Dual-function immunomodulatory compounds, formulations, and uses thereof

Abstract

The present disclosure provides dual function compounds, compositions, formulations, and methods for inducing or modulating immune or inflammatory responses and treating diseases or disorders (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases) using the compounds or compositions thereof. In particular, dual function compounds comprising a stimulator of interferon (IFN) genes (STING) agonist moiety and a second active moiety selected from an indoleamine 2,3-dioxygenase (IDO) inhibitor and a phosphatidylinositol 3 kinase (PI3K) inhibitor, as well as compositions and formulations thereof, are disclosed herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 334,441, filed April 25, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure provides dual function compounds, compositions, formulations, and methods for inducing or modulating an immune or inflammatory response and treating a disease or disorder (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases) using the compounds 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 embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof is disclosed herein, wherein: X 1 , O, NR w , S, and a bond; R1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, haloC1-C4 alkyl, aminoC1-C4 alkyl, hydroxyC1-C4 alkyl, C1-C4 alkoxyC1-C4 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, and cyano; R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b 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, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, haloC1-C6 alkyl, haloC1-C6 alkoxy, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, cyano, -COOR x , -CON(R y )2, -SO2R z , an oligo or polyethylene glycol chain, and a group -YR 8 Selected from; R 4 and R 5 , R5 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 selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and haloC1-C6 alkyl; L is a linker, Z is a moiety of formula (a) or formula (b); [ka] R 10 is hydrogen or C1-C6 alkyl; [ka] Q is CH or N; A is aryl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P; R 20 is hydrogen, halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, -OR a1 , -N(R a2 )(R a3 ), -SO2R a4 , -SO2N(R a5 )(R a6 ), and -NHSO2R a7 Selected from R a1 , R a2 , R a3 , R a4 , Ra5 , R a6 , and R a7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 21 is hydrogen and the group -L 21 -E is selected from L 21 is a bond, C1-C2 alkylene, -CH=CH-, -C≡C-, -C(O)-, -O-, -NH-, -S-, -C(O)O-, -C(O)NH-, -C(O)S-, arylene, cycloalkylene, heteroarylene, or heterocyclylene; 21 includes a combination of any two of these groups, E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-4 alkyl, C1-C4 haloalkyl, oxo, -OR b1 , -N(R b2 )(R b3 ), -SO2R b4 , -SO2N(R b5 )(R b6 ), and -NHSO2R b7 and R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , and R b7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L b is -(CR c1 R c2 ) m -G b - and R c1 and R c2 is independently selected from hydrogen and C1-C4 alkyl; m is 0, 1, or 2; G bis a bond, -NHC(O)-, -NH-, -O-, or -S-; B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, optionally substituted aryl, -OR d1 , -N(R d2 )(R d3 ), -SO2R d4 , -SO2N(R d5 )(R d6 ), and -NHSO2R d7 and R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0005] In some embodiments, X 4 CR 4 and X 5 CR 5 and X 6 CR 6 and X 7 CR 7 It is.

[0006] In some embodiments, R 4 is selected from hydrogen and halo. 4 is hydrogen.

[0007] In some embodiments, R 5 and R 6are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, cyano, -COOR x , -CON(R y )2, and -SO2R z In some embodiments, R 5 and R 6 are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylthio, haloC1-C4 alkyl, haloC1-C4 alkoxy, hydroxy, halo, and C1-C4 alkylamino. 5 and R 6 are each independently selected from C1-C4 alkyl, C1-C4 alkoxy, and halo. 5 and R 6 are each independently selected from C1-C4 alkoxy.

[0008] In some embodiments, R 7 is hydrogen.

[0009] In some embodiments, R 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxyC1-C4 alkyl, and hydroxy. 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen and C1-C4 alkyl. 1b , R 2a , and R2b is hydrogen and R 1a is selected from hydrogen and C1-C4 alkyl. In some embodiments, R 1a and R 2a is hydrogen and R 1b and R 2b form a three-membered ring together with the carbon atoms to which they are attached.

[0010] In some embodiments, R 3 is selected from hydrogen and halo. 3 is hydrogen.

[0011] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, Z is a moiety of formula (a). 10 is methyl.

[0013] In some embodiments, Z is a moiety of formula (b). In some embodiments, the moiety of formula (b) is a moiety of formula (bi): [ka]

[0014] In some embodiments, A is phenyl. In some embodiments, R 20 is hydrogen.

[0015] In some embodiments, Q is CH. In some embodiments, R 21 is hydrogen and the formula [ka] is selected from the group:

[0016] In some embodiments, the moiety of formula (b) is: [ka]

[0017] In some embodiments, L comprises one or more groups independently selected from -C(R')-, -CH=CH-, -C≡C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)-, arylene, heteroarylene, cycloalkylene, and heterocyclylene, and each R' is independently selected from hydrogen, C-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 and each R' is independently selected from hydrogen, C1-C10, C2-C3, C4-C4-C6, C8-C8-C9-C10-C11-C12-C13-C14-C15-C28-C16-C17-C18-C29-C30-C19-C28-C31-C29-C32-C41-C19-C29-C32-C31-C41-C29-C32-C41-C19-C29-C32-C41 ...41-C29-C32-C41-C41-C41-C51-C61-C29-C32-C41-C41-C51-C61-C41-C29-C32-C41-C41-C51-C61-C41-C41-C51-C61-C7 40 and selected from alkyl, phenyl, and -CH2-heterocyclyl (e.g., heterocyclyl is a 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S), wherein phenyl and heterocyclyl are each independently unsubstituted or substituted with 1 or 2 substituents.

[0018] In some embodiments, the compound is [ka] and pharma- ceutically acceptable salts thereof.

[0019] 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 pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0020] 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.

[0021] 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, an immunotherapy, 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), short 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, a PD-1 or PD-L1 antibody, and a PI3K inhibitor. 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 a microbial agent.

[0022] 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 pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof), and an antigen or a nucleic acid encoding same.

[0023] 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).

[0024] In another aspect, disclosed herein is a method of treating or preventing a disease or disorder, the method comprising administering an effective amount of a compound disclosed herein (e.g., a compound of formula (I), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof) to a subject in need thereof. 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, has had, is susceptible to, 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.

[0025] In another aspect, disclosed herein is a method of inducing or modulating an immune or inflammatory response in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of Formula (I), or a pharma- ceutically acceptable salt thereof) to a subject in need thereof. 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 antibacterial agent, an immunotherapy, or a combination thereof.

[0026] In another aspect, disclosed herein is the use of a compound disclosed herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I) 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.

