STING agonists, formulations, and uses thereof

Abstract

The present disclosure provides STING agonists, as well as compositions, formulations, and methods for treating a disease or disorder (e.g., cancer, inflammatory diseases, autoimmune diseases, and infectious diseases) using STING agonists or compositions thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 334,433, filed April 25, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Field The present disclosure discloses stimulator of interferon (IFN) genes (STING) agonists, compositions, formulations, and methods for inducing or modulating an immune or inflammatory response, and methods for treating a disease or disorder (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases) using STING agonists or compositions thereof. [Background technology]

[0003] The innate immune agonist STING (stimulator of interferon genes) binds to the natural ligand 2'3'-cGAMP (cyclic guanosine adenosine monophosphate), which then induces the expression of interferon, inflammatory factors, and autophagy genes through a signaling pathway. Microbial infection, tumor DNA, and self-damaged DNA are three factors that induce the activation of the cGAS-STING signaling pathway and link STING to the pathogenesis of cancer, as well as autoimmune, infectious, and inflammatory diseases. Many natural and synthetic STING agonists have entered clinical development (especially for the purpose of cancer treatment), and the first generation demonstrates safety but only minor systemic effects. Therefore, most STING agonists require local administration due to their low stability, which limits their usefulness. Summary of the Invention

[0004] In one aspect, disclosed herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1is a lipid moiety having at least 8 carbon atoms, hydrogen; X 1 , O, NR w , S, and a bond; R 2a , R 2b , R 2c , and R 2d are each independently hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, HaloC 1 -C 4 Alkyl, Amino C 1 -C 4 Alkyl, Hydroxy C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 R is selected from alkylamino, alkylamino, and cyano; 2a and R 2b , or R 2b and R 2c , or R 2c and R 2d optionally form, together with the carbon atom(s) to which they are attached, an optionally substituted 3- to 6-membered ring; X 4 CR 4 or N, X 5 CR 5 or N, X 6 CR 6 or N, X 7 CR 7 or N, R 3 , R 4 , R 5 , R 6 , and R7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , -SO 2 R z , an oligo or polyethylene glycol chain, and a group -YR 8 Selected from; R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 optionally form, together with the carbon atoms to which they are attached, an optionally substituted 5- or 6-membered ring; Y is -C(O)-, -C(O)O-, -C(O)NR v- and -C(O)S-; R 8 is a lipid moiety having at least 8 carbon atoms, R v , R w , R x , Ry , and R z are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl and haloC 1 -C 6 alkyl, R 1 If is hydrogen, R 3 , R 4 , R 5 , R 6 , and R 7 At least one of the following is -YR 8 (Based on

[0005] In some embodiments, the compound is a compound of formula (Ia): [ka]

[0006] In some embodiments, R 2a , R 2b , R 2c , and R 2d are each independently hydrogen, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C 4 In some embodiments, R 2a , R 2b , R 2c , and R 2d are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a , R 2b , and R 2d is hydrogen and R 2cis hydrogen and C 1 -C 4 In some embodiments, R 2a and R 2d is hydrogen and R 2b and R 2c form a three-membered ring together with the carbon atoms to which they are attached.

[0007] In some embodiments, R 3 is selected from hydrogen and halo. 3 is hydrogen.

[0008] In some embodiments, R 4 is selected from hydrogen and halo. 4 is hydrogen.

[0009] In some embodiments, R 5 and R 6 are each independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z In some embodiments, R 5 and R 6 are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4 Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 In some embodiments, R 5 and R 6 are each independently 1 -C 4 Alkyl, C 1 -C 4 In some embodiments, R 5 and R 6 are each independently 1 -C 4 alkoxy.

[0010] In some embodiments, X 1 is O or a bond.

[0011] In some embodiments, R 1 is a lipid moiety having at least 8 carbon atoms, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z is selected from.

[0012] In some embodiments, R 1 is C 8 -C 80 Alkyl, C 8 -C 80 Alkenyl, C 8 -C 80 Alkynyl, C 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 heteroalkynyl, each of which is optionally substituted with one or more substituents selected from hydroxy and amino. In some embodiments, R 1 is C 12 -C 40 Alkyl and C 12 -C 40 alkenyl.

[0013] In some embodiments, R 1 has the formula (A): [ka] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a and R b are each independently 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8.

[0014] In some embodiments, R 1 has the formula (D), (E), or (F): [ka] wherein n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 and R a2 are each independently 6 -C 40 Alkyl and C 6 -C 40 alkenyl. In some embodiments, n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0015] In some embodiments, R 1 is selected from: [ka] [ka] [ka]

[0016] In some embodiments, the compound is selected from the group consisting of: [ka] and pharma- ceutically acceptable salts thereof.

[0017] In another aspect, disclosed herein is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 1a and R 1b are each independently a lipid moiety having at least 8 carbon atoms; X 1a and X 1b are each independently O, NR w , S, and a bond; R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, HaloC 1 -C 4 Alkyl, Amino C 1 -C4 Alkyl, Hydroxy C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 R is selected from alkylamino, alkylamino, and cyano; 2a’ and R 2b’ , R 2b’ and R 2c’ , R 2c’ and R 2d’ , R 2a’’ and R 2b’’ , R 2b’’ and R 2c’’ , or R 2c’’ and R 2d’’ optionally form, together with the carbon atom(s) to which they are attached, an optionally substituted 3- to 6-membered ring; X 4a CR 4a or N, X 4b CR 4b or N, X 5a CR 5a or N, X 5b CR 5b or N, X 6a CR 6a or N, X 6b CR 6b or N, X 7a CR 7a or N, X 7b CR 7b or N, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R6b , R 7a , and R 7b are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z and R 4a and R 5a , R 5a and R 6a , or R 6a and R 7a optionally form, together with the carbon atom to which they are attached, a 5- or 6-membered ring; R 4b and R 5b , R 5b and R 6b , or R 6b and R 7b together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring; R w , R x , R y , and Rz are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl and haloC 1 -C 6 alkyl).

[0018] In some embodiments, the compound is a compound of formula (IIa): [ka]

[0019] In some embodiments, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C 4 In some embodiments, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a’ , R 2b’ , R 2d’ , R 2a’’ , R 2b’’ , and R 2d’’ is hydrogen and R2c’ and R 2c’’ are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a’ , R 2d’ , R 2a’’ , and R 2d’’ is hydrogen and R 2b’ and R 2c’ form a three-membered ring together with the carbon atom to which they are attached; R 2b’’ and R 2c’’ form a three-membered ring together with the carbon atoms to which they are attached.

[0020] In some embodiments, R 3a and R 3b are each independently selected from hydrogen and halo.

[0021] In some embodiments, R 3a and R 3b are each hydrogen.

[0022] In some embodiments, R 4a and R 4b are each independently selected from hydrogen and halo. 4a and R 4b are each hydrogen.

[0023] In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4 Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 4 Alkyl, C 1 -C 4 In some embodiments, R 5a , R 5b , R 6a , and R6b are each independently 1 -C 4 alkoxy.

[0024] In some embodiments, R 7a and R 7b are each independently hydrogen.

[0025] In some embodiments, X 1a and X 1b are each O or a bond.

[0026] In some embodiments, R 1a and R 1b are each independently 8 -C 80 Alkyl, C 8 -C 80 Alkenyl, C 8 -C 80 Alkynyl, C 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 heteroalkynyl, each of which is optionally substituted with one or more substituents selected from hydroxy and amino. In some embodiments, R 1a and R 1b are each independently 12 -C 40 Alkyl and C 12 -C 40 alkenyl.

[0027] In some embodiments, R 1a and R 1b each independently have the formula (A): [ka] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a and R b are each independently 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8.

[0028] In some embodiments, R 1a and R 1b each independently have the formula (D) or (E): [ka] wherein n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 and R a2 are each independently 6 -C 40 Alkyl and C 6 -C 40 alkenyl. In some embodiments, n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, or 8.

[0029] In some embodiments, R 1a and R 1b are each independently selected from: [ka] [ka] [ka]

[0030] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or a compound of Formula (II)), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0031] In some embodiments, the composition comprises an albumin nanoparticle, a liposome, a micelle, or a lipid nanoparticle. In some embodiments, the composition further comprises an albumin nanoparticle. In some embodiments, the albumin is human serum albumin or an albumin from an animal species.

[0032] In some embodiments, the composition further comprises at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises an immunomodulatory agent, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic agent, an antimicrobial agent, or a combination thereof. In some embodiments, the at least one additional therapeutic agent comprises an RNA selected from the group consisting of small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA), and mixtures thereof. In some embodiments, the at least one additional therapeutic agent is selected from a chemotherapeutic agent, an IDO inhibitor, a Stat3 inhibitor, a TLR agonist, and a PI3K inhibitor.

[0033] In some embodiments, the composition further comprises one or more cell targeting epitopes. In some embodiments, the one or more cell targeting epitopes are covalently bound or directly conjugated to albumin. In some embodiments, the cell targeting epitopes comprise immune cell epitopes. In some embodiments, the composition further comprises one or more epitopes from microbial agents.

[0034] In another aspect, disclosed herein is a vaccine comprising an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof) or a composition disclosed herein (e.g., a composition comprising a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof) and an antigen or a nucleic acid encoding same. In some embodiments, the antigen is a tumor antigen, an autoantigen, or an antigen from an infectious disease. In some embodiments, the nucleic acid is messenger RNA (mRNA).

[0035] In another aspect, disclosed herein is a method of treating or preventing a disease or disorder comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof), or a composition disclosed herein (e.g., a composition comprising a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof).

[0036] In some embodiments, the disease or disorder comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease. In some embodiments, the disease or disorder is cancer. In some embodiments, the subject has cancer, has had cancer, is susceptible to cancer, or has a family history of cancer. In some embodiments, the cancer comprises a solid tumor or a hematological cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the method inhibits or eliminates metastasis of the cancer, reduces tumor growth, prevents tumor recurrence, or any combination thereof. In some embodiments, the administration comprises an initial immunization and at least one subsequent immunization.

[0037] In another aspect, disclosed herein is a method of inducing or modulating an immune or inflammatory response in a subject comprising administering to a subject in need thereof a composition of a compound disclosed herein (e.g., a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof), or a composition disclosed herein (e.g., a composition comprising a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of formula (I) or a compound of formula (II), or a pharma- ceutically acceptable salt thereof).

[0038] In some embodiments, the subject is a human. In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises an immunomodulatory agent, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic agent, an antimicrobial agent, or a combination thereof.

[0039] In another aspect, disclosed herein is the use of a compound disclosed herein (e.g., a compound of Formula (I) or a compound of Formula (II), or a pharma- ceutically acceptable salt thereof), or a composition disclosed herein (e.g., a composition comprising a compound of Formula (I) or a compound of Formula (II), or a pharma- ceutically acceptable salt thereof), in the manufacture of a medicament for the treatment or prevention of a disease or disorder. In some embodiments, the disease or disorder comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease.

[0040] Other aspects and embodiments of the present disclosure will become apparent in light of the following detailed description and accompanying figures. [Brief description of the drawings]

[0041] [Figure 1A] ELISA measurement of TNF-α concentration under different polarization states of RAW264.7 cells and treatment with compounds. TNFα_M1 (left) represents RAW264.7 cells polarized to M1 macrophages by LPS (100 ng / mL) / IFNγ (10 ng / mL), and TNFα_M2 (right) represents RAW264.7 cells polarized to M2 macrophages by IL4 (20 ng / mL) / IL10 (20 ng / mL) before incubation with the indicated compounds. Concentrations of compounds in Figure 1A: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL). Concentrations of compounds in Figure 1C: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL), LPS (100 ng / mL), IFNγ (10 ng / mL), IL4 (20 ng / mL), IL10 (20 ng / mL) in Figure 1B. [Figure 1B]ELISA measurement of TNF-α concentration under different polarization states of RAW264.7 cells and treatment with compounds. TNFα_M1 (left) represents RAW264.7 cells polarized to M1 macrophages by LPS (100 ng / mL) / IFNγ (10 ng / mL), and TNFα_M2 (right) represents RAW264.7 cells polarized to M2 macrophages by IL4 (20 ng / mL) / IL10 (20 ng / mL) before incubation with the indicated compounds. Concentrations of compounds in Figure 1A: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL). Concentrations of compounds in Figure 1C: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL), LPS (100 ng / mL), IFNγ (10 ng / mL), IL4 (20 ng / mL), IL10 (20 ng / mL) in Figure 1B. [Figure 1C] ELISA measurement of TGFβ concentration under different polarization states of RAW264.7 cells and treatment with compounds: TGFβ_M1 (left) represents RAW264.7 cells polarized to M1 macrophages by LPS (100 ng / mL) / IFNγ (10 ng / mL), and TGFβ_M2 (right) represents RAW264.7 cells polarized to M2 macrophages by IL4 (20 ng / mL) / IL10 (20 ng / mL) before incubation with compounds listed on the x-axis. Concentrations of compounds: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2, (10 μg / mL), DMA01-139 (10 μg / mL), LPS (100 ng / mL), IFNγ (10 ng / mL), IL4 (20 ng / mL), IL10 (20 ng / mL). [Figure 1D]ELISA measurements of TNF-α (Figure 1D) or TGFβ (Figure 1E) concentrations in bone marrow-derived macrophages (BMDMs) under different polarization states and treatment with compounds: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL), LPS (100 ng / mL), IFNγ (10 ng / mL), as indicated. [Figure 1E] ELISA measurements of TNF-α (Figure 1D) or TGFβ (Figure 1E) concentrations in bone marrow-derived macrophages (BMDMs) under different polarization states and treatment with compounds: IPI549 (10 μM), DMA01-148 (10 μM), DMA01-143 (10 μM), DMA01-132 (10 μM), MSA-2 (10 μg / mL), DMA01-139 (10 μg / mL), LPS (100 ng / mL), IFNγ (10 ng / mL), as indicated.

[0042] [Figure 2A] Graphs showing the ability of STING agonists to stimulate the STING pathway with (FIG. 2A) or without (FIG. 2B) the addition of xerosine or various solvents (FIG. 2C).Interferon regulatory factor (IRF)-inducible SEAP reporter (OD655 values) was monitored for expression levels of interferon secretion. [Figure 2B] Graphs showing the ability of STING agonists to stimulate the STING pathway with (FIG. 2A) or without (FIG. 2B) the addition of xerosine or various solvents (FIG. 2C).Interferon regulatory factor (IRF)-inducible SEAP reporter (OD655 values) was monitored for expression levels of interferon secretion. [Figure 2C]Graphs showing the ability of STING agonists to stimulate the STING pathway with (FIG. 2A) or without (FIG. 2B) the addition of xerosine or various solvents (FIG. 2C).Interferon regulatory factor (IRF)-inducible SEAP reporter (OD655 values) was monitored for expression levels of interferon secretion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Described herein are stimulator of interferon (IFN) genes (STING) agonists, and compositions and formulations thereof. The disclosed STING agonists can be formulated into lipid-based and albumin-based nanocarriers, which allow them to be delivered as combination therapies with currently available cancer and immunomodulatory drugs, and are used in vaccines and biomolecule delivery (e.g., nucleic acid delivery).

[0044] The section headings used in this section and throughout this disclosure are for organizational purposes only and are not intended to be limiting.

[0045] 1.Definition As used herein, the terms "comprise," "include," "having," "has," "can," "containing," and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise," "consist," and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly stated.

