / kg, preferably 0.0001 to 70 mg / kg, more preferably 0.5 to 10 mg / kg body weight / day, by oral administration; and about 0.00001 to 50 mg / kg, preferably 0.0001 to 1 mg / kg body weight / day, by intravenous administration.

[0141] Combination therapy includes the administration of a single dosage form containing one or more of the compounds described herein and one or more further pharmaceuticals, as well as the administration of the compounds and each of the further pharmaceuticals in their own separate dosage forms. For example, the compounds described herein and one or more further pharmaceuticals may be administered together to a patient in a single oral administration composition having a certain ratio of each active ingredient, such as a tablet or capsule; or each drug may be administered in a separate oral dosage form. When separate dosage forms are used, the compounds and one or more further pharmaceuticals may be administered essentially simultaneously (e.g., at the same time) or separately at staggered times (e.g., consecutively).

[0142] Further pharmaceuticals include antibiotics or antibacterial agents, anticancer agents, antiemetics, antifungal agents, and anti-inflammatory drugs. These include antiviral agents, immunomodulators (e.g., immune checkpoint inhibitors), and other Toll-like receptor modulators.

[0143] Anticancer drugs (i.e., chemotherapy drugs) include alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferative agents, aurora kinase inhibitors, Bcl-2 family protein (e.g., Bcl-xL, Bcl-2, Bcl-w) inhibitors, Bcr-Abl kinase inhibitors, bioresponse modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia virus oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormone therapy, and APTO Examples include inhibitors of cis protein (lAP), inserts, kinase inhibitors, mammalian targets of rapamycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors, microRNAs, small molecule inhibitory ribonucleic acid (siRNA), nonsteroidal anti-inflammatory drugs (NSAIDs), poly(ADP)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutic agents, polo-like kinase inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid / deltoid plant alkaloids, and topoisomerase inhibitors.

[0144] Preferred anticancer chemotherapy drugs: cyclophosphamide, doxo / daunorubicin, carboplatin derivatives (e.g., cisplatin, oxaliplatin, carboplatin), HDAC inhibitors, gemcitabine, 5-fluorouracil, taxol derivatives (e.g., taxol, paclitaxel, taxotere), mitomycin C, immune checkpoint inhibitors.

[0145] Examples of HDAC inhibitors include suberoylanilide hydroxamic acid (SAHA), [4-(2-amino-phenylcarbamoyl)-benzyl]-carbamate pyridine-3-yl methyl ester and its derivatives, butyric acid, pyroxamide, trichostatin A, oxamflatin, apicidine, depsipeptide, depdesin, trapoxin, vorinostat (Zolinza®), and compounds disclosed in International Publication No. 02 / 22577.

[0146] Immunomodulators include interferons, antigens, tumor phagocytic inducers, and other immune enhancers (e.g., immune checkpoint inhibitors).

[0147] Examples of interferons include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-la, ACTIMMUNE® (interferon γ-lb), or interferon γ-nl, as well as combinations thereof.

[0148] Examples of tumor phagocytic inducers include anti-CD47 monoclonal antibodies (e.g., Hu5F9-G4, CC-90002, ZF1, AMMS4-G4, IBI188, SRF231), anti-SIRPα fusion proteins (e.g., TTI-621, TTI-622), anti-SIRPα monoclonal antibodies (e.g., OSE-172), anti-CD47 / antitumor-associated antigen bispecific antibodies, and inhibitors of leukocyte immunoglobulin-like receptor B1 (LILRB1) that bind to major histocompatibility complex class 1 β2-microglobulin (MHC class 1 β2M).

[0149] Examples of anti-CD47 / antitumor-related antigen bispecific antibodies include anti-CD47 / CD19 bispecific antibodies (e.g., TG-1801), anti-CD47 / mesoterin bispecific antibodies (e.g., NI-1801), anti-CD47 / 4-1BB bispecific antibodies (e.g., DSP107), anti-CD47 / CD20 bispecific antibodies, and anti-CD47 / CD33 bispecific antibodies (e.g., HMBD004) is one example.

[0150] Examples of immune checkpoint inhibitors include PD-1 inhibitors (e.g., nivolumab, pidilizumab, sintilimab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab, BMS-936559), CTLA4 inhibitors (e.g., ipilimumab, tremelimumab), or IDO inhibitors (e.g., indoximod, epacadostat).

[0151] Other immunomodulatory agents include ALFAFERONE®, BAM-002, BEROMUN® (Tasonelmin), BEXXAR® (Tositumomab), CamPath® (Alemtuzumab), CTLA4 (Cytotoxic Lymphocyte Antigen 4), Dacarbazine, Denileukin, Epiratuzumab, GRANOCYTE® (Lenograstim), Lentinan, Leukocyte Alpha Interferon, Imiquimod, MDX-010, Melanoma Vaccine, Mitsumomab, Morglamostim, MYLOTARG™ (Gemtuzumab Ozogamicin), NEUPOGEN® (Filgrastim), OncoVAC-CL, OvaRex (Registered Trademark). Examples include (olegobomab), pemtumomab (Y-muHMFGl), PROVENGE®, salglamostim, schizophyllan, teseroykin, TheraCys®, ubenimex, VIRULIZIN®, Z-IOO, WF-IOO, PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-ibritumomab / tiuxetan), and similar products including, but not limited to, STING (interferon gene stimulant) and NOD (nucleotide-binding oligomeric domain-like receptor) agonists.

[0152] In one embodiment, the pharmaceutical composition of the present invention is a vaccine comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and an antigen optionally.

[0153] The antigens for use in the immunogenic compositions provided herein are provided in effective amounts (e.g., amounts effective for use in therapeutic or prophylactic methods). For example, the immunogenic compositions of the present invention may be used to treat or prevent diseases or conditions such as infectious diseases and cancer. Exemplary antigens include, but are not limited to, tumor antigens and infectious disease antigens. The antigens for use in the immunogenic compositions provided herein are typically macromolecules (e.g., polypeptides, polysaccharides, polynucleotides) that are foreign to the host.

[0154] An antigen can be any target epitope, molecule (including biomolecules), molecular complex (including molecular complexes containing biomolecules), intracellular aggregate, cell, or tissue in which induction or enhancement of immune activity is required. Often, the term antigen can refer to the polypeptide antigen of interest. However, as used herein, antigen can also refer to a recombinant construct (e.g., an expression construct) encoding the polypeptide antigen of interest. In some preferred embodiments, the antigen may be, derived from, or immunologically cross-reactive with infectious pathogens and / or epitopes, biomolecules, cells, or tissues associated with infectious diseases, cancer, autoimmune diseases, allergies, asthma, or any other pathological conditions in which stimulation of an antigen-specific immune response is desirable or beneficial.

[0155] Bacterial antigens. Suitable bacterial antigens for use in the immunogenic compositions provided herein include, but are not limited to, proteins, polysaccharides, lipopolysaccharides, polynucleotides, and outer membrane vesicles isolated, purified, or derived from bacteria. In certain embodiments, the bacterial antigen comprises bacterial lysates and inactivated bacterial preparations. In certain embodiments, the bacterial antigen is produced by recombinant expression. In certain embodiments, bacterial anti The antigen includes an epitope exposed on the surface of the bacterium during at least one stage of its life cycle. The bacterial antigen is preferably conserved in multiple serotypes. In certain embodiments, bacterial antigens include antigens derived from one or more of the bacteria described below, as well as specific antigen examples specified below.

[0156] Neisseria meningitidis: Meningitis antigens include, but are not limited to, proteins, sugars (including polysaccharides, oligosaccharides, lipooligosaccharides, or lipopolysaccharides) or outer membrane vesicles purified from or derived from the Neisseria meningitidis serotype group, such as A, C, W135, Y, X, and / or B. In certain embodiments, meningitis protein antigens are selected from adhesion proteins, autotransporters, toxins, iron-acquiring proteins, and membrane-associated proteins (preferably endogenous outer membrane proteins).

[0157] Streptococcus pneumoniae: Antigens of Streptococcus pneumoniae include, but are not limited to, sugars (including polysaccharides or oligosaccharides) and / or proteins derived from Streptococcus pneumoniae. The sugars may be polysaccharides of a certain size that arise during the purification of bacterial sugars, or they may be oligosaccharides obtained by the fragmentation of such polysaccharides. In the heptavalent PREVNAR® product, for example, six sugars are shown as intact polysaccharides, while one (1 SC serotype) is shown as an oligosaccharide. In certain embodiments, the sugar antigen is selected from one or more of the following Streptococcus pneumoniae serotypes: 1, 2, 3, 4, 5, 6A, 68, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and / or 33F. The immunogenic composition may comprise multiple serotypes, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or more. Combinations of 7-valent, 9-valent, 10-valent, 11-valent, and 13-valent conjugates are already known in the art, as are combinations of 23-valent unconjugates. For example, a decavalent combination may include sugars derived from serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F. An eleven-valent combination may further include sugars derived from serotype 3. A dodecavalent combination may be added to the decavalent mixture: serotypes 6A and 19A; 6A and 22F; 19A and 22F; 6A and 15B; 19A and 15B; 22F and 15B; a thirteen-valent combination may be added to the eleven-valent mixture: serotypes 19A and 22F; 8 and 12F; 8 and 15B; 8 and 19A; 8 and 22F; 12F and 15B; 12F and 19A; 12F and 22F; 15B and 19A; 15B and 22F, etc.In certain embodiments, the protein antigen is described in International Publication No. 98 / 18931, International Publication No. 98 / 18930, U.S. Patent No. 6,699,703, U.S. Patent No. 6,800,744, International Publication No. 97 / 43303, International Publication No. 97 / 37026, International Publication No. 02 / 079241, International Publication No. 02 / 34773, International Publication No. 00 / 06737, International Publication No. 00 / 06738, International Publication No. 00 / 58475, International Publication No. 2003 / 0 Pamphlet No. 82183, International Publication No. 00 / 37105, International Publication No. 02 / 22167, International Publication No. 02 / 22168, International Publication No. 2003 / 104272, International Publication No. 02 / 08426, International Publication No. 01 / 12219, International Publication No. 99 / 53940, International Publication No. 01 / 81380, International Publication No. 2004 / 092209, International Publication No. 00 / 76540, International Publication No. 2007 / 116322, LeMieux. et al., Infect. Imm. (2006) 74:2453-2456, Hoskins et al., J. Bacterial. (2001) 183:5709-5717, Adamou et al., Infect. Immun. (2001) 69 Proteins can be selected from those identified in (2):949-958, Briles et al., J. Infect. Dis. (2000) 182:1694-1701, Talkington et al., Microb. Pathog. (1996) 21(1):17-22, Bethe et al., FEMS Micro biol. Lett. (2001) 205(1):99-104, Brown et al., Infect. Immun. (2001) 69:6702-6706, Whalen et al., FEMS Immunol. Med. Microbial. (2005) 43:73-80, and Jomaa et al., Vaccine (2006) 24(24):5133-5139. In other embodiments, the Streptococcus pneumoniae protein may be selected from the Poly Histidine Triad family (PhtX), Choline-binding protein family (CbpX), CbpX truncate, LytX family, LytX truncate, CbpX truncate-LytX truncate chimeric protein, Pneumolysin (Ply), PspA, PsaA, Sp128, Sp101, Sp130, Spl25, Sp133, and the pneumococcal pneumoniae subunit.

[0158] Streptococcus pyogenes (Group A Streptococcus): Group A Streptococcus Examples of Streptococcus antigens include, but are not limited to, proteins identified in International Publication No. 02 / 34771 or International Publication No. 2005 / 032582 (including GAS 40), fusions of GAS M protein fragments (including those described in International Publication No. 02 / 094851 and Dale, Vaccine (1999) 17:193-200 and Dale, Vaccine 14(10):944-948), fibronectin-binding protein (Sfb 1), streptococcal heme-related protein (Shp), and streptolynzin S (SagA).

[0159] Moraxella catarrhalis: Moraxella antigens include, but are not limited to, those identified in International Publication No. 02 / 18595 and International Publication No. 99 / 58562, outer membrane protein antigen (HMW-OMP), C-antigen, and / or LPS.

[0160] Bordetella pertussis: Pertussis antigens include, but are not limited to, pertussis holotoxin (PT) and filamentous hemagglutinin (FHA) derived from Bordetella pertussis, and optionally include combinations with partactin and / or agglutinogens 2 and 3.

[0161] Burkholderia: The Burkholderia genus is not limited to antigens, but includes Bacillus subtilis (Burkholderia) Examples include Burkholderia pseudomallei and Burkholderia cepacia.

[0162] Staphylococcus aureus: Staphylococcus aureus antigens include, but are not limited to, polysaccharides and / or proteins derived from Staphylococcus aureus. Staphylococcus aureus polysaccharides include, but are not limited to, type 5 and type 8 capsular polysaccharides (CPS and CPS), e.g., Staph VAX®, type 336 polysaccharide (336PS), and polysaccharide intercellular adhesion (PIA, also known as PNG), which are optionally conjugated with non-toxic recombinant Pseudomonas aeruginosa exotoxin A. Examples of Staphylococcus aureus (S. aureus) proteins include, but are not limited to, antigens derived from surface proteins, invasine (leucocidine, kinase, hyaluronidase), surface factors that inhibit phagocytic uptake (capsules, protein A), carotenoids, catalase products, protein A, coagulase, coagulation factors, and / or membrane-damaging toxins that lyse eukaryotic cell membranes (optionally detoxified) (hemolysin, leukotoxin, leucocidine). In certain embodiments, the Staphylococcus aureus (S. aureus) antigen is described in International Publication No. 02 / 094868, International Publication No. 2008 / 019162, International Publication No. 02 / 059148, International Publication No. 02 / 102829, International Publication No. 03 / 011899, International Publication No. 2005 / 079315, International Publication No. 02 / 077183, International Publication No. 99 / 27109, International Publication No. 01 / Proteins may be selected from those identified in Brochure No. 70955, International Publication No. 00 / 12689, International Publication No. 00 / 12131, International Publication No. 2006 / 032475, International Publication No. 2006 / 032472, International Publication No. 2006 / 032500, International Publication No. 2007 / 113222, International Publication No. 2007 / 113223, and International Publication No. 2007 / 113224. In other embodiments, the Staphylococcus aureus (S. aureus) antigen may be selected from IsdA, IsdB, IsdC, SdrC, SdrD, SdrE, ClfA, ClfB, SasF, SasD, SasH(AdsA), Spa, EsaC, EsxA, EsxB, Emp, HlaH35L, CPS, CPS, PNGA, and 336PS.

[0163] Staphylococcus epidermis: While not limited to specific antigens, slime-associated antigens (SAA) can be cited as examples of antigens associated with Staphylococcus epidermis (S. epidermidis).

[0164] Clostridium tetani (tetanus): Examples of tetanus antigens include, but are not limited to, tetanus toxoid (TT). In certain embodiments, such antigens are used as carrier proteins to be used in combination with / conjugated with immunogenic compositions provided herein.

[0165] Clostridium perfringens: While not limited to specific antigens, epsilon toxin derived from Clostridium perfringens is a possible candidate.