[0027] Other aspects and embodiments of the present disclosure will become apparent in light of the following detailed description. [Brief description of the drawings]

[0028] [Figure 1] Graph of STING activation for various concentrations of compounds as determined by incubating with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution, and measuring OD655. [Diagram 2]Graph of STING activation in response to various concentrations of DMA01-166 as determined by incubating with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution, and measuring OD655. [Diagram 3] Graph of STING activation in response to various concentrations of MSA-2 as determined by incubating with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution, and measuring OD655. [Figure 4] FIG. 13 is a graph of BMDC activation measured by upregulation of CD80 and CD86 by flow cytometry for different concentrations of compounds (cGAMP (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-166 (10 μM)) after 24 hours of incubation with mouse bone marrow-derived dendritic cells (BMDCs). [Diagram 5] 1 is a graph of mouse bone marrow derived dendritic cell (BMDC) activation as measured by upregulation of CD80 and CD86 by flow cytometry for different concentrations of DMA01-166 incubated with BMDC for 24 hours. [Figure 6] Graph of mIFNβ concentration, measured by ELISA, in supernatants of mouse bone marrow-derived dendritic cells (BMDCs) incubated for 24 hours with different concentrations of compounds: cGAMP (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-166 (10 μM). [Figure 7] 1 is a graph of mIFNβ concentrations, as measured by ELISA, in supernatants of mouse bone marrow derived dendritic cells (BMDCs) incubated with different concentrations of DMA01-166 for 24 hours. [Figure 8]FIG. 13 is a graph of TNFα concentration, measured by ELISA, in supernatants of M2-polarized RAW264.7 cells incubated for 2 days with different concentrations of compounds: cGAMP (10 μg / mL), ADU (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-170 (10 μM), DMA01-166 (10 μM). [Figure 9] FIG. 1 is a graph of the M1 macrophage ratio determined by flow cytometry measuring CD80 and CD86 as markers of M1 macrophages from M2 polarized RAW264.7 cells incubated for 2 days with different concentrations of compounds (cGAMP (10 μg / mL), ADU (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-170 (10 μM), DMA01-166 (10 μM)). [Figure 10] 1 is a graph of the M1 macrophage ratio determined by flow cytometry measuring CD80 and CD86 as markers of M1 macrophages from M2 polarized RAW264.7 cells incubated for 2 days with various concentrations of DMA01-166. [Figure 11] Graph of inhibition of different isoforms of PI3K alpha, beta, gamma, and delta by IPI-549, DMA01-148, 143, 132, 166, 170, and 173. Inhibition of PI3K activity by IPI-549, DMA01-148, 143, 132, 166, 170, and 173 (0.1-10,000 nM) was measured using Kinase-GloMax assays for purified enzymes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. IC50 of compounds inhibiting various PI3K isoforms was calculated using Prism8. [Figure 12] Size distribution plot (left) and changes in mean diameter and PDI (center) and TEM images (right) of exemplary albumin nanoformulations of DMA01-166. [Figure 13]1 is a graph showing the in vivo efficacy of exemplary albumin nanoformulations of DMA01-166 (D166) and DMA01-166 with PD-1 antibody (D166+PD-1) with or without paclitaxel (Nano-P) in the KPC transgenic pancreatic cancer model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Disclosed herein are dual-function compounds, including a stimulator of interferon (IFN) genes (STING) agonist portion and a second active portion selected from an indoleamine 2,3-dioxygenase (IDO) inhibitor and a phosphatidylinositol 3 kinase (PI3K) inhibitor, as well as compositions and formulations thereof. One portion of the disclosed molecules functions as a STING agonist that targets the cGAS-STING pathway, which is a cytoplasmic DNA-sensing pathway that leads to the activation of type I IFN and other inflammatory cytokines. The other portion of the dual-function compound acts as either a PI3K inhibitor or an IDO inhibitor, allowing the compound to stimulate an immune response.

[0030] The section headings used in this section and throughout this disclosure are for organizational purposes only and are not intended to be limiting.

[0031] 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 referents unless the context clearly indicates otherwise. The present disclosure also contemplates other embodiments that "comprising," "consisting of," and "consisting essentially of" the embodiments or elements presented herein, whether or not expressly stated.

[0032] With respect to references to numerical ranges herein, each intervening numerical value is expressly contemplated with the same degree of precision, for example, in the range 6 to 9, the numerical values ​​7 and 8 are 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.

[0033] 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.

[0034] 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 the application or administration of a composition described herein to a 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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, pp. 111-115, 1997; and in: Sorrell, Organic Chemistry, 2001, pp. 111-115, 1997. 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).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The term "amino" as used herein refers to the group -NH2. The term "alkylamino" as used herein refers to the group -NHR, where R is an alkyl group as defined herein. The term "dialkylamino" as used herein refers to the group -NR2, where each R is independently an alkyl group as defined herein.

[0050] 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.

[0051] 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.

[0052] As used herein, the term "cyano" refers to a group of formula -CN.

[0053] The term "halogen" or "halo" as used herein means F, Cl, Br, or I.

[0054] 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.

[0055] 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.

[0056] 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).

[0057] 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 replaced with a heteroatom group, such as -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. Heteroalkenyl groups may also contain one or more carbonyl moieties (i.e., a carbon atom of an alkyl group is oxidized to a -C(O)- group).

[0058] 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 replaced with a heteroatom group, such as -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 may also contain one or more carbonyl moieties (i.e., a carbon atom of an alkyl group is oxidized to a -C(O)- group).

[0059] As used herein, the term "hydroxy" refers to an --OH group.

[0060] 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.

[0061] As used herein, the term "substituent" refers to a group substituted on an atom of a designated group.

[0062] 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.

[0063] As used herein, in chemical structures, the indications: [ka] represents the point of attachment of one moiety to another.

[0064] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkylalkenyl) is indicated by the prefix “C x -C y" (where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent). Thus, for example, "C1-C3 alkyl" refers to an alkyl substituent containing 1 to 3 carbon atoms.

[0065] 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.

[0066] Where substituents are designated 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, -CHO- is intended to include -OCH-, -C(O)NH- is intended to include -NHC(O)-.

[0067] 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 the present 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.

