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 conditions (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases) using the compounds or compositions thereof. In particular, disclosed herein are dual function compounds comprising an interferon (IFN) gene stimulator (STING) agonist moiety and a second active moiety selected from the group consisting of an indoleamine 2, 3-dioxygenase (IDO) inhibitor and a phosphatidylinositol 3 kinase (PI3K) inhibitor, and compositions and formulations thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 334,441, filed on April 25, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure provides dual-functional compounds, compositions, formulations, and methods for using the compounds or compositions thereof to induce or modulate immune or inflammatory responses and to treat diseases or disorders (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases). Background Art

[0004] The innate immune agonist STING (stimulator of interferon genes) binds to its natural ligand 2'3'-cGAMP (cyclic guanosine monophosphate adenosine), and then induces the expression of interferon, inflammatory factors and autophagy genes through its signaling pathway. Microbial infection, tumor DNA and self-damaged DNA are three factors that induce activation of the cGAS-STING signaling pathway, and STING is linked to the etiology of cancer, autoimmune diseases, infectious diseases and inflammatory diseases. Many natural and synthetic STING agonists have entered clinical development, especially for cancer treatment, of which the first generation showed safety but only had moderate systemic activity. Therefore, due to the poor stability of STING agonists, most of them require local delivery, which limits their practicality. Summary of the invention

[0005] In one aspect, disclosed herein is a compound of formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein:

[0008] X 1 Selected from O, NR w , S and key;

[0009] R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, halo-C1-C4-alkyl, amino-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, halo, hydroxy, amino, C1-C4-alkylamino, di-C1-C4-alkylamino and cyano; wherein R 1a and R 1b , or R1a and R 2a , or R 2a and R 2b optionally taken together with the carbon atom to which it is attached to form an optionally substituted 3 to 6 membered ring;

[0010] X 4 CR 4 or N;

[0011] X 5 CR 5 or N;

[0012] X 6 CR 6 or N;

[0013] X 7 CR 7 or N;

[0014] R 3 , R 4 , R 5 , R 6 and R 7 each independently selected from hydrogen, 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y 2. -SO2R z , oligoethylene glycol chains or polyethylene glycol chains and groups -YR 8 ; where R 4 and R 5 , R 5 and R 6 or R 6 and R 7 optionally taken together with the carbon atom to which it is attached to form an optionally substituted 5- or 6-membered ring;

[0015] Y is selected from -C(O)-, -C(O)O-, -C(O)NR v -and -C(O)S-;

[0016] R 8 is a lipid moiety having at least 8 carbon atoms;

[0017] R v , R w , R x , Ry and R z Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and halo-C1-C6-alkyl;

[0018] L is a connector; and

[0019] Z is a moiety of formula (a) or formula (b):

[0020]

[0021] Where R 10 is hydrogen or C1-C6 alkyl;

[0022]

[0023] in:

[0024] Q is CH or N;

[0025] A is aryl or a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O, S and P;

[0026] R 20 Selected from 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 , where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 and R a7 Each independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0027] R 21 Selected from hydrogen and the group -L 21 -E, where:

[0028] 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, or wherein L 21 Combinations comprising any two of such groups;

[0029] E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6-cycloalkyl-C 1-4 -alkyl, C1-C4 haloalkyl, oxo, -OR b1 、-N(R b2 )(R b3 ),-SO2R b4 、-SO2N(R b5 )(R b6 ) and -NHSO2R b7 Substituents, where R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 Each independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0030] L b For –(CR c1 R c2 ) m -G b -,in:

[0031] R c1 and R c2 independently selected from hydrogen and C1-C4 alkyl;

[0032] m is 0, 1 or 2; and

[0033] G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; and

[0034] B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from 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 Substituents, where R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0035] In some embodiments, X 4 CR 4 , X 5 CR 5 , X 6 CR 6 And X 7 CR 7 .

[0036] In some embodiments, R 4 is selected from hydrogen and halo. 4 For hydrogen.

[0037] In some embodiments, R 5 and R 6 Each is independently selected from 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y )2 and -SO2R z In some embodiments, R 5 and R 6 Each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylthio, halo-C1-C 4- Alkyl, halo-C1-C 4- alkoxy, hydroxy, halo and C1-C4-alkylamino. In some embodiments, R 5 and R 6 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo. 5 and R 6 Each is independently selected from C1-C4 alkoxy.

[0038] In some embodiments, R 7 For hydrogen.

[0039] In some embodiments, R 1a , R 1b , R 2a and R 2bEach is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl and hydroxy. 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen and C1-C4 alkyl. 1b , R 2a and R 2b is hydrogen, and R 1a is selected from hydrogen and C1-C4 alkyl. 1a and R 2a is hydrogen, and R 1b and R 2b Together with the carbon atom to which it is attached, it forms a 3-membered ring.

[0040] In some embodiments, R 3 is selected from hydrogen and halo. 3 For hydrogen.

[0041] In some embodiments, the compound is a compound of formula (Ia):

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, Z is a moiety of formula (a). 10 It's methyl.

[0045] In some embodiments, Z is a moiety of formula (b). In some embodiments, the moiety of formula (b) is a moiety of formula (bi):

[0046]

[0047] In some embodiments, A is phenyl. In some embodiments, R 20 For hydrogen.

[0048] In some embodiments, Q is CH. In some embodiments, R 21 A group selected from hydrogen and the following formula:

[0049] In some embodiments, the moiety of formula (b) is:

[0050]

[0051] In some embodiments, L comprises one or more groups independently selected from -C(R')2-, -CH=CH-, -C≡C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene, wherein each R' is independently selected from hydrogen, C1-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, and 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, wherein each R' is independently selected from hydrogen, C1-C 40 Alkyl, phenyl and -CH2-heterocyclyl (eg, wherein 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.

[0052] In some embodiments, the compound is selected from:

[0053]

[0054] and pharmaceutically acceptable salts thereof.

[0055] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed herein (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0056] In some embodiments, the composition comprises albumin nanoparticles, liposomes, micelles, or lipid nanoparticles. In some embodiments, the composition further comprises albumin nanoparticles. In some embodiments, the albumin is human serum albumin or albumin from an animal species.

[0057] In some embodiments, the composition further comprises at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent includes an immunomodulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antibacterial agent, an immunotherapy, or a combination thereof. In some embodiments, at least one additional therapeutic agent includes an RNA selected from the group consisting of: small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA) and a mixture thereof. In some embodiments, 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, one or more cell targeting epitopes are covalently linked or directly conjugated to albumin. In some embodiments, the cell targeting epitope includes an immune cell epitope. In some embodiments, the composition further comprises one or more epitopes from a microbial agent.

[0058] On the other hand, disclosed herein is a vaccine comprising an effective amount of: a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof); and an antigen or a nucleic acid encoding the same.

[0059] In some embodiments, the antigen is a tumor antigen, an autoantigen, or an infectious disease derived antigen. In some embodiments, the nucleic acid is messenger RNA (mRNA).