[0166] Clostridium botulinum (botulism): While not limited to botulism antigens, those derived from Clostridium botulinum are often cited as causes of botulism.

[0167] Diphtheriae (Cornynebacterium diphtheriae): Diphtheria antigens include, but are not limited to, diphtheria toxins, preferably detoxified, such as CRM197. Furthermore, antigens that can modulate, inhibit, or are associated with ADP-ribosylation are envisioned for combination / conjugation with immunogenic compositions provided herein. In certain embodiments, diphtheria toxoids are used as carrier proteins.

[0168] Haemophilus influenzae B (Hib): Hib antigens are not limited to Hib antigens, but Hib sugar antigens are a possibility. Pseudomonas aeruginosa: Pseudomonas genus Antigens include, but are not limited to, endotoxin A, Wzz protein, Pseudomonas aeruginosa LPS, LPS isolated from PAOI (serotype 05) and / or outer membrane proteins (including outer membrane protein F (OprF)).

[0169] Legionella pneumophila. Bacterial antigen derived from Legionella pneumophila.

[0170] Coxiella burnetii. Bacterial antigen derived from Coxiella burnetii.

[0171] Bacterial antigens derived from the genus Brucella, including but not limited to B. abortus, B. canis, B. melitensis, B. neotomae, B. ovis, B. suis, and B. pinnipediae.

[0172] The genus Francisella. While not limited to these, bacterial antigens derived from the genus Francisella include F. nobicida, F. philomiragia, and F. tularensis.

[0173] Streptococcus agalactiae (Group B Streptococcus): Group B Streptococcus antigens include, but are not limited to, those specified in International Publication No. 02 / 34771, International Publication No. 03 / 093306, International Publication No. 04 / 041157, or International Publication No. 2005 / 002619, including proteins or sugar antigens (including proteins GBS 80, GBS 104, GBS 276, and GBS 322, and sugar antigens derived from serotypes Ia, lb, Ia / c, II, III, IV, V, VI, VII, and VIII).

[0174] Neiserria gonorrhoeae: Gonorrhoeae antigens are not limited to those listed above, but include Por (or porin) proteins, e.g., PorB (see Zhu et al., Vaccine (2004) 22:660-669), transferrin-binding proteins, e.g., TbpA and TbpB (see Price et al., Infection and Immunity (2004) 71(1):277-283), turbidity proteins (such as Opa), reducible proteins (Rmp), and outer membrane vesicle (OMV) preparations (see Plante et al., J Infectious Diseases). See Disease (2000) 182:848-855 for more information; see also, for example, International Publication No. 99 / 24578, International Publication No. 99 / 36544, International Publication No. 99 / 57280, and International Publication No. 02 / 079243).

[0175] Chlamydia trachomatis: Chlamydia trachomatis antigens include, but are not limited to, antigens derived from serotypes A, B, Ba, and C (drugs for trachoma, a cause of blindness), serotypes L1, L2, and L3 (associated with lymphogranuloma inguinalis), and serotype DK. In certain embodiments, Chlamydia trachomatis antigens include, but are not limited to, PepA(CT045), Antigens identified in International Publications 00 / 37494, 03 / 049762, 03 / 068811, or 05 / 002619 include LcrE (CT089), ArtJ (CT381), DnaK (CT396), CT398, OmpH-like (CT242), L7 / L12 (CT316), OmcA (CT444), AtosS (CT467), CT547, Eno (CT587), HrtA (CT823), and MurG (CT761).

[0176] Treponema pallidum (syphilis): While not limited to syphilis antigens, the TmpA antigen is a notable example.

[0177] Haemophilus ducreyi (causes chancroid): While not limited to all, the outer membrane protein (DsrA) is a known antigen of Haemophilus ducreyi.

[0178] Enterococcus faecalis or Enterococcus faecium: Antigens include, but are not limited to, trisaccharide repeats or antigens derived from other Enterococcus species.

[0179] Helicobacter pylori: While not limited to specific antigens, H pylori antigens include Cag, Vac, Nap, HopX, HopY, and / or urease antigens.

[0180] Staphylococcus saprophyticus: While not limited to specific antigens, the 160kDa hemagglutinin of the S. saprophyticus antigen is a possible candidate.

[0181] While not limited to Yersinia enterocolitica antigens, LPS is one example.

[0182] E. coli: E. coli antigens include enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAggEC), and homoadherent E. coli (E. coli). i) (DAEC), enteropathogenic E. coli (E. coli) (EPEC), extraintestinal pathogenic E. coli (E. coli) (ExPEC) and / or enterohemorrhagic E. coli (EHEC). ExPEC antigens are not limited to, but include co-colony-forming factors (orf3526), ​​orf353, bacterial Ig-like domain (group 1) proteins (orf405), orf1364, NodT family outer membrane factor lipoprotein efflux transporter (orfl 767), gspK (orf3515), gspJ (orf3516), tonB-dependent siderophore receptor (orf3597), ciliated protein (orf3613), upec-948, upec-1232, A-chain precursor of type I ciliated protein (upec-1875), yap H homolog (upec-2820), and hemolyzin A (recp-3768).

[0183] Bacillus anthracis (anthrax): The Bacillus anthracis antigen is not limited to, but may include component A (lethal factor (LF) and edema factor (EF)), and both factors may have a common component B known as a protective antigen (PA). In certain embodiments, the Bacillus anthracis antigen is selectively detoxified.

[0184] Plague bacterium (Yersinia pestis) (plague): Plague antigens include, but are not limited to, F1 capsule antigen and Yersinia pestis V antigen.

[0185] Humanized Mycobacterium tuberculosis: Tuberculosis antigens include, but are not limited to, lipoproteins, BCG antigen, antigen 858 fusion protein (Ag85B), M72, M72F, ID93, ESAT-6 (selectively formulated in cationic lipid vesicles), humanized Mycobacterium tuberculosis (Mtb) isocitrate dehydrogenase-related antigen, and MPT51 antigen.

[0186] Rickettsia genus: Antigens include, but are not limited to, outer membrane proteins (including outer membrane proteins A and / or B (OmpB)) and surface protein antigens (SPAs).

[0187] Listeria monocytogenes: While not limited to bacterial antigens, those derived from Listeria monocytogenes are often cited.

[0188] Chlamydia pneumoniae: Antigens include, but are not limited to, those identified in International Publication No. 02 / 02606.

[0189] Vibrio cholerae: Antigens include, but are not limited to, proteinase antigens, LPS, especially the lipopolysaccharide of Vibrio cholerae II, O1 Inaba O-specific polysaccharide, Vibrio cholerae O139, the antigen of the IEM108 vaccine, and Zonula occludens toxin (Zot).

[0190] Salmonella typhi (typhoid fever): Antigens include, but are not limited to, capsular polysaccharides, preferably conjugates (Vi, i.e., vax-TyVi).

[0191] Borrelia burgdorferi (Lyme disease): Antigens are not limited to lipoproteins (OspA, OspB, Osp Other surface proteins (such as C and Osp D), other surface proteins such as OspE-related proteins (Erps), decorin-binding proteins (such as DbpA), and antigen-mutating VI proteins, such as antigens associated with P39 and P13 (intrinsic membrane proteins, VIsE antigen mutant proteins).

[0192] Porphyromonas gingivalis: While not limited to specific antigens, P. gingivalis outer membrane protein (OMP) is a possible antigen.

[0193] Klebsiella genus: Antigens include, but are not limited to, OMP (including OMP A) or polysaccharides conjugated to tetanus toxoids as optional.

[0194] Other bacterial antigens used in the immunogenic compositions provided herein include, but are not limited to, any of the above-mentioned capsular antigens, polysaccharide antigens, protein antigens, or polynucleotides. Examples include cytoplasmic antigens. Other bacterial antigens used in the immunogenic compositions provided herein include, but are not limited to, outer membrane vesicle (OMV) preparations. Furthermore, other bacterial antigens used in the immunogenic compositions provided herein include, but are not limited to, live, attenuated, and / or purified forms of any of the above-mentioned bacteria. In certain embodiments, the bacterial antigens used in the immunogenic compositions provided herein are derived from Gram-negative bacteria, while in other embodiments, they are derived from Gram-positive bacteria. In certain embodiments, the bacterial antigens used in the immunogenic compositions provided herein are derived from aerobic bacteria, while in other embodiments, they are derived from anaerobic bacteria.

[0195] Viral antigens. Suitable viral antigens for use in the immunogenic compositions provided herein include, but are not limited to, inactivated (or dead) viruses, attenuated viruses, split virus preparations, purified subunit preparations, viral proteins isolated, purified from or derived from viruses, virus-like particles (VLPs), and polynucleotide antigens isolated, purified from or derived from viruses, or that can be recombinantly synthesized. In certain embodiments, the viral antigen is derived from a virus grown in a cell culture or other substrate. In other embodiments, the viral antigen is expressed by recombinant means. In certain embodiments, the viral antigen preferably includes an epitope exposed on the surface of the virus during at least one stage of its life cycle. The viral antigen is preferably conserved in multiple serotypes or isolates. Suitable viral antigens for use in the immunogenic compositions provided herein include, but are not limited to, antigens derived from one or more of the viruses described below, as well as specific antigen examples specified below.

[0196] Orthomyxovirus: Viral antigens may include, but are not limited to, those derived from orthomyxoviruses, such as influenza A, B, and C. In certain embodiments, the orthomyxovirus antigen is selected from one or more viral proteins, which include one or more hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), substrate protein (M1), membrane protein (M2), and transcriptase components (PB1, PB2, and PA). In certain embodiments, the viral antigen includes HA and NA. In certain embodiments, the influenza antigen is derived from an inter-pandemic (perennial) influenza strain, while in other embodiments, the influenza antigen is derived from a strain that has the potential to cause a pandemic (i.e., an influenza strain having a novel hemagglutinin compared to the hemagglutinins in currently circulating strains, or an influenza strain that is pathogenic to birds and has the potential to spread horizontally in human populations, or an influenza strain that is pathogenic to humans).

[0197] Paramyxoviridae viruses: Viral antigens are not limited to those derived from Paramyxoviridae viruses, such as Pneumovirus (RSV), Paramyxovirus (PIV), Metapneumovirus, and Morbillivirus (measles).

[0198] Pneumovirus: The viral antigen is not limited to pneumoviruses, but examples include those derived from pneumoviruses such as respiratory syncytial virus (RSV), bovine respiratory syncytial virus, mouse pneumonia virus, and turkey rhinotracheitis virus. Preferably, the pneumovirus is RSV. In one embodiment, the pneumovirus antigen is selected from one or more of the following proteins, which include a surface protein fusion (F), glycoprotein (G), and small hydrophobic protein (SH), substrate proteins M and M2, nucleocapsid proteins N, P, and L, and non-structural proteins NS1 and NS2. In another embodiment, the pneumovirus antigen comprises F, G, and M. In a particular embodiment, the pneumovirus antigen is formulated in or derived from a chimeric virus, such as a chimeric RSV / PIV virus containing components of both RSV and PIV, as merely one example.

[0199] Paramyxovirus: Viral antigens include, but are not limited to, those derived from paramyxoviruses, such as parainfluenza viruses types 1-4 (PIV), mumps, Sendai virus, Simian virus 5, bovine parainfluenza virus, Nipah virus, henipavirus, and Newcastle disease virus. In certain embodiments, the paramyxovirus is PIV or mumps. In certain embodiments, the paramyxovirus antigen is selected from one or more of the following proteins: hemagglutinin-neuraminidase (HN), fusion proteins F1 and F2, nucleoprotein (NP), phosphoprotein (P), macroprotein (L), and substrate protein (M). In other embodiments, the paramyxovirus protein includes HN, F1, and F2. In certain embodiments, the paramyxovirus antigen is formulated in or derived from a chimeric virus, such as a chimeric RSV / PIV virus containing components of both RSV and PIV, as merely one example. Commercially available mumps vaccines include attenuated live mumps virus in monovalent form or in combination with the measles and rubella vaccine (MMR). In other embodiments, the paramyxovirus is Nipahvirus or Henipavirus, and the antigen is selected from one or more of the following proteins: fusion (F) protein, glycoprotein (G) protein, substrate (M) protein, nucleocapsid (N) protein, giant (L) protein, and phosphoprotein (P).

[0200] Poxyiridae: Viral antigens include, but are not limited to, those derived from orthopoxviruses such as Variola vera, which includes Variola major and Variola minor.

[0201] Metapneumovirus: The viral antigen may include, but is not limited to, metapneumoviruses, such as human metapneumovirus (hMPV) and trimetaphenovirus (aMPV). In certain embodiments, the metapneumovirus antigen is selected from one or more of the following proteins, which include a surface protein fusion (F), glycoprotein (G) and small hydrophobic protein (SH), substrate proteins M and M2, and nucleocapsid proteins N, P and L. In other embodiments, the metapneumovirus antigen includes F, G and M. In certain embodiments, the metapneumovirus antigen is formulated in or derived from a chimeric virus.

[0202] Morbillivirus: Viral antigens include, but are not limited to, those derived from morbillivirus, such as measles. In certain embodiments, the morbillivirus antigen is selected from one or more of the following proteins: hemagglutinin (H), glycoprotein (G), fusion factor (F), macroprotein (L), nucleoprotein (NP), polymerase phosphoprotein (P), and substrate (M). Commercially available measles vaccines typically include those for mumps and rubella (MMR). One example is a combination of attenuated live measles viruses.

[0203] Picornavirus: Viral antigens may be derived from picornaviruses, such as enterovirus, rhinovirus, hepamavirus, cardiovirus, and aphthovirus, but are not limited to these. In certain embodiments, the antigen is derived from enterovirus, while in other embodiments, the enterovirus is poliovirus. In yet another embodiment, the antigen is derived from rhinovirus. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0204] Enterovirus: Viral antigens may be derived from enteroviruses, such as poliovirus types 1, 2, or 3, coxsackievirus types 1-22 and 24, coxsackievirus types 1-6, echovirus (ECHO) types 1-9, 11-27 and 29-34, and enterovirus types 68-71. In certain embodiments, the antigen is derived from an enterovirus, while in other embodiments, the enterovirus is poliovirus. In certain embodiments, the enterovirus antigen is selected from one or more of the following capsid proteins: VPO, VP1, VP2, VP3, and VP4. Commercially available polio vaccines include inactivated polio vaccine (IPV) and oral poliovirus vaccine (OPV). In certain embodiments, the antigen is formulated into virus-like particles.

[0205] Bunyavirus: The viral antigens are not limited to those derived from orthobunyaviruses, such as California encephalitis virus; phleboviruses, such as Rift Valley fever virus; or nairoviruses, such as Crimean-Congo hemorrhagic fever virus.

[0206] Rhinovirus: Viral antigens include, but are not limited to, those derived from rhinovirus. In certain embodiments, the rhinovirus antigen is selected from one or more of the following capsid proteins: VPO, VP1, VP2, VP2, and VP4. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0207] Hepamavirus: While not limited to specific viral antigens, hepamaviruses, such as those derived from hepatitis A virus (HAY), are commonly cited as examples. Inactivated HAY vaccines are commercially available.