[0068] 2.Compound In one embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 1 , O, NR w , S, and a bond; R 1a , R 1b , R 2a , and R 2bare each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, haloC1-C4 alkyl, aminoC1-C4 alkyl, hydroxyC1-C4 alkyl, C1-C4 alkoxyC1-C4 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, and cyano; R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b 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, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, haloC1-C6 alkyl, haloC1-C6 alkoxy, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, cyano, -COOR x , -CON(R y )2, -SO2R 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 7optionally 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 selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and haloC1-C6 alkyl; L is a linker, Z is a moiety of formula (a) or formula (b); [ka] R 10 is hydrogen or C1-C6 alkyl; [ka] Q is CH or N; A is aryl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P; R 20 is hydrogen, halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, -OR a1 , -N(R a2 )(R a3 ), -SO2R a4 , -SO2N(R a5 )(R a6 ), and -NHSO2R a7 Selected from R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , and R a7are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 21 is hydrogen and the group -L 21 -E is selected from L 21 is a bond, C1-C2 alkylene, -CH=CH-, -C≡C-, -C(O)-, -O-, -NH-, -S-, -C(O)O-, -C(O)NH-, -C(O)S-, arylene, cycloalkylene, heteroarylene, or heterocyclylene; 21 includes a combination of any two of these groups, E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-4 alkyl, C1-C4 haloalkyl, oxo, -OR b1 , -N(R b2 )(R b3 ), -SO2R b4 , -SO2N(R b5 )(R b6 ), and -NHSO2R b7 and R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , and R b7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L b is -(CR c1 R c2 ) m -G b - and R c1 and R c2 is independently selected from hydrogen and C1-C4 alkyl; m is 0, 1, or 2; G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, optionally substituted aryl, -OR d1 , -N(R d2 )(R d3 ), -SO2R d4 , -SO2N(R d5 )(R d6 ), and -NHSO2R d7 and R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0069] In some embodiments, R 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxyC1-C4 alkyl, and hydroxy. 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy. 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen and C1-C4 alkyl. 1a , R 1b , R 2a , and R 2b are each independently selected from hydrogen and methyl. 1a , R 1b , R 2a, and R 2b In some embodiments, one of R is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxyC1-C4 alkyl, and hydroxy, and the remaining three are hydrogen. 1a , R 1b , R 2a , and R 2b In some embodiments, one of R is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl, and hydroxy, and the remaining three are hydrogen. 1b , R 2a , and R 2b is hydrogen and R 1a is selected from hydrogen and C1-C4 alkyl. In some embodiments, R 1b , R 2a , and R 2b is hydrogen and R 1a is selected from hydrogen and methyl. In some embodiments, R 1a , R 1b , R 2a , and R 2b are each hydrogen.

[0070] In some embodiments, R 1a and R 2a is hydrogen and R 1b and R 2b form a three-membered ring together with the carbon atom to which they are attached (eg, a cyclopropyl ring).

[0071] 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.

[0072] In some embodiments, X 4 CR 4 and X 5 CR 5 and X 6 CR6 and X 7 CR 7 It is.

[0073] 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.

[0074] In some embodiments, R 5 and R 6 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, cyano, -COOR x , -CON(R y )2, and -SO2R z In some embodiments, R 5 and R 6 are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylthio, haloC1-C4 alkyl, haloC1-C4 alkoxy, hydroxy, halo, and C1-C4 alkylamino. 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 selected from C1-C4 alkyl, C1-C4 alkoxy, and halo. 5 and R6 are each independently selected from methyl, ethyl, n-propyl, methoxy, ethoxy, fluoro, chloro, and bromo. In some embodiments, R 5 and R 6 are each independently selected from C1-C4 alkoxy. 5 and R 6 are each methoxy.

[0075] 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.

[0076] 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 selected from hydrogen and C1-C6 alkyl. 1 is NH. In some embodiments, X 1 is NR w and R w is methyl. In some embodiments, X 1 is S.

[0077] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0078] In some embodiments, Z is a moiety of formula (a). 10is C1-C6 alkyl. In some embodiments, R 10 is methyl. In some embodiments, Z is a moiety of the formula: [ka]

[0079] In some embodiments, Z is a moiety of formula (b).

[0080] In some embodiments, A is phenyl or a monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P. In some embodiments, A is phenyl or a monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, A is phenyl or a monocyclic heteroaryl having one heteroatom independently selected from N, O, and S. In some embodiments, A is selected from phenyl, pyridyl, furan, and thiophene. In some embodiments, A is phenyl. In some embodiments, R 20 is hydrogen. In some embodiments, A is phenyl and R 20 is hydrogen.

[0081] In some embodiments, B is a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P. In some embodiments, B is a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, B is a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl having 1, 2, 3, or 4 nitrogen atoms. In some embodiments, B is a pyrazolopyrimidine. In some embodiments, -R 21 and B is independently halo, C1-C4 alkyl, C1-C4 haloalkyl, -OR e1, -N(R e2 )(R e3 ), -SO2R e4 , -SO2N(R e5 )(R e6 ), and -NHSO2R e7 and R e1 , R e2 , R e3 , R e4 , R e5 , R e6 , and R e7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. 21 In addition, B is halo, C1-C4 alkyl, C1-C4 haloalkyl, -OR e1 , -N(R e2 )(R e3 ), -SO2R e4 , -SO2N(R e5 )(R e6 ), and -NHSO2R e7 In some embodiments, -R 21 In addition, B is halo, methyl, trifluoromethyl, -OR e1 , -N(R e2 )(R e3 ), -SO2R e4 , -SO2N(R e5 )(R e6 ), and -NHSO2R e75 and R e1 , R e2 , R e3 , R e4 , R e5 , R e6 , and R e7 are each independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, and trifluoromethyl.

[0082] In some embodiments, R 21 is selected from hydrogen and groups of the formula: [ka]

[0083] In some embodiments, L b is -(CR c1 R c2 ) m -G b m is 0, 1, or 2; R c1 and R c2 is independently selected from hydrogen and methyl; G b is a bond, -NHC(O)-, -NH-, -O-, or -S-. In some embodiments, L b has a formula selected from the following: [ka]

[0084] In some embodiments, the moiety of formula (b) is a moiety of formula (bi): [ka] A, Q, R 20 , and R 21 is any of the groups defined and described herein.

[0085] In some embodiments, the moiety of formula (b) is: [ka]

[0086] The compounds of formula (I) include a linker moiety, L. In some embodiments, L provides sufficient distance between the two elements of the compound (i.e., the STING agonist moiety and the group Z, which is either a group of formula (a) (IDO1 inhibitor) or a group of formula (b) (PI3K agonist)) to allow each to function unhindered (or minimally hindered) by binding to the other. In some embodiments, L separates the two groups by about 5 Å to about 1000 Å. In some embodiments, L separates the two groups by 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, 1000 Å, or any suitable range therebetween (e.g., 5-100 Å, 50-500 Å, 150-700 Å, etc.). In some embodiments, L separates the two groups by 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.)).

[0087] L can include one or more groups independently selected from -C(R')-, -CH=CH-, -C≡C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)-, arylene, heteroarylene, cycloalkylene, and heterocyclylene, where each R' is independently hydrogen, C-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80and selected from alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and lipid moieties, where each alkyl, arylene, heteroarylene, cycloalkylene, and heterocyclylene is independently unsubstituted or substituted with 1, 2, or 3 substituents. In some embodiments, L comprises one or more groups independently selected from -C(R')2-, -C≡C-, -O-, -NH-, -C(O)-, and heteroarylene (e.g., a 5-membered heteroarylene having 1, 2, or 3 nitrogen atoms), where each R' is independently selected from hydrogen, C1-C 40 and selected from alkyl, phenyl, and -CH2-heterocyclyl (e.g., heterocyclyl is a 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S), wherein phenyl and heterocyclyl are each independently unsubstituted or substituted with 1 or 2 substituents.