[0060] On the other hand, disclosed herein is a method for treating or preventing a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the disease or condition comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease. In some embodiments, the disease or condition is cancer. In some embodiments, the subject suffers from cancer, has suffered from cancer, is susceptible to cancer, or has a family history of cancer. In some embodiments, cancer comprises solid tumors or hematological cancers. In some embodiments, cancer is a metastatic cancer. In some embodiments, the method inhibits or eliminates cancer metastasis, reduces tumor growth, prevents tumor recurrence, or any combination thereof. In some embodiments, administration comprises an initial immunization and at least one subsequent immunization.

[0061] In another aspect, disclosed herein is a method of inducing or regulating an immune or inflammatory response in a subject, comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a vaccine disclosed herein (e.g., a vaccine comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the subject is 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 immunomodulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antibacterial agent, an immunotherapy, or a combination thereof.

[0062] In another aspect, disclosed herein is a use of a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a disease or condition. In some embodiments, the disease or condition comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease.

[0063] Other aspects and embodiments of the present disclosure will be apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 is a graph of STING activation by different concentrations of compounds as determined by incubation with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution and measuring OD655.

[0065] Figure 2 is a graph of STING activation by different concentrations of DMA01-166 as determined by incubation with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution and measuring OD655.

[0066] Figure 3 is a graph of STING activation by different concentrations of MSA-2 as determined by incubation with THP-1 ISG Blue cells for 24 hours, mixing with "QUANTI-Blue" solution and measuring OD655.

[0067] Figure 4Graph of BMDC activation as measured by flow cytometry based on upregulation of CD80 and CD86 following incubation of mouse bone marrow derived dendritic cells (BMDC) with varying concentrations of compounds (cGAMP (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-166 (10 μM)) for 24 hours.

[0068] Figure 5 Graph showing BMDC activation as measured by flow cytometry based on upregulation of CD80 and CD86 following incubation of mouse bone marrow derived dendritic cells (BMDC) with varying concentrations of DMA01-166 for 24 hours.

[0069] Figure 6 Is a graph of mIFNβ concentrations as measured by ELISA from supernatants of mouse bone marrow-derived dendritic cells (BMDCs) incubated with varying concentrations of compounds (cGAMP (10 μg / mL), IPI-549 (10 μM), MSA-2 (10 μM), DMA01-173 (10 μM), DMA01-166 (10 μM)) for 24 hours.

[0070] Figure 7 is a graph of mIFN[beta] concentrations as measured by ELISA from supernatants of mouse bone marrow derived dendritic cells (BMDCs) incubated with various concentrations of DMA01-166 for 24 hours.

[0071] Figure 8 Is a graph of mIFNα concentrations as measured by ELISA from supernatants of M2-polarized RAW264.7 cells incubated for 2 days with varying 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)).

[0072] Fig. 9is a graph of the ratio of M1 macrophages as determined by flow cytometry by measuring CD80 and CD86 as markers of M1 macrophages, based on incubation of M2 polarized RAW264.7 cells with varying 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)) for 2 days.

[0073] Fig.10 is a graph of the ratio of M1 macrophages as determined by flow cytometry by measuring CD80 and CD86 as markers of M1 macrophages, following incubation of M2 polarized RAW264.7 cells with various concentrations of DMA01-166 for 2 days.

[0074] Fig.11 Graph showing inhibition of different isoforms of PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ 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 the Kinase-Glo Max assay against purified enzymes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. IC50s for inhibition of different PI3K isoforms by compounds were calculated using Prism 8.

[0075] Fig.12 The size distribution diagram (left) and average diameter and PDI variation (middle) and TEM image (right) of exemplary albumin nanoformulation DMA01-166 are shown.

[0076] Fig.13 is a graph of the in vivo efficacy of exemplary albumin nanoformulations (DMA01-166 (D166) and DMA01-166 plus PD-1 antibody (D166+PD-1), with or without paclitaxel (Nano-P)) on the KPC transgenic pancreatic cancer model. DETAILED DESCRIPTION

[0077] Dual-functional compounds are described herein, which include an interferon (IFN) gene stimulator (STING) agonist portion and a second active portion selected from an indoleamine 2,3-dioxygenase (IDO) inhibitor and a phosphatidylinositol 3-kinase (PI3K) inhibitor, and compositions and formulations thereof. A portion of the disclosed molecule acts as a STING agonist, targeting the cGAS-STING pathway, which is a cytosolic DNA sensing pathway that drives activation of type I IFN and other inflammatory cytokines. Other portions of the dual-functional compound can act as a PI3K inhibitor or an IDO inhibitor, such that the compound stimulates an immune response.

[0078] The section headings used in this section and throughout the disclosure herein are for organizational purposes only and are not intended to be limiting.

[0079] 1. Definition

[0080] As used herein, the terms "comprise," "including," "having," "has," "may," "contain," and variations thereof are intended to be open transitional phrases, terms, or words that do not exclude the possibility of additional actions or structures. Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentially of" the embodiments or elements set forth herein, whether or not explicitly stated.

[0081] For the recitation of numerical ranges herein, each intermediate value with the same degree of precision is expressly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range of 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are expressly contemplated.

[0082] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms shall be clear; however, if there is any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. In addition, unless the context requires otherwise, 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.

[0083] As used herein, "treat," "treating," and the like means to slow, stop, or reverse the progression of a disease or condition when a compound or composition described herein is provided to an appropriate control subject. The term also means to reverse the progression of such a disease or condition to the extent that the symptoms are eliminated or greatly alleviated. Thus, "treating" refers to applying or administering a composition described herein to a subject, wherein the subject suffers from a disease or symptom of a disease, for the purpose of curing, healing, alleviating, alleviating, altering, remedying, improving, modifying, or affecting the disease or symptom of a disease.

[0084] A "subject" or "patient" can be human or non-human, and can include, for example, animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Likewise, patients can include adults or adolescents (e.g., children). In addition, a patient can refer to any living organism, preferably a mammal (e.g., human and non-human), that can benefit from the administration of the compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals include rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In one embodiment, the mammal is a human.

[0085] 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 to a desired site. The compound or composition can be administered by any appropriate route that results in delivery to the desired location in the subject.

[0086] As used herein, the term "vaccine" 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, which can be used to prevent or treat a disease or condition in a subject.

[0087] As used herein, the term "immunization" refers to the process of increasing an organism's response to an antigen and thereby improving its ability to resist or overcome infection.

[0088] As used herein, "polynucleotide" or "oligonucleotide" or "nucleic acid" means at least two nucleotides covalently linked together. A polynucleotide can be a DNA, a genome and cDNA, an RNA or a hybrid, wherein the polynucleotide can contain a combination of deoxyribonucleotides and ribonucleotides and a combination of bases, including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine, hypoxanthine, isocytosine and isoguanine. Nucleic acids, whether DNA or RNA, can contain non-natural nucleotides, modified nucleotides and / or non-nucleotide building blocks (building blocks) (e.g., "nucleotide analogs") that can exhibit the same functions as natural nucleotides. Nucleic acids can be obtained by chemical synthesis methods or by recombinant methods. A polynucleotide can be single-stranded or double-stranded or can contain parts of double-stranded sequences and single-stranded sequences. The depiction of a single strand also defines the sequence of a complementary strand. Therefore, nucleic acids also encompass the complementary strands of the depicted single strands. Many variants of nucleic acids can be used for the same purpose as a given nucleic acid. Therefore, nucleic acids also encompass substantially identical nucleic acids and their complementary sequences.