[0208] Togavirus: Viral antigens may be derived from togaviruses, such as rubivirus, alphavirus, or arterivirus, but are not limited to these. In certain embodiments, the antigen is derived from rubivirus, for example, rubella virus. In certain embodiments, the togavirus antigen is selected from E1, E2, E3, C, NSP-1, NSPO-2, NSP-3, or NSP-4. In certain embodiments, the togavirus antigen is selected from E1, E2, or E3. A typical example of a commercially available rubella vaccine is Mump. Examples include cold-adapted live viruses combined with the measles vaccine (MMR).

[0209] Flavivirus: Viral antigens may include, but are not limited to, those derived from flaviviruses, such as tick-borne encephalitis (TBE) virus, dengue fever (types 1, 2, 3, or 4) virus, yellow fever virus, Japanese encephalitis virus, Kyasanur forest disease virus, West Nile encephalitis virus, St. Louis encephalitis virus, Russian spring-summer encephalitis virus, and Poissant encephalitis virus. In certain embodiments, the flavivirus antigen is selected from PrM, M, C, E, NS-1, NS-2a, NS2b, NS3, NS4a, NS4b, and NS5. In certain embodiments, the flavivirus antigen is selected from PrM, M, and E. Commercially available TBE vaccines include inactivated viral vaccines. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0210] Pestivirus: Viral antigens are not limited to those derived from pestiviruses, such as bovine viral diarrhea (BVDV), classical swine cholera (CSFV), or border disease (BDV).

[0211] Hepadnavirus: Viral antigens can be derived from hepadnavirus, such as hepatitis B virus, but are not limited to those derived from hepadnavirus. In certain embodiments, the hepadnavirus antigen is selected from surface antigens (L, M, and S) and core antigens (HBc, HBe). Commercially available HBV vaccines include subunit vaccines containing the surface antigen S protein.

[0212] Hepatitis C virus: Viral antigens include, but are not limited to, those derived from the hepatitis C virus (HCV). In certain embodiments, the HCV antigen is selected from one or more of the following: E1, E2, E1 / E2, NS345 polyprotein, NS 345-core polyprotein, and peptides from the core and / or non-structural regions. In certain embodiments, the hepatitis C virus antigen comprises one or more of the following: HCV E1 and / or E2 proteins, E1 / E2 heterodimer complexes, core proteins and non-structural proteins, or fragments of these antigens, where the non-structural proteins may be optionally modified to eliminate enzymatic activity while retaining immunogenicity. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0213] Rhabdovirus: Viral antigens can be derived from rhabdoviruses, such as lyssavirus (rabies virus) and vesculovirus (VSV), though not limited to these. Rhabdovirus antigens can be selected from glycoproteins (G), nucleoproteins (N), macroproteins (L), and non-structural proteins (NS). Commercially available rabies virus vaccines contain dead viruses grown in human diploid cells or rhesus monkey fetal lung cells.

[0214] Caliciviridae; Viral antigens may include, but are not limited to, those derived from Caliciviridae viruses, such as Norwalk virus and Norwalk-like viruses, such as Hawaiian virus and Snow Mountain virus. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0215] Coronavirus: While not limited to specific viral antigens, this includes coronavirus, SARS, human respiratory coronavirus, avian infectious bronchitis virus (IBV), mouse hepatitis virus (MHV), and porcine infectious gastroenteritis virus. Examples include those derived from the virus (TGEV). In certain embodiments, the coronavirus antigen is selected from the spike (S), envelope (E), substrate (M), nucleocapsid (N), and hemagglutinin-esterase glycoprotein (HE). In certain embodiments, the coronavirus antigen is derived from the SARS virus. In certain embodiments, the coronavirus is derived from the SARS virus antigen, as described in International Publication No. 04 / 92360.

[0216] Retrovirus: Viral antigens may be derived from retroviruses, such as oncovirus, lentivirus, or spumavirus, but are not limited to these. In certain embodiments, the oncovirus antigen is derived from HTLV-1, HTLV-2, or HTLV-5. In certain embodiments, the lentivirus antigen is derived from HIV-1 or HIV-2. In certain embodiments, the antigen is derived from HIV-1 subtypes (or clades), including, but not limited to, HIV-1 subtypes (or clades) A, B, C, D, F, G, H, JK, and O. In other embodiments, the antigen is derived from HIV-1 recombinant epidemic strains (CRFs), including, but not limited to, A / B, A / E, A / G, A / G / 1, etc. In certain embodiments, the retroviral antigen is selected from gag, pol, env, tax, tat, rex, rev, nef, vif, vpu, and vpr. In certain embodiments, the HIV antigens include gag (p24 gag and p55 gag), env (gp160 and gp41), pol, tat, nef, rev vpu, miniproteins, (preferably p5 5 gag and gp Selected from (140v deletion). In certain embodiments, the HIV antigen is derived from one or more of the following strains: HIVIIIb, HIVSF2, HIVLAV, HIVLAI, HIVMN, HIV-1CM235, HIV-1US4, HIV-I SF 162, HIV-1 TVl, HIV-1MJ4. In certain embodiments, the antigen is derived from human endogenous retroviruses, including, but not limited to, HERV-K ("old" HERV-K and "new" HERV-K).

[0217] Reovirus: Viral antigens may include, but are not limited to, those derived from reoviruses, such as orthoreovirus, rotavirus, orbivirus, or coltivirus. In certain embodiments, the reovirus antigen is selected from structural proteins λ1, λ2, λ3, μ1, μ2, σ1, σ2, or σ3 or non-structural proteins σNS, μNS, or σ1s. In certain embodiments, the reovirus antigen is derived from rotavirus. In certain embodiments, the rotavirus antigen is selected from VP1, VP2, VP3, VP4 (or cleavage products VP5 and VP8), NSP1, VP6, NSP3, NSP2, VP7, NSP4, or NSP5. In certain embodiments, the rotavirus antigen includes VP4 (or cleavage products VP5 and VP8) and VP7.

[0218] Parvovirus: The viral antigen may be derived from, but is not limited to, parvovirus, such as parvovirus B19. In certain embodiments, the parvovirus antigen is selected from VP-1, VP-2, VP-3, NS-1, and NS-2. In certain embodiments, the parvovirus antigen is the capsid protein VP1 or VP-2. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0219] Delta hepatitis virus (HDV): As viral antigens, there are no limitations, but those derived from HDV, especially δ- Antigens are mentioned.

[0220] Hepatitis E virus (HEV): While not limited to specific viral antigens, those derived from HEV can be cited.

[0221] Hepatitis G virus (HGV): While not limited to specific viral antigens, those derived from HGV are among the possible candidates.

[0222] Human Herpesvirus: Viral antigens may be derived from, but are not limited to, human herpesviruses, such as, for example, herpes simplex virus (HSY), varicella-zoster virus (VZV), Epstein-Barr virus (EBY), cytomegalovirus (CMV), human herpesvirus 6 (HHV6), human herpesvirus 7 (HHV7), and human herpesvirus 8 (HHV8). In certain embodiments, the human herpesvirus antigen is selected from a pre-initial protein (α), an initial protein (β), and a late protein (γ). In certain embodiments, the HSY antigen is derived from an HSV-1 or HSV-2 strain. In certain embodiments, the HSV antigen is selected from glycoproteins gB, gC, gD, and gH, a fusion protein (gB), or an immune-evading protein (gC, gE, or gI). In certain embodiments, the VZV antigen is selected from core, nucleocapsid, tegument, or envelope proteins. Attenuated live VZV vaccines are commercially available. In certain embodiments, the EBV antigen is selected from early antigen (EA) protein, viral capsid antigen (VCA), and membrane antigen (MA) glycoproteins. In certain embodiments, the CMV antigen is selected from capsid protein, envelope glycoproteins (such as gB and gH), and tegument protein.In other embodiments, the CMV antigen is the following proteins: pp65, 1E1, gB, gD, gH, gL, gM, gN, gO, UL128, UL129, gUL130, UL150, UL131, UL33, UL78, US27, US28, RL5A, RL6, RL10, RL11, RL12, RL13, UL1, UL2, UL4, UL5, UL6, UL7, UL8, UL9, UL10, UL11, UL14, UL15A, UL16, UL17, UL18, UL22A, UL38, UL40, UL41A, UL42, UL116, UL1 One or more of the following may be selected: 19, UL120, UL121, UL124, UL132, UL147A, UL148, UL142, UL144, UL141, UL140, UL135, UL136, UL138, UL139, UL133, UL135, UL148A, UL148B, UL148C, UL148D, US2, US3, US6, US7, USB, US9, US10, US11, US12, US13, US14, US15, US16, US17, US18, US19, US20, US21, US29, US30, and US34A. The CMV antigen may be a fusion of one or more CMV proteins, for example, pp 65 / IE1 (Reap et al., Vaccine (2007) 25:7441-7449) as just one example. In certain embodiments, the antigen is formulated into virus-like particles (VLPs).

[0223] Papovavirus: Antigens may include, but are not limited to, those derived from papovaviruses, such as papillomavirus and polyomavirus. In certain embodiments, papillomavirus includes HPV serotypes 1, 2, 4, 5, 6, 8, 11, 13, 16, 18, 31, 33, 35, 39, 41, 42, 47, 51, 57, 58, 63, and 65. In certain embodiments, the HPV antigen is derived from serotype 6, 11, 16, or 18. In certain embodiments, the HPV antigen is selected from capsid proteins (L1) and (L2) or E1-E7 or fusions thereof. In certain embodiments, the HPV antigen is formulated into virus-like particles (VLPs). In certain embodiments, polyomavirus (Polyo The myavirus includes BK virus and JK virus. In certain embodiments, the polyomavirus antigen is selected from VP1, VP2, or VP3.

[0224] Adenovirus: Antigens may be derived from adenovirus. In certain embodiments, the adenovirus antigen is derived from adenovirus serotype 36 (Ad-36). In certain embodiments, the antigen is derived from a protein or a peptide sequence or fragment thereof encoding the Ad-36 coated protein (International Publication No. 2007 / 120362).

[0225] Fungal antigens. Fungal antigens for use in the immunogenic compositions provided herein include, but are not limited to, those derived from one or more of the fungi listed below.

[0226] The fungal antigens include Epidermophyton jloccusum, Microsporum audouini, Microsporum canis, Microsporum distortum, and Microsporum equinum. Trichophyton equinum, Microsporum gypsum, Microsporum nanum, Trichophyton concentricum, Trichophyton equinum, Trichophyton gallinae, Trichophyton gyopseum Trichophyton gypseum), Trichophyton megnini, Trichophyton mentagrophytes, Trichophyton quinckeanum, Trichophyton rubrum, Trichophyton schoenleini, Trichophyton tonsurans, Trichophyton verrucosum, T. verrucosum var. album, var. discoides, var. ochraceum, Trichophyton violaceum and / or Trichophyton fabiforme The fungal pathogens are derived from dermatophytes, including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, Aspergillus sydowi, Aspergillus flavatus, Aspergillus glaucus, Blastoschizomyces capitatus, Candida albicans, and Candida enolase. Candida enolase, Candida tropicalis, Candida glabrata, Candida krusei, Candida parapsilosis, Candida stellatoidea Candida stellatoidea, Candida kusei, Candida parakwsei, Candida lusitaniae, Candida pseudotropicalis, Candida guilliermondi, Cladosporium carrionii, Coccidioides immitis, Blastomyces dermatidis, Cryptococcus neoformans, Geotrichum clavatum, Histoplasma capsulatum, Klebsiella pneumoniae Septata pneumoniae, Microsporidia, Encephalitozoon spp., Septata intestinalis It originates from *intestinalis* and *Enterocytozoon bieneusi*; less common are species of the genera Brachiola, Microsporidium, Nosema, Pleistophora, Trachipleistophora, Vittaforma, Paracoccidioides brasiliensis, Pneumocystis carinii, Pythium insidiosum, and Pityrosporum ovale. Saccharomyces cerevisae, Saccharomyces boulardii, Saccharomyces pombe, Scedosporium apiosperum, Sporothrix schenckii, Trichosporon beigelii, Toxoplasma gondii), Penicillium marneffei, Malassezia spp., Fonsecaea spp., Wangiella spp., Sporothrix spp., Basidiobolus spp., Conidiobolus spp., Rhizopus spp., Mucor spp., Absidia spp., Mortierella spp., Cunninghamella spp. These include species of the genera Saksenaea, Alternaria, Curvularia, Helminthosporium, Fusarium, Aspergillus, Penicillium, Monolinia, Rhizoctonia, Paecilomyces, Pithomyces, and Cladosporium.

[0227] In a particular embodiment, a method for producing a fungal antigen is a method in which a solubilized fraction is extracted and separated from an insoluble fraction obtained from fungal cells from which the cell wall has been substantially or at least partially removed, comprising the steps of: obtaining viable fungal cells; obtaining fungal cells from which the cell wall has been substantially or at least partially removed; and The method includes the steps of: rupturing fungal cells that have been destroyed or at least partially removed; obtaining an insoluble fraction; and extracting and separating a solubilized fraction from the insoluble fraction.

[0228] Plant antigens / pathogens. Plant antigens / pathogens for use in the immunogenic compositions provided herein include, but are not limited to, those derived from castor bean (Ricinus communis).

[0229] Cancer / tumor antigen. In certain embodiments, the tumor antigen or cancer antigen is used in conjunction with the immunogenic composition provided herein. In certain embodiments, the tumor antigen is a peptide-containing tumor antigen, e.g., a polypeptide tumor antigen or a glycoprotein tumor antigen. In certain embodiments, the tumor antigen is a sugar-containing tumor antigen, e.g., a glycolipid tumor antigen or a ganglioside tumor antigen. In certain embodiments, the tumor antigen is a polynucleotide-containing tumor antigen expressing a polypeptide-containing tumor antigen, e.g., an RNA vector construct or a DNA vector construct, e.g., plasmid DNA. In certain embodiments, the tumor antigen is whole, live, or dead cancer cells or leachate-transfer cancer cells.

[0230] Tumor antigens suitable for use with the immunogenic compositions provided herein include a wide variety of molecules, such as (a) polypeptide-containing tumor antigens comprising polypeptides (for example, in the range of 8 to 20 amino acid lengths, but lengths outside this range are also common), lipopolypeptides, and glycoproteins; (b) sugar-containing tumor antigens comprising polysaccharides, mucins, gangliosides, glycolipids, and glycoproteins; and (c) polynucleotides expressing antigenic polypeptides.

[0231] In certain embodiments, the tumor antigen is, for example, (a) a full-length molecule associated with cancer cells, (b) its homologous and modified forms, including molecules having deletions, additions, and / or substitutions, and (c) its fragments. In certain embodiments, the tumor antigen is provided in recombinant form. In certain embodiments, examples of tumor antigens include class I restrictive antigens recognized by CD8+ lymphocytes or class II restrictive antigens recognized by CD4+ lymphocytes.