[0088] In some embodiments, L comprises one or more -(CH2CHO)-(oxyethylene) groups, e.g., 1 to 20 -(CH2CHO)- groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 -(CH2CHO)- groups, or any range therebetween). In some embodiments, L is -(CH2CHO)-, -(CH2CHO)2-, -(CH2CHO)3-, -(CH2CHO)4-, -(CH2CHO)5-, -(CH2CHO)6-, -(CH2CHO)7-, -(CH2CHO)8-, -(CH2CHO)9-, or -(CH2CHO) 10 - group.

[0089] In some embodiments, L is one or more alkylene groups (e.g., -(CH) n-, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). In some embodiments, L comprises one or more branched alkylene groups. In some embodiments, L comprises at least one -C(O)NH- group. In some embodiments, L comprises at least one -O- group. In some embodiments, L comprises at least one 5-membered heteroarylene group having 2 or 3 nitrogen atoms (e.g., a group of the formula [ka] The group

[0090] In some embodiments, the group -X 1 -L- together form a group of the formula -O-(CR'2) n -O-, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and each R' is independently hydrogen, C-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 In some embodiments, L is selected from alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and lipid moieties, where each alkyl, arylene, heteroarylene, cycloalkylene, and heterocyclylene is independently unsubstituted or substituted with 1, 2, or 3 substituents. In some embodiments, L is represented by the formula -O-(CR'2) n -O-, n is 1, 2, 3, 4, or 5, and one R' is C-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 is selected from alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, and the remaining R's are all hydrogens.

[0091] In some embodiments, L includes one or more substituents, pendants, side chains, etc., including any suitable organic functional group (e.g., -OH, -NH2, -SH, -CN, =O, =S, halogens (e.g., -F, -Cl, -Br, -I), -COOH, -CONH2, -CH3, etc.).

[0092] In some embodiments, the group -X 1 -L- taken together have a formula selected from the following: [ka]

[0093] In some embodiments, the compound of formula (I) comprises a lipid moiety having at least 8 carbon atoms. For example, in some embodiments, R 3 , R 4 , R 5 , R 6 , and R 7 One of the groups is -YR 8 and R 8 is a lipid moiety having at least 8 carbon atoms. In some embodiments, the linker group L includes a lipid moiety (e.g., as part of the group -C(R')2-), where one R' is a lipid moiety.

[0094] 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.

[0095] In some embodiments, the lipid moiety is a C8-C 80Alkyl, C8-C 80 Alkenyl, C8-C 80 Alkynyl, C8-C 80 Heteroalkyl, C8-C 80 Heteroalkenyl, and C8-C 80 heteroalkynyl, each of which is optionally substituted with one or more substituents selected from hydroxy and amino.

[0096] For example, in some embodiments, the lipid moiety is a C8-C 80 Alkyl and C8-C 80 In some embodiments, the lipid moiety is selected from the group consisting of C8-C alkenyl. 40 Alkyl and C8-C 40 In some embodiments, the lipid moiety is selected from 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 8is a lipid moiety and Y is -C(O)O-, the lipid moiety is derived from a saturated or unsaturated fatty alcohol. In some embodiments, the lipid moiety is 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-(2-methyl-2-phenylpropanedi ... -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), ol), γ-linolenyl alcohol ((6E,9E,12E)-octadeca-6,9,12-trien-1-ol), eleostearyl alcohol (octadeca-9,11,13-trien-1-ol), icosa-5,8,11-trien-1-ol, icosa-13-en-1-ol, icosa-11,14-17-trien-1-ol, octadeca-6,9,12,15-tetraen-1-ol, arachidyl alcohol, Donyl 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.

[0097] In some embodiments, the lipid moiety is a C8-C 80 Heteroalkyl, C8-C 80 Heteroalkenyl, and C8-C 80 In such embodiments, the lipid moiety may be derived from a lipid that includes one or more heteroatom groups (e.g., -O-, -NH-, -C(O)-, etc., or combinations thereof (e.g., -C(O)O- groups).

[0098] For example, in some embodiments, the lipid moiety 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 C6-C 40 Alkyl, C6-C 40 Alkenyl, C6-C 40 Heteroalkyl and C6-C 40 heteroalkenyl).

[0099] 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.

[0100] In some embodiments, R a and R b are each independently C6-C 40 Alkyl and C6-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.

[0101] In some embodiments, the lipid moiety 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 C6-C 40 Alkyl and C6-C 40 alkenyl, R b is C6-C 40 Alkyl, C6-C 40 Alkenyl, C6-C 40 Heteroalkyl and C6-C 40 heteroalkenyl).

[0102] 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.

[0103] 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.

[0104] In some embodiments, R a1 is C6-C 24 Alkyl or C6-C 24 In some embodiments, R is alkenyl. a1is C9-C 22 Alkyl and C9-C 22 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 are linear or branched C6, C7, C8, 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 a1 are linear or branched C6, C7, C8, 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 is selected from linoleyl, n-nonyl, n-undecyl, henicosan-11-yl, pentadecan-7-yl, and heptadecan-9-yl.

[0105] In some embodiments, R b is C6-C 40 Alkyl and C6-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.

[0106] In some embodiments, the lipid moiety 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 C6-C 40 Alkyl and C6-C 40 alkenyl).

[0107] In some embodiments, the lipid moiety has formula (D). In some embodiments, the lipid moiety has formula (E). In some embodiments, the lipid moiety 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.

[0108] 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.

[0109] In some embodiments, R a1 and R a2 are each independently C6-C 24 Alkyl and C6-C24 In some embodiments, R is selected from the group consisting of alkenyl and aryl. a1 and R a2 are each independently C9-C 22 Alkyl and C9-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 C6, C7, C8, 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 a1 and R a2 are each independently a linear or branched C6, C7, C8, 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.

[0110] In some embodiments, the lipid moiety is derived from a steroid, for example, in some embodiments, the lipid moiety is derived from cholesterol, beta cholesterol, or BHEM cholesterol.

[0111] In some embodiments, the lipid moiety is selected from the following: [ka] [ka] [ka]

[0112] In some embodiments, the compound of formula (I) is selected from: [ka] and pharma- ceutically acceptable salts thereof.