[0089] A "peptide" or "polypeptide" is a linked sequence of two or more amino acids linked by peptide bonds. Peptides and polypeptides include proteins, such as binding proteins, receptors, and antibodies. The terms "polypeptide" and "protein" are used interchangeably herein.

[0090] As used herein, "nucleic acid", "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 pages 793-800 (Worth Pub. 1982)). The present technology contemplates any deoxyribonucleotide, ribonucleotide or peptide nucleic acid component and any chemical variant thereof, such as methylated, hydroxymethylated or glycosylated forms of these bases, etc. The polymer or oligomer may be heterogeneous or homogeneous in composition and may be isolated from a naturally occurring source or may be artificially or synthetically produced. In addition, 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 homoduplex, heteroduplex and hybrid states. In some embodiments, the nucleic acid or nucleic acid sequence comprises other types of nucleic acid structures, such as, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholino nucleic acids (see, for example, Braasch and Corey, Biochemistry, 41(14):4503-4510 (2002)) and U.S. Pat. No. 5,034,506), locked nucleic acids (LNAs; see Wahlestedt et al., Proc. Natl. Acad. Sci. USA, 97:5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, J. Am. Chem. Soc., 122:8595-8602 (2000)) and / or ribozymes. Therefore, the term "nucleic acid" or "nucleic acid sequence" may also encompass chains comprising non-natural nucleotides, modified nucleotides, and / or non-nucleotide building blocks (e.g., "nucleotide analogs") that may exhibit the same functions as natural nucleotides; in addition, as used herein, the term "nucleic acid sequence" refers to oligonucleotides, nucleotides, or polynucleotides, 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 represent sense or antisense strands. The terms "nucleic acid," "polynucleotide," "nucleotide sequence," and "oligonucleotide" are used interchangeably. It refers to a polymeric form of nucleotides (deoxyribonucleotides or ribonucleotides, or analogs thereof) of any length.

[0091] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic table, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional parts and reactivity are described in the following: Sorrell, Organic Chemistry, 2nd edition, University Science Books, Sausalito, 2006; Smith, March's Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7th edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rd edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987; The entire contents of each of them are incorporated herein by reference.

[0092] The term "alkyl" as used herein refers to a straight or branched saturated 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-dimethylpent-2-yl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl.

[0093] 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 may be located at any position of the hydrocarbon chain. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0094] As used herein, the term "alkynyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The triple bond may be located at any position of the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, and butynyl.

[0095] As used herein, the term "alkoxy" 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.

[0096] As used herein, the term "alkoxyalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced by an alkoxy group as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, methoxymethyl.

[0097] As used herein, the term "alkylthio" 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.

[0098] As used herein, the term "amino" refers to a -NH2 group. As used herein, the term "alkylamino" refers to a group -NHR, wherein R is an alkyl group as defined herein. As used herein, the term "dialkylamino" refers to a group -NR2, wherein each R is independently an alkyl group as defined herein.

[0099] As used herein, the term "aminoalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced by an amino group.

[0100] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl can be monocyclic, bicyclic, bridged, fused or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl and bicyclo[5.2.0]nonyl.

[0101] As used herein, the term "cyano" refers to a group of formula -CN.

[0102] As used herein, the term "halogen" or "halo" means F, Cl, Br or I.

[0103] The term "haloalkyl" as used herein refers to an alkyl as defined herein, wherein at least one hydrogen atom (e.g., one, two, three, four, five, six, seven, or eight hydrogen atoms) is replaced by halogen. In some embodiments, each hydrogen atom of the alkyl is replaced by 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.

[0104] 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.

[0105] As used herein, the term "heteroalkyl" means an alkyl group, as defined herein, in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatom group such as -NH-, -O-, -S-, -S(O)-, -S(O)2-, -OP(O)(O)2-, -NH-, -O-, -S-, -S(O)-, -S(O)2 ... - )O-, etc. For example, 1, 2, 3, 4, 5, 6 or more carbon atoms can be independently replaced by the same or different heteroatom groups. The heteroalkyl group can also contain one or more carbonyl moieties (i.e., wherein the carbon atoms of the alkyl group are oxidized to -C(O)- groups).

[0106] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatom group such as -NH-, -O-, -S-, -S(O)-, -S(O)2-, and the like. For example, 1, 2, 3, 4, 5, 6 or more carbon atoms may be independently replaced by the same or different heteroatom groups. The heteroalkenyl group may also contain one or more carbonyl moieties (i.e., wherein a carbon atom of an alkyl group is oxidized to a -C(O)- group).

[0107] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein, wherein one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatom group such as -NH-, -O-, -S-, -S(O)-, -S(O)2-, and the like. For example, 1, 2, 3, 4, 5, 6 or more carbon atoms may be independently replaced by the same or different heteroatom groups. The heteroalkynyl group may also contain one or more carbonyl moieties (i.e., wherein a carbon atom of the alkyl group is oxidized to a -C(O)- group).

[0108] As used herein, the term "hydroxy" refers to an -OH group.

[0109] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced with a hydroxy group.

[0110] As used herein, the term "substituent" refers to a group that replaces an atom of the indicated group.

[0111] When 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 indicated in the expression using "substituted" can be replaced with a series of listed indicated groups or with suitable substituents known to those skilled in the art (e.g., one or more of the groups listed below), provided that the normal valence of the designated 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, hydrazine, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamido, thiol, thiol, thioketone, thioloxy, or a combination thereof.

[0112] As used herein, in chemical structures, indicates:

[0113]

[0114] Indicates the point where one part joins another.

[0115] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkylalkenyl) is indicated by the prefix "C x -C y ” indicates an alkyl group containing from 1 to 3 carbon atoms, wherein x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. Thus, for example, “C1-C3 alkyl” refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0116] For the compounds described herein, radicals and substituents may be chosen with regard to the allowed valences of atoms and substituents such that selection and substitution results in stable compounds, eg, which do not spontaneously transform such as by rearrangement, cyclization, elimination, and the like.

[0117] Where substituent groups are designated by conventional chemical formulas written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- is intended to encompass -OCH2-, and -C(O)NH- is intended to encompass -NHC(O)-.

[0118] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and embodiments disclosed herein are illustrative only and are not restrictive.