[0232] In certain embodiments, tumor antigens may include, but are not limited to, (a) cancer-testicular antigens, e.g., NYESO-1, SSX2, SCP1, and RAGE, BAGE, GAGE, and MAGE family polypeptides, e.g., GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12 (e.g., which may be used to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumors); (b) mutant antigens, e.g., p53 (associated with various solid tumors, e.g., colorectal, lung, and head and neck cancers), p21 / Ras (e.g., associated with melanoma, pancreatic cancer, and colorectal cancer), CDK4 (e.g., associated with melanoma), MUM1 (e.g., associated with melanoma), caspase-8 (e.g., associated with head and neck cancer), CIA 0205 (e.g., associated with bladder cancer), HLA-A2-Rl 701, β-catenin (e.g., associated with melanoma), TCR (e.g., associated with T-cell non-Hodgkin lymphoma), BCR-abl (e.g., associated with chronic myeloid leukemia), triose phosphate isomerase, KIA 0205, CDC-27 and LDLR-FUT, (c) overexpressed antigens, e.g., galectin 4 (e.g., associated with colorectal cancer), galectin 9 (e.g., associated with Hodgkin's disease), proteinase 3 (e.g., associated with chronic myeloid leukemia), WT 1 (e.g., associated with various leukemias), carbonic anhydrase (e.g., associated with renal cancer), aldolase A (e.g., associated with lung cancer), PRAME (e.g., associated with melanoma), HER-2 / neu (e.g., associated with breast, colon, lung and ovarian cancer), α-fetoprotein (e.g., associated with hepatocellular carcinoma), KSA (e.g., associated with colorectal cancer), gas (d) Common antigens, e.g., melanoma / melanocyte differentiation antigens, e.g., MART-1 / Melan A, gp 100, MC1 R, melanocyte-stimulating hormone receptor, tyrosinase, tyrosinase-related protein-1 / TRP1 and tyrosinase-related protein-2 / TRP2 (e.g., associated with melanoma), (e) prostate-related antigens, e.g., PAP, PSA, PSMA, PSHP1, PSM-P1, PSM-P2, e.g., associated with prostate cancer, (f) immunoglobulin idiotypes (e.g., associated with myeloma and B-cell lymphoma), and (g) other tumor antigens, e.g., (i) glycoproteins, e.g., sialyl Tn and sialyl Lex (e.g., associated with breast and colorectal cancer), and various mucins; glycoproteins are bound to carrier proteins (e.g., MUC-1 is bound to KLH); (ii) lipopolypeptides (e.g., MUC-1 linked to the lipid portion); (iii) polysaccharides (e.g., Globo Examples include polypeptide-containing antigens and sugar-containing antigens, including (iv) a synthetic hexasaccharide (H) (bound to a carrier protein (e.g., KLH)), and gangliosides, such as GM2, GM12, GD2, and GD3 (e.g., associated with brain, lung cancer, and melanoma) (these are also bound to carrier proteins (e.g., KLH)).

[0233] In certain embodiments, tumor antigens include, but are not limited to, p15, Hom / MeI-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigen, EBNA, human papillomavirus (HPV) antigen (including E6 and E7), hepatitis B and C virus antigens, human T-cell lymphotropic virus antigen, TSP-180, p185erbB2, p180erbB-3, c-met, nm-23H1, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, p16, TAGE, PSCA, CT7, 43-9F, 5T4, 791, Tgp72, β-HCG, BCA225, BTAA, CA 125, CA Examples include 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, C0-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophyllin C-related protein), TAAL6, TAG72, TLP, and TPS.

[0234] Polynucleotide-containing antigens used with the immunogenic compositions provided herein include polynucleotides encoding polypeptide cancer antigens, such as those listed above. In certain embodiments, the polynucleotide-containing antigen may include, but is not limited to, DNA or RNA vector constructs capable of expressing polypeptide cancer antigens in vivo, such as plasmid vectors (e.g., pCMV).

[0235] In certain embodiments, tumor antigens are derived from mutated or altered cellular components. After alteration, the cellular components no longer perform their regulatory functions, and as a result, the cells may undergo uncontrolled proliferation. Representative examples of altered cellular components include, but are not limited to, altered proteins encoded by ras, p53, Rb, Wilms oncogenes, ubiquitin, mucin, proteins encoded by DCC, APC, and MCC genes, and receptors or receptor-like structures, such as neu, thyroid hormone receptors, platelet-derived growth factor (PDGF) receptors, insulin receptors, epidermal growth factor (EGF) receptors, and colony-stimulating factor (CSF) receptors.

[0236] Furthermore, bacterial and viral antigens are provided herein for the treatment of cancer. It is used in combination with epidemiogenic compositions. In certain embodiments, carrier proteins, such as CRM197, tetanus toxoid, or Salmonella typhimurium antigen, are used in combination / conjugation with the compounds provided herein for the treatment of cancer. Cancer antigen combination therapy exhibits improved efficacy and bioavailability compared to existing therapies.

[0237] In certain embodiments, an immunogenic composition comprising at least one compound of formula (I) comprises a capsular sugar derived from at least two serotypes A, C, W135, and Y of Neisseria meningitides. In other embodiments, such a vaccine further comprises: (a) serotype B meningitidis; (b) Haemophilus influenzae type B; and / or (c) antigens derived from one or more Streptococcus pneumoniae.

[0238] In certain embodiments, the immunogenic composition containing at least one compound of formula (I) includes serotypes C, W135, and Y of Neisseria meningitidis. In certain embodiments, the immunogenic composition containing at least one compound of formula (I) includes serotypes A, C, W135, and Y of Neisseria meningitidis. In certain embodiments, the immunogenic composition containing at least one compound of formula (I) includes serotypes B, C, W135, and Y of Neisseria meningitidis. In certain embodiments, the immunogenic composition containing at least one compound of formula (I) includes serotypes A, B, C, W135, and Y of Neisseria meningitidis. In certain embodiments, the immunogenic composition containing at least one compound of formula (I) includes Neisseria meningitidis type B and serotypes C, W135, and Y of Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes Haemophilus influenzae type B and serotypes A, C, W135, and Y of Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes Haemophilus influenzae type B and serotypes B, C, W135, and Y of Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes Haemophilus influenzae type B and serotypes A, B, C, W135, and Y of Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes Streptococcus pneumoniae and serotypes C, W135, and Y of Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes serotypes A, C, W135, and Y of Streptococcus pneumoniae and Neisseria meningitidis.In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes serotypes B, C, W135 and Y of Streptococcus pneumoniae and Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes serotypes A, B, C, W135 and Y of Streptococcus pneumoniae and Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes type B of Haemophilus influenzae, Streptococcus pneumoniae, and serotypes C, W135 and Y of Neisseria meningitidis. In certain embodiments, the immunogenic composition containing at least one compound of formula (I) is Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis serotypes A, C, and W13. This includes 5 and Y. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes serotypes B, C, W135 and Y of Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis. In certain embodiments, an immunogenic composition containing at least one compound of formula (I) includes serotypes A, B, C, W135 and Y of Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis.

[0239] In one embodiment, the antigen is an allergen. An allergen is a substance that can induce an allergic or asthmatic reaction in a susceptible object. Examples of allergens include pollen, insect toxins, animal scales, dust, fungal spores, foods (e.g., peanuts, milk, eggs), and drugs (e.g., penicillin).

[0240] Autoantigens include any antigen of host origin, but they include antigens specific to autoimmune diseases or conditions. Autoantigens specific to autoimmune diseases or conditions may be associated with autoimmune diseases, but are not necessarily established as the cause of autoimmune diseases. Specific examples of autoantigens specific to autoimmune diseases or conditions include, but are not limited to, insulin, thyroglobulin, glomerular basement membrane, acetylcholine receptors, DNA, and myelin basic proteins.

[0241] The disclosed compounds may be included in a kit comprising a compound or a pharmaceutically acceptable salt, a pharmaceutical composition, or both; and information, instructions, or both, the use of which provides treatment for medical conditions in mammals (especially humans). The information and instructions may be in the form of text, images, or both. In addition or alternatively, the kit may include a drug, composition, or both, which, regardless of the method of application of the drug or composition, preferably has the benefit of treating or preventing medical conditions in mammals (e.g., humans); and information, instructions, or both.

[0242] The kit may comprise one or more containers containing further therapeutic agents, including, but not limited to, those listed above. In certain embodiments, the kit may comprise one or more containers containing an antigen, as described herein. In some embodiments, the kit may be provided in the form of a vaccine composition as described herein and may comprise a syringe for optionally injecting the vaccine composition into a target.

[0243] 5.Chemical synthesis The compounds of the present invention can be prepared as shown in the following scheme and examples.

[0244] Abbreviation: Bn: Benzyl Calcd: Calculated value Cbz: Benzyloxycarbonyl DIAD: Diisopropyl azodicarboxylate DPPA: Diphenylformolyl azide EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide Et: Ethyl ESI-TOF: Time-of-Flight Electrospray Ionization FA: fatty acid HRMS: High resolution mass spectrometry Me: Methyl Ph: Phenyl ppm: parts per million psig: pounds per square inch Pyr: Pyridine Tf: Triflat TFA: Trifluoroacetic acid

[0245] Schemes 1-5 show methods for preparing a common intermediate and a compound of formula (I). The schemes involve several variables (e.g., R) for the intermediate and the final compound. 1 , R 5 , R 6 The definition of ) is shown, but those skilled in the art will recognize that the synthesis method can be similarly applied to compounds having definitions for other variables. For example, R 1 Fragments (for example, [ka] Other intermediates that supply ) can be similarly used in the following scheme.

[0246] Scheme 1 shows a method for preparing a common advanced intermediate 2. [ka]

[0247] Scheme 2 shows another method for preparing a common advanced intermediate 2 from a common intermediate 1. [ka]

[0248] Scheme 3 uses common intermediate 2 to form equation (I) (where R 3aThis shows a method for preparing the compound -OP(O)(OH)2. [ka]

[0249] Scheme 4 uses common intermediate 2 to form equation (I) (where R 3a This describes a method for preparing the compound (which is -OSO3H). [ka]

[0250] Scheme 5 uses common intermediate 2 to form equation (I) (where R 3a This shows a method for preparing the compound -OCH2P(O)(OH)2. [ka] [Examples]

[0251] Example 1 Preparation of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside (compound 1) [ka] Example 1 uses the process shown in Scheme A.

[0252] Example 1A A solution of 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-glucopyranose hydrochloride (76.47 g, 0.23 mol) in methylene chloride (350 mL) and H2O (350 mL) was treated with sodium bicarbonate (149.94 g, 1.79 mol) added slowly and gradually. Benzyl chloroformate (79.17 g, 0.46 mol) was added gradually to control gas generation, and the reaction mixture was vigorously stirred for 2.5 hours. The layers were separated, and the aqueous layer was extracted with methylene chloride (100 mL). The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to approximately 100 mL. 200 mL of methyl t-butyl ether was added, the resulting mixture was stirred, cooled to 0°C, the precipitate was collected by filtration, washed with cold methyl t-butyl ether, and dried in a vacuum oven to obtain 88.89 g (81%) of 1,3,4,6-tetra-O-acetyl-2-(benzyloxycarbonylamino)2-deoxy-β-D-glucopyranoside.

[0253] Example 1B A solution of the compound prepared in Example 1A (10 g, 20.8 mmol) and benzyl N-(2-hydroxyethyl) carbamate (4.48 g, 22.9 mmol) in anhydrous methylene chloride (80 mL), cooled to -15°C, was treated dropwise with trimethylsilyl triflate (0.37 mL, 2.08 mmol). The reaction mixture was left for 5.5 hours. The mixture was heated to room temperature for a period of time. The reaction product was quenched with saturated sodium bicarbonate aqueous solution (40 mL), and the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 20 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was crystallized from methylene chloride / heptane to obtain 10.4 g (81%) of 2-(benzyloxycarbonylamino)ethyl 3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranoside as a white solid.

[0254] Example 1C A solution of the compound prepared in Example 1B (10 g, 16.3 mmol) in methanol (160 mL) was treated with ammonium hydroxide (20 equivalents) at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under high vacuum to obtain 8 g (100%) of 2-(benzyloxycarbonylamino)ethyl 2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranoside as a white solid, which was used without further purification.

[0255] Example 1D A solution of the compound prepared in Example 1C (8 g, 16.3 mmol) in acetonitrile (180 mL) was treated with benzaldehyde dimethyl acetal (4.9 mL, 32.6 mmol) and camphor sulfonic acid (1.9 g, 8.2 mmol). The reaction mixture was stirred for 3 hours, neutralized with saturated sodium bicarbonate aqueous solution, filtered, and concentrated under reduced pressure. The crude product was crystallized from ethyl acetate / heptane to obtain 7.1 g (75%) of 2-(benzyloxycarbonylamino)ethyl 4,6-O-benzylidene-2-deoxy-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranoside as a white solid.

[0256] Example 1E A solution of the compound prepared in Example 1D (1.5 g, 2.59 mmol) in anhydrous tetrahydrofuran (40 mL) was treated with triethylamine (0.54 mL, 3.89 mmol) and triphenylphosphine (1.09 g, 4.14 mmol). The reaction mixture was cooled to 0°C and diisopropyl azodicarboxylic acid (0.82 mL, 4.14 mmol) was added. After 45 minutes at 0°C, diphenylphoryl azide (0.89 mL, 4.14 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to chromatography (gradient elution, 20-70% ethyl acetate / heptane) on silica gel to obtain 1.16 g (74%) of 2-(benzyloxycarbonylamino)ethyl 3-azide-4,6-O-benzylidene-2-benzyloxycarbonylamino-2,3-dideoxy-β-D-allopyranoside as a white solid.

[0257] Example 1F A solution of the compound prepared in Example 1E (2.95 g, 4.89 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a solution of 0.1 N sodium hydroxide (9.8 mL, 0.98 mmol) and a solution of 1.0 M trimethylphosphine in tetrahydrofuran (7.8 mL, 7.82 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography (gradient elution, 30 → 100% ethyl acetate / heptane, then 0 → 10% methanol / chloroform) on silica gel to obtain 2.37 g (84%) of 2-(benzyloxycarbonylamino)ethyl 3-amino-4,6-O-benzylidene-2-benzyloxycarbonylamino-2,3-dideoxy-β-D-allopyranoside as a white solid.

[0258] Example 1G A solution of the compound prepared in Example 1F (0.5 g, 0.87 mmol) in anhydrous methylene chloride (10 mL) was acylated with (R)-3-decanoyloxytetradecanoic acid (414 mg, 1.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (310 mg, 1.04 mmol) over 2 hours at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and the layers were separated. The aqueous layer was extracted with chloroform (2 × 5 mL), the combined organic layers were washed with water (5 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 10 → 60% ethyl acetate / heptane) yielded 748 mg (90%) of 2-(benzyloxycarbonylamino)ethyl 4,6-O-benzylidene-2-benzyloxycarbonylamino-3-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a colorless oil.