[0113] Other compounds of formula (I) include: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0114] Also, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof is disclosed herein, wherein: R 1a , R 1b , R 2a , R 2b , R 1a’ , R 1b’ , R 2a’ , and R 2b’are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, haloC1-C4 alkyl, aminoC1-C4 alkyl, hydroxyC1-C4 alkyl, C1-C4 alkoxyC1-C4 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, and cyano; R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b optionally, taken together with the carbon atom(s) to which they are attached, form an optionally substituted 3- to 6-membered ring; R 1a’ and R 1b’ , or R 1a’ and R 2a’ , or R 2a’ and R 2b’ optionally taken together with the carbon atom(s) to which they are attached form 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, 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 , R 7 , R 3’ , R 4’ , R5’ , R 6’ , and R 7’ are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, haloC1-C6 alkyl, haloC1-C6 alkoxy, aminoC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, halo, hydroxy, amino, C1-C4 alkylamino, diC1-C4 alkylamino, cyano, -COOR x , -CON(R y )2, -SO2R 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 atom to which they are attached, an optionally substituted 5- or 6-membered ring; 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 selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and haloC1-C6 alkyl; L, L', and L 2 are each independently a linker, Z and Z′ are each independently a moiety of formula (a) or formula (b): [ka] R 10 is hydrogen or C1-C6 alkyl; [ka] Q is CH or N; A is aryl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P; R 20 is hydrogen, halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, -OR a1 , -N(R a2 )(R a3 ), -SO2R a4 , -SO2N(R a5 )(R a6 ), and -NHSO2R a7 Selected from R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , and R a7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 21 is hydrogen and the group -L 21 -E is selected from L 21 is a bond, C1-C2 alkylene, -CH=CH-, -C≡C-, -C(O)-, -O-, -NH-, -S-, -C(O)O-, -C(O)NH-, -C(O)S-, arylene, cycloalkylene, heteroarylene, or heterocyclylene; 21 includes a combination of any two of these groups, E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-4 alkyl, C1-C4 haloalkyl, oxo, -OR b1 , -N(R b2 )(R b3 ), -SO2R b4 , -SO2N(R b5 )(R b6 ), and -NHSO2R b7 and R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , and R b7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L b is -(CR c1 R c2 ) m -G b - and R c1 and R c2 is independently selected from hydrogen and C1-C4 alkyl; m is 0, 1, or 2; G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is independently halo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, optionally substituted aryl, -OR d1 , -N(R d2 )(R d3 ), -SO2R d4 , -SO2N(R d5 )(R d6 ), and -NHSO2R d7 and R d1 , R d2 , R d3 , Rd4 , R d5 , R d6 , and R d7 are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0115] In formula (I), the group [ka] Compounds that contain other STING agonists instead of are also within the scope of the disclosure.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.

[0116] Certain compounds disclosed herein (e.g., in the Examples) may have additional single or dual function activity (e.g., activity as a PI3K inhibitor or activity as a dual function PI3K-IDO compound). For example, certain compounds prepared as intermediates in the Examples herein have individual activity as PI3K inhibitors, including, but not limited to, the following compounds: [ka] The present disclosure is also intended to encompass such compounds, along with their pharma- ceutically acceptable salts, their pharmaceutical compositions, and their methods of use.

[0117] 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.

[0118] It should be understood that the compounds may have tautomeric and geometric isomeric forms and that these also constitute embodiments of the present disclosure.

[0119] 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. 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 analogous to those described in the accompanying Examples, using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents.

[0120] 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 provide the salts. 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.

[0121] 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.

[0122] 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.

[0123] 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) (incorporated herein by reference in its entirety). Synthesis of the compounds of the present disclosure can be accomplished by methods similar to those described in the above synthetic schemes and specific examples.

[0124] 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).

[0125] 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.

[0126] 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.

[0127] 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).

[0128] 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.

[0129] 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.

[0130] 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 composition 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, aural, ocular, liposome delivery system, or iontophoresis).In some embodiments, the composition is for oral administration.

[0131] 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.

[0132] 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%.

[0133] 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%.

[0134] 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%.

[0135] 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%.

[0136] 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%.

[0137] 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%.

[0138] 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%.

[0139] 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%.

[0140] 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%.

[0141] Suitable glidants include silicon dioxide. The amount of lubricant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0142] 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%.

[0143] 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%.

[0144] 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%.

[0145] 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%.

[0146] 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).

[0147] 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 dosage compositions contain about 50% to about 95%, more specifically about 50% to about 75% of carrier.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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).

[0156] 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.

[0157] 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.

[0158] 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%.

[0159] 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%.

[0160] 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%.

[0161] 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%.

[0162] The amount of thickening agent(s) in a topical composition is typically from about 0% to about 95%.

[0163] 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%.

[0164] 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%.

[0165] Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0166] B. Albumin composition The present disclosure 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.

[0167] 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.

[0168] 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).

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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 amines, secondary amines, 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).

[0174] 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.

[0175] Sterols may include cholesterol, fecosterol, ergosterol, campesterol, sitosterol, stigmasterol, brassicasterol, or sterol esters (eg, cholesteryl hemisuccinate, cholesteryl sulfate), or any other derivative of cholesterol.

[0176] 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.

[0177] 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).

[0178] 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.

[0179] 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).

[0180] 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.

[0181] d. Additional Formulations 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.

[0182] In some embodiments, the disclosed compounds are incorporated into polymeric drug delivery systems formed from polymers of natural substances (e.g., polyarginine, chitosan, dextrin, polysaccharides, poly(glycolic acid), poly(lactic acid), and hyaluronic acid) or synthetic polymers (e.g., poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(ethyleneimine), dendritic polymers, etc.). The 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.

[0183] In some embodiments, the disclosed compounds are incorporated into organic nanoparticles formed from peptides, proteins, nucleic acids, or any combination thereof.

[0184] In some embodiments, the disclosed compounds are incorporated into inorganic nanoparticles formed from silica, gold, silver, iron, and the like.

[0185] 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 interference RNA, an antisense, and an antigen nucleic acid), a decongestant, a steroid, an analgesic, an antimicrobial agent, an immunotherapy, or a combination thereof. In some embodiments, the at least one additional therapeutic agent is selected from a chemotherapeutic agent, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a Stat3 inhibitor, a TLR agonist, a PD-1 or PD-L1 antibody, and a phosphatidylinositol 3 kinase (PI3K) inhibitor (e.g., a class IPI3K inhibitor, an isoform-selective PI3K inhibitor).

[0186] 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).

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] In other embodiments, the at least one additional therapeutic agent is an siRNA. The siRNA can selectively knock down or down regulate 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 include a sequence that is complementary to the mRNA sequence that codes for the gene or protein of interest. In some embodiments, the siRNA can be an immunomodulatory siRNA.

[0192] 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.

[0193] PI3K inhibitors may target any class of PI3K, including class I (e.g., IA and IB), class II, or class III. In some embodiments, the PI3K inhibitor is a compound disclosed herein. In some embodiments, the PI3K inhibitor includes isoform-selective PI3K inhibitors, dual pan-class I PI3K / m-TOR inhibitors, and pan-class I PI3K inhibitors without significant m-TOR activity. PI3K inhibitors useful in the present compositions and methods include, but are not limited to, IPI-549, idelalisib, copanlisib, duvelisib, alpelisib, leniolisib, umbralisib, buparlisib, taselisib, pictilisib, PX-886, piralalisib, BEZ235, GSK2126458, GSK2636771, AZD8186, SAR260301, gedatolicib, apitolisib, PQR309, MLN1117, and perifosine.

[0194] f. 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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).

[0202] 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.

[0203] 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.

[0204] 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.

[0205] Suitable adjuvants are commercially available, for example, as glucopyranosyl lipid adjuvant (GLA); Pam3CSK4; Freund's incomplete and complete adjuvant (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(SO4)2, AlNa(SO4)2, AlNH4(SO4), and Al(OH)3); calcium salts (e.g., Ca3(PO4)2); iron or zinc; insoluble suspensions of acylated tyrosines; 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 such as 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 include a protein fragment that contains at least the immunostimulatory portion of the molecule.