[0119] 2. Compounds

[0120] In one aspect, disclosed is a compound of formula (I):

[0121]

[0122] or a pharmaceutically acceptable salt thereof, wherein:

[0123] X 1 Selected from O, NR w , S and key;

[0124] R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, halo-C1-C4-alkyl, amino-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, halo, hydroxy, amino, C1-C4-alkylamino, di-C1-C4-alkylamino and cyano; wherein R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b optionally taken together with the carbon atom to which it is attached to form an optionally substituted 3 to 6 membered ring;

[0125] X 4 CR 4 or N;

[0126] X 5 CR 5 or N;

[0127] X 6 CR 6 or N;

[0128] X 7 CR 7 or N;

[0129] R 3 , R 4 , R 5 , R 6 and R 7each independently selected from hydrogen, 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y 2. -SO2R z , oligoethylene glycol chains or polyethylene glycol chains and groups -YR 8 ; where R 4 and R 5 , R 5 and R 6 or R 6 and R 7 optionally taken together with the carbon atom to which it is attached to form an optionally substituted 5- or 6-membered ring;

[0130] Y is selected from -C(O)-, -C(O)O-, -C(O)NR v -and -C(O)S-;

[0131] R 8 is a lipid moiety having at least 8 carbon atoms;

[0132] R v , R w , R x , R y and R z Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and halo-C1-C6-alkyl;

[0133] L is a connector; and

[0134] Z is a moiety of formula (a) or formula (b):

[0135]

[0136] Where R 10 is hydrogen or C1-C6 alkyl;

[0137]

[0138] in:

[0139] Q is CH or N;

[0140] A is aryl or a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O, S and P;

[0141] R 20 Selected from 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 , where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 and R a7 Each independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0142] R 21 Selected from hydrogen and the group -L 21 -E, where:

[0143] 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, or wherein L 21 Combinations comprising any two of such groups;

[0144] E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6-cycloalkyl-C 1-4 -alkyl, C1-C4 haloalkyl, oxo, -OR b1 、-N(R b2 )(R b3 ),-SO2R b4 、-SO2N(R b5 )(R b6 ) and -NHSO2R b7 Substituents, where R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 Each independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0145] L bFor –(CR c1 R c2 ) m -G b -,in:

[0146] R c1 and R c2 independently selected from hydrogen and C1-C4 alkyl;

[0147] m is 0, 1 or 2; and

[0148] G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; and

[0149] B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from 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 Substituents, where R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0150] In some embodiments, R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl and hydroxy. 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxymethyl and hydroxy. 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen and C1-C4 alkyl. 1a , R 1b , R 2a and R2b 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-alkoxy-C1-C4-alkyl and hydroxyl, 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 hydroxyl, 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. 1b , R 2a and R 2b is hydrogen, and R 1a In some embodiments, R 1a , R 1b , R 2a and R 2b Each is hydrogen.

[0151] In some embodiments, R 1a and R 2a is hydrogen, and R 1b and R 2b Together with the carbon atom to which it is attached, it forms a 3-membered ring (eg, a cyclopropyl ring).

[0152] In some embodiments, R 3 is selected from hydrogen and halo (eg, fluoro, chloro, or bromo). 3 In some embodiments, R 3 For hydrogen.

[0153] In some embodiments, X 4 CR 4 , X 5 CR 5 , X 6 CR 6 And X 7 CR 7 .

[0154] In some embodiments, R 4 is selected from hydrogen and halo (eg, fluoro, chloro, or bromo). 4 In some embodiments, R4 For hydrogen.

[0155] In some embodiments, R 5 and R 6 Each is independently selected from 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y )2 and -SO2R z In some embodiments, R 5 and R 6 Each is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylthio, halo-C1-C4-alkyl, halo-C1-C4-alkoxy, hydroxy, halo and C1-C4-alkylamino. In some embodiments, R 5 and R 6 Each is independently selected from methyl, ethyl, n-propyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, 2-fluoroethyl, difluoromethoxy, hydroxy, fluorine, chlorine, bromine and methylamino. In some embodiments, R 5 and R 6 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo. 5 and R 6 Each is independently selected from methyl, ethyl, n-propyl, methoxy, ethoxy, fluorine, chlorine and bromine. 5 and R 6 Each is independently selected from C1-C4 alkoxy. 5 and R 6 Each is a methoxy group.

[0156] In some embodiments, R 7 is selected from hydrogen and halo (eg, fluoro, chloro, or bromo). 7 In some embodiments, R 7 For hydrogen.

[0157] In some embodiments, X 1 In some embodiments, X 1 is O. In some embodiments, X 1In some embodiments, X 1 NR w , where R w is selected from hydrogen and C1-C6 alkyl. 1 In some embodiments, X 1 NR w , where R w In some embodiments, X 1 For S.

[0158] In some embodiments, the compound is a compound of formula (Ia):

[0159]

[0160] or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, Z is a moiety of formula (a). 10 is C1-C6 alkyl. 10 In some embodiments, Z is a moiety of the formula:

[0162]

[0163] In some embodiments, Z is a moiety of formula (b).

[0164] 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 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 In some embodiments, A is phenyl and R 20 It's hydrogen.

[0165] In some embodiments, B is a nine-membered bicyclic heteroaryl or nine-membered bicyclic heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and P. In some embodiments, B is a nine-membered bicyclic heteroaryl or nine-membered bicyclic heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, B is a nine-membered bicyclic heteroaryl or nine-membered bicyclic heterocyclyl having 1, 2, 3, or 4 nitrogen atoms. In some embodiments, B is a pyrazolopyrimidine. In some embodiments, in addition to -R 21, B is optionally replaced by 1, 2, 3, 4 or 5 independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, -OR e1 、-N(R e2 )(R e3 ),-SO2R e4 、-SO2N(R e5 )(R e6 ) and -NHSO2R e7 Substituents, where 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 , B is replaced by a group selected from 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, in addition to -R 21 , B is replaced by a group selected from halo, methyl, trifluoromethyl, -OR e1 、-N(R e2 )(R e3 ),-SO2R e4 、-SO2N(R e5 )(R e6 ) and -NHSO2R e75 Substituents, where R e1 , R e2 , R e3 , R e4 , R e5 , R e6 and R e7 Each is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl.

[0166] In some embodiments, R 21 A group selected from hydrogen and the following formula:

[0167]

[0168] In some embodiments, L b Yes – (CR c1 R c2 )m -G b –, where m is 0, 1, or 2, R c1 and R c2 are independently selected from hydrogen and methyl, and G b is a bond, -NHC(O)-, -NH-, -O-, or -S-. In some embodiments, L b Having a formula selected from the following:

[0169]

[0170] In some embodiments, the moiety of formula (b) is a moiety of formula (bi):

[0171]

[0172] Among them, A, Q, R 20 and R 21 is any group as defined and described herein.

[0173] In some embodiments, the moiety of formula (b) is:

[0174]

[0175] The compound of formula (I) comprises L, which is a linker moiety. 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 a group of formula (a) (IDO1 inhibitor) or a group of formula (b) (PI3K agonist)) to allow each element to function without interference (or minimal interference) from being connected to the other. In some embodiments, L separates the two groups by about to about In some embodiments, L separates the two groups or any suitable range therebetween (e.g., 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.)).