[0046] In the description of numerical ranges herein, each intervening numerical value is expressly contemplated with the same precision, for example, in the range 6 to 9, the numerical values ​​7 and 8 are expressly contemplated in addition to 6 and 9, and in the range 6.0 to 7.0, the numerical values ​​6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0047] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those skilled in the art. The meaning and scope of the terms shall be clear. However, in the event of potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. Furthermore, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0048] As used herein, "treat", "treating" and the like refer to slowing, stopping, or reversing the progression of a disease or disorder when a compound or composition described herein is provided to a suitable control subject. The term also refers to reversing the progression of such a disease or disorder to the point where symptoms are eliminated or significantly reduced. Thus, "treating" refers to applying or administering a composition described herein to a subject, the subject having a disease or symptoms of a disease, with the purpose of curing, curing, alleviating, mitigating, altering, treating, improving, enhancing, or affecting the disease or symptoms of the disease.

[0049] A "subject" or "patient" may be human or non-human, and may include animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Similarly, a patient may include an adult or a minor (e.g., a child). Furthermore, a patient may refer to any organism, preferably a mammal (e.g., human and non-human), that may benefit from administration of the compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the class Mammalia; humans, non-human primates (e.g., chimpanzees and other ape and monkey species); livestock animals (e.g., cows, horses, sheep, goats, wild boars); farm animals (e.g., rabbits, dogs, and cats); laboratory animals, including rodents (e.g., rats, mice, and guinea pigs, etc.). Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0050] As used herein, the terms "providing," "administering," and "introducing" are used interchangeably herein and refer to placing a compound or composition of the present disclosure into a subject by a method or route that results in at least partial localization of the compound or composition at a desired site. The compound or composition can be administered by any suitable route that results in delivery to the desired location in the subject.

[0051] The term "vaccine" as used herein refers to any pharmaceutical composition containing at least one antigenic or immunogenic peptide or other immunogen, or at least one nucleic acid encoding at least one antigenic or immunogenic peptide or other immunogen, that can be used to prevent or treat a disease or condition of a subject.

[0052] As used herein, the term "immunization" refers to the process of mounting an organism's response to an antigen, thereby improving resistance to or ability to overcome infection.

[0053] As used herein, "polynucleotide" or "oligonucleotide" or "nucleic acid" refers to at least two nucleotides covalently linked together. A polynucleotide may be DNA, both genomic and cDNA, RNA, or hybrid, and a polynucleotide may contain a combination of deoxyribonucleotides and ribonucleotides, and a combination of bases (e.g., uracil, adenine, thymine, cytosine, guanine, inosine, xanthine, hypoxanthine, isocytosine, and isoguanine). A nucleic acid may contain non-natural nucleotides, modified nucleotides, and / or non-nucleotide building blocks (e.g., "nucleotide analogs") that allow DNA or RNA to exhibit the same function as natural nucleotides. A nucleic acid may be obtained by chemical synthesis or recombinant methods. A polynucleotide may be single-stranded or double-stranded, or may contain portions of both double-stranded and single-stranded sequences. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a nucleic acid also contains the complementary strand of a depicted single strand. Many variants of a nucleic acid can be used for the same purpose as a given nucleic acid. Thus, a nucleic acid also encompasses substantially identical nucleic acids and their complements.

[0054] A "peptide" or "polypeptide" is a linked sequence of two or more amino acids joined by peptide bonds. Peptides and polypeptides include proteins such as binding proteins, receptors, and antibodies. The terms "polypeptide" and "protein" are used interchangeably herein.

[0055] As used herein, "nucleic acid" or "nucleic acid sequence" refers to a polymer or oligomer of pyrimidine and / or purine bases, preferably cytosine, thymine, and uracil, and adenine and guanine, respectively (see Albert L. Lehninger, Principles of Biochemistry, at 793-800 (Worth Pub. 1982)). The present technology contemplates any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated, or glycosylated forms of these bases. The polymer or oligomer may be heterogeneous or homogeneous in composition, and may be isolated from naturally occurring sources or may be artificially or synthetically produced. Furthermore, the nucleic acid may be DNA or RNA, or a mixture thereof, and may exist permanently or transiently in single-stranded or double-stranded form, including homoduplexes, heteroduplexes, and hybrid states. In some embodiments, the nucleic acid or nucleic acid sequence comprises other types of nucleic acid structures, such as, for example, a DNA / RNA helix, a peptide nucleic acid (PNA), a morpholino nucleic acid (see, e.g., Braaschand Corey, Biochemistry, 41(14):4503-4510 (2002), and U.S. Pat. No. 5,034,506), a locked nucleic acid (LNA; see, Wahlestedtetal., Proc. Natl. Acad. Sci. USA, 97:5633-5638 (2000)), a cyclohexenyl nucleic acid (see, Wang, J. Am. Chem. Soc., 122:8595-8602 (2000)), and / or a ribozyme.Thus, the term "nucleic acid" or "nucleic acid sequence" may also encompass a strand that includes non-natural nucleotides, modified nucleotides, and / or non-nucleotide building blocks (e.g., "nucleotide analogs") that may perform the same function as natural nucleotides; furthermore, the term "nucleic acid sequence" as used herein refers to an oligonucleotide, nucleotide, or polynucleotide, and fragments or portions thereof, as well as DNA or RNA of genomic or synthetic origin, which may be single-stranded or double-stranded and may represent the sense or antisense strand. The terms "nucleic acid," "polynucleotide," "nucleotide sequence," and "oligonucleotide" are used interchangeably. They refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.

[0056] Definitions of certain functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in: Sorrell, Organic Chemistry, 2001, ed., Organic Chemistry, 2001, pp. 117-119, 1997; and specific functional groups are generally defined as described therein. nd edition,University Science Books,Sausalito,2006;Smith,March's Advanced Organic Chemistry:Reactions,Mechanism,and Structure,7 th Edition,John Wiley & Sons,Inc.,New York,2013;Larock,Comprehensive Organic Transformations,3 rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987 (the entire contents of each of which are incorporated herein by reference).

[0057] The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon chain. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl.

[0058] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. The double bond(s) can be located at any position of the hydrocarbon chain. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0059] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The triple bond(s) may be located at any position of the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, and butynyl.

[0060] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

[0061] The term "alkoxyalkyl" as used herein refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one hydrogen atom) is replaced with an alkoxy group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, methoxymethyl.

[0062] The term "alkylthio" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of alkoxy include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and tert-butylthio.

[0063] As used herein, the term "amino" refers to -NH 2 As used herein, the term "alkylamino" refers to the group -NHR, where R is an alkyl group as defined herein. As used herein, the term "dialkylamino" refers to the group -NR 2 where each R is independently an alkyl group as defined herein.

[0064] The term "aminoalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one hydrogen atom (eg, one hydrogen atom) has been replaced with an amino group.

[0065] The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring system containing 3 to 10 carbon atoms and 0 heteroatoms. Cycloalkyls can be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

[0066] As used herein, the term "cyano" refers to a group of formula -CN.

[0067] The term "halogen" or "halo" as used herein means F, Cl, Br, or I.

[0068] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen. Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0069] The term "haloalkoxy" as used herein means a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0070] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and associated hydrogen atoms) are each independently selected from the group consisting of a heteroatom group (e.g., -NH-, -O-, -S-, -S(O)-, -S(O) 2 -,-OP(O)(O - )O-, etc. As an example, 1, 2, 3, 4, 5, 6, or more carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroalkyl groups can also contain one or more carbonyl moieties (i.e., a carbon atom of the alkyl group is oxidized to a -C(O)- group).

[0071] The term "heteroalkenyl" as used herein refers to an alkenyl group, as defined herein, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 -. As an example, 1, 2, 3, 4, 5, 6, or more carbon atoms may be independently substituted with the same or different heteroatom groups. Heteroalkenyl groups can also contain one or more carbonyl moieties (i.e., a carbon atom of an alkyl group is oxidized to a -C(O)- group).

[0072] The term "heteroalkynyl" as used herein refers to an alkynyl group, as defined herein, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -. As an example, 1, 2, 3, 4, 5, 6, or more carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroalkynyl groups can also contain one or more carbonyl moieties (i.e., a carbon atom of an alkyl group is oxidized to a -C(O)- group).

[0073] As used herein, the term "hydroxy" refers to an --OH group.

[0074] The term "hydroxyalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one hydrogen atom (eg, one hydrogen atom) has been replaced with a hydroxy group.

[0075] As used herein, the term "substituent" refers to a group substituted on an atom of a designated group.

[0076] Where a group or moiety can be substituted, the term "substituted" indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6, in some embodiments, 1, 2, or 3, and in other embodiments, 1 or 2) hydrogen atoms on the group designated by the phrase can be replaced with the specified group recited or with suitable substituents known to those of skill in the art (e.g., one or more of the groups recited below), provided that the normal valence of the given atom is not exceeded. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamide, thiol, thione, thioxo, or combinations thereof.

[0077] As used herein, in chemical structures, the indications: [ka] represents the point of attachment of one moiety to another.

[0078] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkylalkenyl) is indicated by the prefix “C x -C y" (wherein x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent). Thus, for example, "C 1 -C 3 "Alkyl" refers to an alkyl substituent containing 1 to 3 carbon atoms.

[0079] In the compounds described herein, groups and substituents thereof may be selected according to the allowed valences of atoms and substituents such that the selection and substitution result in stable compounds that do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like.

[0080] Where substituents are specified in a conventional chemical formula written from left to right, they optionally include the substituents resulting from writing the structure from right to left. For example, -CH 2 O- is -OCH 2 - is intended to include -, and -C(O)NH- is intended to include -NHC(O)-.

[0081] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0082] 2.Compound In one embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is a lipid moiety having at least 8 carbon atoms or hydrogen, X 1 , O, NR w , S, and a bond; R 2a , R 2b , R2c , and R 2d are each independently hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, HaloC 1 -C 4 Alkyl, Amino C 1 -C 4 Alkyl, Hydroxy C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 R is selected from alkylamino, alkylamino, and cyano; 2a and R 2b , or R 2b and R 2c , or R 2c and R 2d optionally form, together with the carbon atom(s) to which they are attached, an optionally substituted 3- to 6-membered ring; X 4 CR 4 or N, X 5 CR 5 or N, X 6 CR 6 or N, X 7 CR 7 or N, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1-C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , -SO 2 R z , an oligo or polyethylene glycol chain, and a group -YR 8 Selected from; R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 optionally form, together with the carbon atoms to which they are attached, an optionally substituted 5- or 6-membered ring; Y is -C(O)-, -C(O)O-, -C(O)NR v- and -C(O)S-; R 8 is a lipid moiety having at least 8 carbon atoms, R v , R w , R x , R y , and R z are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 3 -C 6 Cycloalkyl and haloC 1 -C 6 alkyl, R 1 If is hydrogen, R 3 , R 4 , R 5 , R 6 , and R 7 At least one of the following is -YR 8 (Based on

[0083] In some embodiments, X 4 , X 5 , X 6 , and X 7 In some embodiments, one or two of X 4 , X 5 , X 6 , and X 7 In some embodiments, one of X is N. 4 CR 4 and X 5 CR 5 and X 6 CR 6 and X 7 CR 7 It is.

[0084] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, R 2a , R 2b , R 2c , and R 2d are each independently hydrogen, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C4 In some embodiments, R 2a , R 2b , R 2c , and R 2d are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy. 2a , R 2b , R 2c , and R 2d are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a , R 2b , R 2c , and R 2d are each independently selected from hydrogen and methyl. 2a , R 2b , R 2c , and R 2d One of them is C. 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C 4 alkyl, and hydroxy, and the remaining three are hydrogen. 2a , R 2b , R 2c , and R 2d In some embodiments, one of R is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy, and the remaining three are hydrogen. 2a , R 2b , and R 2d is hydrogen and R 2c is hydrogen and C 1 -C 4 In some embodiments, R 2a , R 2b , and R 2d is hydrogen and R 2cis selected from hydrogen and methyl. In some embodiments, R 2a , R 2b , R 2c , and R 2d are each hydrogen.

[0086] In some embodiments, R 2a and R 2d is hydrogen and R 2b and R 2c form a three-membered ring (i.e., a cyclopropyl ring) together with the carbon atom to which they are attached.

[0087] In some embodiments, R 3 is selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 3 is fluoro. In some embodiments, R 3 is hydrogen.

[0088] In some embodiments, R 4 is selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 4 is fluoro. In some embodiments, R 4 is hydrogen.

[0089] In some embodiments, R 5 and R 6 are each independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1-C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z In some embodiments, R 5 and R 6 are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4 Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 In some embodiments, R 5 and R 6 are each independently selected from methyl, ethyl, n-propyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, 2-fluoroethyl, difluoromethoxy, hydroxy, fluoro, chloro, bromo, and methylamino. 5 and R 6 are each independently 1 -C 4 Alkyl, C 1 -C 4 In some embodiments, R 5 and R 6are each independently selected from methyl, ethyl, n-propyl, methoxy, ethoxy, fluoro, chloro, and bromo. 5 and R 6 are each independently 1 -C 4 In some embodiments, R 5 and R 6 are each methoxy.

[0090] In some embodiments, R 7 is selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 7 is fluoro. In some embodiments, R 7 is hydrogen.

[0091] In some embodiments, X 1 is O or a bond. In some embodiments, X 1 is O. In some embodiments, X 1 is a bond. In some embodiments, X 1 is NR w and R w is hydrogen and C 1 -C 6 In some embodiments, X is selected from alkyl. 1 is NH. In some embodiments, X 1 is NR w and R w is methyl. In some embodiments, X 1 is S.

[0092] In some embodiments, R 1 is a lipid moiety having at least 8 carbon atoms, R 3 , R 4 , R 5 , R 6 , and R 7 All of the above are groups -YR 8 In some embodiments, R 1If is hydrogen, R 3 , R 4 , R 5 , R 6 , and R 7 Only one of the groups -YR 8 It is.

[0093] In some embodiments, R 1 is a lipid moiety having at least 8 carbon atoms, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z In some embodiments, R 1 is hydrogen and R 3 , R 4 , R 5 , R 6, and R 7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , -SO 2 R z , an oligo or polyethylene glycol chain, and a group -YR 8 Selected from R 3 , R 4 , R 5 , R 6 , and R 7 One of the groups is -YR 8 In some embodiments, R 1 is hydrogen and R 3 is hydrogen and R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2-C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , -SO 2 R z , an oligo or polyethylene glycol chain, and a group -YR 8 Selected from R 4 , R 5 , R 6 , and R 7 One of the groups is -YR 8 In some embodiments, R 1 is hydrogen and R 3 is hydrogen and R 4 , R 5 , R 6 , and R 7 One of the groups is -YR 8 and R 4 , R 5 , R 6 , and R 7 The other three of are each hydrogen. 1 is hydrogen and R 3 is hydrogen and R 4 is the group -YR 8 and R 5 , R6 , and R 7 are each hydrogen.

[0094] In some embodiments, the compound is a compound of formula (Ia): R 1 is a lipid moiety having at least 8 carbon atoms, X 1 is O, R 2a , R 2b , R 2c , and R 2d are each independently hydrogen and C 1 -C 4 alkyl, R 3 , R 4 , and R 7 is hydrogen, R 5 and R 6 are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4 Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 alkylamino.