[0206] 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.

[0207] 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).

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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).

[0213] 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.

[0214] The disease or disorder may include cancer, autoimmune diseases, inflammatory diseases, and infectious diseases.

[0215] 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.

[0216] 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, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITH), and / or other conditions. 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 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.

[0217] 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, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis, and inverse psoriasis. Some autoimmune disorders are also associated with immune dysregulation diseases (e.g., sinus pulmonary infection, opportunistic pneumonia, inflammatory bowel disease, autoimmune hepatitis, and juvenile idiopathic arthritis, as well as myelofibrosis).

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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).

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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 related to administration of another therapeutic agent.Such second therapies include, but are not limited to, surgery, immunotherapy, and radiation therapy.

[0228] 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.

[0229] 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.

[0230] 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, an immunotherapy, or a combination thereof.

[0231] 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).

[0232] 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.

[0233] 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.

[0234] 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).

[0235] 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).

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 6. Working Example Abbreviations used in the schemes and examples below are as follows: Boc is tert-butyloxycarbonyl; BocO is di-tert-butyl dicarbonate; 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; RT or rt is room temperature; THF is tetrahydrofuran.

[0244] All air- and moisture-sensitive manipulations were carried out under argon or in vacuum using standard Schlenk techniques. Anhydrous solvents (Et2O, 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.

[0245] 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).

[0246] NMR spectra 1 H(300MHz), 13C (75 MHz) were recorded on an ARX300 or Avance II 500 Bruker spectrometer, respectively. Chemical shifts (δ, ppm) are given relative to residual 1H or 13C of the deuterated solvent in the solvents indicated (CDCl37.26, 77.00; (CD3)2CO 2.05, 29.84, and 206.26, (CD3)2SO 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 multiplicity of the proton spectra: s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, m: multiplet, br.: broad, dd: doublet, dt: doublet. Coupling constants (J) are reported in Hertz (Hz). Some signals that could not be assigned will be designated as ArH (aromatic hydrogen).

[0247] 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).

[0248] Example 1 Compound synthesis

[0249] General Procedure 1: Esterification Under nitrogen atmosphere, a solution of the carboxylic acid derivative (1 eq.), EDC hydrochloride (1 eq.), and DMAP (0.5 eq.) in dry THF (0.1 M) was stirred at 0° C. for 0.5 h. Then, a solution of alcohol (1 eq.) in dry THF (0.1 M) was added. The solution was stirred at 0° C. to room temperature for 16 h. The progress of the reaction was monitored by TLC using a mixture of CH2-Cl2-MeOH (10:1) as eluent 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, saturated aqueous NaHCO3, and brine, respectively. The solid residue was then purified by manual column chromatography using CH2Cl2-EtOAc or CH2Cl2-MeOH stepwise gradient solvent systems as eluents to give the title product.

[0250] The synthesis of the dual functional compounds used the general esterification procedure described above in the following steps.

[0251] 3-((1-methyl-L-tryptophyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka] Step 1: α -(tert-Butoxycarbonyl)-1-methyl-D-tryptophan. A solution of 1-methyl-D-tryptophan (1 eq.) in anhydrous DCM was treated with trimethylamine (2.5 eq.) and Boc2(O) (1.05 eq.) at 0° C. to room temperature for 16 h. The mixture was washed with 1N aqueous HCl and brine to give the desired product.

[0252] Step 2: 3-Hydroxypropyl N α (tert-Butoxycarbonyl)-1-methyl-D-tryptophanate. N αThe title compound was synthesized from -(tert-butoxycarbonyl)-1-methyl-D-tryptophan (1 equivalent), 1,2-tetradecanediol (1.2 equivalents), EDC hydrochloride (1 equivalent), and DMAP (0.5 equivalents) at room temperature for 4 hours.

[0253] Step 3: 3-((N α -(tert-butoxycarbonyl)-1-methyl-D-tryptophyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate. 3-Hydroxypropyl N α The title compound was synthesized from (tert-butoxycarbonyl)-1-methyl-D-tryptophanate (1 equivalent), 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (1 equivalent), EDC hydrochloride (1 equivalent), and DMAP (0.5 equivalent) at room temperature for 4 hours.

[0254] Step 4: 3-((1-methyl-D-tryptophyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutane. 3-((N α The title compound was synthesized from -(tert-butoxycarbonyl)-1-methyl-D-tryptophyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (1 equivalent).

[0255] (R)-2-(4-(3-(1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-1H-1,2,3-triazol-1-yl)ethyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (DMA01-166) [ka] Synthesis of DMA01-148: To a solution of (S)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) and 2-azidoethanol (38.83 mg, 0.44 mmol) in CHCl (3 mL), CuI.A-21 catalyst (16.5 mg, 10 mol%) was added. The reaction mixture was sonicated for 1 h and stirred overnight at room temperature. Upon completion of the reaction, the catalyst was filtered using CHCl and the solvent was evaporated under vacuum. The crude product was then purified by column chromatography to give compound DMA01-148 (95 mg, 80% yield). 1 H NMR (500 MHz, CDCl3) δ 8.44 (dd, J = 23.4, 5.4 Hz, 2H), 8.03 - 7.83 (m, 2H), 7.74 (d, J = 7.4 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.54 - 7.35 (m, 5H), 6.80 (dd, J = 6.5, 4.4 Hz, 1H), 6.71 (s, 1H), 4.80 (p, J = 6.8 Hz, 1H), 4.46 - 4.25 (m, 2H), 3.89 (t, J = 4.9 Hz, 2H), 1.41 (d, J = 6.8 Hz, 3H).

[0256] Synthesis of DMA01-166 (esterification): A solution of 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (48.27 mg, 0.16 mmol) and EDC hydrochloride (28.65 mg, 0.15 mmol) in DMF (3 mL) was stirred at 0° C. for 0.5 h. DMA01-148 (80 mg, 0.15 mmol) and DMAP (18.25 mg, 0.15 mmol) were added and the reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 48 h. Upon completion of the reaction, the reaction mixture was diluted with CHCl and washed with saturated aqueous NaHCO, water, and brine, respectively. The organic layer was dried over NaSO, filtered, and concentrated under vacuum. Purification by column chromatography afforded compound DMA01-166 (90 mg, 74% yield). 1 H NMR (500 MHz, CDCl3) δ 8.48 - 8.39 (m, 2H), 8.09 (s, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.87 (dd, J = 7.5, 1.4 Hz, 1H), 7.82 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.53 - 7.36 (m, 5H), 7.22 (s, 1H), 7.18 (s, 1H), 6.81 (dd, J = 6.7, 4.4 Hz, 1H), 6.69 (s, 1H), 4.80 (p, J = 6.8 Hz, 1H), 4.59 (dd, J = 5.8, 4.3 Hz, 2H), 4.49 (t, J = 5.1 Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.26 - 3.03 (m, 2H), 2.64 (td, J = 6.6, 1.8 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H).