[0176] L may comprise one or more groups independently selected from -C(R')2-, -CH=CH-, -C≡C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene and heterocyclylene, wherein each R' is independently selected from hydrogen, C1-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and lipid moieties, and 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 five-membered heteroarylene having 1, 2 or 3 nitrogen atoms), wherein each R' is independently selected from hydrogen, C1-C 40 Alkyl, phenyl and -CH2-heterocyclyl (eg, wherein 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.

[0177] In some embodiments, L comprises one or more -(CH2CH2O)-(oxyvinyl) groups, such as 1-20 -(CH2CH2O)- groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 -(CH2CH2O)- groups, or any range therebetween). In some embodiments, L comprises -(CH2CH2O)-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -(CH2CH2O)6-, -(CH2CH2O)7-, -(CH2CH2O)8-, -(CH2CH2O)9-, or -(CH2CH2O) 10 -group.

[0178] In some embodiments, L comprises one or more alkylene groups (e.g., -(CH2) n-, wherein 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 five-membered heteroarylene group having 2 or 3 nitrogen atoms (e.g., formula of groups).

[0179] In some embodiments, the group -X 1 -L- together have the formula -O-(CR'2) n -O-, wherein each n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and each R' is independently selected from hydrogen, C1-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and lipid moieties, and wherein each alkyl, arylene, heteroarylene, cycloalkylene and heterocyclylene is independently unsubstituted or substituted with 1, 2 or 3 substituents. In some embodiments, L has the formula -O-(CR'2) n -O-, wherein n is 1, 2, 3, 4 or 5, and one R' is selected from C1-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, and the remaining R' are all hydrogen.

[0180] In some embodiments, L comprises one or more substituents, overhangs, side chains, etc., comprising any suitable organic functional group (e.g., -OH, -NH2, -SH, -CN, =O, =S, halogen (e.g., -F, -Cl, -Br, -I), -COOH, -CONH2, -CH3, etc.).

[0181] In some embodiments, the group -X 1 -L- together have a formula selected from the following:

[0182]

[0183]

[0184] In some embodiments, the compound of formula (I) comprises a lipid portion having at least 8 carbon atoms. For example, in some embodiments, R 3 , R 4 , R5 , R 6 and R 7 One of them is the group -YR 8 , where R 8 is a lipid moiety having at least 8 carbon atoms. In some embodiments, the linker group L comprises a lipid moiety (eg, as part of a group -C(R')2-, where one R' is a lipid moiety.

[0185] The lipid portion can be derived from any suitable lipid, such as a fatty alcohol, a fatty acid, a phospholipid, a steroid, or a synthetic lipid. In some embodiments, the lipid portion is derived from a lipid having a functional group (such as a hydroxyl group, a carboxylic acid group, or an amino group), and the lipid portion is attached to the compound of formula (I) via the 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 a functional group; for example, if the lipid moiety is derived from a fatty alcohol, then X 1 is O.

[0186] In some embodiments, the lipid moiety is selected from C8-C 80 Alkyl, 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.

[0187] For example, in some embodiments, the lipid moiety is selected from C8-C 80 Alkyl and C8-C 80 In some embodiments, the lipid moiety is selected from C8-C 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., wherein R 1 is the lipid part 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)-hexadeca-9-en-1-ol), oleyl alcohol ((Z)-octadeca-9-en-1-ol), anti-oleyl alcohol (trans-9-octadecaenol), cis-isooctadecaenol (cis-11-octadecaenol), gadol ((Z)-eicos-9-en-1-ol), 11-eicosene alcohol, erucyl alcohol (cis-13-eicosene alcohol), 15-eicosene-1-ol, eicosene alcohol (eicos-11,14-dien-1-ol), linoleyl alcohol ((9Z, 12Z, 15Z)-9 ,12,15-octadecatriene-1-ol), γ-linolenic acid ((6E,9E,12E)-octadecatriene-6,9,12-triene-1-ol), tung oil alcohol (octadecatriene-9,11,13-triene-1-ol), eicosa-5,8,11-triene-1-ol, docos-13-ene-1-ol, eicosa-11,14-17-triene-1-ol, octadecatriene-6,9,12,15-tetraene-1-ol, arachidonic acid ((5Z,8Z,11Z,14Z)-eicosatetraene-1-ol), 4E,6Z-hexadecadiene-1-ol, eicosa-5,8,11,14,17-pentaene-1-ol, docosahexaenol (docosahexaenol) -4,7,10,13,16,19-hexaen-1-ol), docosyl-7,10,13,16,19-pentaen-1-ol, tetracosyl-6,9,12,15,18,21-hexaen-1-ol, n-octanol (1-octanol), nonanol (1-nonanol), decanol (1-decanol), undecanol (1-undecanol), lauryl alcohol (1-dodecanol), tridecanol (1-tridecanol), myristyl alcohol (1-tetradecanol), pentadecanol (1-pentadecanol), cetyl alcohol (1-hexadecanol), palmitoleyl alcohol (cis-9-hexadecene-1-ol), heptadecanol (1-n-heptadecanol), stearyl alcohol (1-octadecanol), oleyl alcohol (1-octadecenol), nonadecanol (1-nonadecanol) , arachidyl alcohol (1-eicosanol), heneicosanol (1-heneicosanol), behenyl alcohol (1-docosanol), erucyl alcohol (cis-13-docosan-1-ol), 1-tricosanol, tetracosanol (1-tetracosanol), pentacosanol (1-pentacosanol), hexacosanol (1-hexacosanol), 1-heptacosanol, montanol (1-octacosanol), 1-nonacosanol, myricanol (1-triacontanol), 1-triacontanol, 1-dotriacontanol (margarine alcohol), 1-triacontanol, candacetyl alcohol (1-tetratriacontanol), 1-hexatriacontanol, 1-heptatriacontanol, 1-octaticontanol, 1-octacosanol, nonacosanol, 1-triacontanol, 1-triacontanol, 1-triacontanol, candacetyl alcohol (1-tetratriacontanol), 1-hexatriacontanol, 1-heptatriacontanol, 1-octaticontanol, nonacosanol or 1-tetracontanol.

[0188] In some embodiments, the lipid moiety is selected from C8-C 80 Heteroalkyl, C8-C 80 Heteroalkenyl and C8-C 80 In such embodiments, the lipid moiety can be derived from a lipid comprising one or more heteroatom groups (such as -O-, -NH-, -C(O)-, etc.) or combinations thereof (e.g., a -C(O)O- group).

[0189] For example, in some embodiments, the lipid moiety has formula (A):

[0190]

[0191] in:

[0192] 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; and

[0193] R a and R b Each independently selected from C6-C 40 Alkyl, C6-C 40 Alkenyl, C6-C 40 Heteroalkyl and C6-C 40 Heteroalkenyl.

[0194] 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.