[0095] Compounds of formula (I) (e.g., compounds of formula (Ia)) include a lipid moiety having at least 8 carbon atoms. For example, as described above, in some embodiments, R 1 is a lipid moiety having at least 8 carbon atoms; in other embodiments, R 3 , R 4 , R 5 , R 6 , and R 7 One of the groups is -YR8 and R 8 is a lipid moiety having at least 8 carbon atoms. The lipid moiety may be derived from any suitable lipid (e.g., a fatty alcohol, a fatty acid, a phospholipid, a steroid, or a synthetic lipid). In some embodiments, the lipid moiety is derived from a lipid having a functional group (e.g., a hydroxyl group, a carboxylic acid group, or an amino group), and the lipid moiety is attached to the compound of formula (I) via that functional group. For example, in some embodiments, R 1 is a lipid moiety having at least 8 carbon atoms, and in such embodiments, the group X in formula (I) 1 is derived from the functional group; for example, if the lipid moiety is derived from an aliphatic alcohol, X 1 is O.

[0096] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is C 8 -C 80 Alkyl, C 8 -C 80 Alkenyl, C 8 -C 80 Alkynyl, C 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 heteroalkynyl, each of which is optionally substituted with one or more substituents selected from hydroxy and amino.

[0097] For example, in some embodiments, a lipid moiety (e.g., R 1 or R 8 ) is C 8 -C 80 Alkyl and C 8 -C 80 In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is C 8 -C 40 Alkyl and C 8 -C40 In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is C 12 -C 40 Alkyl and C 12 -C 40 In some such embodiments (e.g., R 1 is a lipid moiety and X 1 is O, or R 8 In some embodiments, when the lipid moiety (e.g., R 1 or R 8) are derived from: linoleyl alcohol ((9Z,12Z)-octadeca-9,12-dien-1-ol), myristyl alcohol (1-tetradecanol), palmitoleyl alcohol ((Z)-hexadec-9-en-1-ol), oleyl alcohol ((Z)-octadec-9-en-1-ol), elaidyl alcohol (trans-9-octadecenol), cis-vaccenyl alcohol (cis-11-octadecenol), gadoleyl alcohol ((Z)-icos-9-en-1-ol), 11-eicosenol, erucyl alcohol (cis-13-docosenol), 15-tetracosen-1-ol, eicosadienyl alcohol (icosa-11,14-dien-1-ol), linolenyl alcohol ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-ol), γ- Linolenyl alcohol ((6E,9E,12E)-octadeca-6,9,12-trien-1-ol), eleostearyl alcohol (octadeca-9,11,13-trien-1-ol), icos-5,8,11-trien-1-ol, icos-13-en-1-ol, icos-11,14-17-trien-1-ol, octadeca-6,9,12,15-tetraen-1-ol, arachidonyl alcohol Alcohol ((5Z,8Z,11Z,14Z)-icosatetraen-1-ol), 4E,6Z-hexadecadien-1-ol, icosa-5,8,11,14,17-pentaen-1-ol, docosahexaenoyl alcohol (docosa-4,7,10,13,16,19-hexaen-1-ol), docosa-7,10,13,16,19-pentaen-1-ol, tetracosa-6,9,12,15,18,21-Hexaen-1-ol, Capryl Alcohol (1-Octanol), Pelargonic Alcohol (1-Nonanol), Decyl Alcohol (1-Decanol), Undecyl Alcohol (1-Undecanol), Lauryl Alcohol (1-Dodecanol), Tridecyl Alcohol (1-Tridecanol), Myristyl Alcohol (1-Tetradecanol), Pentadecyl Alcohol (1-Pentadecanol), Cetyl Alcohol (1-Hexadecanol), Palmitoleic Alcohol (cis-9-Hexadecen-1-ol), Heptadecyl Alcohol (1-n-Heptadecanol), Stearyl Alcohol (1-Octadecanol), Oleyl Alcohol (1-Octadecenol), Nonadecanyl Alcohol (1-Nonadecanol), Arachidyl Alcohol (1-Eicosanol), Heneicosyl Alcohol 1-Heneicosanol, Behenyl Alcohol, 1-Docosanol, Erucyl Alcohol, 1-Tricosyl Alcohol, 1-Tetracosanol, Pentacosyl Alcohol, 1-Pentacosanol, Seryl Alcohol, 1-Heptacosanol, Montanyl Alcohol, 1-Octacosanol, 1-Nonacosanol, Myricyl Alcohol, 1-Triacontanol, 1-Hentriacontanol, 1-Dotriacontanol, Laceryl Alcohol, 1-Tritriacontanol, Gedil Alcohol, 1-Tetratriacontanol, 1-Hexatriacontanol, 1-Heptatriacontanol, 1-Octatriacontanol, Nonatriacontan-1-ol, or 1-Tetracontanol.

[0098] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is C 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 In such embodiments, the lipid moiety (e.g., R 1 or R 8) can be derived from a lipid that contains one or more heteroatom groups (e.g., -O-, -NH-, -C(O)-, etc., or combinations thereof (e.g., -C(O)O- groups)).

[0099] For example, in some embodiments, a lipid moiety (e.g., R 1 or R 8 ) has the formula (A): [ka] (In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a and R b are each independently 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 heteroalkenyl).

[0100] For example, in some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0101] In some embodiments, R a and R b are each independently 6 -C 40 Alkyl and C 6 -C 40 For example, in some embodiments, R a and R bare each independently selected from the following: n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, hentriacontyl, dotriacontyl, tritriacontyl, tetratriacontyl, pentatriacontyl, pentyl, hexatriacontyl, heptatriacontyl, octatriacontyl, nonatriacontyl, tetracontyl, linoleyl ((9Z,12Z)-octadeca-9,12-dien-1-yl), palmitoleyl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), elaidyl (trans-9-octadecenyl), cis-vaccenyl (cis-11-octadecenyl), gadoleyl ((Z)-icos-9-en-1-yl), 11-eicosenyl, elci cis-13-docosenyl, 15-tetracosen-1-yl, eicosadienyl (icosa-11,14-dien-1-yl), linolenyl ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-yl), γ-linolenyl ((6E,9E,12E)-octadeca-6,9,12-trien-1-yl), eleostearyl (octadeca-9,11,13-trien-1-yl), icos-5,8,11-trien-1-yl, eicos-13-en-1-yl, icos-11,14-17- In some embodiments, R is selected from the group consisting of icosatetraen-1-yl, octadeca-6,9,12,15-tetraen-1-yl, arachidonyl ((5Z,8Z,11Z,14Z)-icosatetraen-1-yl), 4E,6Z-hexadecadien-1-yl, icosa-5,8,11,14,17-pentaen-1-yl, docosahexaenoyl (docosa-4,7,10,13,16,19-hexaen-1-yl), docosa-7,10,13,16,19-pentaen-1-yl, and tetracosa-6,9,12,15,18,21-hexaen-1-yl. a and R b are linoleyl, respectively.

[0102] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) has the formula (B) or (C): [ka] (In the formula, n and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 is C 6 -C 40 Alkyl and C 6 -C 40 alkenyl, R b is C 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 heteroalkenyl).

[0103] In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0104] In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 3, 4, 5, 6, or 7. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7.

[0105] In some embodiments, R a1 is C 6 -C 24 Alkyl or C 6 -C 24 In some embodiments, R is alkenyl. a1 is C 9 -C 22 Alkyl and C 9 -C 22 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 is linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R a1 is linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 is selected from linoleyl, n-nonyl, n-undecyl, henicosan-11-yl, pentadecan-7-yl, and heptadecan-9-yl.

[0106] In some embodiments, R b is C 6 -C 40 Alkyl and C 6 -C 40 For example, in some embodiments, R bis selected from the following: n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, hentriacontyl, dotriacontyl, tritriacontyl, tetratriacontyl, pentatriacontyl, hexatriacontyl, Satriacontyl, heptatriacontyl, octatriacontyl, nonatriacontyl, tetracontyl, linoleyl ((9Z,12Z)-octadeca-9,12-dien-1-yl), palmitoleyl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), elaidyl (trans-9-octadecenyl), cis-vaccenyl (cis-11-octadecenyl), gadoleyl ((Z)-icos-9-en-1-yl), 11-eicosenyl, erucyl (cis -13-docosenyl), 15-tetracosen-1-yl, eicosadienyl (icosa-11,14-dien-1-yl), linolenyl ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-yl), γ-linolenyl ((6E,9E,12E)-octadeca-6,9,12-trien-1-yl), eleostearyl (octadeca-9,11,13-trien-1-yl), icos-5,8,11-trien-1-yl, eicos-13-en-1-yl, icos-11,14-17-trien-1-yl In some embodiments, R is selected from the group consisting of octadeca-6,9,12,15-tetraen-1-yl, arachidonyl ((5Z,8Z,11Z,14Z)-icosatetraen-1-yl), 4E,6Z-hexadecadien-1-yl, icosa-5,8,11,14,17-pentaen-1-yl, docosahexaenoyl (docosa-4,7,10,13,16,19-hexaen-1-yl), docosa-7,10,13,16,19-pentaen-1-yl, and tetracosa-6,9,12,15,18,21-hexaen-1-yl. b is linoleyl.

[0107] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) has the formula (D), (E), or (F): [ka] (In the formula, n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 and R a2 are each independently 6 -C 40 Alkyl and C 6 -C 40 alkenyl).

[0108] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) has the formula (D). In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) has the formula (E). In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) has formula (F). In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0109] In some embodiments, p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p and q are each independently selected from 3, 4, 5, 6, and 7. In some embodiments, p and q are each independently selected from 3, 5, and 7. In some embodiments, p and q are each 5. In some embodiments, p and q are each 6. In some embodiments, p and q are each 7.

[0110] In some embodiments, R a1 and R a2 are each independently 6 -C 24 Alkyl and C 6 -C 24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently 9 -C 22 Alkyl and C 9 -C 22 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently a linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R a1 and R a2 are each independently a linear or branched C 6 , C 7 , C 8 , C9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently selected from linoleyl, n-nonyl, n-undecyl, henicosan-11-yl, pentadecan-7-yl, and heptadecan-9-yl.

[0111] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is derived from a steroid. For example, in some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is derived from cholesterol, beta-sisterol, or BHEM-cholesterol.

[0112] In some embodiments, the lipid moiety (e.g., R 1 or R 8 ) is selected from: [ka] [ka] [ka]

[0113] In some embodiments, the compound of formula (I) is selected from: [ka] and pharma- ceutically acceptable salts thereof.

[0114] In another aspect, a compound of formula (II) is disclosed: [ka] or a pharma- ceutically acceptable salt thereof, R 1a and R 1b are each independently a lipid moiety having at least 8 carbon atoms; X 1a and X 1b are each independently O, NR w , S, and a bond; R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, HaloC 1 -C 4 Alkyl, Amino C 1 -C 4 Alkyl, Hydroxy C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 R is selected from alkylamino, alkylamino, and cyano; 2a’ and R 2b’ , R 2b’ and R 2c’ , R 2c’ and R 2d’ , R 2a’’ and R 2b’’ , R 2b’’and R 2c’’ , or R 2c’’ and R 2d’’ optionally form, together with the carbon atom(s) to which they are attached, an optionally substituted 3- to 6-membered ring; X 4a CR 4a or N, X 4b CR 4b or N, X 5a CR 5a or N, X 5b CR 5b or N, X 6a CR 6a or N, X 6b CR 6b or N, X 7a CR 7a or N, X 7b CR 7b or N, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C 6 Alkoxy, Amino C 1 -C6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z and R 4a and R 5a , R 5a and R 6a , or R 6a and R 7a optionally form, together with the carbon atom to which they are attached, a 5- or 6-membered ring; R 4b and R 5b , R 5b and R 6b , or R 6b and R 7b together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring; R w , R x , R y , and R z are each independently hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl and haloC 1 -C 6 alkyl).

[0115] In some embodiments, X 4a , X 5a , X 6a , and X 7a One or two of the following are N and X 4b , X5b , X 6b , and X 7b In some embodiments, one or two of X 4a , X 5a , X 6a , and X 7a One of them is N and the other is X 4b , X 5b , X 6b , and X 7b In some embodiments, one of X is N. 4a CR 4a and X 5a CR 5a and X 6a CR 6a and X 7a CR 7a and X 4b CR 4b and X 5b CR 5b and X 6b CR 6b and X 7b CR 7b It is.

[0116] In some embodiments, the compound is a compound of formula (IIa): [ka]

[0117] In some embodiments, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C 4In some embodiments, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy. 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently selected from hydrogen and methyl. 2a’ , R 2b’ , R 2c’ , and R 2d’ One of them is C. 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy C 1 -C 4 alkyl, and hydroxy, and the remaining three are hydrogen. 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ One of them is C. 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4Alkoxy C 1 -C 4 alkyl, and hydroxy, and the remaining three are hydrogen. 2a’ , R 2b’ , R 2c’ , and R 2d’ In some embodiments, one of R is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy, and the remaining three are hydrogen. 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ In some embodiments, one of R is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy, and the remaining three are hydrogen. 2a’ , R 2b’ , R 2d’ , R 2a’’ , R 2b’’ , and R 2d’’ is hydrogen and R 2c’ and R 2c’’ are each independently hydrogen and C 1 -C 4 In some embodiments, R 2a’ , R 2b’ , R 2d’ , R 2a’’ , R 2b’’ , and R 2d’’ is hydrogen and R 2c’ and R 2c’’ are each independently selected from hydrogen and methyl. 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each hydrogen.

[0118] In some embodiments, R 2a’ , R 2d’ , R 2a’’ , and R 2d’’ is hydrogen and R 2b’and R 2c’ form a three-membered ring (i.e., a cyclopropyl ring) together with the carbon atom to which they are attached; R 2b’’ and R 2c’’ form a three-membered ring (i.e., a cyclopropyl ring) together with the carbon atom to which they are attached.

[0119] In some embodiments, R 3a and R 3b are each independently selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 3a and R 3b Each is fluoro. In some embodiments, R 3a and R 3b are each hydrogen.

[0120] In some embodiments, R 4a and R 4b are each independently selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 4a and R 4b Each is fluoro. In some embodiments, R 4a and R 4b are each hydrogen.

[0121] In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, HaloC 1 -C 6 Alkyl, haloC 1 -C6 Alkoxy, Amino C 1 -C 6 Alkyl, Hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, DiC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4 Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently selected from methyl, ethyl, n-propyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, 2-fluoroethyl, difluoromethoxy, hydroxy, fluoro, chloro, bromo, and methylamino. 5a , R 5b , R 6a , and R 6b are each independently1 -C 4 Alkyl, C 1 -C 4 In some embodiments, R 5a , R 5b , R 6a , and R 6b are each independently selected from methyl, ethyl, n-propyl, methoxy, ethoxy, fluoro, chloro, and bromo. 5a , R 5b , R 6a , and R 6b are each independently 1 -C 4 In some embodiments, R 5a , R 5b , R 6a , and R 6b are each methoxy.

[0122] In some embodiments, R 7a and R 7b are each independently selected from hydrogen and halo (e.g., fluoro, chloro, or bromo). 7a and R 7b Each is fluoro. In some embodiments, R 7a and R 7b are each hydrogen.

[0123] In some embodiments, X 1a and X 1b are each O or a bond. 1a and X 1b are each O. In some embodiments, X 1a and X 1b Each of X is a bond. 1a and X 1b are NR, w and R w is hydrogen and C 1 -C 6In some embodiments, X is selected from alkyl. 1a and X 1b Each is NH. In some embodiments, X 1a and X 1b are NR, w and R w is methyl. In some embodiments, X 1a and X 1b are S, respectively.