[0257] 2-(4-(3-((R)-1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-1H-1,2,3-triazol-1-yl)ethyl (9Z,12E)-octadeca-9,12-dienoate (DMA01-170) [ka] Synthesis of DMA01-170: Compound DMA01-170 was obtained from DMA01-148 and linoleic acid following the esterification method described above.

[0258] 2-(4-(3-((R)-1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-1H-1,2,3-triazol-1-yl)ethyl 1-methyl-D-tryptophanate (DMA01-173) [ka] Synthesis of DMA01-173: Compound DMA01-173 was prepared by esterification of DMA01-148 and N-(N-acetylglucosamine) according to the above esterification method and deprotection of Boc with HCl in dioxane. α -(tert-butoxycarbonyl)-1-methyl-D-tryptophan.

[0259] (S)-2-(4-(3-(1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-1H-1,2,3-triazol-1-yl)acetic acid (DMA01-143) [ka] Synthesis of DMA01-132: (S)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (155 mg, 0.35 mmol), ethyl azide ethyl acetate (25% in toluene, 180 μL, 0.35 mmol, 1 equiv.), and CuI (8 mg, 10 mol%) in DMSO (0.9 mL, 0.4 M) were triturated in an ultrasonic bath for 0.5 h and then heated to 60 °C overnight, followed by column purification (SiO, CHCl-MeOH (97:3)) to give the desired product as an off-white solid (150 mg, 75% yield). 1 H NMR (300 MHz, MeOD) δ 8.66 (dd, J = 6.8, 1.6 Hz, 1H), 8.49 (dd, J = 4.5, 1.6 Hz, 1H), 8.02 (s, 1H), 7.79 - 7.27 (m, 8H), 7.00 - 6.84 (m, 2H), 5.25 (s, 2H), 4.75 (t, J = 6.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0260] Synthesis of DMA01-143: DMA01-132 (31 mg, 0.05 mmol, 1 equiv) in THF (1 mL) was treated with an aqueous solution of LiOH (2 mg, 0.08 mmol, 1.5 equiv) and NaCl (5 mg, 0.081 mmol, 1.5 equiv) in HO (0.3 mL). Methanol (0.3 mL) was added to the mixture and the reaction was stirred at room temperature overnight, after which pTLC purification (SiO, CHCl-MeOH (9:1), time required: 18 h) afforded the desired product as an off-white solid (5 mg, 17% yield). 1H NMR (300 MHz, MeOD) δ 8.70 (dd, J = 6.7, 1.7 Hz, 1H), 8.51 (dd, J = 4.5, 1.6 Hz, 1H), 8.21 (d, J = 7.0 Hz, 1H), 7.95 (s, 1H), 7.78 - 7.69 (m, 2H), 7.69 - 7.61 (m, 1H), 7.58 - 7.31 (m, 5H), 7.02 - 6.91 (m, 2H), 5.49 (s, 2H), 4.79 (t, J = 6.9 Hz, 1H), 1.47 (d, J = 6.7 Hz, 3H).

[0261] 1-(4-(3-((R)-1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-1H-1,2,3-triazol-1-yl)propan-2-yl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (SH-233) [ka] SH-233 was synthesized in a manner similar to that shown in DMA01-166 above, using 2-azidopropan-1-ol instead of 2-azidoethanol. 1H NMR (500 MHz, cdcl3) δ 8.44 (dd, J = 14.6, 5.7 Hz, 2H), 8.15 - 7.57 (m, 5H), 7.54 - 7.32 (m, 7H), 7.25 - 7.10 (m, 3H), 6.81 (t, J = 5.7 Hz, 1H), 6.67 (t, J = 6.1 Hz, 1H), 5.57 (s, 2H), 4.83 - 4.74 (m, 1H), 4.40 (dd, J = 14.6, 6.6 Hz, 1H), 4.00 - 3.95 (m, 3H), 3.95 - 3.90 (m, 3H), 3.64 (s, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.12 - 2.99 (m, 1H), 2.60 (q, J = 6.8 Hz, 1H), 1.39 (dd, J = 9.6, 7.0 Hz, 6H).

[0262] Example 2 STING activation by dual-function NCE. The THP-1 ISG Blue cell assay is a standard assay to test STING activation in vitro. DMA01-166 showed enhanced interferon signals compared to the control and cGAMP groups. DMA01-166 showed similar STING activation compared to MSA-2 and ADU, both of which are potent STING agonists (Figure 1). In contrast, DMA01-173 did not stimulate STING activation. Different concentrations of DMA01-166 (Figure 2) and MSA-2 (Figure 3) were incubated with THP-1 ISG Blue cells for 24 hours. Both DMA01-166 and MSA-2 showed similar dose-independent STING activation effects.

[0263] Example 3 Activation of bone marrow dendritic cells (BMDCs) by dual-function NCEs. STING activation leads to the activation of BMDCs. To test the BMDC activation ability of DMA01-166, BMDC activation was measured based on the upregulation of CD80 and CD86 by flow cytometry. DMA01-166 showed similar STING activation compared to MSA-2 (Figure 4). In contrast, DMA01-173 did not stimulate DC activation. Different concentrations of DMA01-166 were incubated with BMDC cells for 24 hours. DMA01-166 showed a dose-independent BMDC activation effect (Figure 5).

[0264] Example 4 mIFNβ secretion induced a dual-function NCE. STING activation in BMDCs resulted in mIFNβ secretion. DMA01-166 showed higher mIFNβ secretion compared to MSA-2 (Figure 6). In contrast, DMA01-173 cannot enhance mIFNβ secretion. Different concentrations of DMA01-166 (Figure 7) were incubated with BMDC cells for 24 hours. DMA01-166 showed a dose-independent BMDC activation effect.

[0265] Example 5 Macrophage polarization by dual-function NCE. Both STING activation and PI3K inhibition induced macrophage polarization from M2 to M1 phenotype and caused higher TNFα secretion compared to four well-studied compounds (IPI-549, MSA-2, ADU, and cGAMP) for their efficacy on macrophage polarization (Figure 8). DMA01-173 and DMA01-170 also showed macrophage polarization effects compared to the M2 control group (Figure 8). We further tested the macrophage polarization effects of the dual-function NCEs by first inducing RAW264.7 cells into M2 macrophages and then treating them with various drugs to test the percentage of M1 macrophages among all macrophages. DMA01-166 induced a higher percentage of M1 macrophages compared to IPI-549, cGAMP, ADU, and MSA-2. DMA01-173 and DMA01-170 also showed modest effects on increasing the proportion of M1 (Figure 9).DMA01-166 showed dose-independent macrophage polarizing effects (Figure 10).