[0259] Example 1H A solution of the compound prepared in Example 1G (745 mg, 0.78 mmol) in anhydrous tetrahydrofuran (20 mL) was hydrogenated with 10% palladium carbon (220 mg) in a Parr hydrogenator at room temperature and 50 psig over 24 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in methylene chloride (10 mL) and acylated with (R)-3-decanoyloxytetradecanoic acid (680 mg, 1.71 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (510 mg, 1.71 mmol) over 2 hours at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 10 mL), and the combined organic layer was washed with water (10 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20-80% ethyl acetate / heptane) yielded 732 mg (65%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 4,6-O-benzylidene-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a glassy solid.

[0260] Example 1 A solution of the compound prepared in Example 1H (400 mg, 0.282 mmol) in anhydrous methylene chloride (20 mL) cooled to 0°C was treated with sodium borohydride cyanohydride (42 mg, 0.655 mmol), and then trifluoroacetic acid (0.06 mL, 0.786 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with methanol (2 mL), concentrated under reduced pressure, then returned with methylene chloride and washed with a saturated solution of sodium bicarbonate. The layers were separated, the aqueous layer was extracted with methylene chloride (2 × 10 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 10 → 95% ethyl acetate / heptane) yielded 380 mg (93%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 6-O-benzyl-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a colorless oil.

[0261] Example 1J A solution of the compound prepared in Example 1I (150 mg, 0.103 mmol) in anhydrous methylene chloride (10 mL) was phosphorylated with dibenzyl diisopropyl phosphoramidite (0.049 mL, 0.144 mmol) and 4,5-dicyanoimidazole (17 mg, 0.144 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C and treated with hydrogen peroxide (2 mL) for 30 minutes. The reaction mixture was then treated with saturated sodium bicarbonate aqueous solution. The mixture was quenched by adding 5 mL of solution and stirred at room temperature for 15 minutes. The aqueous layer was extracted with methylene chloride (3 × 5 mL), the combined organic layer was washed with water (5 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 10 → 70% ethyl acetate / heptane) yielded 112 mg (64%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 6-O-benzyl-4-O-dibenzylphosphino-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a foamy solid.

[0262] Example 1K A solution of the compound prepared in Example 1J (110 mg, 0.064 mmol) in anhydrous tetrahydrofuran (3 mL) was hydrogenated over 36 hours at room temperature and 50 psig using a Parr hydrogenator in the presence of 10% palladium-carbon (30 mg). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Chromatography was performed on silica gel using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5). The fractions containing the purified product were combined, concentrated under reduced pressure, redissolved in 2:1 chloroform-methanol (14 mL) at low temperature, and washed with 0.1 N aqueous hydrochloride solution (5.52 mL) at low temperature. The lower organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 64 mg (70%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside as a glassy solid: 1H NMR(CDCl3 / CD3OD):δ(ppm)5.21(br s,3H), 4.60-4.50(m,3H), 4.08-4.01(m,2H), 3.85-3.80(m,2H), 3.71-3.68(m,1H), 3.52-3.31(m,4H), 2.64-2.18(m,12H), 1.59(br s,12H), 1.40-1.15(m,90H), 0.88(t,J=6.4Hz, 18H);HRMS(ESI-TOF)m / z:C 80 H 152 N3O 16 P[MH] - The calculated value for this is 1441.0832, and the measured value is 1441.0755.

[0263] Example 2 Preparation of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranoside (compound 2) [ka] Example 2A A solution of the compound prepared in Example 1I-(9) (105 mg, 0.072 mmol) in anhydrous dimethylformamide (5 mL) is prepared as a sulfur trioxide triethylamine complex (78 The mixture was treated with (mg, 0.43 mmol). The reaction mixture was heated at 50°C for 5 hours. An additional amount of sulfur trioxide triethylamine complex (100 mg, 0.55 mmol) was added, and the reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure. 18 Chromatography on a column (gradient elution, 5 → 20% methylene chloride + 1% triethylamine / methanol) yielded 90 mg (82%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 6-O-benzyl-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranoside triethylammonium salt as a white salt.

[0264] Example 2B A solution of the compound prepared in Example 2A (70 mg, 0.045 mmol) in a 2:1 anhydrous tetrahydrofuran:methanol mixture (5 mL) was hydrogenated over 18 hours at room temperature and 50 psig using a Parr hydrogenator in the presence of 20% palladium hydroxide / carbon (30 mg) and triethylamine (0.034 mL, 0.00024 mmol). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. 18 Chromatography (gradient elution, 5 → 20% methylene chloride + 1% triethylamine / methanol) was performed on a silica column, and the purified material was dissolved in 2:1 chloroform-methanol (8 mL) at low temperature and washed with 0.1 N hydrochloride aqueous solution (1.6 mL) at low temperature. The lower organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The residue was salted with (1-2 equivalents) triethylamine to obtain 28 mg (43%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranoside triethylammonium salt as a glassy solid: 1 H NMR (CDCl3 / CD3OD): δ(ppm)7.84(t,J=5.5Hz, 1H), 7.55(d,J=8.0Hz, 1H), 7.22(d,J=9.0Hz, 1H), 5.27-5.23(m,3H), 4.65(br s,1H), 4.59-4.55(m,2H), 4.26-4.21(m,1H), 4.19-4.15(m,1H), 3.85-3.79(m,2H), 3.73-3.70(m,1H), 3.51-3.43(m,2H), 3.18(q,J=7.5Hz, 7H, CH2 of triethylamine (approx. 1.2 equivalents)), 2.62-2.19(m,12), 1.64-1.52(m,12H), 1.37-1.26(m,100H, containing 10 CH3 of triethylamine), 0.88(t,J=7.0Hz, 18H);HRMS(ESI-TOF)m / z:C 80 H 151 N3O 16 S[MH] -The calculated value for this is 1441.0737, and the measured value is 1441.0714.

[0265] Example 3 Preparation of N-[(R)-3-decanoyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranosyl]-L-serine methyl ester (compound 3) [ka] Example 3A A suspension of L-serine methyl ester hydrochloride (11.4 g, 73.3 mmol) in a 1:1 methylene chloride:water (160 mL) was treated with sodium bicarbonate (74 g, 879 mmol), and then benzyl chloroformate (12.4 mL, 87.9 mmol) was added dropwise. The reaction mixture was vigorously stirred for 18 hours. The layers were separated, the aqueous layer was extracted with methylene chloride (2 × 30 mL), and the combined organic layers were dried on anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 10 → 50% ethyl acetate / heptane) yielded 16.8 g (91%) of N-benzyloxycarbonyl-L-serine methyl ester as a colorless oil.

[0266] Example 3B In a method similar to that described in Example 1B, a solution of the compound prepared in Example 3A (16.8 g, 66.3 mmol) and the compound prepared in Example 1A (38 g, 73.0 mmol) was reacted in the presence of boron trifluoride etherate (11.3 mL, 79.6 mmol) to obtain 45.5 g (quantitatively) of N-benzyloxycarbonyl-O-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranosyl)-L-serine-methyl ester as a viscous oil, which was used without further purification.

[0267] Example 3C In a manner similar to that described in Example 1C, a solution of the compound prepared in Example 3B (15 g, 22.2 mmol) was deacylated in the presence of a 6-10% solution of magnesium methoxide in methanol (6 mL, 44.5 mmol) to obtain 4.7 g (39%) of N-benzyloxycarbonyl-O-[2-benzyloxycarbonylamino)-2-deoxy-β-D-glucopyranosyl]-L-serine-methyl ester as a colorless oil.

[0268] Example 3D In a manner similar to that described in Example 1D, a solution of the compound prepared in Example 3C (4.7 g, 8.57 mmol) in acetonitrile (20 mL) was protected with benzaldehyde dimethyl acetal (2.6 mL, 17.14 mmol) and camphor sulfonic acid (1.0 g, 4.28 mmol) to obtain 4.08 g (75%) of N-benzyloxycarbonyl-O-[4,6-O-benzylidene-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranosyl]-L-serine methyl ester as a white solid.

[0269] Example 3E In a manner similar to that described in Example 1E, a solution of the compound prepared in Example 3D (2.0 g, 3.14 mmol) was subjected to the Mitsunobu reaction with triethylamine (0.66 mL, 4.71 mmol), triphenylphosphine (1.32 g, 5.03 mmol), and diisopropyl azodicarboxylic acid (1.0 mL, 5.03 mmol). Then, diphenylphoryl azide (1.08 mL, 5.03 mmol) was added to obtain 1.37 g (66%) of N-benzyloxycarbonyl-O-[3-azide-4,6-O-benzylidene-2-benzyloxycarbonylamino-2,3-dideoxy-β-D-allopyranosyl]-L-serine-methyl ester as a white foamy solid.

[0270] Example 3F A solution of the compound prepared in Example 3E (0.52 g, 0.79 mmol) in anhydrous tetrahydrofuran (10 mL) was hydrogenated with 10% palladium carbon (100 mg) and (0.10 mL) pyridine using a Parr hydrogenator at room temperature and 50 psig for 36 hours. The reaction mixture was passed through a Celite pad, concentrated under reduced pressure, washed azeotropically with toluene (2 × 10 mL), then concentrated under reduced pressure and kept under reduced pressure for 48 hours. The resulting foamy solid in anhydrous methylene chloride (10 mL) cooled to 0°C was acylated with (R)-3-decanoyloxytetradecanoic acid (1.0 g, 2.50 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (0.74 g, 2.50 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and the layers were separated. The aqueous layer was extracted with chloroform (2 × 10 mL), the combined organic layer was washed with water (10 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20 → 60% ethyl acetate / heptane) yielded 230 mg (20%) of N-[(R)-3-decanoyloxytetradecanoyl]-O-[4,6-O-benzylidene-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid.

[0271] Example 3G In a method similar to that of Example 1I, the compound prepared in Example 3F (210 mg, 0.15 mmol) was treated with sodium borohydride cyanohydride (46 mg, 0.73 mmol) and trifluoroacetic acid (0.066 mL, 0.87 mmol) to obtain 200 mg (91%) of N-[(R)-3-decanoyloxytetradecanoyl]-O-[6-O-benzyl-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranosyl]-L-serine methyl ester as a colorless oil.

[0272] Example 3H In a method similar to that of Example 1J, a solution of the compound prepared in Example 3G (200 mg, 0.13 mmol) was phosphorylated with dibenzyldiisopropylphosphoramidite (0.079 mL, 0.234 mmol), 4,5-dicyanoimidazole (27 mg, 0.234 mmol), and hydrogen peroxide (1 mL) to obtain 45 mg (19%) of N-[(R)-3-decanoyloxytetradecanoyl]-O-[6-O-benzyl-4-O-dibenzylphosphino-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranosyl]-L-serine methyl ester as a foamy solid.

[0273] Example 3I In a method similar to Example 1K, the compound prepared in Example 3H above (45 A solution of (mg, 0.025 mmol) was hydrogenated over 16 hours at room temperature and 50 psig using a Parr hydrogenator in the presence of 10% palladium-carbon (30 mg). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. 18 The material was obtained by chromatography on a column (gradient elution, 5 → 20% methylene chloride + 1% triethylamine / methanol), dissolved in 8 mL of chloroform-methanol at low temperature, and washed with 1.6 mL of 1.1 N hydrochloride aqueous solution at low temperature. The lower organic layer was separated, dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28 mg (82%) of N-[(R)-3-decanoyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid: 1H NMR (CDCl3 / CD3OD): δ(ppm)7.93(d,J=8.0Hz, 1H), 7.21(d,J=9.0Hz, 1H), 5.26-5.19(m,3H), 4.67-4.64(m,1H), 4.59(d,J=2.5Hz, 1H), 4 .51-4.45(m,2H), 4.21-4.19(m,1H), 4.09-4.06(m,2H), 3.76(s,3H), 3.74-3.70(m,1H), 3.66-3.63(m,2H), 2.64-2.19(m,12H), 1.60(br s,12H), 1.26(br s,90H), 0.88(t,J=7.0Hz, 18H);HRMS(ESI-TOF)m / z:C 82 H 154 N3O 18 P[MH] - The calculated value for this is 1499.0887, and the measured value is 1499.0816.

[0274] Example 4 Preparation of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-]-β-D-allopyranosyl]-L-serine (compound 4) [ka] Example 4A In a method similar to that of Example 3F, a solution of the compound prepared in Example 3E (1.37 g, 2.07 mmol) was hydrogenated over 36 hours at room temperature and 50 psig using a Parr hydrogenator in the presence of 10% palladium carbon (200 mg) and (0.20 mL) pyridine. The corresponding residues were acylated with (R)-3-decyloxytetradecanoic acid (2.64 g, 7.24 mmol) (U.S. Patent No. 7,960,522) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (2.15 g, 7.24 mmol) to obtain 940 mg (31%) of N-[(R)-3-decyloxytetradecanoyl]-O-[4,6-O-benzylidene-2-deoxy-2-[(R)-3-decyloxytetradecanoylamino]-3-deoxy-3-[(R)-3-decyloxytetradecanoylamino]-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid.

[0275] Example 4B In a method similar to that of Example 1I, a solution of the compound prepared in Example 4A (940 mg, 0.64 mmol) was treated with sodium cyanoborohydride (242 mg, 3.84 mmol) and trifluoroacetic acid (0.24 mL, 3.2 mmol) to obtain 600 mg (64%) of N-[(R)-3-decyloxytetradecanoyl]-6-benzyl-4-hydroxy-2-deoxy-2-decyloxytetradecanamide-3-deoxy-3-[(R)-3-decyloxytetradecanoylamino-β-D-allopyranoside]-L-serine methyl ester as a colorless oil.

[0276] Example 4C In a method similar to that of Example 1J, a solution of the compound prepared in Example 4B (450 mg, 0.31 mmol) was phosphorylated with dibenzyldiisopropylphosphoamidite (0.14 mL, 0.44 mmol), 4,5-dicyanoimidazole (51 mg, 0.44 mmol), and hydrogen peroxide (3 mL) to obtain 410 mg (78%) of N-[(R)-3-decyloxytetradecanoyl]-O-[6-O-benzyl-4-O-dibenzylphosphino-2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranosyl]-L-serine methyl ester as a foamy solid.

[0277] Example 4D In a manner similar to Example 1K, a solution of the compound prepared in Example 4C (200 mg, 0.12 mmol) was hydrogenated over 16 hours at room temperature and 50 psig using a Parr hydrogenator in the presence of 10% palladium-carbon (80 mg). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. 18 70 mg (40%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphino-β-D-allopyranosyl]-L-serine methyl ester was obtained as a glassy solid by chromatography on a column (gradient elution, 5 → 20% methylene chloride + 1% triethylamine / methanol).