[0124] In some embodiments, the compound is a compound of formula (IIa): R 1a and R 1b are each independently a lipid moiety having at least 8 carbon atoms; X 1a and X 1b is O, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ are each independently hydrogen and C 1 -C 4 alkyl, R 3a , R 3b , R 4a , R 4b , R 7a , and R 7b is hydrogen, R 5a , R 5b , R 6a , and R 6b are each independently 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 Alkoxy, C 1 -C 6 Alkylthio, HaloC 1 -C 4Alkyl, haloC 1 -C 4 Alkoxy, hydroxy, halo, and C 1 -C 4 alkylamino.

[0125] R 1a Groups and R 1b The group R of the compound of formula (I) 1 As described above for the group, R is a lipid moiety having at least 8 carbon atoms. 1a and R 1b are each independently 8 -C 80 Alkyl, C 8 -C 80 Alkenyl, C 8 -C 80 Alkynyl, C 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 heteroalkynyl, each of which is optionally substituted with one or more substituents selected from hydroxy and amino.

[0126] For example, in some embodiments, R 1a and R 1b are each independently 8 -C 80 Alkyl and C 8 -C 80 In some embodiments, R is selected from the group consisting of alkenyl and aryl. 1a and R 1b are each independently 8 -C 40 Alkyl and C 8 -C 40 In some embodiments, R is selected from the group consisting of alkenyl and aryl. 1a and R 1b are each independently 12 -C 40 Alkyl and C 12 -C 40In some such embodiments (e.g., X 1 is O), then R 1a and R 1b is derived from a saturated or unsaturated fatty alcohol. In some embodiments, R 1a and R 1bare derived from: linoleyl alcohol ((9Z,12Z)-octadeca-9,12-dien-1-ol), myristyl alcohol (1-tetradecanol), palmitoleyl alcohol ((Z)-hexadec-9-en-1-ol), oleyl alcohol ((Z)-octadec-9-en-1-ol), elaidyl alcohol (trans-9-octadecenol), cis-vaccenyl alcohol ( cis-11-octadecenol), gadoleyl alcohol ((Z)-icos-9-en-1-ol), 11-eicosenol, erucyl alcohol (cis-13-docosenol), 15-tetracosen-1-ol, eicosadienyl alcohol (icosa-11,14-dien-1-ol), linolenyl alcohol ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-ol), γ-linoleyl alcohol ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-ol), Norenyl alcohol ((6E,9E,12E)-octadeca-6,9,12-trien-1-ol), eleostearyl alcohol (octadeca-9,11,13-trien-1-ol), icos-5,8,11-trien-1-ol, icos-13-en-1-ol, icos-11,14-17-trien-1-ol, octadeca-6,9,12,15-tetraen-1-ol, arachidonyl alcohol Alcohol ((5Z,8Z,11Z,14Z)-icosatetraen-1-ol), 4E,6Z-hexadecadien-1-ol, icosa-5,8,11,14,17-pentaen-1-ol, docosahexaenoyl alcohol (docosa-4,7,10,13,16,19-hexaen-1-ol), docosa-7,10,13,16,19-pentaen-1-ol, tetracosa-6,9,12,15,18,21-Hexaen-1-ol, Capryl Alcohol (1-Octanol), Pelargonic Alcohol (1-Nonanol), Decyl Alcohol (1-Decanol), Undecyl Alcohol (1-Undecanol), Lauryl Alcohol (1-Dodecanol), Tridecyl Alcohol (1-Tridecanol), Myristyl Alcohol (1-Tetradecanol), Pentadecyl Alcohol (1-Pentadecanol), Cetyl Alcohol (1-Hexadecanol), Palmitoleic Alcohol (cis-9-Hexadecen-1-ol), Heptadecyl Alcohol (1-n-Heptadecanol), Stearyl Alcohol (1-Octadecanol), Oleyl Alcohol (1-Octadecenol), Nonadecanyl Alcohol (1-Nonadecanol), Arachidyl Alcohol (1-Eicosanol), Heneicosyl Alcohol 1-Heneicosanol, Behenyl Alcohol, 1-Docosanol, Erucyl Alcohol, 1-Tricosyl Alcohol, 1-Tetracosanol, Pentacosyl Alcohol, 1-Pentacosanol, Seryl Alcohol, 1-Heptacosanol, Montanyl Alcohol, 1-Octacosanol, 1-Nonacosanol, Myricyl Alcohol, 1-Triacontanol, 1-Hentriacontanol, 1-Dotriacontanol, Laceryl Alcohol, 1-Tritriacontanol, Gedil Alcohol, 1-Tetratriacontanol, 1-Hexatriacontanol, 1-Heptatriacontanol, 1-Octatriacontanol, Nonatriacontan-1-ol, or 1-Tetracontanol.

[0127] In some embodiments, R 1a and R 1b are each independently 8 -C 80 Heteroalkyl, C 8 -C 80 Heteroalkenyl, and C 8 -C 80 In such embodiments, R 1a and R 1bcan be derived from a lipid that contains one or more heteroatom groups (e.g., -O-, -NH-, -C(O)-, etc., or combinations thereof (e.g., -C(O)O- groups)).

[0128] In some embodiments, R 1a and R 1b each independently have the formula (A): [ka] (In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a and R b are each independently 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 heteroalkenyl).

[0129] In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0130] In some embodiments, R a and R b are each independently 6 -C 40 Alkyl and C 6 -C 40 For example, in some embodiments, R a and R bare each independently selected from the following: n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, hentriacontyl, dotriacontyl, tritriacontyl, tetratriacontyl, pentatriacontyl, pentyl, hexatriacontyl, heptatriacontyl, octatriacontyl, nonatriacontyl, tetracontyl, linoleyl ((9Z,12Z)-octadeca-9,12-dien-1-yl), palmitoleyl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), elaidyl (trans-9-octadecenyl), cis-vaccenyl (cis-11-octadecenyl), gadoleyl ((Z)-icos-9-en-1-yl), 11-eicosenyl, elci cis-13-docosenyl, 15-tetracosen-1-yl, eicosadienyl (icosa-11,14-dien-1-yl), linolenyl ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-yl), γ-linolenyl ((6E,9E,12E)-octadeca-6,9,12-trien-1-yl), eleostearyl (octadeca-9,11,13-trien-1-yl), icos-5,8,11-trien-1-yl, eicos-13-en-1-yl, icos-11,14-17- In some embodiments, R is selected from the group consisting of icosatetraen-1-yl, octadeca-6,9,12,15-tetraen-1-yl, arachidonyl ((5Z,8Z,11Z,14Z)-icosatetraen-1-yl), 4E,6Z-hexadecadien-1-yl, icosa-5,8,11,14,17-pentaen-1-yl, docosahexaenoyl (docosa-4,7,10,13,16,19-hexaen-1-yl), docosa-7,10,13,16,19-pentaen-1-yl, and tetracosa-6,9,12,15,18,21-hexaen-1-yl. a and R b are linoleyl, respectively.

[0131] In some embodiments, R 1a and R 1b each independently have the formula (B) or (C): [ka] (In the formula, n and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 is C 6 -C 40 Alkyl and C 6 -C 40 alkenyl, R b is C 6 -C 40 Alkyl, C 6 -C 40 Alkenyl, C 6 -C 40 Heteroalkyl, and C 6 -C 40 heteroalkenyl).

[0132] In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0133] In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 3, 4, 5, 6, or 7. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7.

[0134] In some embodiments, R a1 is C 6 -C 24 Alkyl or C 6 -C 24 In some embodiments, R is alkenyl. a1 is C 9 -C 22 Alkyl and C 9 -C 22 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 is linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R a1 is linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 is selected from linoleyl, n-nonyl, n-undecyl, henicosan-11-yl, pentadecan-7-yl, and heptadecan-9-yl.

[0135] In some embodiments, R b is C 6 -C 40 Alkyl and C 6 -C 40 For example, in some embodiments, R bis selected from the following: n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, hentriacontyl, dotriacontyl, tritriacontyl, tetratriacontyl, pentatriacontyl, hexatriacontyl, Satriacontyl, heptatriacontyl, octatriacontyl, nonatriacontyl, tetracontyl, linoleyl ((9Z,12Z)-octadeca-9,12-dien-1-yl), palmitoleyl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), elaidyl (trans-9-octadecenyl), cis-vaccenyl (cis-11-octadecenyl), gadoleyl ((Z)-icos-9-en-1-yl), 11-eicosenyl, erucyl (cis -13-docosenyl), 15-tetracosen-1-yl, eicosadienyl (icosa-11,14-dien-1-yl), linolenyl ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-yl), γ-linolenyl ((6E,9E,12E)-octadeca-6,9,12-trien-1-yl), eleostearyl (octadeca-9,11,13-trien-1-yl), icos-5,8,11-trien-1-yl, eicos-13-en-1-yl, icos-11,14-17-trien-1-yl In some embodiments, R is selected from the group consisting of octadeca-6,9,12,15-tetraen-1-yl, arachidonyl ((5Z,8Z,11Z,14Z)-icosatetraen-1-yl), 4E,6Z-hexadecadien-1-yl, icosa-5,8,11,14,17-pentaen-1-yl, docosahexaenoyl (docosa-4,7,10,13,16,19-hexaen-1-yl), docosa-7,10,13,16,19-pentaen-1-yl, and tetracosa-6,9,12,15,18,21-hexaen-1-yl. b is linoleyl.

[0136] In some embodiments, R1a and R 1b each independently have the formula (D), (E), or (F). [ka] (In the formula, n, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40; R a1 and R a2 are each independently 6 -C 40 Alkyl and C 6 -C 40 alkenyl).

[0137] In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0138] In some embodiments, p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p and q are each independently selected from 3, 4, 5, 6, and 7. In some embodiments, p and q are each independently selected from 3, 5, and 7. In some embodiments, p and q are each 5. In some embodiments, p and q are each 6. In some embodiments, p and q are each 7.

[0139] In some embodiments, R a1 and R a2 are each independently 6 -C 24 Alkyl and C 6 -C 24In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently 9 -C 22 Alkyl and C 9 -C 22 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently a linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R a1 and R a2 are each independently a linear or branched C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently selected from linoleyl, n-nonyl, n-undecyl, henicosan-11-yl, pentadecan-7-yl, and heptadecan-9-yl.

[0140] In some embodiments, R 1 is derived from a steroid. For example, in some embodiments, R 1 is derived from cholesterol, beta-sisterol, or BHEM cholesterol.

[0141] In some embodiments, R 1a and R 1b are each independently selected from: [ka] [ka] [ka]

[0142] The compound of formula (II) includes a linker. In some embodiments, the length of the linker is about 5 Å to 1000 Å. In some embodiments, the length of the linker is about 5 Å, 10 Å, 20 Å, 50 Å, 100 Å, 150 Å, 200 Å, 300 Å, 400 Å, 500 Å, 600 Å, 700 Å, 800 Å, 900 Å, or 1000 Å, or any suitable range therebetween (e.g., 5-100 Å, 50-500 Å, 150-700 Å, etc.). In some embodiments, the linker comprises about 1-200 atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, or any suitable range therebetween (e.g., 2-20, 10-50, etc.)).

[0143] The linkers are independently methylene (-CH 2 -), ethers (-O-), amines (-NH-), alkylamines (-NR-R is an optionally substituted C 1 -C 6alkyl groups), thioethers (-S-), disulfides (-SS-), amides (-C(O)NH-), esters (-C(O)O-), carbamates (-OC(O)NH-), ureas (-NHC(O)NH-), and sulfonamides (-S(O) 2 NH-), and any combination thereof.

[0144] In some embodiments, the linker comprises one or more -(CH 2 CH 2 O)-(oxyethylene) group, for example, 1 to 20 -(CH 2 CH 2 O)- groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 -(CH 2 CH 2 In some embodiments, the linker comprises a -(CH 2 CH 2 O)-, -(CH 2 CH 2 O) 2 -, -(CH 2 CH 2 O) 3 -, -(CH 2 CH 2 O) 4 -, -(CH 2 CH 2 O) 5 -, -(CH 2 CH 2 O) 6 -, -(CH 2 CH 2 O) 7 -, -(CH 2 CH 2 O) 8 -, -(CH 2 CH 2 O) 9 - or -(CH 2 CH 2 O) 10 In some embodiments, the linker comprises one or more -(CH 2 CH 2 CH2 O)-(oxypropylene) group, for example, 1 to 20 -(CH 2 CH 2 CH 2 O)- groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 -(CH 2 CH 2 CH 2 In some embodiments, the linker comprises a -(CH 2 CH 2 CH 2 O)-, -(CH 2 CH 2 CH 2 O) 2 -, -(CH 2 CH 2 CH 2 O) 3 -, -(CH 2 CH 2 CH 2 O) 4 -, -(CH 2 CH 2 CH 2 O) 5 -, -(CH 2 CH 2 CH 2 O) 6 -, -(CH 2 CH 2 CH 2 O) 7 -, -(CH 2 CH 2 CH 2 O) 8 -, -(CH 2 CH 2 CH 2 O) 9 - or -(CH 2 CH 2 CH 2 O) 10 - group.

[0145] In some embodiments, the linker is -OCH 2 CH 2 CH 2 O-, -OCH 2 CH2 CH 2 -, -CH 2 CH 2 CH 2 -, -OCH 2 CH 2 O- and -OCH 2 CH 2 - is selected.

[0146] In some embodiments, the linker can be one or more alkylene groups (e.g., -(CH 2 ) n -, n is 1 to 12, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or any suitable range therebetween. In some embodiments, the linker comprises one or more branched alkylene groups.

[0147] In some embodiments, the linker comprises a cleavable (eg, enzymatically cleavable, chemically cleavable, etc.) moiety.

[0148] In some embodiments, the linker may be any suitable organic functional group (e.g., -OH, -NH 2 , -SH, -CN, =O, =S, halogens (e.g., -F, -Cl, -Br, -I), -COOH, -CONH 2 , -CH 3 etc.) containing one or more substituents, pendants, side chains, etc.

[0149] The scope of the present disclosure is directed to lipid moieties (e.g., groups R 1 or R 8) as well as other STING agonists.Other STING agonists include, for example, cyclic dinucleotides (CDNs) (Krasteva et al. Nat. Chem. Biol. 2017, 13(4), 350-359; Burdette et al. Nature 2011, 478(7370), 515-518), amidobenzimidazole (ABZI) and its derivatives (e.g., diABZI1, diABZI2, and diABZI3) (Ramanjulu et al. Nature 2018, 564, 439-443; Song et al. J. Med. Chem. 2021, 64(3), 1649-1669), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), 10-carboxymethyl-9-acridanone (CMA), SR-717 (Chin et al. Science 2020,369(6506),993-999), α-mangostin (Zhang et al. ChemMedChem 2018,13(19),2057-2064), compound 12b (2-methoxy-5,6-dimethylacridin-9(10H)-one; Hou et al. Bioorg. Chem. 2020,95:103556), compound G10 (4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; Sali et al. PLoS Pathog. 2015,11(12),p.e1005324), compound C11 (N-(methylcarbamoyl)-2-phenyl-2-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)acetamide; Gall et al. J. Virol. 2018,92(6)), (5a'S,10a'R)-5a',6'-dihydro-3'H,5'H-dispiro[indene-2,2'-dithiazolo[3,2-a:3',4'-d]pyrazine-8',2''-indene]-1,1'',3,3'',5',10'(10a'H)-hexaone (DSDP; Liu et al. Antiviral Res. 2017, 147, 37-46), as well as other compounds such as ADU-S100, MK-154, MK-2118, BMS-986301, GSK-3745417, SB-11285, and IMSA-101.STING agonists are also disclosed, for example, in Zhang et al., J. Med. Chem. 2020, 63(8), 3785-3816.