[0195] In some embodiments, R a and R b Each independently selected from C6-C 40 Alkyl and C6-C 40 For example, in some embodiments, R a and R bEach of the following is independently selected from the group consisting of n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonadecyl, triacontyl, triuncontyl, dotriacontyl, trictriacontyl, tetratriacontyl, pentatriacontyl, hexatriacontyl, heptatriacontyl, octatriacontyl, Nonadriatriadecyl, tetradecyl, linoleyl ((9Z,12Z)-octadec-9,12-dien-1-yl), palmityl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), trans-oleyl (trans-9-octadecenyl), cis-11-octadecenyl (cis-vaccenyl) (cis-11-octadecenyl), gadyl ((Z)-eicos-9-en-1-yl), 11-eicosenyl, erucyl (cis-13-eicosenyl), 15 -Eicosyl, docosyl (eicosyl-11,14-dien-1-yl), linoleyl ((9Z,12Z,15Z)-9,12,15-octadecadien-1-yl), γ-linoleyl ((6E,9E,12E)-octadecadien-6,9,12-trien-1-yl), tung oil (octadecadien-9,11,13-trien-1-yl), eicosyl-5,8,11-trien-1-yl, docosyl-13-en-1-yl, eicosyl-11,14-17-trien-1-yl, In some embodiments, R a and R b Each is linoleyl.

[0196] In some embodiments, the lipid moiety has formula (B) or (C):

[0197]

[0198] in:

[0199] 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;

[0200] R a1 Selected from C6-C 40 Alkyl and C6-C 40 alkenyl; and

[0201] R b Selected from C6-C 40 Alkyl, C6-C 40 Alkenyl, C6-C 40 Heteroalkyl and C6-C 40 Heteroalkenyl.

[0202] 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.

[0203] 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.

[0204] In some embodiments, R a1 C6-C 24 Alkyl or C6-C 24 In some embodiments, R a1 Selected from C9-C 22 Alkyl and C9-C 22 In some embodiments, R a1 Selected from 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 24In some embodiments, R a1 Selected from 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 Selected from linoleyl, n-nonyl, n-undecyl, heneicosane-11-yl, pentadecane-7-yl and heptadecan-9-yl.

[0205] In some embodiments, R b Selected from C6-C 40 Alkyl and C6-C 40 For example, in some embodiments, R bis selected from the group consisting of n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, triuncontyl, dotriacontyl, trictriacontyl, tetratriacontyl, pentatriacontyl, hexatriacontyl, heptatriacontyl, octatriacontyl, Nonatriacontyl, tetracontyl, linoleyl ((9Z, 12Z)-octadec-9,12-dien-1-yl), palmityl ((Z)-hexadec-9-en-1-yl), oleyl ((Z)-octadec-9-en-1-yl), transoleyl (trans-9-octadecenyl), cis-11-octadecenyl (cis-11-octadecenyl), gaddenyl ((Z)-eicos-9-en-1-yl), 11-eicosenyl, erucyl (cis-13-eicosenyl), 15-eicosene-1-yl, Docosyl (eicosyl-11,14-dien-1-yl), linoleyl ((9Z,12Z,15Z)-9,12,15-octadecatrien-1-yl), γ-linoleyl ((6E,9E,12E)-octadeca-6,9,12-trien-1-yl), tung oilyl (octadeca-9,11,13-trien-1-yl), eicosyl-5,8,11-trien-1-yl, eicosyl-13-en-1-yl, eicosyl-11,14-17-trien-1-yl, octadeca-6, In some embodiments, R b Linoleyl.

[0206] In some embodiments, the lipid moiety has formula (D), (E), or (F):

[0207]

[0208] in:

[0209] 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; and

[0210] R a1 and R a2 Each independently selected from C6-C 40 Alkyl and C6-C 40 Alkenyl.

[0211] 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.

[0212] 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.

[0213] In some embodiments, R a1 and R a2 Each independently selected from C6-C 24 Alkyl and C6-C 24 In some embodiments, R a1 and R a2 Each independently selected from C9-C 22 Alkyl and C9-C 22 In some embodiments, R a1 and R a2 Each independently selected from 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 , C22 , C 23 , or C 24 In some embodiments, R a1 and R a2 Each independently selected from 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 Each is independently selected from linoleyl, n-nonyl, n-undecyl, heneicos-11-yl, pentadec-7-yl and heptadecan-9-yl.

[0214] In some embodiments, the lipid moiety is derived from a steroid. For example, in some embodiments, the lipid moiety is derived from cholesterol, beta-sistesterol, or BHEM-cholesterol.

[0215] In some embodiments, the lipid moiety is selected from:

[0216]

[0217]

[0218]

[0219] In some embodiments, the compound of formula (I) is selected from:

[0220]

[0221] and pharmaceutically acceptable salts thereof. Other compounds of formula (I) include:

[0222]

[0223]

[0224]

[0225]

[0226] or a pharmaceutically acceptable salt thereof.

[0227] Also disclosed herein are compounds of formula (II):

[0228]

[0229] or a pharmaceutically acceptable salt thereof, wherein:

[0230] R 1a , R 1b , R 2a , R 2b , R 1a’ , R 1b’ , R 2a’ and R 2b’ Each is independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, halo-C1-C4-alkyl, amino-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, halo, hydroxy, amino, C1-C4-alkylamino, di-C1-C4-alkylamino and cyano; wherein R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b optionally together with the carbon atom to which it is attached, form an optionally substituted 3 to 6 membered ring; and wherein R 1a’ and R 1b’ , or R 1a’ and R 2a’ , or R 2a’ and R 2b’ Optionally, together with the carbon atom to which it is attached, form an optionally substituted 3 to 6 membered ring

[0231] X 4 CR 4 or N;

[0232] X 5 CR 5 or N;

[0233] X 6 CR 6 or N;

[0234] X 7 CR 7 or N;

[0235] X 4’ CR 4’ or N;

[0236] X 5’ CR 5’ or N;

[0237] X 6’ CR 6’ or N;

[0238] X 7’ CR 7’ or N;

[0239] R 3 , R 4 , R 5 , R 6 , R 7 , R 3’ , R 4’ , R 5’ , R 6’ and R 7’ each independently selected from hydrogen, 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y 2. -SO2R z , oligo- or polyethylene glycol chains and groups -YR 8 ; where R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 Optionally, together with the carbon atom to which it is attached, form a 5- or 6-membered ring; and wherein R 4’ and R 5’ , R 5’ and R 6’ , or R 6’ and R 7’ optionally taken together with the carbon atom to which it is attached to form an optionally substituted 5- or 6-membered ring;

[0240] Y is selected from -C(O)-, -C(O)O-, -C(O)NR v -and -C(O)S-;

[0241] R 8 is a lipid moiety having at least 8 carbon atoms;

[0242] R v , R w , R x , R y and Rz Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and halo-C1-C6-alkyl;

[0243] L, L' and L 2 each independently a linker; and

[0244] Z and Z' are each independently a moiety of formula (a) or formula (b):

[0245]

[0246] Where R 10 is hydrogen or C1-C6 alkyl;

[0247]

[0248] in:

[0249] Q is CH or N;

[0250] A is aryl or a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O, S and P;

[0251] R 20 Selected from 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 , where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 and R a7 Each independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0252] R 21 Selected from hydrogen and the group -L 21 -E, where:

[0253] 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, or wherein L 21 Combinations comprising any two of such groups;

[0254] E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6-cycloalkyl-C 1-4 -alkyl, C1-C4 haloalkyl, oxo, -OR b1 、-N(R b2 )(R b3 ),-SO2R b4 、-SO2N(R b5 )(R b6 ) and -NHSO2R b7 Substituents, where R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0255] L b For –(CR c1 R c2 ) m -G b -,in:

[0256] R c1 and R c2 independently selected from hydrogen and C1-C4 alkyl;

[0257] m is 0, 1 or 2; and

[0258] G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; and

[0259] B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from 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 Substituents, where R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and Rd7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0260] The scope of the present disclosure also includes other STING agonists to replace the groups in formula (I) 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), amide benzimidazoles (ABZIs) and their derivatives (including 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-dimethylxanthone-4-acetic acid (DMXAA), 10-carboxymethyl-9-acridone (CMA), SR-717 (Chin et al. Science 2020, 369(6506), 993-999), α-mangostinol (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)-hexanone (DSDP; Liu et al. Antiviral Res. 2017, 147, 37-46) and other compounds (including ADU-S100, MK-154, MK-2118, BMS-986301, GSK-3745417, SB-11285 and IMSA-101). STING agonists are also disclosed in, for example, Zhang et al., J. Med. Chem. 2020, 63 (8), 3785–3816.

[0261] Certain compounds disclosed herein (e.g., in the Examples) may have additional monofunctional or bifunctional activities, such as activity as PI3K inhibitors or activity as bifunctional PI3K-IDO compounds. For example, certain compounds prepared as intermediates in the Examples herein have individual activities as PI3K inhibitors, including but not limited to the following compounds:

[0262]

[0263] The present disclosure is also intended to cover such compounds as well as pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof.

[0264] Compounds can exist as stereoisomers, wherein there is an asymmetric or chiral center. A stereoisomer is "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. A single stereoisomer of a compound can be synthesized from commercially available starting materials containing an asymmetric or chiral center, or by preparing a racemic mixture followed by a resolution method well known to those of ordinary skill in the art. Examples of these resolution methods are as follows: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and optionally liberating the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th Edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or its most recent edition), or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0265] It is to be understood that compounds may have tautomeric forms as well as geometric isomers and these also constitute embodiments of the present disclosure.

[0266] The present disclosure also includes isotopically labeled compounds, which are identical to those described in formula (I), but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as, but not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. With heavier isotopes (such as deuterium, e.g. 2 H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. The compounds may incorporate positron emitting isotopes for use in medical imaging and positron emission tomography (PET) studies. Suitable positron emitting isotopes that may be incorporated into the 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 an appropriate isotopically labeled reagent in place of a non-isotopically labeled reagent.

[0267] The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt or zwitterion of a compound that is water-soluble or oil-soluble or dispersible, suitable for treating a condition without excessive toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Salts can be prepared during the final separation and purification of the compound, or prepared separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of an acid (such as hydrochloric acid). The resulting salt can be precipitated, separated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, etc. The amino group of the compound can also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, etc.

[0268] Basic addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium or aluminum, or an organic primary, secondary or tertiary amine. Quaternary ammonium salts 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-diphenylhydroxymethylamine and N,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc. can be prepared.

[0269] Compounds can be synthesized according to a variety of methods, including those shown in the examples. The reaction conditions and reaction times of each individual step can vary according to the specific reactants used and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reaction can be carried out in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methods generally known in the art, such as but not limited to crystallization, distillation, extraction, wet grinding and chromatography. Unless otherwise described, starting materials and reagents are commercially available or can be prepared from commercially available materials by those skilled in the art using the methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by a procedure selected from standard organic chemistry techniques, a technique similar to the synthesis of known structurally similar compounds, or a technique similar to the procedure described in the above-mentioned scheme or the Synthesis Example section.

[0270] Routine experiments, including appropriate manipulation of reaction conditions, reagents and synthetic route sequences, protection of any chemical functional groups incompatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method are all included in the scope of the present disclosure. Suitable protecting groups and methods of using such suitable protecting groups to protect different substituents and deprotection are well known to those skilled in the art; examples thereof can be found in PGM Wuts and TW Greene, in Greene's booktitled Protective Groups in Organic Synthesis (4th edition), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present disclosure can be accomplished by methods similar to those described in the synthetic schemes described above and the specific embodiments.

[0271] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using optically active starting materials (e.g., by asymmetric induced preparation by appropriate reaction steps) or by resolving the mixture of stereoisomers of the compounds or intermediates using standard procedures (such as chromatographic separation, recrystallization or enzymatic resolution).

[0272] Similarly, when pure geometric isomers of compounds are required, they may be obtained by carrying out one of the above procedures using the pure geometric isomers as starting materials, or by resolving a mixture of geometric isomers of compounds or intermediates using standard procedures such as chromatographic separation.

[0273] It should 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 included within the scope of the claims.

[0274] 3. Composition

[0275] The disclosed compounds may be incorporated into compositions suitable for administration to a subject, such as a patient, who may be human or non-human.

[0276] a. Pharmaceutical Composition

[0277] The disclosed compounds may be incorporated into pharmaceutically acceptable compositions. Pharmaceutical compositions may include a "therapeutically effective amount" or a "prophylactic effective amount" of the compound. A "therapeutically effective amount" refers to an effective amount that achieves the desired therapeutic outcome at the necessary dosage and time period. The therapeutically effective amount of a composition can be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of a compound of the invention (e.g., a compound of formula (I)) are exceeded by the therapeutically beneficial effects. A "prophylactic effective amount" refers to an effective amount that achieves the desired prophylactic effect at the necessary dosage and time period. Typically, since a prophylactic dose is used on a subject before or in the early stages of a disease, the prophylactic effective amount will be less than the therapeutically effective amount.

[0278] Pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrin or any type of formulation auxiliary. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as but not limited to lactose, glucose and sucrose; starches, such as but not limited to corn starch and potato starch; cellulose and its derivatives, such as but not limited to sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth; malt; gelatin; talc; excipients, such as but not limited to cocoa butter and suppository waxes; oils, such as but not limited to peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; surfactants, such as but not limited to cremophor EL, cremophor RH 60, Solutol HS15 and polysorbate 80; cyclodextrins, such as but not limited to α-CD, β-CD, γ-CD, HP-β-CD, SBE-β-CD; glycols; such as propylene glycol; esters, such as but not limited to ethyl oleate and ethyl laurate; agar; buffers, such as but not limited to magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, and other non-toxic compatible lubricants, such as but not limited to sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and flavor enhancers, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[0279] The route of administration of the disclosed compound and the form of the composition will determine the type of carrier to be used. The composition can be in a variety of forms, such as suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant or parenteral injection) or local administration (e.g., dermal, pulmonary, nasal, ear, eye, liposome delivery system or iontophoresis). In some embodiments, the composition is for oral administration.

[0280] Carriers for systemic administration generally include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, cyclodextrins, combinations thereof, etc. All carriers are optional in the composition.