[0278] Example 4E A solution of the compound prepared in Example 4D (70 mg, 0.048 mmol) was dissolved in THF (1 mL), cooled to 0°C, and hydrogenated with 1 N sodium hydroxide (0.012 mL, 0.192 mmol) for 1 hour. The reaction mixture was neutralized with ice-cold 1 N hydrochloride to a pH of 3. The layers were separated, the aqueous layer was saturated with sodium chloride, and extracted with chloroform (3 × 5 mL). The organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel was performed using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5). The fractions containing the purified product were combined, concentrated under reduced pressure, then redissolved in cold 2:1 chloroform-methanol (14 mL), and washed with cold 0.1 N hydrochloride aqueous solution (5.52 mL). The lower organic layer was separated, dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 30 mg (41%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranosyl]-L-serine as a glassy solid: 1 H NMR (CDCl3 / CD3OD): δ(ppm)4.68-4.63(m,3H), 4.44-4.40(m,1H), 4.13(dd,J=11&6.5Hz, 1H), 4.08( t,J=4.75Hz, 1H), 3.79-3.66(m,6H), 3.50-3.38(m,7H), 2.52-2.28(m,6H), 1.53-1.50(m,12H), 1.3 3-1.25(m,96)0.87(t,J=7.0Hz, 18H);HRMS(ESI-TOF)m / z:C 81 H 158 N3O 15 P[MH] - The calculated value for this is 1443.1352, and the measured value is 1443.1295.

[0279] Example 5 Preparation of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranosyl]-L-serine (compound 5) [ka] Example 5A A solution of the compound prepared in Example 4B (150 mg, 0.102 mmol), dissolved in anhydrous dimethylformamide (5 mL), was treated with sulfur trioxide triethylamine complex (111 mg, 0.613 mmol). The reaction mixture was heated at 50°C for 5 hours. A further amount of sulfur trioxide triethylamine complex (111 mg, 0.613 mmol) was added again, and the reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure. Chromatography on silica gel was performed using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5) to obtain 96 mg (62%) of N-[(R)-3-decyloxytetradecanoyl]-O-[6-O-benzyl-2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid.

[0280] Example 5B A solution of the compound prepared in Example 5A (96 mg, 0.062 mmol), dissolved in a 2:1 anhydrous tetrahydrofuran:methanol mixture (5 mL), was hydrogenated over 18 hours at room temperature and a pressure of 50 psig using a Parr hydrogenator in the presence of 20% palladium hydroxide / carbon (60 mg) and triethylamine (0.044 mL, 0.0003 mmol). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Chromatography on silica gel was performed using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5) to obtain 58 mg (55%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid.

[0281] Example 5C Solution of the compound (58 mg, 0.040 mmol) prepared in Example 5B above. The compound was dissolved in THF (2 mL), cooled to 0°C, and hydrogenated with 1 N sodium hydroxide (0.08 mL, 0.08 mmol) for 1 hour. The reaction mixture was neutralized with ice-cold 1 N hydrochloride to a pH of 3. The layers were separated, the aqueous layer was saturated with sodium chloride, and extracted with chloroform (3 × 5 mL). The combined organic layers were dried on anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel was performed using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5). The fractions containing the purified product were combined, concentrated under reduced pressure, then redissolved in cold 2:1 chloroform-methanol (14 mL), and washed with cold 0.1 N hydrochloride aqueous solution (5.52 mL). The lower organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 15 mg (26%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-sulfoxy-β-D-allopyranosyl]-L-serine as a glassy solid: 1 H NMR (CDCl3 / CD3OD): δ(ppm)7.74(d,J=7.0Hz, 1H), 7.30(d,J=8.0Hz, 1H), 7.02(d,J=8.0Hz, 1H), 4.62-4.55(m,3H), 4.17-4.08(m,3H), 3.7 1-3.60(m,5H), 3.45-3.31(m,6H), 2.49-2.25(m,6H), 1.48-1.45(m,12H), 1.33-1.25(m,96H)0.87(t,J=7.0Hz, 18H);HRMS(ESI-TOF)m / z:C 81 H 157 N3O 15 S[MH] - The calculated value for this is 1443.1257, and the measured value is 1443.1187.

[0282] Example 6 Preparation of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-methylphosphono-β-D-allopyranoside (compound 6) [ka] Example 6A A solution of paraformaldehyde (190 mg, 6.3 mmol) in dibenzyl phosphite (1.54 g, 5.87 mmol) was treated with anhydrous triethylamine (100 mg, mmol). The reaction mixture was heated to 50°C for 15 minutes, and the temperature was gradually increased to 85°C over 2 hours. The reaction mixture was diluted with chloroform (20 mL) and then concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20 → 100% ethyl acetate / heptane) yielded 1.04 g (58%) of dibenzyl hydroxymethylphosphonate as a colorless oil.

[0283] Example 6B In Example 6A above, in anhydrous methylene chloride (5 mL), cooled to -50°C A solution of the prepared compound (500 mg, 1.71 mmol) and 2,6-lutidine (5.0 mL, 42.8 mmol) was treated by dropwise addition of trifluoromethanesulfonic anhydride (0.33 mL, 2.05 mmol). The reaction mixture was gradually warmed to 0°C. The reaction mixture was diluted with Et2O (30 mL) and washed sequentially with H2O (10 mL), 1N HCl (10 mL), and brine (10 mL). The organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure to obtain 724 mg (quantitatively) of [di(benzyloxy)phosphoryl]methyl triflate as a pink oil.

[0284] Example 6C A solution of the compound prepared in Example 1I (100 mg, 0.065 mmol) in anhydrous THF (2 mL) was cooled to 0°C under an inert atmosphere and treated with a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.089 mL, 0.085 mmol). The reaction mixture was stirred at 0°C for 10 minutes, and then treated by dropwise addition of a tetrahydrofuran solution (0.5 mL) of the compound prepared in Example 6B (50 mg, 0.24 mmol). The reaction mixture was quenched with 0.1 N hydrochloride (5 drops), diluted with chloroform (5 mL), separated, and the organic matter was washed with saturated sodium bicarbonate aqueous solution (2 mL). The aqueous layer was extracted with chloroform (2 × 5 mL), and the combined organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20 → 100% ethyl acetate / heptane) yielded 43 mg (36%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 6-O-benzyl-4-O-dibenzylmethylphosphono-2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a colorless oil.

[0285] Example 6D A solution of the compound prepared in Example 6C (43 mg, 0.025 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) was hydrogenated with 10% palladium carbon using an H-Cube (30 mm CatCart®, full H2 mode at 60°C for 1 minute; this was hydrogenation at ambient pressure, where the amount of H2 introduced was 30 mL / min). The reaction mixture was concentrated under reduced pressure. After chromatography on silica gel using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5), the fractions containing the purified product were combined, concentrated under reduced pressure, redissolved in cold 2:1 chloroform-methanol (8.6 mL), and washed with cold 0.1 N hydrochloride aqueous solution (3.4 mL). The lower organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 27 mg (75%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-methylphosphono-β-D-allopyranoside as a glassy solid: 1 H NMR(CDCl3 / CD3OD):δ(ppm)5.19-5.16(m,3H);4.54-4.52(m,2H);3.98(s,2H);3.84-3.82(m,1H);3.78-3.75(m,2H); 3.71(s,1H);3.68-3.63(m,2H);3.45-3.37(m,2H);3.31-3.29(m,1H);2.54-2.37(m,6H);2.28-2.22(m,6H);1.56(br s,12H);1.22(br s,90H);0.85(t,J=7.25Hz, 18H);HRMS(ESI-TOF)m / z:C 81 H 154 N3O 16 P[MH] + The calculated value for this is 1457.1145, and the measured value is 1457.1185.

[0286] Example 7 N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-methylphosphorus] Preparation of no-β-D-allopyranosyl]-L-serinetriethylammonium salt (compound 7) [ka] Example 7A In a manner similar to Example 6C, a solution of the compound prepared in Example 4B (150 mg, 0.102 mmol) in anhydrous THF (2 mL) was cooled to 0°C under an inert atmosphere and treated with a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.135 mL, 0.133 mmol). The reaction mixture was stirred at 0°C for 10 minutes, and then treated by dropwise addition of a tetrahydrofuran solution (0.5 mL) of the compound prepared in Example 6B (90 mg, 0.173 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with 0.1 N hydrochloride (5 drops), diluted with chloroform (5 mL), separated, and the organic layer was washed with saturated sodium bicarbonate aqueous solution (2 mL). The aqueous layer was extracted with chloroform (2 × 5 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20 → 100% ethyl acetate / heptane) yielded 48 mg (27%) of N-[(R)-3-decyloxytetradecanoyl]-O-[6-O-benzyl-2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-dibenzylmethylphosphono-β-D-allopyranosyl]-L-serine methyl ester as a colorless oil.

[0287] Example 7B A solution of the compound prepared in Example 7A (160 mg, 0.092 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) was hydrogenated over 18 hours at room temperature and a pressure of 50 psig using a Parr hydrogenator in the presence of 10% palladium carbon (48 mg). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Reverse-phase chromatography using a C18 column (gradient elution, 0 → 100% chloroform / methanol) yielded 91 mg (67%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-methylphosphono-β-D-allopyranosyl]-L-serine methyl ester as a glassy solid.

[0288] Example 7C A solution of the compound prepared in Example 7B (91 mg, 0.062 mmol) was dissolved in THF (2 mL), cooled to 0°C, and hydrogenated with 1 N lithium hydroxide (0.26 mL, 0.26 mmol) for 1 hour. The reaction mixture was neutralized with ice-cold 1 N hydrochloride to pH 5. The layers were separated, the aqueous layer was saturated with sodium chloride, and extracted with chloroform (3 × 5 mL). The combined organic layers were dried on anhydrous sodium sulfate. The mixture was dried and concentrated under reduced pressure. Chromatography on silica gel was performed using a gradient elution (0→30% [90:10 MeOH / H2O] / chloroform). The fractions containing the purified product were combined, concentrated under reduced pressure, then redissolved in 14 mL of 2:1 chloroform-methanol at low temperature, and washed with 5.52 mL of 5.1 N hydrochloride aqueous solution at low temperature. The lower organic layer was separated, dried on anhydrous sodium sulfate, concentrated under reduced pressure, and then salted with triethylamine to obtain 56 mg (62%) of N-[(R)-3-decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-methylphosphono-β-D-allopyranosyl]-L-serinetriethylammonium salt as a glassy solid: 1H NMR(CDCl3 / CD3OD):δ(ppm)4.61-4.54(m,2H);4.14-4.06(m,2H);3.84(br m,2H);3.69(br m,6H);3.47-3.39(m,8H);3.09(q,J=7.6Hz, 2H, CH2 of Et3N (about 1.2 equivalents);2.47-2.33(m,6H); 1.51-1.45(m,12H);1.26-1.14(m,101H);0.88(t,J=7.0Hz, 18H);HRMS(ESI-TOF)m / z:C 82 H 160 N3O 15 P[MH] - The calculated value for this is 1457.1507, and the measured value is 1457.1367.

[0289] Example 8 Preparation of 2-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside triethylammonium salt (compound 8) [ka] Example 8A In a method similar to that of Example 1G, a solution of the compound prepared in Example 1F (250 mg, 0.43 mmol) in anhydrous methylene chloride (10 mL) was acylated with (R)-3-(8-phenyl)octanoyloxytetradecanoic acid (231 mg, 0.52 mmol) (prepared by acyling (R)-3-hydroxyltetradecanoyl ester with 8-phenyloctanoic acid) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (153 mg, 0.52 mmol) to obtain 378 mg (88%) of 2-(benzyloxycarbonylamino)ethyl 4,6-O-benzylidene-2-benzyloxycarbonylamino-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a colorless oil.

[0290] Example 8B In a method similar to Example 1H, the above substance in anhydrous tetrahydrofuran (10 mL) A solution of the compound prepared in Example 8A (189 mg, 0.19 mmol) was hydrogenated with 10% palladium-carbon (50 mg) in a Parr hydrogenator at room temperature and 50 psig for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting oil, dissolved in methylene chloride (10 mL), was acylated with (R)-3-(8-phenyl)octanoyloxytetradecanoic acid (180 mg, 0.402 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (119 mg, 0.402 mmol) over 2 hours at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 10 mL), and the combined organic layer was washed with water (10 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20-80% ethyl acetate / heptane) yielded 290 mg (99%) of 2-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]ethyl 4,6-O-benzylidene-2,3-di-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a glassy solid.

[0291] Example 8C In a method similar to that of Example 1I, a solution of the compound prepared in Example 8B (290 mg, 0.182 mmol) was treated with sodium cyanoborohydride (57 mg, 0.91 mmol) and trifluoroacetic acid (0.083 mL, 1.09 mmol) to obtain 231 mg (80%) of 2-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]ethyl 6-O-benzyl-2,3-di-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a colorless oil.

[0292] Example 8D In a method similar to that of Example 1J, a solution of the compound prepared in Example 8C (231 mg, 0.145 mmol) in anhydrous methylene chloride (10 mL) was phosphorylated with dibenzyldiisopropylphosphoramidite (0.070 mL, 0.203 mmol), 4,5-dicyanoimidazole (24 mg, 0.203 mmol), and hydrogen peroxide (2 mL) to obtain 269 mg (76%) of 2-[(R)-3-(8-phenyloctanoyloxytetradecanoylamino]ethyl 6-O-benzyl-4-O-dibenzylphosphino-2,3-di-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a foamy solid.

[0293] Example 8E In a manner similar to Example 1K, a solution of the compound prepared in Example 8D (269 mg, 0.145 mmol) in anhydrous tetrahydrofuran (5 mL) was hydrogenated for 18 hours under atmospheric hydrogen gas (H2 balloon) in the presence of 10% palladium carbon (50 mg). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5) was performed. The fractions containing the purified product were combined, concentrated under reduced pressure, redissolved in 2:1 chloroform-methanol (17 mL) at low temperature, and washed with 0.1 N aqueous hydrochloride solution (6.72 mL) at low temperature. The lower organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and salted with triethylamine to obtain 75 mg (33%) of 2-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside triethylammonium salt as a glassy solid: 1 1H NMR (CDCl3 / CD3OD): δ(ppm)7 .69(br s,1H), 7.26-7.16(m,15H), 5.21(br s,3H), 4.54-4.39(m,3H), 4.09-4.05(m,2H), 3.78(br CH2, 2.58-2.46(m,12H), 2.27(br m,6H), 1.58(br s,12H), 1.31-1.24(m,81H), 0.87(t,J=6.8Hz, 9H);HRMS(ESI-TOF)m / z:C 92 H 152 N3O 16 P[MH] - The calculated value for this is 1586.0832, and the measured value is 1586.0799.

[0294] Example 9 Preparation of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl and 2-[(R)-3-decanoyloxytetradecanoylamino]-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside triethylammonium salt (compound 9) [ka] Example 9A In a manner similar to Example 1H, a sugar solution of the compound prepared in Example 8A (189 mg, 0.19 mmol) in anhydrous tetrahydrofuran (10 mL) was hydrogenated with 10% palladium carbon (50 mg) in a Parr hydrogenator at room temperature and 50 psig for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting oil, dissolved in methylene chloride (10 mL), was acylated with (R)-3-decanoyloxytetradecanoic acid (160 mg, 0.402 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (119 mg, 0.402 mmol) for 2 hours at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 10 mL), the combined organic layer was washed with water (10 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution, 20 → 80% ethyl acetate / heptane) yielded 145 mg (53%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 4,6-O-benzylidene-2-[(R)-3-decanoyloxytetradecanoylamino]-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a glassy solid.