[0150] Compounds may exist as stereoisomers in which asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are configurations as defined in: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution techniques are exemplified by: (1) binding the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and, optionally, isolating the optically pure products from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or newer versions); or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column; or (3) fractional recrystallization techniques.

[0151] It should be understood that the compounds may have tautomeric and geometric isomeric forms and that these also constitute embodiments of the present disclosure.

[0152] The present disclosure also includes isotopically labeled compounds that are identical to those set forth in formula (I) except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine (such as, but not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Heavier isotopes (e.g., deuterium, e.g., 2 H) may provide certain therapeutic advantages resulting in improved metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some circumstances. Positron-emitting isotopes may be incorporated into the compounds for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that may be incorporated into compounds of formula (I) are: 11 C. 13 N, 15 O, and 18 F. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples, using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents.

[0153] The disclosed compounds may exist as pharma- ceutically acceptable salts. The term "pharma- ceutically acceptable salts" refers to salts or zwitterions of compounds that are water- or oil-soluble or dispersible, suitable for the treatment of disorders without undue toxicity, irritation, and allergic responses, commensurate with a reasonable benefit / risk ratio, and effective for the intended use. The salts may be prepared during the final isolation and purification of the compounds, or may be prepared separately by reacting the amino group of the compounds with a suitable acid. For example, the compounds may be dissolved in a suitable solvent (e.g., but not limited to, methanol and water) and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salts may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to obtain the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides, and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0154] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base (e.g., hydroxide, carbonate, or bicarbonate) of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium, or aluminum) or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0155] The compounds may be synthesized according to a variety of methods, including those shown in the Examples. The reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions may be worked up in a conventional manner, for example by removing the solvent from the residue, and further purified according to methodologies generally known in the art (for example, but not limited to, crystallization, distillation, extraction, trituration, and chromatography). Unless otherwise indicated, starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, procedures analogous to the synthesis of known structurally similar compounds, or procedures analogous to those described in the Schemes or Synthetic Examples sections above.

[0156] Routine experimentation (e.g., proper manipulation of reaction conditions, reagents, and order of synthetic pathways, protection of any chemical functional groups that are not compatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method) is within the scope of the present disclosure. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of this can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present invention can be accomplished by methods similar to those described in the above synthetic schemes and specific examples.

[0157] The optically active forms of the disclosed compounds can be obtained by carrying out one of the procedures described herein using, if necessary, optically active starting materials (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolving a stereoisomeric mixture of the compound or intermediate using standard procedures (for example, chromatographic separation, recrystallization, or enzymatic resolution).

[0158] Similarly, if a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolving a mixture of geometric isomers of the compound or intermediates using standard procedures such as chromatographic separation.

[0159] It can be understood that the synthetic schemes and specific examples described are illustrative and should not be construed as limiting the scope of the disclosure as defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are intended to be within the scope of the claims.

[0160] 3. Composition The disclosed compounds can be incorporated into compositions that can be suitable for administration to a subject (eg, a patient, which can be human or non-human).

[0161] A. Pharmaceutical Composition The disclosed compounds may be incorporated into pharma- ceutically acceptable compositions. The pharmaceutical compositions may include a "therapeutically effective amount" or a "prophylactically effective amount" of the compound(s). A "therapeutically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount of a composition can be determined by one skilled in the art and may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the composition to elicit a desired response in an individual. A therapeutically effective amount is also an amount in which any toxic or adverse effects of the compounds of the present invention (e.g., compounds of formula (I)) are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve a desired prophylactic result. Typically, since a prophylactic dose is used in a subject prior to or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0162] Pharmaceutical compositions and formulations may include a pharma- ceutically acceptable carrier. As used herein, the term "pharma- ceutically acceptable carrier" refers to a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrin, or formulation auxiliary of any type. Some examples of substances that may function as pharma- ceutically acceptable carriers include sugars (e.g., but are not limited to, lactose, glucose, and sucrose); starches (e.g., but are not limited to, corn starch and potato starch); cellulose and its derivatives (e.g., but are not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (e.g., but are not limited to, cocoa butter and suppository wax); oils (e.g., but are not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); surfactants (e.g., but are not limited to, Cremophor EL, Cremophor RH 60, Solutol HS 15, and Polysorbate 80); Chlodextrins (for example, but not limited to, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD); glycols (for example, but not limited to, propylene glycol); esters (for example, but not limited to, ethyl oleate and ethyl laurate); agar; buffers (for example, but not limited to, magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffers, as well as other non-toxic compatible lubricants (for example, but not limited to, sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants may also be present in the composition, at the discretion of the formulator.

[0163] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier to be used. The compositions may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral injection) or local administration (e.g., transdermal, pulmonary, nasal, otic, ocular, liposome delivery system, or iontophoresis).

[0164] Carriers for systemic administration typically include at least one of a diluent, lubricant, binder, disintegrant, colorant, flavorant, sweetener, antioxidant, preservative, glidant, solvent, suspending agent, wetting agent, surfactant, cyclodextrin, combinations thereof, etc. All carriers are optional in the composition.

[0165] Suitable diluents include sugars (e.g., glucose, lactose, dextrose, and sucrose); diols (e.g., propylene glycol); calcium carbonate; sodium carbonate; sugar alcohols (e.g., glycerin, mannitol, and sorbitol). The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0166] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycols, and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0167] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches (e.g., corn starch and potato starch), gelatin, tragacanth, and cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose). The amount of binder(s) in the systemic composition is typically about 5 to about 50%.

[0168] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0169] Suitable coloring agents include colorants such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0170] Suitable flavorings include menthol, peppermint, and fruit flavors. The amount of flavoring(s) used in a systemic or topical composition is typically from about 0.1 to about 1.0%.

[0171] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically from about 0.001 to about 1%.

[0172] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically from about 0.1 to about 5%.

[0173] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0174] Suitable glidants include silicon dioxide. The amount of lubricant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0175] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohol (e.g., ethanol), dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, and phosphate (or other suitable buffer). The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0176] Suitable suspending agents include AVICEL RC-591 (FMC Corporation, Philadelphia, Pa.) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0177] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS (Atlas Powder Company, Wilmington, Del.). Suitable surfactants include those disclosed in: CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in a systemic or topical composition is typically about 0.1% to about 5%.

[0178] Suitable cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl betadex (HP-beta-CD), and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD). The amount of cyclodextrin in a systemic or topical composition is typically about 0% to about 40%.

[0179] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but in general, a systemic composition will contain 0.01%-50% of an active compound (e.g., a compound of formula (I)) and 50%-99.99% of one or more carriers. Compositions for parenteral administration will usually contain 0.1%-10% of an active ingredient and 90%-99.9% of a carrier (e.g., a diluent and a solvent).

[0180] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of active ingredient, usually at least about 5%, more specifically about 25% to about 50%. Oral administration compositions contain about 50% to about 95%, more specifically about 50% to about 75% of carrier.

[0181] Tablets can be compressed tablets, powder tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multiple compressed tablets. Tablets usually contain active ingredients and carriers (e.g., components selected from diluents, lubricants, binders, disintegrants, colorants, flavorants, sweeteners, glidants, and combinations thereof). Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Particular colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners (e.g., aspartame and saccharin) or flavors (e.g., menthol, peppermint, fruit flavors), or combinations thereof.

[0182] Capsules (e.g., implants, sustained release formulations, and extended release formulations) typically contain the active compound (e.g., a compound of formula (I)) and a carrier comprising one or more diluents disclosed above, within a capsule comprising gelatin. Granules typically contain a disclosed compound, preferably a glidant (e.g., silicon dioxide) to improve flow properties. Implants can be of the biodegradable or non-biodegradable type.

[0183] The choice of carrier components for oral compositions is determined by secondary considerations such as taste, cost, and storage stability, which are not critical for the purposes of the present invention.

[0184] The solid compositions can be coated in a conventional manner, usually with a pH or time dependent coating, such that the disclosed compounds are released in the gastrointestinal tract near the desired application or at various times and for extended periods of time to prolong the desired effect. The coating usually comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coating (available from Evonik Industries, Essen, Germany), wax, and shellac.

[0185] Compositions for oral administration can be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. Liquid compositions for oral administration usually include the disclosed compounds and carriers (i.e. carriers selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants). Oral liquid compositions preferably include one or more components selected from colorants, flavorants, and sweeteners.

[0186] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions usually include one or more of soluble fillers (e.g., diluents including sucrose, sorbitol, and mannitol) and binders (e.g., acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose). Such compositions may further include lubricants, colorants, flavorings, sweeteners, antioxidants, and glidants.

[0187] The disclosed compounds can be administered topically. The topical compositions that can be applied topically to the skin can take any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, rinse-off hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical compositions include the disclosed compounds (e.g., compounds of formula (I)) and a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the skin. The carrier may further include one or more optional components.

[0188] The amount of carrier used in combination with the disclosed compounds is sufficient to provide a practical amount of the composition for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms useful in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0189] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier comprises a topical carrier. Suitable topical carriers include one or more components selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetric alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, etc. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetric alcohol.

[0190] The topical composition carrier may further comprise one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0191] Suitable emollients include: stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, diisopropyl ... -n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linolate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically from about 5% to about 95%.

[0192] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically from about 0% to about 95%.

[0193] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohol. The amount of solvent(s) in the topical composition is usually about 0% to about 95%.

[0194] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.Specific humectants include glycerin.The amount of humectant(s) in the topical composition is usually 0% to 95%.

[0195] The amount of thickening agent(s) in a topical composition is typically from about 0% to about 95%.

[0196] Suitable powders include beta cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in the topical composition is typically 0% to 95%.

[0197] The amount of fragrance in a topical composition is typically from about 0% to about 0.5%, particularly from about 0.001% to about 0.1%.

[0198] Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0199] B. Albumin composition The present invention further provides compositions comprising albumin nanoparticles. In some embodiments, the compounds disclosed herein are incorporated into compositions comprising albumin nanoparticles. Albumin nanoparticle compositions and formulations may also comprise a pharma- ceutically acceptable carrier, as described above.

[0200] Albumin comprises the most abundant plasma protein in mammals, and numerous and diverse mammalian albumins have been characterized by biochemical methods and / or sequence information. Any natural, synthetic, or engineered albumin may be used in conjunction with the nanoparticle compositions described herein. In some embodiments, the albumin is human serum albumin.

[0201] In some embodiments, the albumin nanoparticles further comprise one or more cell targeting epitopes. In some embodiments, the epitopes are covalently bound or directly conjugated to albumin. In some embodiments, the epitopes are cross-linked to albumin. In selected embodiments, the albumin nanoparticles further comprise one or more immune cell epitopes (e.g., B cell and T cell epitopes). One or more immune cell antigens may facilitate targeting to the lymphatic system. In selected embodiments, the albumin nanoparticles further comprise one or more epitopes from microbial agents (e.g., Clostridioides difficile, Bacillus anthracis, clostridium botulinum, Helicobacter pylori, Rotavirus sp., Coronaviridae).

[0202] C. Lipophilic formulations In some embodiments, the compounds disclosed herein are incorporated into lipophilic compositions, including liposomes, lipid nanoparticles, micelles, etc. In some embodiments, the disclosed compounds are encapsulated within liposomes, lipid nanoparticles, or micelles. The formulation may also include a pharma- ceutically acceptable carrier, as described above.

[0203] In some embodiments, the disclosed compounds are incorporated into a lipophilic composition that includes one or more vesicle-forming lipids. Methods for preparing lipophilic compositions include, for example, lipid film hydration (optionally combined with sonication or extrusion), solvent evaporation (e.g., ethanol injection, ether injection, or reverse phase evaporation), solvent diffusion method, high temperature homogenization process, detergent removal method, or combinations thereof. The disclosed compounds can be combined with lipid(s) before vesicle formation (passive loading) or after vesicle formation (active loading). Lipophilic compositions can increase circulation time in vivo, increase the stability of the compound, and prevent degradation in the bloodstream. Lipophilic compositions can increase the distribution of the compound in the lung, breast, pancreas, and spleen.

[0204] Natural or synthetic vesicle-forming lipids, or combinations thereof, can be used. One or more vesicle-forming lipids can be selected from dialiphatic chain lipids (e.g., phospholipids); diglycerides; dialiphatic glycolipids; single lipids (e.g., sphingomyelin or glycosphingolipids); steroid lipids; hydrophilic polymer-derivatized lipids; or mixtures thereof.

[0205] The lipophilic compositions of the present disclosure may comprise one or more cationic and / or ionizable lipids, phospholipids, neutral or non-cationic lipids, polyethylene glycol (PEG) lipid conjugates, and / or sterols. In some embodiments, the lipid nanoparticles comprise cationic and / or ionizable lipids, neutral or non-cationic lipids, and cholesterol.

[0206] Cationic lipids and / or ionizable lipids include, for example, amine-containing lipids, which can be readily protonated and have a positive or partial positive charge at physiological pH, since they have pKa values ​​between pH 5 and 8. The polar head groups of the cationic lipids preferably include amine derivatives, such as primary, secondary, and / or tertiary amines, quaternary ammonium, various combinations of amines, amidinium salts, or guanidine and / or imidazole groups, as well as pyridinium, piperazine, and amino acid head groups (e.g., lysine, arginine, ornithine, and / or tryptophan). Cationic lipids include, but are not limited to, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and / or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dimyristoyl-3-trimethylammonium propane (DMTAP), 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)dimethylazanium bromide (DMRIE), didodecyl(dimethyl)ammonium bromide (DDAB), 1,2-dioleyloxypropyl-3-dimethylhydroxyethylammonium bromide (DORIE), 3β-[N-(N,N′-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol), or dioleyl ether phosphatidylcholine (DOEPC). Ionizable lipids include, but are not limited to, 1,2-dioleyloxy-3-dimethylaminopropane (DODMA).

[0207] In some embodiments, the lipophilic composition comprises a polyethylene glycol (PEG)-lipid conjugate. The PEG-lipid conjugate may include, but is not limited to, a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. For example, the PEG lipid may be a PEG-DMG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol), PEG-c-DOMG (R-3-[(ω-methoxypoly(ethylene glycol)2000)carbamoyl)]-1,2-dimyristyloxypropyl-3-amine), PEG-DMA (PEG-dimethacrylate), PEG-DLPE (1,2-didodecanoyl-sn-glycero-3-phosphoethanolamine-PEG), PEG-DMPE (PEG-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), PEG-DPPC (PEG-dipalmitoylphosphatidylcholine), PEG-N,N-di(tetradecyl)acetamide, or PEG-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)) lipid. In some embodiments, the lipid nanoparticles comprise PEG-DMG and / or PEG-N,N-di(tetradecyl)acetamide.

[0208] Sterols may include cholesterol, fecosterol, ergosterol, campesterol, sitosterol, stigmasterol, brassicasterol, or sterol esters (eg, cholesteryl hemisuccinate, cholesteryl sulfate), or any other derivative of cholesterol.

[0209] The neutral or non-cationic lipid may comprise one or more phospholipids. The phospholipid comprises a phospholipid portion and one or more fatty acid portions. The phospholipid portion may comprise, but is not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine, and sphingomyelin. The fatty acid portion may comprise, but is not limited to, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, erucic acid, phytanic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid.

[0210] Phospholipids suitable for use in the composition may include, but are not limited to, phosphatidylglycerol (PG), (e.g., dimyristoylphosphatidylglycerol (DMPG) and 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG)); phosphatidylcholine (PC), (e.g., egg yolk phosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG)); 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine; phosphatidylethanolamines (PE) (e.g., 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine); phosphatidic acid (PA); phosphatidylinositol (PI); phosphatidylserine (PS); and sphingomyelin (SM).