[0266] Example 6 PI3K inhibition by dual-function NCEs. PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ binding assay kits were obtained from BPS Bioscience (San Diego, CA, USA). The assays were performed in 96-well microplates according to the manufacturer's protocol. Briefly, 5 μL of PI3K lipid substrate was added to all wells. Then, 5 μL of different concentrations of IPI-549, DMA01-148, 143, 132, or 166 were added, followed by 5 μL of ATP (12.5 μM). The reaction was initiated by adding 10 μL of PI3Kα (0.5 ng / μL), PI3Kβ (4 ng / μL), PI3Kγ (4 ng / μL), or PI3Kδ1 (3 ng / μL). The plates were carefully shaken and the reaction mixture was incubated at 30° C. for 40 min. Next, 25 μL of ADP-Glo ​​reagent (Promega, Madison, WI, USA) was added to each well and the reaction was carried out in the dark for 45 min. Finally, 50 μL of Kinase Detection Reagent (Promega, Madison, WI, USA) was added to each well and the reaction was carried out in the dark for 30 min. The luminescence of the reaction mixture was read on a Synergy2 microplate reader (Biotek).

[0267] Inhibition of different isoforms of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ by IPI-549, DMA01-148, DMA01-143, DMA01-132, DMA01-166, DMA01-170, and DMA01-173 was tested (Figure 11). Prism8 was used to calculate the IC50 of the compounds against the different PI3K isoforms (Table 1). DMA01-148 selectively inhibited PI3Kγ with similar efficacy compared to IPI-549. DMA01-143 and DMA01-132 inhibited both PI3Kγ and PI3Kδ. DMA01-166 showed no effect on PI3Kα and PI3Kβ, but inhibited both PI3Kγ at 349 nM. [Table 1]

[0268] Example 7 DMA01-166 Nanoformulation DMA01-166 was dissolved in 1 mL of chloroform (organic phase) and added dropwise to human serum albumin (66 kDa) dissolved in 20 mL of milli-Q water (aqueous phase) to obtain a milky emulsion using a rotor-stator homogenizer. Crude Nano-166 emulsion was obtained after six cycles of low pressure (20000 psi) in a high-pressure homogenizer (Nano DeBEE). The organic solvent was removed in a rotary evaporator at 25°C. The resulting Nano-PI suspension was filtered through a 0.22 μm strainer and then freeze-dried to obtain a dry powder for long-term storage at -20°C. The size of Nano-166 is about 120 nm and the PDI is less than 0.2 (tested by dynamic light scattering (DLS)). The size measured by TEM is less than 100 nm. Nano-166 remains stable even after 10,000-fold dilution (Figure 12).

[0269] The in vivo efficacy of DMA01-166 and its albumin nanoformulation was tested in the KPC transgenic model. DMA01-166 with PD-1 antibody (D166+PD-1) shows a longer median survival time (185.5 days) compared to DMA01-166 (D166 157.5 days) or PD-1 alone (PD-1 132.5 days). Nano-D with PD-1 antibody (Nano-D+PD-1) shows the longest median survival time (185.5 days). Addition of the albumin nanoformulation of paclitaxel (Nano-P) did not change the median survival time (Figure 13).

[0270] 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.

[0271] 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, X 1 O, NR w Selected from , S, and combination, R 1a 、 R 1b 、 R 2a 、 and R 2b 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 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b may optionally form a 3- to 6-membered ring, 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 - and -C(O)S- are selected, 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 L is a linker, Z is a part of equation (a) or equation (b), 【Chemistry 2】 R 10 is hydrogen, or C 1 -C 6 It is alkyl, 【Transformation 3】 Q is either CH or N, A is a 5-membered or 6-membered monocyclic heteroaryl having aryl or 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P. R 20 is hydrogen, halo, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Haloalkyl, -OR a1 , -N(R a2 ) (Caution a3 ), -SO 2 R a4 , -SO 2 N(R) a5 ) (Caution a6 ), and -NHSO 2 R a7 Selected from, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , and R a7 These are, independently, hydrogen and C 1 -C 4 Alkyl and C 1 -C 4 Selected from haloalkyls, R 21 is hydrogen and group-L 21 - Selected from E, L 21 C 1 -C 2 Alkylene, -CH=CH-, -C≡C-, -C(O)-, -O-, -NH-, -S-, -C(O)O-, -C(O)NH-, -C(O)S-, arylene, cycloalkylene, heteroarylene, or heterocyclylene, or L 21 This includes any two combinations of those groups, E is a bicyclic heterocyclyl or bicyclic heteroaryl, and each of these is a halo, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl-C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, oxo, -OR b1 , -N(R b2 ) (Caution b3 ), -SO 2 R b4 , -SO 2 N(R) b5 ) (Caution b6 ), and -NHSO 2 R b7 R is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above, b1 , R b2 , R b3 , R b4 , R b5 , R b6 , and R b7 These are, independently, hydrogen and C 1 -C 4 Alkyl and C 1 -C 4 Selected from haloalkyls, L b is, -(CR c1 R c2 ) m -G b - and R c1 and R c2 These are, independently, hydrogen and C 1 -C 4 Selected from alkyl groups, m is 0, 1, or 2. G b These are bonds, -NHC(O)-, -NH-, -O-, or -S-, B is a bicyclic heteroaryl or bicyclic heterocyclil, each of which is a halo, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Haloalkyl, optionally substituted aryl, -OR d1 , -N(R d2 ) (Caution d3 ), -SO 2 R d4 , -SO 2 N(R) d5 ) (Caution d6 ), and -NHSO 2 R d7 R is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above, d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 These are, independently, hydrogen and C 1 -C 4 Alkyl and C 1 -C 4 (Selected from haloalkyl groups).

2. X 4 However, CR 4 X 5 However, CR 5 X 6 However, CR 6 X 7 However, CR 7 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

4. 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.

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

6. R 1a , R 1b , R 2a , and R 2b 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.

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

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia): 【Chemistry 4】

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is the part of formula (a) and R 10 is methyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is the part of formula (b), and the part of formula (b) is the part of formula (bi): 【Transformation 5】

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

12. R 20 The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

13. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein Q is CH.

14. The part of formula (b) is 【Transformation 6】 The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

15. L is -C(R') 2 It comprises one or more groups independently selected from -, -C≡C-, -O-, -NH-, -C(O)-, and heteroarylene, where each R' is independently hydrogen, C 1 -C 40 Alkyl, phenyl, and -CH 2 - A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from a heterocyclyl (for example, the heterocyclyl is a six-membered heterocyclyl having one or two heteroatoms independently selected from N, O, and S), wherein the phenyl and the heterocyclyl are each independently unsubstituted or substituted with one or two substituents.

16. The aforementioned compound, 【Transformation 7】 The compound according to claim 1, as well as selected from pharmaceutically acceptable salts thereof.

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

18. It is a vaccine, and the effective amount A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a composition containing the same, Antigen or nucleic acid that codes for it The vaccine, including the aforementioned vaccine.

19. A pharmaceutical composition for treating or preventing a disease or disorder, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, or the vaccine described in claim 18.

20. A pharmaceutical composition for inducing or modulating an immune response or inflammatory response in a subject, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, or the vaccine described in claim 18.

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