[0295] Example 9B In a method similar to Example 1I, a solution of the compound prepared in Example 9A (145 mg, 0.097 mmol) was treated with sodium cyanoborohydride (30 mg, 0.48 mmol) and trifluoroacetic acid (0.044 mL, 0.58 mmol) to obtain 103 mg (71%) of 2-[(R)-decanoyloxytetradecanoylamino]e Tyl 6-O-benzyl-2-[(R)-3-decanoyloxytetradecanoylamino]-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside was obtained as a colorless oil.

[0296] Example 9C In a method similar to that of Example 1J, a solution of the compound prepared in Example 9B (103 mg, 0.069 mmol) in anhydrous methylene chloride (10 mL) was phosphorylated with dibenzyl diisopropyl phosphoramidite (0.033 mL, 0.096 mmol) and 4,5-dicyanoimidazole (11 mg, 0.096 mmol), and treated with hydrogen peroxide (2 mL) to obtain 105 mg (87%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 6-O-benzyl-4-O-dibenzylphosphino-2-[(R)-3-decanoyloxytetradecanoylamino]-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-β-D-allopyranoside as a glassy solid.

[0297] Example 9D In a manner similar to Example 1K, a solution of the compound prepared in Example 9C (100 mg, 0.057 mmol) in anhydrous tetrahydrofuran (5 mL) was hydrogenated for 18 hours using a hydrogen atmospheric pressure (H2 balloon) in the presence of 10% palladium carbon (30 mg). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using chloroform-methanol-water-triethylamine (gradient elution; 90:10:0.5:0.5 → 70:30:2:0.5) was performed. The fractions containing the purified product were combined, concentrated under reduced pressure, redissolved in 2:1 chloroform-methanol (12 mL) at low temperature, and washed with 0.1 N aqueous hydrochloride solution (4.8 mL) at low temperature. The lower organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and salted with triethylamine to obtain 36 mg (43%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2-[(R)-3-decanoyloxytetradecanoylamino]-3-[(R)-3-(8-phenyl)octanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside as a glassy solid: 1H NMR (CDCl3 / CD3OD): δ(ppm)7.56(br s,1H), 7.10-7.18(m,5H), 5.14(br m,3H), 4.33-4.47(m,3H), 3.97-4.03(m,2H), 3.63-3.75(m,3H), 3.13-3.40 (m,3H), 3.01(q,J=6.8Hz, 6H, CH2 of Et3N (about 1 equivalent), 2.38-2.52(m,8H), 2.21(br s,6H), 1.52(br s,12H), 1.18-1.25(m,87H), 0.88(t,J=6.4Hz, 15H);HRMS(ESI-TOF)m / z:C 84 H 152 N3O 16 P[M] - The calculated value for this is 1490.0910, and the measured value is 1490.0813.

[0298] 6. Biological and Stability Data In vitro assays were performed using compounds 1-9 and the commercially available TLR4 agonist MPL. To measure biological activity, various cells were stimulated with each compound across a wide dose range, followed by evaluation of either transcriptional activation (HEK hTLR4 NF-κB-SEAP cells) or cytokine production (hMM6 or hPBMC). Dose-response curves for each compound were developed starting at either 100 μM or 20 μM, followed by 5-fold serial dilutions in a vehicle (2% glycerol or glycine, "IN"), with a final concentration of 1.6 × 10⁻⁶. -8 μM (1.6 fM) or 3.3 × 10⁻⁶ -8 The concentration was μM (3.3 fM). After incubation with compounds within the dose range for 18–24 hours, the cell supernatant was collected for analysis.

[0299] hTLR4 activation. HEK hTLR4-expressing cells were treated with a 100 μM concentration of the test compound, followed by a 5-fold dilution series. HEK hTLR4-expressing cells also contained an NF-κB-driven SEAP reporter. After 18 hours of stimulation with the indicated concentrations of the test compound (Figures 1A-1C), the cell supernatant was evaluated for SEAP using the Quantikine SEAP assay (InvivoGen). The SEAP assay was used to examine the secretion of the NF-κB-driven alkaline phosphatase reporter gene in response to TLR4 activation by the compound. The results are interpreted as both the potency of the compound inducing SEAP activation (i.e., lower EC50 indicates higher potency) and the efficacy in receptor activation (i.e., maximum SEAP induction). The EC50 values ​​for each compound in HEK hTLR4 cells are shown in Tables 1a and 1b. The EC50 values ​​were determined by fitting the dose-response curves to a nonlinear four-parameter equation.

[0300] [Table 1]

[0301] [Table 2]

[0302] Induction of MIP-1β cytokine from hMM6 cells. Next, the compound was tested in an established MM6 efficacy assay measuring MIP-1β cytokine production as an output measure of the compound's potency. Human monocyte cell line, Mono-Mac-6 (hMM6), was obtained from DSMZ (Brunswick, Germany). Cells were maintained in T-75 flasks and cultured in 96-well tissue culture plates containing RPMI-1640 medium (HyClone®, Logan, UT), Pen / Strep / Glutamine (HyClone®, Logan, UT), 2-Mercaptoethanol (Gibco, Grand Island, NY), and 10% thermally inactivated FBS (Corning, Manassas, VA), yielding 1.53 × 10⁶ cells. 5hMM6 cells were cultured in individual cells / well. hMM6 cells were treated with increasing concentrations of the compound shown over 18 hours (Figures 2A-2B). Treatment was started at a concentration of 100 μM and continued using a 16-point 5-fold dilution series. The supernatant was collected and analyzed for MIP-1β production by ELISA (R&D Systems, catalog number DY271). EC50 values ​​for each compound in hMM6 cells are shown in Table 2. EC50 values ​​were determined by fitting the dose-response curves to a nonlinear four-parameter equation.

[0303] [Table 3]

[0304] Induction of MIP-1β cytokine from mRAW264.7 cells. To determine whether the compounds are active in mouse cells, all compounds were tested in RAW cells and mouse macrophage cell lines. mRAW264.7 cells were subjected to treatment with increasing concentrations of the compounds over 18 hours (Figure 3). Treatment was started at a concentration of 20 μM and serially diluted 5-fold to 3.2768E-09 μM. The supernatant was collected and ELISA (R&C) was performed. The production of MIP-1β was analyzed using D Systems (catalog number DY451). The EC50 values ​​for each compound in mRAW264.7 cells are shown in Table 3. The EC50 values ​​were determined by fitting the dose-response curve to a nonlinear four-parameter equation.

[0305] [Table 4]

[0306] Induction of MIP-1β, RANTES, or TNFα cytokines from primary hPBMCs. In addition to MIP-1β production from the MM6 cell line, MIP-1β, TNF-α, and RANTES production from primary human peripheral mononuclear cells (PBMCs) was also investigated. Analysis of these cytokines is useful for evaluating the activation of MYD88-dependent (TNF-α) or TRIF-TRAM (RANTES) intracellular signaling pathways in response to the compounds. PBMCs were obtained from different donors for the bioassays, and the cell supernatants treated with the compounds were used for three cytokine ELISAs. Figures 4A, 5A, and 6A show the mean responses from three donors for compounds 1, 2, 3, and 4. Figures 4B, 5B, and 6B show the responses for compounds 1, 2, 4, 5, 6, and 7 in one donor, and Figures 4C, 5C, and 6C show the responses for compounds 8 and 9 in one donor. It should be noted that although all donors showed the same compound potency trend, there was greater inter-donor variability for RANTES and TNF-α, but less variability for MIP-1β. All compounds were able to induce all three cytokines with nearly equivalent potency, suggesting that MyD88 / TRIF balanced cytokine skewing. Primary human peripheral blood mononuclear cells were isolated from donor whole blood using a Ficoll gradient. The cells were then treated with compounds showing increasing concentrations over 18 hours (Figures 4A-4C, 5A-5C, and 6A-6C), and the supernatant was analyzed by ELISA for the production of MIP-1β, RANTES, or TNFα. The EC50 values ​​for each compound in each hPBMC donor are shown in Tables 4a-4d. The EC50 values ​​were determined by fitting the dose-response curves to a nonlinear four-parameter equation.

[0307] [Table 5]

[0308] [Table 6]

[0309] [Table 7]

[0310] [Table 8]

[0311] Vaccine adjuvant study. Compounds 2, 4, 5, and 7 were evaluated as vaccine adjuvants in a mouse influenza virus vaccination model. Influenza virus antigen A / Victoria / 210 / 2009-H3N2 (0.2 μg / mouse) was intramuscularly injected into the hind limbs of 7-9 week old BALB / c mice (10 mice per group) with or without 0.1, 0.01, or 0.001 μg of compound 2, 4, 5, or 7 (formulated in 2% glycine). Fourteen days after a single immunization, the animals were induced to bleed via the submandibular gland vein, and serum was collected to assay for A / Victoria-specific antibodies by ELISA assay (Figure 7). Compounds 2, 4, 5, and 7 showed dose-dependent adjuvant effects by increasing influenza-specific IgG2a antibody titers compared to the vaccine response with the antigen alone.

[0312] Nonspecific resistance (NSR) study. 12-14 week old BALB / c mice (9 mice per group) were administered 10, 1, and 0.1 μg aqueous formulations of compound 4 intranasally (10 μL / nostril) on day 2. On day 0, the animals were inoculated with 1 LD50 dose of influenza virus antigen A / HK / 68 (mouse-adapted H3N2 human influenza virus). Body weight, disease indicators, and body temperature were recorded daily for 20 days after antigen inoculation. Compound 4 provided strong, dose-dependent nonspecific protection from lethal influenza virus antigen inoculation (Figure 8).

[0313] Formulation. The compound, converted to a salt, was accurately weighed into a glass vial from which pyrogens had been removed, and the required volume of aqueous vehicle was added to obtain the desired concentration. The vial was placed in an ultrasonic bath (ultrasonic bath temperature ≤ 45°C) to promote dissolution and reduce particle size, and sterile filtration was performed without significant loss of compound. Once the solution was homogeneous, the particle size was periodically monitored by dynamic light scattering until the solution became clear and the particle size was less than 200 mn, or until the particle size no longer decreased even with continued ultrasonic treatment. The formulation was passed through a 0.22 μm PVDF membrane filter and filtered into a glass vial from which pyrogens had been removed, and the obtained solution was quantified by RP-HPLC.

[0314] Stability testing Aqueous formulations of compounds 1, 2, 3, 4, 5, and 6 were divided equally into small vials with pyrogens removed at temperatures of 2°C–8°C, 25°C, and 40°C for stability evaluation. This reflects the ICH stability temperature guidelines, but humidity was not controlled. Vials were taken at each time point / temperature and analyzed by reverse-phase HPLC according to the following schedule, starting from 2 weeks to 12 months (Figures 9–14).

[0315] [Table 9]

[0316] Compound 1 showed good stability with no degradation up to T=6 weeks at 40°C. Compound 2 showed excellent stability with no degradation up to 8 weeks at 40°C and 12 months at 25°C when formulated in 2% glycine (Figure 10A), and with less than 10% degradation after 12 months at 40°C when formulated in 2% glycerol (Figure 0B). Compound 4 showed high stability with no degradation up to 8 weeks at 40°C. Excellent formulation stability is necessary for reliable safety, efficacy, reduced cold chain dependence, and increased product shelf life.

[0317] For the sake of completeness, various aspects of the present invention are described in the following numbered sections.

[0318] Term 1. Formula (II) [ka] (In the formula, R 10 C 1~21 It is alkyl; R 11 Each time it appears, it is independently -OC(=O)C 1~15 Alkyl, -OC 2~16 Alkyl, -OC(=O)C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 and; R 3a These are -OP(O)(OH)2, -OSO3H, or -OCH2-P(O)(OH)2; R 3b is H, CO2H, or an ester of CO2H; and Z 2 Each instance is independently a phenyl or a 5- to 6-membered heteroaryl, where Z 2 C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 (Optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen groups.) A compound of or a pharmaceutically acceptable salt thereof.

[0319] Term 2. Formula (I) [ka] (In the formula, R 1 teeth, [ka] and; R 2a , R 2b and R 2c Each of them is independent of C 4~22 Alkyl, -X 1-C 3~21 Alkyl, -CH2-X 1 -C 2~20 Alkyl or -CH(R 10 )(R 11 ) and; R 10 Each time it appears, C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 It is alkyl; R 11 Each time it appears, C 3~17 Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 2 or -X 2 -C 2~16 Alkilen-Z 2 and; R 3a , R 3b and R3c These are, independently, CO2H, -OSO3H, -OP(O)(OH)2, and -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene -P(O)(OH)2, H or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of haloalkylene-P(O)(OH)2; R 3d is CO2H, -SO3H, -P(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene-P(O)(OH)2,H,C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of haloalkylene-P(O)(OH)2; R 4ais an ester of CO2H, CH2OSO3H, CH2CO2H, CH2P(O)(OH)2, CH2OH, H, or CO2H, CH2SO3H, CH2CO2H, or CH2P(O)(OH)2; R 4b Each instance is independently an ester of CO2H, CH2OSO3H, CH2CO2H, CH2P(O)(OH)2, CH2OH, H, or CO2H, CH2SO3H, CH2CO2H, or CH2P(O)(OH)2; R 5 and R 6 Each time they appear, H and C are independent. 1~6 Alkyl, C 1~6 Haloalkyl, -OC 1~6 Alkyl or -C 1~6 It is alkylene-OH; X 1 and X 2 Each instance is independently O, S, or NH; X 3 is O, S, NH, or CH2; Y 1 , Y 2 and Y 3 These are independently O, S, NH, or H2; Y 4 Each instance is independently O, S, or NH; Z 1 Each instance is independently phenylene or a 5- to 6-membered heteroarylene, and phenylene and heteroarylene are C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 Optionally substituted with 1 to 4 substituents independently selected from haloalkyl, cyano, and halogen; Z 2 Each instance is independently a phenyl or a 5- to 6-membered heteroaryl, where Z 2 C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4Optionally substituted with 1 to 5 substituents independently selected from haloalkyl, cyano, and halogen; and k and q are each independent integers between 0 and 4. A compound of or a pharmaceutically acceptable salt thereof.