[0211] The positively charged lipid structures described herein may also contain other components that are typically used in the formation of vesicles (e.g., for stabilization). Examples of such other components include, but are not limited to, fatty alcohols, fatty acids, and / or any other pharma- ceutically acceptable excipients that can affect surface charge, membrane fluidity, and aid in the incorporation of lipids into lipid assemblies.

[0212] The lipophilic composition may also be targeted, e.g., contain one or more targeting moieties or biodistribution modifiers on the surface. The targeting moiety may be any agent capable of specifically binding or interacting with a desired target, and is generally known in the art, e.g., a ligand (e.g., folic acid, a protein, an antibody, or an antibody fragment, etc.). In some embodiments, the targeting moiety is an immune cell epitope (e.g., B cell and T cell epitope). In selected embodiments, the targeting moiety comprises one or more epitopes from microbial agents (e.g., Clostridioides difficile, Bacillus anthracis, clostridium botulinum, Helicobacter pylori, Rotavirus sp., Coronaviridae).

[0213] The lipophilic composition may have any structure (e.g., a structure with an internal space separated from the external medium by one or more lipid bilayers) or any microcapsule with a semipermeable membrane with a lipophilic central portion that separates the membrane from the interior. In some embodiments, the lipophilic composition may comprise a unilamellar liposome with a single lipid layer. The disclosed compounds may be located completely or partially in the internal space of the liposome or completely or partially within the bilayer membrane of the liposome. In some embodiments, the lipophilic composition comprises a micelle.

[0214] In some embodiments, the disclosed compounds are incorporated into formulations that include PLA and / or PLGA. PLA or PLGA formulations can be prepared by a variety of methods known in the art, such as single / double emulsion solvent evaporation techniques, spray drying, spray freeze drying, supercritical fluid drying, and nanoprecipitation.

[0215] d. Additional therapeutic agents Any of the above compositions or formulations disclosed herein may further comprise at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises an immunomodulatory agent, a chemotherapeutic agent, a nucleic acid (e.g., mRNA, an aptamer, an antisense oligonucleotide, a ribozyme nucleic acid, an interfering RNA, an antisense and antigene nucleic acid), or a combination thereof.

[0216] Exemplary immunomodulatory agents include: indoleamine 2,3-dioxygenase (IDO) inhibitors and analogs thereof (e.g., epacadostat, BMS-986205, indoximod, PF-06840003, and analogs thereof); signal transducer and activator of transcription 3 (Stat3) inhibitors and analogs thereof (e.g., SM-36 and analogs thereof); toll-like receptor (TLR) agonists and analogs thereof (e.g., imiquimod, resiquimod, sergantolimod, galdiquimod, SM-360320, TMX-101, TMX-202, TMX-302, TMX-306, GSK2245035, C L097, 852A, AZD-8848, DSP-3025, GS-9620, RO7020531, RO6871765, ANA773, DSP-0509, NJH395, BNT411, TQ-A3334, JNJ-4964, LHC165, CV8102, VTX-1463, VTX-2337, IMO-8400, IMO-3100, IRS-954, and their analogs); and statins or other lipid-lowering drugs and their analogs (e.g., atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, mevastatin, pitavastatin, rosuvastatin, and their analogs).

[0217] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term "chemotherapeutic agent" or "anti-cancer agent" includes any small molecule or other agent used in the treatment or prevention of cancer. Chemotherapeutic agents include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacirb, afinitor (everolimus), alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib.

[0218] In some embodiments, the at least one additional therapeutic agent comprises a polynucleotide or nucleic acid (e.g., ribonucleic acid or deoxyribonucleic acid). The term "polynucleotide" in its broadest sense includes any compound and / or substance that is or can be incorporated into an oligonucleotide chain. Exemplary polynucleotides for use in accordance with the present disclosure include, but are not limited to, one or more of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) (e.g., messenger mRNA (mRNA)), hybrids thereof, RNAi inducers, RNAi agents, siRNA, shRNA, miRNA, antisense RNA, ribozymes, catalytic DNA, RNA that induces triple helix formation, aptamers, vectors, and the like.

[0219] In some embodiments, the at least one additional therapeutic agent is an RNA. The RNA useful in the compositions and methods described herein can be selected from the group consisting of, but not limited to, shortmers, antagomirs, antisense RNA, ribozymes, small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), and mixtures thereof.

[0220] In certain embodiments, at least one additional therapeutic agent is an mRNA. The mRNA can encode any polypeptide of interest, including any naturally occurring or non-naturally occurring or otherwise modified polypeptide. The polypeptide encoded by the mRNA can be of any size and have any secondary structure or activity. In some embodiments, the polypeptide encoded by the mRNA can have a therapeutic effect when expressed in a cell.

[0221] In other embodiments, the at least one additional therapeutic agent is an siRNA. The siRNA can be capable of selectively knocking down or downregulating the expression of a gene of interest. For example, the siRNA can be selected to silence a gene associated with a particular disease, disorder, or condition when a nanoparticle composition comprising the siRNA is administered to a subject in need thereof. The siRNA can comprise a sequence complementary to the mRNA sequence that codes for the gene or protein of interest. In some embodiments, the siRNA can be an immunomodulatory siRNA.

[0222] In some embodiments, at least one additional therapeutic agent is shRNA or its encoding vector or plasmid.shRNA can be produced in target cell when appropriate construct is delivered to nucleus.The structure and mechanism related to shRNA are well known in the related art.

[0223] e. Vaccine The compounds and compositions may also be used in vaccines. Vaccines include the disclosed compounds or compositions and an antigen or a nucleic acid encoding the same. Suitable antigens include microbial pathogens, bacteria, viruses, proteins, glycoproteins, lipoproteins, peptides, glycopeptides, lipopeptides, toxoids, carbohydrates, and tumor-specific antigens. Mixtures of two or more antigens may be used.

[0224] Antigens can be derived from and / or isolated from essentially any desired source, depending on the infectious disease, autoimmune disease, condition, cancer, pathogen, or disease to be treated with the particular vaccine composition.

[0225] The vaccines described herein may be capable of providing immunity against one or more conditions associated with an infectious disease (e.g., but not limited to, influenza, measles, human papilloma virus (HPV), rabies, meningitis, whooping cough, tetanus, plague, hepatitis, and tuberculosis) and may include antigens and / or epitopes from an infectious disease, or nucleic acids encoding them.

[0226] The vaccines described herein may also induce an immune response against cancer cells and may include antigens, epitopes, and / or neoepitopes, or portions thereof, or nucleic acids encoding antigens, epitopes, and / or neoepitopes from tumor cells. Tumor antigens are surface molecules that are differentially expressed on tumor cells compared to non-tumor tissues. Tumor antigens immunologically distinguish tumor cells from normal cells and provide targets for the diagnosis and treatment of human cancer. Tumor antigens have been characterized as membrane proteins or altered carbohydrate molecules of glycoproteins or glycolipids on the cell surface. Cancer cells often have characteristic tumor antigens on their surface (e.g., truncated epidermal growth factor, folate binding protein, epithelial mucin, melanopherin, carcinoembryonic antigen, prostate specific membrane antigen, HER2-neu), which are candidates for use in therapeutic cancer vaccines. Because tumor antigens are normal or associated with normal components of the body, the immune system often cannot mount an effective immune response against those antigens to destroy tumor cells. Illustrative cancer types in which this approach can be used include prostate cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer, head and neck cancer, melanoma, leukemia, lymphoma, and the like.

[0227] In other embodiments, the antigen present in the vaccine composition is not a foreign antigen, but an autoantigen, for example, the vaccine composition is directed to an autoimmune disease. Examples of autoimmune diseases include type 1 diabetes, conventional organ-specific autoimmunity, neurological diseases, rheumatic diseases / connective tissue diseases, autoimmune cytopenias, and related autoimmune diseases. Such conventional organ-specific autoimmunity may include thyroiditis (Graves' disease + Hashimoto's disease), gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, hypogonadism, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, anti-receptor antibody disease, and vitiligo. Such neurological diseases may include schizophrenia, Alzheimer's disease, depression, hypopituitarism, diabetes insipidus, sicca syndrome, and multiple sclerosis. Such rheumatic / connective tissue diseases may include rheumatoid arthritis, systemic lupus erythematosus (SLE) or lupus, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren's syndrome. Other autoimmune-related diseases may include autoimmune uveoretinitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, and other immune-related diseases presented herein and known in the relevant art.

[0228] In one embodiment, the antigen in the vaccine composition is a peptide, polypeptide, or immunogenic portion thereof. As used herein, an "immunogenic portion" is a portion of a protein that is recognized (e.g., specifically binds) by a B-cell and / or T-cell surface antigen receptor. Such an immunogenic portion generally comprises at least 5 amino acid residues, more preferably at least 10, and even more preferably at least 20 amino acid residues of an antigenic protein or a variant thereof.

[0229] Immunogenic portions of an antigenic polypeptide may generally be identified using well-known techniques, such as those summarized in Paul, Fundamental Immunology, 3rd ed., 243-247 (Raven Press, 1993) and references cited therein. Such techniques include screening the polypeptide for the ability to react with antigen-specific antibodies, antisera, and / or T-cell lines or clones. As used herein, antisera and antibodies are "antigen-specific" if they specifically bind to the antigen (e.g., react with the protein in an ELISA or other immunoassay and show no detectable reaction with unrelated proteins). Such antisera and antibodies may be prepared using well-known techniques. An immunogenic portion of a protein is one that reacts with such antisera and / or T cells (e.g., in an ELISA and / or T-cell reactivity assay) at a level not substantially lower than the reactivity of the full-length polypeptide. Such immunogenic portions may react within such assays at a level equal to or greater than the reactivity of the full-length polypeptide. Such screening may generally be performed using methods well known to those of skill in the art, such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. For example, the polypeptide may be immobilized on a solid support and contacted with patient serum to allow binding of antibodies in the serum to the immobilized polypeptide. Unbound serum may then be removed, e.g., by removing sera from the patient. 125 I-labeled protein A is used to detect bound antibody.

[0230] Peptide and polypeptide antigens can be prepared using any of a variety of well-known techniques. Recombinant polypeptides encoded by DNA sequences can be readily prepared from isolated DNA sequences using any of a variety of expression vectors known to those skilled in the art. Expression can be achieved in any suitable host cell that has been transformed or transfected with an expression vector containing a DNA molecule encoding a recombinant polypeptide. Suitable host cells include prokaryotes, yeast, and higher eukaryotic cells (e.g., mammalian cells and plant cells). Preferably, the host cells used are E. coli, yeast, or mammalian cell lines (e.g., COS or CHO).

[0231] Portions and other variants of protein antigens having fewer than about 100 amino acids, generally fewer than about 50 amino acids, can also be produced by synthetic means using techniques well known to those of skill in the art. For example, such polypeptides can be synthesized using any of the commercially available solid-phase methods, such as the Merrifield solid-phase synthesis method, in which amino acids are added sequentially to a growing amino acid chain. See, Merrifield, J. Am. Chem. Soc. 85:2149-2146, 1963. Automated polypeptide synthesizers are commercially available from suppliers, such as Perkin Elmer / Applied BioSystems Division (Foster City, Calif.), and can be operated according to the manufacturer's instructions.

[0232] In certain embodiments, the nucleic acid encoding the antigen is DNA. This type of exemplary DNA-based vaccine contains DNA encoding one or more polypeptide antigens, so that the antigen is generated in situ. Alternatively, the vaccine may be an RNA-based vaccine. In certain embodiments, the nucleic acid encoding the antigen is mRNA. The mRNA may encode any polypeptide antigen of interest, including any naturally occurring or non-naturally occurring or otherwise modified polypeptide. The polypeptide encoded by the mRNA may be of any size and may have any secondary structure or activity. In some embodiments, the polypeptide encoded by the mRNA may stimulate an immune response when expressed in a cell.

[0233] The vaccine compositions of the present disclosure may also contain other compounds, which may be biologically active or inactive. The vaccine or medicament may include an adjuvant or immunostimulant, or a polynucleotide encoding an adjuvant or immunostimulant (e.g., an adjuvant polypeptide). Adjuvants and immunostimulants are compounds or compositions that directly or indirectly stimulate the immune system's response to a co-administered antigen. In some embodiments, the vaccine is unadjuvanted or self-adjuvanted.

[0234] Suitable adjuvants are commercially available, for example, as glucopyranosyl lipid adjuvant (GLA); Pam3CSK4; Freund's incomplete and complete adjuvants (Difco Laboratories, Detroit, Mich.); Merck adjuvant 65 (Merck and Company, Inc., Rahway, NJ); AS-2 (SmithKline Beecham); mineral salts (e.g., aluminum, silica, kaolin, and carbon); aluminum salts (e.g., aluminum hydroxide gel (alum), AlK(SO 4 ) 2 , AlNa(SO 4 ) 2 , AlNH 4 (SO4 ), and Al(OH) 3 ); calcium salts (e.g., Ca 3 (PO 4 ) 2 ); iron or zinc; insoluble suspensions of acylated tyrosine; acylated sugars; cationic or anionic derivatized polysaccharides; polynucleotides (e.g., poly IC, poly AU acid, and CpG oligodeoxynucleotides (e.g., class A or B); polyphosphazenes; cyanoacrylates; polymerase-(DL-lactide-co-glycoside); bovine serum albumin; diphtheria toxoid; tetanus toxoid; edestin; keyhole limpet hemocyanin; Pseudomonas aeruginosa toxin A; choleragenoids; cholera toxin; pertussis toxin; viral proteins; Quil A, aminoalkyl glucosamine phosphate compounds. Additionally, adjuvants (e.g., cytokines (e.g., GM-CSF or interleukin-2, interleukin-7, or interleukin-12), interferons, or tumor necrosis factors) may also be used as adjuvants. Protein and polypeptide adjuvants may be obtained from natural or recombinant sources according to methods well known to those of skill in the art. If obtained from recombinant sources, the adjuvant may comprise a protein fragment that contains at least the immunostimulatory portion of the molecule.

[0235] Other known immunostimulatory polymers that can be used include, but are not limited to, polysaccharides, tRNA, non-metabolizable synthetic polymers (e.g., polyvinylamine, polymethacrylic acid, polyvinylpyrrolidone), mixed (relatively high molecular weight) polycondensates of 4',4-diaminodiphenylmethane-3,3'-dicarboxylic acid and 4-nitro-2-aminobenzoic acid (see Sela, M., Science 166:1365-1374 (1969)), or glycolipids, lipids, or carbohydrates.

[0236] In some embodiments, the adjuvant polypeptide comprises an immune activating protein (e.g., CD70, CD40 ligand, and constitutively active TLR4) or a polycationic peptide (e.g., protamine). In some embodiments, the adjuvant polypeptide is a flagellin polypeptide. Commercially available mRNA encoding the adjuvant polypeptide is available, for example, as TriMix (see Bonehill, A. et al. Mol. Ther. 16, 1170-1180 (2008), incorporated herein by reference). In some embodiments, the vaccine may comprise at least two separate polynucleotides, one encoding the anti-Mullerian hormone receptor II extracellular domain (AMHR2-ED) as described above, and the other encoding the adjuvant polypeptide (e.g., a flagellin polypeptide or an immune activating protein).