[0320] Term 3. Formula (I) [ka] (In the formula, R 1 teeth, [ka] and; R 2a , R 2b and R 2c Each of them is independent of C 4~22 Alkyl, -X 1 -C 3~21 Alkyl, -CH2-X 1 -C 2~20 Alkyl or -CH(R 10 )(R 11 ) and; R 10 C 1~21 Alkyl, -X 1 -C 2~20 Alkyl or -CH2-X 1 -C 1~19 It is alkyl; R 11 C 3~17 Alkyl, -X 2 -C 2~16 Alkyl, -CH2-X 2 -C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkyl, -CH2-C(=Y 4 )C 1~15 Alkyl, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 Alkyl, -CH2-C(=Y 4 )C1~15 Alkilen-Z 1 -C 1~15 Alkyl, -C 3~17 Alkilen-Z 1 -C 1~15 Alkyl, -X 2 -C 2~16 Alkilen-Z 1 -C 1~15 Alkyl or -CH2-X 2 -C 1~15 Alkilen-Z 1 -C 1~15 It is alkyl; R 3a , R 3b and R 3c These are, independently, CO2H, -OSO3H, -OP(O)(OH)2, and -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene -P(O)(OH)2, H or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of haloalkylene-P(O)(OH)2; R 3d is CO2H, -SO3H, -P(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2, -C 1~6 Haloalkylene-P(O)(OH)2,H,C 1~6 Alkyl, C1~6 Haloalkyl, C 3~8 Cycloalkyl or CO2H, -OSO3H, -OP(O)(OH)2, -C 1~6 Alkylene-CO2H, -C 1~6 Alkylene-OSO3H, -C 1~6 Alkylene-OP(O)(OH)2,-OC 1~6 Alkylene-P(O)(OH)2, -C 1~6 Alkylene-P(O)(OH)2 or -C 1~6 It is an ester of haloalkylene-P(O)(OH)2; R 4a and R 4b Each of these is independently an ester of CO2H, CH2OSO3H, CH2CO2H, CH2P(O)(OH)2, CH2OH, H, or CO2H, CH2SO3H, CH2CO2H, or CH2P(O)(OH)2; R 5 and R 6 Each time they appear, H and C are independent. 1~6 Alkyl, C 1~6 Haloalkyl, -OC 1~6 Alkyl or -C 1~6 It is alkylene-OH; X 1 and X 2 These are independently O, S, or NH; X 3 is O, S, NH, or CH2; Y 1 , Y 2 and Y 3 These are independently O, S, NH, or H2; Y 4 is O, S, or NH; Z 1 It is phenylene or 5- to 6-membered heteroarylene, and phenylene and heteroarylene Leeren is C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 Optionally substituted with 1 to 4 substituents independently selected from haloalkyl, cyano, and halogen; and k and q are each independent integers between 0 and 4. A compound of or a pharmaceutically acceptable salt thereof.

[0321] Section 4.R 2a , R 2b and R 2c Each of them operates independently, -CH(R 10 )(R 11 ) the compound described in item 2 or 3 or a pharmaceutically acceptable salt thereof.

[0322] Section 5.R 10 At least one occurrence of C 1~19 A compound that is alkyl, as described in any of items 1 to 4, or a pharmaceutically acceptable salt thereof.

[0323] Section 6.R 10 At least one occurrence of C 3~21 A compound that is alkyl, as described in any of items 1 to 5, or a pharmaceutically acceptable salt thereof.

[0324] Section 7.R 11 At least one occurrence of -OC(=O)C 1~15 A compound that is alkyl, as described in any of items 1 to 6, or a pharmaceutically acceptable salt thereof.

[0325] Section 8.R 11 At least one occurrence of -OC(=O)C 1~15 Alkilen-Z 2 The compound described in any of items 1 to 6, or a pharmaceutically acceptable salt thereof.

[0326] Section 9.R 11 At least one occurrence of -OC 2~16 Alkilen-Z 2 The compound described in any of items 1 to 6, or a pharmaceutically acceptable salt thereof.

[0327] Section 10.R 11 At least one occurrence of -OC 2~16A compound that is alkyl, as described in any of items 1 to 6, or a pharmaceutically acceptable salt thereof.

[0328] Section 11.R 10 C 1~19 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1-5 or 7-10.

[0329] Section 12.R 10 C 3~21 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 1-4 or 6-10.

[0330] Section 13.R 10 is, -X 1 -C 2~20 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-4 or 7-10.

[0331] Section 14.R 10 is -CH2-X 1 -C 1~19 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-4 or 7-10.

[0332] Section 15.R 11 is, -X 2 -C(=Y 4 )C 1~15 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-6 or 11-14.

[0333] Section 16.R 11 is, -X 2 -C(=Y 4 )C 1~15 Alkilen-Z 1 -C 1~15 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-6 or 11-14.

[0334] Section 17.R 11 is, -X 2 -C(=Y 4 )C 1~15Alkilen-Z 2 The compound described in any of items 2-6 or 11-14, or a pharmaceutically acceptable salt thereof.

[0335] Section 18.R 11 is, -X 2 -C 2~16 Alkilen-Z 2 This is the case for items 2-6 or 11- A compound or a pharmaceutically acceptable salt thereof as described in any of item 14.

[0336] Section 19.Y 4 is a compound or a pharmaceutically acceptable salt thereof, as described in any of items 2-6 or 11-18, wherein the compound is O.

[0337] Section 20.R 11 is, -X 2 -C 2~16 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-6 or 11-14.

[0338] Section 21.R 11 is -CH2-X 2 -C 1~15 A compound or pharmaceutically acceptable salt thereof, which is alkyl, as described in any of items 2-6 or 11-14.

[0339] Section 22.X 2 is a compound or a pharmaceutically acceptable salt thereof, as described in any of items 2-6 or 11-21, wherein the compound is O.

[0340] Section 23.Y 1 , Y 2 and Y 3 is a compound or a pharmaceutically acceptable salt thereof, as described in any of items 2-6 or 11-22, wherein the compound is O.

[0341] Section 24.X 3 is a compound or a pharmaceutically acceptable salt thereof, as described in any of items 2 to 23, wherein the compound is O.

[0342] Section 25.R 3ais a compound described in any of items 1 to 24, or a pharmaceutically acceptable salt thereof, which is -OP(O)(OH)2.

[0343] Section 26.R 3a is a compound or a pharmaceutically acceptable salt thereof, which is -OSO3H, as described in any of items 1 to 24.

[0344] Section 27.R 3a is a compound described in any of items 1 to 24, or a pharmaceutically acceptable salt thereof, which is -OCH2P(O)(OH)2.

[0345] Section 28.R 4a The compound is CH2OH, as described in any of items 2 to 27, or a pharmaceutically acceptable salt thereof.

[0346] Section 29. R 1 teeth, [ka] The compound described in any of items 2 to 28, or a pharmaceutically acceptable salt thereof.

[0347] Section 30. k is 1; R 3b is hydrogen or COOH or its ester; and R 3d , R 5 and R 6 Each of the compounds described in item 29 or their pharmaceutically acceptable salts, wherein each is a hydrogen atom.

[0348] Section 31. R 1 teeth, [ka] The compound described in any of items 2 to 28, or a pharmaceutically acceptable salt thereof.

[0349] Section 32. [ka] [ka] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following:

[0350] Item 33. The compound is a TLR4 antagonist, one of the compounds described in any of items 1 to 32, or a pharmaceutically acceptable salt thereof.

[0351] Item 34. The compound is a TLR4 agonist, one of the compounds described in any of items 1 to 32, or a pharmaceutically acceptable salt thereof.

[0352] Item 35. A pharmaceutical composition comprising a compound described in any of items 1 to 34 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0353] Item 36. The pharmaceutical composition according to item 35, further comprising an antigen.

[0354] Item 37. The pharmaceutical composition according to item 36, comprising an immunogenic amount of antigen.

[0355] Item 38. A pharmaceutical composition according to item 36 or 37, wherein the antigen is derived from bacteria, viruses, fungi, prions, neoplasms, autoantigens, animals, plants, recombinants, or synthetic materials.

[0356] Item 39. A pharmaceutical composition according to any one of items 36 to 38, wherein the antigen is in the form of a polypeptide.

[0357] Item 40. A pharmaceutical composition according to any one of items 36 to 38, wherein the antigen is an allergen.

[0358] Item 41. A pharmaceutical composition described in any of items 35 to 40, which is a vaccine.

[0359] Item 42. The pharmaceutical composition according to item 35, further comprising a further therapeutic agent selected from chemotherapeutic agents and immunomodulators or oncological phagocytic inducers such as immune checkpoint inhibitors.

[0360] Item 43. A pharmaceutical composition according to any one of items 35 to 42, which is a TH1-inducing adjuvant.

[0361] Item 44. A pharmaceutical composition according to any one of items 35 to 43, in the form of an aqueous solution, emulsion, liposome, nanoparticles adsorbed to an inorganic or organic substance, gel, capsule, lozenge, or tablet.

[0362] Item 45. A method for inducing, enhancing, or modulating an immune response in a subject, comprising administering to a subject in need of such response a therapeutically effective dose of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in any of items 35 to 44.

[0363] Item 46. The method described in Item 45, which involves an immune response to treat cancer in a subject.

[0364] Item 47. The method described in Item 45 for treating an infection in a subject by an immune response.

[0365] Section 48. The method described in Section 47, wherein the infection is a bacterial, viral, fungal, or prion infection.

[0366] Item 49. The method described in Item 45 for treating an immune response to an allergy in a subject.

[0367] Item 50. A method for treating, preventing, or reducing susceptibility to cancer in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in any of items 35 to 44.

[0368] Item 51. A method for treating, preventing, or reducing susceptibility to an infection in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in any of items 35 to 44.

[0369] Item 52. The method described in Item 51, wherein the infection is a bacterial, viral, fungal, or prion infection.

[0370] Item 53. A method for treating, preventing, or reducing susceptibility to an allergy in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in any of items 35 to 44.

[0371] Item 54. A method for treating, preventing, or reducing susceptibility to an autoimmune disease in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in any of items 35 to 44.

[0372] Item 55. A method for treating, preventing, or reducing susceptibility to a bacterial, viral, prion infection, autoimmune disease, cancer, or allergy, comprising, to a subject in need, a therapeutically effective amount of any of the compounds or pharmacopoeias described in items 1 to 34. A method comprising administering a generally acceptable salt or a pharmaceutical composition described in any of items 35 to 44.

[0373] Item 56. Administration to the subject is by intramuscular, intradermal, subcutaneous, local, intravenous, or mucosal administration, as described in any of items 45 to 55.

[0374] Item 57. The method according to any one of items 45 to 56, further comprising administering a therapeutically effective dose of radiotherapy or chemotherapeutic agents and further therapeutic agents selected from immunomodulators or oncology phagocytic inducers such as immune checkpoint inhibitors.

[0375] Item 58. The method according to any one of items 45 to 57, further comprising administering an immunogenic amount of antigen to a target.

[0376] Item 59. The method described in any of items 45-58 for generating an IgA immune response.

[0377] Item 60. The method described in any of items 45-59, which induces an IgG immune response.

[0378] Item 61. A method for treating or preventing autoimmunity, allergy, ischemia-reperfusion, or sepsis in a subject, or for reducing susceptibility thereto, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in items 35 to 44.

[0379] Item 62. A method for treating or preventing epileptic seizures or reducing their severity, comprising administering to a subject in need of such treatment an effective dose of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in items 35 to 44.

[0380] Item 63. A method for treating or preventing or reducing susceptibility to eye diseases such as macular degeneration, ocular hypertension and eye infections, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any of items 1 to 34 or a pharmaceutical composition described in items 35 to 44.

[0381] Section 64. A compound described in any of items 1 to 34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any of items 35 to 44; Instructions for use of the pharmaceutical composition and A kit that includes this.

[0382] The above description discloses and describes only exemplary embodiments of the present invention. Those skilled in the art will readily recognize from this description, the accompanying drawings, and the claims that various variations, modifications, and alterations can be made without departing from the spirit and scope of the invention as defined in the following claims.

Claims

1. An immunologically effective amount of antigen, and formula (II): 【Chemistry 1】 (In the formula, R ３ａ is, -OSO ３ H, -OP(O)(OH) ２ , or -OCH ２ P(O)(OH) ２ And; R ３ｂ is H or CO ２ It is H; R １０ each time it appears, independently, is C ８～１４ alkyl; R １１ Each time it appears, it independently becomes -O-C(=O)C ９ Alkyl or -O-C １０ (It is alkyl.) A vaccine composition comprising the compound or a pharmaceutically acceptable salt thereof, A vaccine composition wherein the aforementioned antigen is an infectious disease antigen.

2. The composition according to claim 1, wherein the infectious disease antigen is a viral antigen.

3. The composition according to claim 2, wherein the viral antigen is an antigen derived from the family Orthomyxoviridae.

4. The composition according to claim 3, wherein the orthomyxoviridae antigen is one or more viral proteins selected from the group consisting of hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), substrate protein (Ml), and membrane protein (M2).

5. An immunologically effective amount of antigen, and formula (II): 【Chemistry 2】 (In the formula, R 3a is -OSO 3 H, -OP(O)(OH) 2, or -OCH 2 P(O)(OH) 2; R 3b is either H or CO 2H; Each instance of R 10 is independently a C8-14 alkyl group; Each instance of R11 is independently either an -O-C(=O)C9 alkyl group or an -O-C10 alkyl group. A vaccine composition comprising the compound or a pharmaceutically acceptable salt thereof, A vaccine composition wherein the antigen is an allergen.

6. The composition according to claim 5, wherein the allergen is selected from the group consisting of pollen allergens, insect venom allergens, animal scale allergens, dust allergens, fungal spore allergens, food allergens, and drug allergens.

7. The composition according to claim 6, wherein the allergen is a pollen allergen.

8. The composition according to claim 6, wherein the allergen is a food allergen.

9. Pharmacochemically acceptable carriers, and formula (II): 【Transformation 3】 (In the formula, R ３ａ is, -OSO ３ H, -OP(O)(OH) ２ , or -OCH ２ P(O)(OH) ２ And; R ３ｂ is H or CO ２ It is H; R １０ Each time it appears, C ８～１４ It is alkyl; R １１ Each time it appears, it independently becomes -O-C(=O)C ９ Alkyl, or -O-C １０ (It is alkyl.) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, in combination with an immunogenic amount of an antigen, for treating, preventing, or reducing susceptibility to allergies or infections.

10. The composition according to claim 9, wherein the antigen is an allergen, for treating, preventing, or reducing sensitivity to an allergy.

11. The composition according to claim 9 or 10, wherein the allergy is selected from the group consisting of food allergy, allergic rhinitis, allergic asthma, allergic skin disease, seasonal allergy, related allergic condition, allergic conjunctivitis, atopic dermatitis, and psoriasis.

12. The composition according to claim 11, wherein the allergy is a food allergy.

13. The composition according to claim 11, wherein the allergy is allergic rhinitis.

14. The composition according to claim 11, wherein the allergy is a seasonal allergy.

15. The composition according to claim 9, wherein the antigen is an infectious disease antigen, for treating, preventing, or reducing susceptibility to an infectious disease.

16. The composition according to claim 9 or 15, wherein the infectious disease is a bacterial infection or a viral infection.

17. The composition according to claim 16, wherein the infectious disease is a viral infectious disease.

18. The composition according to claim 17, wherein the infectious disease is influenza.

19. A composition according to any one of claims 1 to 18 for intramuscular, intradermal, subcutaneous, topical, intravenous, or mucosal administration.

20. The composition according to claim 19 for intranasal administration.

21. -CH(R) １０ ) (Caution １１ )teeth, 【Chemistry 4】 The composition according to any one of claims 1 to 20.

22. The aforementioned compound 【Transformation 5】 The composition according to claim 21.

23. The aforementioned compound 【Transformation 6】 The composition according to claim 21.

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