[0237] The preparation of vaccines is a highly developed art, and general guidelines on vaccine preparation and formulation are readily available from any of a variety of sources. One such example is New Trends and Developments in Vaccines, edited by Volier et al. University Park Press, Baltimore, Md., USA 1978. Vaccine compositions may generally be used for prophylactic and therapeutic purposes.

[0238] The amount of antigen in each vaccine administration is generally selected as an amount that will induce an immunoprotective response without significant side effects in a typical vaccine. Such an amount will vary depending on which particular immunogen is used and how it is presented. Of course, the dosage administered may vary with age, weight, type of concurrent treatment, if any, and the nature of the antigen administered.

[0239] The immunogenic activity of a given amount of the vaccine composition can be readily determined, for example, by monitoring the increase in antibody titers against the antigen used in the vaccine composition (Dalsgaard, K. Acta Veterinia Scandinavica 69:1-40 (1978)). Another common method involves intradermal injection of various amounts of the vaccine composition into CD-1 mice, after which serum is collected from the mice and tested for anti-immunogen antibodies, for example, by ELISA. These and other similar approaches will be apparent to those skilled in the art.

[0240] 4.How to use The present disclosure provides a method for inducing or modulating an immune or inflammatory response. As used herein, the term "modulate" generally refers to the ability to change a particular concentration, level, expression, function, or behavior (e.g., of an immune or inflammatory response) by increasing or decreasing, for example, directly or indirectly promoting / stimulating / upregulating, or interfering / inhibiting / downregulating. In some embodiments, modulating is an increase and / or decrease in a particular concentration, level, activity, or function compared to a control, or compared to a generally expected average activity level, or compared to a control activity level.

[0241] Thus, in some embodiments, modulating immune or inflammatory responses refers to the ability of the compounds of the present invention to alter or modulate one or more aspects of immune or inflammatory responses. In some embodiments, the method polarizes macrophages. In some embodiments, the method induces an interferon response. In some embodiments, the method activates transcription factors of the innate immune response (e.g., STAT6, IRF3).

[0242] The present disclosure further provides a method for treating a disease or disorder, comprising administering a compound or composition disclosed herein to a subject in need thereof. In some embodiments, the subject is a human.

[0243] The disease or disorder may include cancer, autoimmune diseases, inflammatory diseases, and infectious diseases.

[0244] In some embodiments, the disease or disorder is an inflammatory disease or disorder. Inflammatory diseases are characterized by activation of the immune system of a tissue or organ to abnormal levels that can cause abnormal function and / or disease of the tissue or organ. Inflammatory diseases and disorders that can be treated by the methods of the present invention include, but are not limited to, arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu's arteritis, or Behcet's syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SLE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren's syndrome, or Churg-Strauss syndrome.

[0245] In some embodiments, the disease or disorder is an autoimmune disease or disorder. Autoimmune diseases and disorders refer to a condition in a subject characterized by cell, tissue, and / or organ damage caused by the subject's immune response to its own cells, tissues, and / or organs. Autoimmune diseases and disorders that may be treated by the methods of the present invention include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune disease of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, mixed essential cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura. Irritable bowel disease (ITP), Irritable bowel disease (IBD), IgA neuropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff man syndrome, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis (e.g., dermatitis herpetiformis, vasculitis), vitiligo, and Wegener's granulomatosis.

[0246] Some autoimmune disorders are also associated with inflammatory conditions.Examples of inflammatory disorders that are also autoimmune disorders that can be prevented, treated or managed according to the method of the present invention include, but are not limited to, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergy disorders, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation caused by chronic viral or bacterial infection.Examples of types of psoriasis that can be treated according to the composition and method of the present invention include, but are not limited to, psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis, and inverse psoriasis.

[0247] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a hematological cancer or lymphoma. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the disclosed compounds, compositions, or methods result in the inhibition of removal of metastases. In some embodiments, the disclosed compounds, compositions, or methods result in a reduction in tumor growth. In some embodiments, the disclosed compounds, compositions, or methods prevent tumor recurrence.

[0248] The compounds and compositions herein may be useful to treat a wide variety of cancers (e.g., carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma). The cancer may be of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, lymph node, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testis, thyroid, or uterus.

[0249] In some embodiments, the cancer is an invasive and / or metastatic cancer (e.g., stage II cancer, stage III cancer, or stage IV cancer). In some embodiments, the cancer is an early stage cancer (e.g., stage 0 cancer, stage I cancer) and / or is not an invasive and / or metastatic cancer.

[0250] In some embodiments, the disease or disorder is an infectious disease. Infectious diseases that can be treated or prevented by the methods of the present invention are caused by infectious agents (such as, but not limited to, viruses, bacteria, fungi, protozoa, helminths, and parasites). The present invention is not limited to treating or preventing infectious diseases caused by intracellular or extracellular pathogens. Infectious diseases can be derived from bacteria (e.g., Mycobacterium tuberculosis, Chlamydia, Francisella tularensis), DNA viruses (e.g., Herpesviridae (Herpes simplex virus type 1, Kaposi's sarcoma-associated virus, and Epstein-Barr virus), Papillomaviridae (human papillomavirus), adenovirus, and Hepadnaviridae (Hepatitis B virus)), or RNA viruses (e.g., Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronavirus and SARS coronavirus).

[0251] The compounds and compositions disclosed herein can be administered to a subject in a variety of ways. In any of the uses or methods described herein, administration can be by a variety of routes known to those skilled in the art, including, but not limited to, oral, inhaled, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof.

[0252] The amount of the disclosed compound required for use in the disclosed method will vary depending on the particular compound selected, as well as the route of administration, the nature and / or symptoms of the disease, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. The determination of effective dosage levels (dosage levels required to achieve the desired results) can be performed by those skilled in the art using routine methods (e.g., human clinical trials, in vivo studies, and in vitro studies). For example, effective dosages can be determined by comparing in vitro activity and in vivo activity in animal models.

[0253] Dosage and dosing intervals can be individually adjusted to provide plasma levels of the active moiety sufficient to maintain the modulating effect, or minimum effective concentration (MEC). The MEC will vary from compound to compound, but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will be determined by individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosing intervals can also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels above the MEC 10-90% of the time, preferably 30-90%, most preferably 50-90%. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0254] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the administered dose in the management of the disorder of interest will vary with the severity of the condition to be treated and the route of administration. Furthermore, the dose, and perhaps the frequency of administration, will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above may also be used in veterinary medicine.

[0255] The compounds and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of a particular compound, or a subset of compounds sharing a particular chemical moiety, or a composition thereof, can be established by determining in vitro toxicity on a cell line (e.g., a mammalian cell line, preferably a human cell line). The results of such studies are often predictive of toxicity to animals (e.g., mammals), and more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model (e.g., mice, rats, rabbits, dogs, or monkeys) can be determined using known methods. Efficacy can be established using several recognized methods (e.g., in vitro methods, animal models, or human clinical trials). When selecting a model to determine efficacy, one skilled in the art can be guided by the state of the art to select the appropriate model, dose, route of administration, and / or regimen.

[0256] A wide range of second therapies can be used in combination with the compounds of the present disclosure.Second therapies can be administration of additional therapeutic agents or second therapies that are not associated with administration of another therapeutic agent.Such second therapies include, but are not limited to, surgery, immunotherapy, and radiation therapy.

[0257] The second therapy may be administered simultaneously with the first therapy, in the same composition, or in a separate composition that is administered substantially simultaneously with the first composition. In some embodiments, the second therapy may precede or follow the treatment of the first therapy by a time interval ranging from a few hours to a few months.

[0258] In some embodiments, a therapeutically effective amount of a compound disclosed herein or a composition thereof is administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, an effective combination therapy is achieved using a single composition or pharmacological formulation that contains both agents, or two different compositions or formulations, administered simultaneously or separated by a time interval, one composition containing a compound of the present invention and the other containing at least one additional therapeutic agent.

[0259] In some embodiments, the at least one additional therapeutic agent comprises an immunomodulatory agent, a chemotherapeutic agent, a nucleic acid (e.g., an mRNA, an aptamer, an antisense oligonucleotide, a ribozyme nucleic acid, an interfering RNA, an antigenic nucleic acid), a decongestant, a steroid, an analgesic, an antibacterial agent, or a combination thereof.

[0260] Exemplary immunomodulatory agents include: indoleamine 2,3-dioxygenase (IDO) inhibitors and analogs thereof (e.g., epacadostat, BMS-986205, indoximod, PF-06840003, and analogs thereof); signal transducer and activator of transcription 3 (Stat3) inhibitors and analogs thereof (e.g., SM-36 and analogs thereof); toll-like receptor (TLR) agonists and analogs thereof (e.g., imiquimod, resiquimod, sergantolimod, galdiquimod, SM-360320, TMX-101, TMX-202, TMX-302, TMX-306, GSK2245035, C L097, 852A, AZD-8848, DSP-3025, GS-9620, RO7020531, RO6871765, ANA773, DSP-0509, NJH395, BNT411, TQ-A3334, JNJ-4964, LHC165, CV8102, VTX-1463, VTX-2337, IMO-8400, IMO-3100, IRS-954, and their analogs); and statins or other lipid-lowering drugs and their analogs (e.g., atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, mevastatin, pitavastatin, rosuvastatin, and their analogs).

[0261] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term "chemotherapeutic agent" or "anti-cancer agent" includes any small molecule or other agent used in the treatment or prevention of cancer. Chemotherapeutic agents include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacirb, afinitor (everolimus), alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib. In selected embodiments, the chemotherapy agent comprises paclitaxel.

[0262] In some embodiments of the methods disclosed herein, the compound or composition can be administered in combination with an antimicrobial agent (eg, an antiviral or antibacterial agent). In some embodiments, the additional antibacterial agent is an antiviral agent (e.g., abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, baloxavir marboxil, bictarvy, boceprevir, brevirtide, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, doravirine, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfinavir, nevirapine, nexavir, nitazoxanide, oseltamivir, penciclovir, peramivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, remdesivir, ribavirin, rilpivirine, rimantadine, lintatolimod, ritonavir, saquinavir, simeprevir, sovosbuvir, stavudine, taribavirin, telaprevir, telbivudine, tenofovir (e.g., tenofovir alafenamide or tenofovir disoproxil), tipranavir, trifluridine, tromantadine, umifenovir, valacyclovir, valganciclovir, vicriviroc, vidarabine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0263] In some embodiments, the additional antimicrobial agent is an antibacterial agent. Examples of antibacterial agents include sulfonamides, amphenicol, spectinomycin, trimethoprim, glycylcyclines, macrolides (e.g., erythromycin, clarithromycin, azithromycin, roxithromycin), oxazolidinones (e.g., linezolid), tetracyclines (e.g., doxycycline, tetracycline, minocycline), β-lactams (e.g., penicillin, methicillin, cloxacillin), carbapenems (e.g., imipenem, meropenem, aztreonam), aminoglycosides (e.g., gentamicin, tobramycin, amikacin), quinolones and fluoroquinolones (e.g., levofloxacin, ciprofloxacin, moxifloxacin), glycopeptides (e.g., vancomycin), polymyxins (e.g., polymyxin, colistin).

[0264] In some embodiments, the second therapy comprises immunotherapy, which comprises chimeric antigen receptor (CAR) T cell therapy or T cell transfer therapy, cytokine therapy, immunomodulatory drugs, cancer vaccines, or administration of antibodies (e.g., monoclonal antibodies).

[0265] In some embodiments, immunotherapy involves the administration of antibodies. The antibodies may target either antigens specifically expressed by tumor cells or antigens shared with normal cells. In some embodiments, immunotherapy may include antibodies targeting, for example, CD20, CD33, CD52, CD30, HER (also called erbB or EGFR), VEGF, CTLA-4 (also called CD152), epithelial cell adhesion molecule (EpCAM, also called CD326), and PD-1 / PD-L1. Suitable antibodies include, but are not limited to, rituximab, blinatumomab, trastuzumab, gemtuzumab, alemtuzumab, ibritumomab, tositumomab, bevacizumab, cetuximab, panitumumab, ofatumumab, ipilimumab, brentuximab, pertuzumab, and the like. In some embodiments, the additional therapeutic agent may include an anti-PD-1 / PD-L1 antibody, including, but not limited to, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab. The antibody may also be conjugated to a chemotherapeutic agent. Thus, in some embodiments, the antibody is an antibody drug conjugate.

[0266] Immunotherapy (e.g., administration of an antibody) may be administered to a subject in a variety of ways. In any of the uses or methods described herein, administration may be by a variety of routes known to those skilled in the art (e.g., but not limited to, oral, inhaled, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof). Immunotherapy may be administered parenterally (e.g., but not limited to, subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac, and intraarticular injection). In some embodiments, immunotherapy may be administered in the same manner or in a different manner than the disclosed compounds or compositions.

[0267] 5. Kit In another aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharma- ceutically acceptable salt thereof, or a composition comprising the compound or a pharma- ceutically acceptable salt thereof, and instructions for using the compound or composition.

[0268] The kits may also include other agents and / or products that are co-packaged, combined, and / or co-delivered with other components. For example, a drug manufacturer, drug reseller, physician, compounding store, or pharmacist may provide a kit containing the disclosed compounds and / or products and another agent for delivery to a patient.

[0269] The kit may also include instructions for use of the components of the kit. Instructions are materials or methodologies related to the kit. The materials may include any combination of background information, list of components, simple or detailed protocols for using the compositions, troubleshooting, reference materials, technical support, and other related documentation. The instructions may be provided with the kit or as a separate member component, in paper or electronic form, provided on a computer readable memory device, downloaded from an internet website, or provided as a recorded presentation.

[0270] It is understood that the disclosed kits can be used in connection with the disclosed methods. The kits may further include containers or devices for use in the methods or compositions disclosed herein. The kits may optionally provide additional components, such as buffers and disposable, single-use equipment, such as pipettes, cell culture plates, or flasks.

[0271] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, etc. Individual member components of the kit may be physically packaged together or separately. EXAMPLES

[0272] 6. Working Example Abbreviations used in the schemes and examples below are as follows: DCM is dichloromethane; DMAP is 4-dimethylaminopyridine; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq is equivalents; EtOAc is ethyl acetate; MeOH is methanol; OAc is acetyloxy; RT or rt is room temperature; THF is tetrahydrofuran.

[0273] All air- and moisture-sensitive manipulations were carried out under argon or in vacuum using standard Schlenk techniques. Anhydrous solvents (Et 2 O, THF, dioxane, DMSO, DMF, DCM, and toluene) were purchased from Fischer Scientific. All chemicals were purchased from Fischer Scientific, Sigma Aldrich, TCI, WUXI Apptec, and DC Chemicals Europe and used without further purification unless otherwise stated.

[0274] Analytical thin layer chromatography (TLC) was performed using Merck SIL G / UV254 plates. Compounds were visualized by exposure to UV light or by immersing the plates in a solution of ninhydrin or potassium permanganate followed by heating or staining with iodine vapor in a wide jar chamber. Column chromatography was performed in air with silica gel 60 (Fluka). Column chromatography was performed with Merck Kieselgel 60 (200-500 mm). Solvent systems were administered (s / sv:v).

[0275] NMR spectra 1 H(300MHz) and 13 C (75 MHz) were recorded on an ARX300 on an Avance II 500 Bruker spectrometer, respectively. Chemical shifts (δ, ppm) are given relative to residual 1H or 13C of the deuterated solvents indicated (CDCl 3 7.26, 77.00; (CD3 ) 2 CO 2.05, 29.84, and 206.26, (CD 3 ) 2 SO 2.50, 39.52). 1H-NMR and 13C-NMR chemical shifts (δ) are given in parts per million (ppm) relative to the TMS scale. Coupling constants J are given in Hz. The following abbreviations are used for the multiplicities of the proton spectra: s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, m: multiplet, br.: broad, dd: double doublet, dt: double triplet. Coupling constants (J) are reported in Hertz (Hz). Some signals that could not be assigned will be designated ArH (aromatic hydrogen).

[0276] Mass spectra (MS) were recorded on an LCQ-advantage (ThermoFinnigan) mass spectrometer equipped with positive (ESI+) or negative (ESI-) electrospray ionization (ionization voltage 4.5 kV, injection temperature 240°C).

[0277] Example 1 General procedure 1: Esterification. Under nitrogen atmosphere, a solution of carboxylic acid derivative (1 equiv.), EDC hydrochloride (1 equiv.), and DMAP (0.5 equiv.) in dry THF (0.1 M) was stirred at 0 °C for 0.5 h. Then, a solution of alcohol (1 equiv.) in dry THF (0.1 M) was added. The solution was stirred at 0 °C to room temperature for 16 h. CH was used as the eluent. 2 -Cl 2 The progress of the reaction was monitored by TLC using a mixture of 0.2 M HCl, 1H NMR and 1H NMR using an ARX300 Brucker spectrometer. Upon completion of the reaction, the mixture was extracted with dichloromethane (3×). The combined organic layers were washed with 0.2 M aqueous HCl, NaHCO 3 The mixture was washed with saturated aqueous solution and brine. 2 Cl 2 -EtOAc or CH 2 Cl 2The solid residue was purified by manual column chromatography using a -MeOH step gradient solvent system to give the title product. (9Z,12Z)-Octadeca-9,12-dien-1-yl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid [ka]

[0278] Following general procedure 1, (9Z,12Z)-octadeca-9,12-dien-1-yl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid was synthesized from 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (1 equiv.), EDC hydrochloride (1 equiv.), DMAP (0.5 equiv.), and linoleyl alcohol (1 equiv.) in dry THF (0.1 M) at room temperature for 4 h. ((4-((4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoyl)oxy)butyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) [ka]

[0279] The title compound was synthesized from 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (1 equiv.), EDC hydrochloride (1 equiv.), DMAP (0.5 equiv.), and ALC-0315 (CAS=2036272-55-4, 1 equiv.) in dry THF (0.1 M) according to general procedure 1 at room temperature for 4 h. Heptadecan-9-yl 8-((4-((4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoyl)oxy)butyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoic acid [ka]

[0280] The title compound was synthesized according to general procedure 1 from 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (1 equiv.), EDC hydrochloride (1 equiv.), DMAP (0.5 equiv.), and SM-102 (CAS=2089251-47-6, 1 equiv.) in dry THF (0.1 M) at room temperature for 4 h.

[0281] Example 2 Albumin nanoformulation Compounds were dissolved in 1 mL of chloroform (organic phase) and then added dropwise to 200 mg of mouse serum albumin (66 kDa) dissolved in 20 mL of Milli-Q water (aqueous phase) to generate a milky emulsion using a rotor-stator homogenizer. A crude emulsion was then obtained after two cycles of low pressure (5000 psi) and 15 cycles of high pressure (3000 psi) in a high pressure homogenizer (Nano DeBEE) at 4 °C. The organic solvent was removed in a rotary evaporator at 25 °C. After filtration through a 0.22 μm strainer, the resulting nanosuspension was freeze-dried in 2 mL portions per vial to obtain a white dry powder and stored at -20 °C.

[0282] Example 3 Lipophilic formulations of STING agonists Lipophilic formulations of the disclosed compounds can be formed using a variety of methods with a variety of lipids.

[0283] In one exemplary formulation, soybean phosphatidylcholine (SPC), N-(carbonylmethoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG-DSPE), cholesterol, and STING agonist analogs were dissolved in chloroform in a round-bottom flask, alone or with other small molecule drugs (e.g., IPI-549 analogs, paclitaxel). After removing the organic solvent by rotary evaporation at 40° C., the dried lipid film was hydrated in PBS (pH 7.4) and vortexed six times for 30 seconds every 5 minutes at 45° C. The resulting lipid suspension was then subjected to 10 freeze-thaw cycles between liquid nitrogen and a 37° C. water bath and extruded with an extruder equipped with a 0.2 μm polycarbonate filter membrane to obtain homogeneity.

[0284] In another exemplary formulation, lipid nanoparticles were prepared using a composite technique by using both the solvent diffusion method and the high-temperature homogenization process, either STING agonist analogs alone or in combination with other small molecule drugs. Briefly, 50 mg of lipids (e.g., phosphatidylcholine and phosphatidylethanolamine), STING agonist analogs (0.1 mg / mL) were completely dissolved in a solvent (1 mL) containing an equal amount of a mixture of acetone and ethanol (1:1 (v / v)), and then heated to 70°C in a water bath. The resulting clear organic phase was quickly mixed with 20 mL of an aqueous phase containing an emulsifier preheated to the same temperature. The mixture was then emulsified at 24,500 rpm at 70°C for 5 minutes. The samples were then cooled in an ice-water bath to rapidly crystallize the lipids, thereby obtaining lipid nanoparticles either STING agonist analogs alone or in combination with other small molecule drugs, respectively.

[0285] Example 4 Liposome formulation of nucleic acid containing STING agonist Preparation method 1: Cationic liposomes were produced by the dry film method. Cationic lipids (e.g., 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), DOSPA, ePC, quaternary ammonium lipids), phospholipids (e.g., phosphatidylcholine and phosphatidylethanolamine), cholesterol or polyethylene glycol (PEG)-functionalized lipids (PEG lipids), and STING agonist analogs were dissolved in chloroform alone or together with other small molecule drugs in a round-bottom flask. After removing the organic solvent by a rotary evaporator at 40°C, the dry lipid film was hydrated in PBS (pH 7.4) and vortexed six times for 30 s every 5 min at 45°C. The resulting lipid suspension was then subjected to 10 freeze-thaw cycles between liquid nitrogen and a 37°C water bath and extruded with an extruder equipped with a 0.2 μm polycarbonate filter membrane to obtain a homogenous nanosuspension. The nucleic acid(s) were then mixed with the liposomes and incubated at room temperature for 20 minutes to allow for sufficient encapsulation.

[0286] Preparation method 2: Nucleic acids were prepared in acetate buffer at pH 4.0. Depending on the desired formulation, ethanol solutions were prepared containing ionizable cationic lipids (e.g., DLinKC2-DMA, ALC-0315, lipid H (SM-102), A2-Iso5-2DC18, BAME-O16B, 9A1P9, C12-200, cKK-E12, OF-Deg-Lin, 306Oi10, TT3, FTT5), phospholipids (e.g., phosphatidylcholine and phosphatidylethanolamine), cholesterol or polyethylene glycol (PEG) functionalized lipids (PEG lipids) and STING agonist prodrugs, other small molecule drugs in appropriate molar ratios. The microfluidic devices used in this study were fabricated by soft lithography, which is replica molding of an elastomer microfabricated master.

[0287] Example 4 Macrophage polarization Bone marrow-derived macrophages (BMDMs) were obtained from the femurs and tibias of BALB / c mice (female, 7 weeks old). Briefly, after euthanasia of the mice, the femurs and tibias of the hind legs were harvested, and then the bone marrow cells were gradually flushed out with pre-cold RIPA1640 medium using a 5 mL syringe with a 26G needle. After centrifugation at 500 g for 10 min, the cells were resuspended in complete DMEM medium containing 2 mM L-glutamine, 10% FBS, 10 ng / mL macrophage colony-stimulating factor (M-SF) (PeproTech, Inc, USA), 50 U / mL penicillin, and 50 μg / mL streptomycin, and then aliquots of 5 × 10 cells were placed in sterile plastic Petri dishes (10 mL). 6 The cells were seeded at a density of 100 cells / dish. The medium was renewed on day 3, and BMDM cells were harvested on day 7 and used in the following experiments.

[0288] For M1 and M2 macrophage differentiation, BMDM and RAW264.7 cells were cultured at 1 × 10 5 Cells were seeded at a density of 24 × 10 in plates and stimulated with LPS (100 ng / mL) and IFNγ (50 ng / mL) or IL-4 (20 ng / mL) and IL-13 (10 ng / mL) for 24 and 48 h, respectively. Cells treated with PBS served as M0 macrophages.

[0289] 10uM DMA01-132, DMA01-143, DMA01-148, and DMA01-139, compared with IPI549, were incubated with M2 macrophages generated by RAW264.7 cells for 24 hours after the medium was refreshed with serum-free DMEM. Then, the morphology of macrophages was observed using an inverted fluorescent microscope (Olympus, Japan). Furthermore, the cells and supernatant medium of each well were harvested, and secreted cytokines, including TNF-α and TGF-β, were detected by ELISA analysis.

[0290] Example 5 STING pathway stimulation The synthesized STING agonist prodrugs were evaluated for their ability to stimulate the STING signaling pathway in the presence (Figure 2A) and absence (Figure 2B) of Xerocine (200ug / ml).

[0291] THP1-blue ISG cells (5000 / well) were seeded in 96-well plates and cultured overnight, then various concentrations of DMA01-129 and DMA01-139 were added in comparison with MSA-2, cGAMP (10 μg / mL), and ADU-S100 (10 μg / mL) in fresh medium. Secreted fetal alkaline phosphatase (SEAP) activity was measured after 36 hours by using the QUANTI-Blue kit (InvivoGen) according to the manufacturer's instructions.

[0292] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and do not limit the scope of the present disclosure, which is defined solely by the appended claims and equivalents thereof.

[0293] Various changes and modifications to the disclosed embodiment, which will be apparent to those skilled in the art, can be made without departing from the spirit and scope thereof.

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, R 1 This is a lipid moiety having at least eight carbon atoms, and hydrogen. X 1 O, NR w Selected from , S, and combination, R 2a 、 R 2b 、 R 2c 、 and R 2d are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, halo C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, halo, hydroxy, amino, C 1 -C 4 alkylamino, di C 1 -C 4 alkylamino, and cyano; R 2a and R 2b , or R 2b and R 2c , or R 2c and R 2d may optionally form a 3- to 6-membered ring which is optionally substituted, together with the carbon atom to which they are attached. X 4 CR 4 or N, X 5 CR 5 or N, X 6 CR 6 or N, X 7 CR 7 or N, R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, Halo C 1 -C 6 Alkyl, Halo C 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, diC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , -SO 2 R z , oligo or polyethylene glycol chain, and group -Y-R 8 Selected from; R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These may form optionally substituted five-membered or six-membered rings together with the carbon atoms to which they are bonded. Y is -C(O)-, -C(O)O-, -C(O)NR v- Selected from , and -C(O)S-, R 8 This is a lipid portion having at least eight carbon atoms, R v 、R w 、R x 、R y 、and R z are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and halo C 1 -C 6 alkyl, and are selected from R 1 If R is hydrogen, 3 , R 4 , R 5 , R 6 , and R 7 At least one of them is -Y-R 8 (It is the basis.)

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is the compound of formula (Ia): 【Chemistry 2】

3. R 2a , R 2b , R 2c , and R 2d However, each independently, hydrogen and C 1 -C 4 A compound according to claim 1 or 2, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

4. R 3 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

5. R 4 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

6. R 5 and R 6 However, each is independent of C 1 -C 4 A compound according to claim 1 or 2, selected from alkoxys, or a pharmaceutically acceptable salt thereof.

7. R 7 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

8. X 1 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is oxygen or bonded.

9. R 1 However, it is a lipid portion having at least 8 carbon atoms, R 3 , R 4 , R 5 , R 6 , and R 7 However, each independently, hydrogen and C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, Halo C 1 -C 6 Alkyl, Halo C 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, diC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

10. R 1 However, C 12 -C 40 Alkyl and C 12 -C 40 A compound selected from alkenyls, according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

11. R 1 However, a compound according to claim 1 or 2 having formula (A), or a pharmaceutically acceptable salt thereof: 【Transformation 3】 (In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. R a and R b Each of them is independent of C 6 -C 40 Alkyl, C 6 -C 40 Alkenil, C 6 -C 40 Heteroalkyl and C 6 -C 40 (Selected from heteroalkenyls).

12. R 1 However, the compound according to claim 1 or 2 having formula (D), (E), or (F), or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 (In the formula, n, p, and q are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. R a1 and R a2 Each of them is independent of C 6 -C 40 Alkyl and C 6 -C 40 (Selected from Alkenil).

13. R 1 However, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】

14. A compound according to claim 1, selected from the group consisting of the following: 【Transformation 6】 and its pharmaceutically acceptable salts.

15. Compound of formula (II): 【Transformation 7】 or a pharmaceutically acceptable salt thereof (In the formula, R 1a and R 1b Each of these is an independent lipid moiety having at least eight carbon atoms. X 1a and X 1b These are O and NR, respectively, independently. w Selected from , S, and combination, R 2a’ , R 2b’ , R 2c’ , R 2d’ , R 2a’’ , R 2b’’ , R 2c’’ , and R 2d’’ These are, independently, hydrogen and C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, Halo C 1 -C 4 Alkyl, amino C 1 -C 4 Alkyl, hydroxy C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, diC 1 -C 4 Selected from alkylamino and cyano; R 2a’ and R 2b’ , R 2b’ and R 2c’ , R 2c’ and R 2d’ , R 2a’’ and R 2b’’ , R 2b’’ and R 2c’’ , or R 2c’’ and R 2d’’ These may form optionally substituted 3- to 6-membered rings together with the carbon atoms to which they are bonded. X 4a CR 4a or N, X 4b CR 4b or N, X 5a CR 5a or N, X 5b CR 5b or N, X 6a CR 6a or N, X 6b CR 6b or N, X 7a CR 7a or N, X 7b CR 7b or N, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b These are, independently, hydrogen and C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 3 -C 6 Cycloalkyl, Halo C 1 -C 6 Alkyl, Halo C 1 -C 6 Alkoxy, Amino C 1 -C 6 Alkyl, hydroxy C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, halo, hydroxy, amino, C 1 -C 4 Alkylamino, diC 1 -C 4 Alkylamino, cyano, -COOR x , -CON(R y ) 2 , and -SO 2 R z And R 4a and R 5a , R 5a and R 6a , or R 6a and R 7a They may form a five-membered ring or a six-membered ring together with the carbon atoms to which they are bonded; R 4b and R 5b , R 5b and R 6b , or R 6b and R 7b These may form optionally substituted five-membered or six-membered rings together with the carbon atoms to which they are bonded. R w , R x , R y , and R z These are, independently, hydrogen and C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 3 -C 6 Cycloalkyl and halo C 1 -C 6 (Selected from alkyl groups).

16. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, wherein the composition comprises albumin nanoparticles, liposomes, micelles, or lipid nanoparticles.

18. It is a vaccine, and the effective amount A compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, or a composition containing the same, Antigens or nucleic acids that encode them The vaccine, including the aforementioned vaccine.

19. A pharmaceutical composition for treating or preventing a disease or disorder, A compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, It is a vaccine, and the effective amount A compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, or a composition containing the same, Antigens or nucleic acids that encode them vaccines including The pharmaceutical composition comprising the above.

20. A pharmaceutical composition for inducing or modulating an immune response or inflammatory response in a subject, A compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, It is a vaccine, and the effective amount A compound according to claim 1 or 15 or a pharmaceutically acceptable salt thereof, or a composition containing the same, Antigens or nucleic acids that encode them vaccines including The pharmaceutical composition comprising the above.

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