[0281] Suitable diluents include sugars such as glucose, lactose, dextrose and sucrose; glycols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerol; mannitol; and sorbitol. The amount of one or more diluents in a systemic or topical composition is generally about 50% to about 90%.

[0282] Suitable lubricants include silicon dioxide, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter. The amount of one or more lubricants in the systemic or local composition is generally about 5% to about 10%.

[0283] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of one or more binders in the systemic composition is generally from about 5% to about 50%.

[0284] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, cross-linked carboxymethylcellulose, cross-linked povidone, sodium carboxymethyl starch, sodium starch glycolate, clays and ion exchange resins. The amount of one or more disintegrants in the systemic or topical composition is generally from about 0.1% to about 10%.

[0285] Suitable coloring agents include colorants such as FD&C dyes.When used, colorants are generally present in systemic or topical compositions in amounts of from about 0.005% to about 0.1%.

[0286] Suitable flavors include menthol, mint, and fruit flavors.When used, the amount of one or more flavors in the systemic or topical compositions is generally from about 0.1% to about 1.0%.

[0287] Suitable sweeteners include aspartame and saccharin.The amount of one or more sweeteners in the systemic or topical compositions is generally from about 0.001% to about 1%.

[0288] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of one or more antioxidants in the systemic or topical compositions is generally from about 0.1% to about 5%.

[0289] Suitable preservatives include benzalkonium chloride, methylparaben and sodium benzoate.The amount of one or more preservatives in the systemic or topical compositions is generally from about 0.01% to about 5%.

[0290] Suitable glidants include silicon dioxide.The amount of glidant in the systemic or topical composition is generally from about 1% to about 5%.

[0291] Suitable solvents include water, isotonic saline, ethyl oleate, glycerol, hydroxylated castor oil, alcohols such as ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide and phosphate (or other suitable buffers). The amount of one or more solvents in a systemic or topical composition is generally from about 0% to about 100%.

[0292] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, Pa.) and sodium alginate. The amount of one or more suspending agents in the systemic or topical compositions is generally from about 1% to about 8%.

[0293] Suitable surfactants include lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEENS from Atlas Powder Company of Wilmington, Del. Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th edition 1975, pp. 335-337; and McCutcheon, Vol. 1, Emulsifiers & Detergents, 1994, North American edition, pp. 236-239. The amount of one or more surfactants in the systemic or topical composition is generally from about 0.1% to about 5%.

[0294] Suitable cyclodextrins include α-CD, β-CD, γ-CD, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether β-cyclodextrin (SBE-β-CD).The amount of cyclodextrin in the systemic or topical composition is generally from about 0% to about 40%.

[0295] Although the amounts of the components in systemic compositions may vary depending on the type of systemic composition being prepared, in general, systemic compositions include 0.01% to 50% of the active compound (e.g., a compound of Formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of the active substance and 90% to 99.9% of a carrier, including diluents and solvents.

[0296] Compositions for oral administration can have a variety of dosage forms. For example, solid forms include tablets, capsules, granules and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, more particularly about 25% to about 50% of the active substance. Oral dosage form compositions include about 50% to about 95% of a carrier, more particularly, about 50% to about 75%.

[0297] Tablets can be compressed, tablet milled, enteric coated, sugar coated, film coated or multi-compressed. Tablets typically include active ingredients, and carriers containing ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, 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 cross-linked carboxymethyl cellulose. Specific lubricants include magnesium stearate, stearic acid and talc. Specific colorants are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners, such as aspartame and saccharin, or flavors, such as menthol, mint, fruit flavors, or combinations thereof.

[0298] Capsules (including implants, timed release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)) and a carrier of one or more of the above disclosed diluents included in a capsule comprising gelatin. The particles typically contain the disclosed compound and preferably a glidant such as silicon dioxide to improve flow characteristics. The implant may be biodegradable or non-biodegradable.

[0299] The choice of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost, and shelf stability, which factors are not critical for the purposes of the present invention.

[0300] Solid compositions can be coated by conventional methods, usually with a pH or time-dependent coating, so that the disclosed compounds are released in the gastrointestinal tract near the desired administration, or at different points and times to prolong the desired effect. The coating generally includes one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0301] Compositions for oral administration can have liquid form.For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions redissolved by non-effervescent granules, suspensions redissolved by non-effervescent granules, effervescent preparations redissolved by effervescent granules, elixirs, tinctures, syrups, etc.Liquid oral administration compositions generally include disclosed compounds and carriers, i.e., carriers selected from diluents, colorants, spices, sweeteners, preservatives, solvents, suspending agents and surfactants.Oral liquid compositions preferably include one or more components selected from colorants, spices and sweeteners.

[0302] Other compositions that can be used to achieve systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials, such as diluents, including sucrose, sorbitol and mannitol; and binders, such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Such compositions may also include lubricants, colorants, flavors, sweeteners, antioxidants and glidants.

[0303] The disclosed compounds can be applied topically. Topical compositions that can be topically applied to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, emulsions, shampoos, leave-on and rinse-off conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, etc. The topical composition includes: a disclosed compound (e.g., a compound of formula (I)) and a carrier. The carrier of the topical composition preferably helps the compound penetrate into the skin. The carrier may also include one or more optional components.

[0304] The amount of carrier used in conjunction with the disclosed compounds is sufficient to provide a composition for the practical amount of compound administered per unit dose. Techniques and compositions for making 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).

[0305] The carrier may include a single component or a combination of two or more components. In topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more components selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerol, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More particularly, carriers for skin application include propylene glycol, dimethyl isosorbide and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.

[0306] The carrier of the topical composition may also include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments and preservatives, all of which are optional.

[0307] 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, isohexadecanol, cetyl palmitate, di-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, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Skin-specific emollients include stearyl alcohol and dimethicone.The amount of one or more emollients in the skin-based topical composition is generally from about 5% to about 95%.

[0308] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.The amount of one or more propellants in the topical composition is generally from about 0% to about 95%.

[0309] Suitable solvents include water, ethanol, 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 ethanol and isotopic alcohols. The amount of one or more solvents in the topical composition is generally from about 0% to about 95%.

[0310] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of one or more humectants in the topical composition is typically from 0% to 95%.

[0311] The amount of one or more thickening agents in the topical composition is generally from about 0% to about 95%.

[0312] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fullerene earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium montmorillonite, trialkyl aryl ammonium montmorillonite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of one or more powders in the topical composition is typically 0% to 95%.

[0313] The amount of fragrance in topical compositions is generally from about 0% to about 0.5%, especially from about 0.001% to about 0.1%.

[0314] Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0315] b. Albumin composition

[0316] The present disclosure also provides compositions comprising albumin nanoparticles. In some embodiments, the compounds disclosed herein are incorporated into compositions comprising albumin nanoparticles. As described above, the albumin nanoparticle compositions and formulations may also include a pharmaceutically acceptable carrier.

[0317] Albumin comprises the most abundant plasma protein in mammals, and albumin from a large number of different mammals has been characterized by biochemical methods and / or sequence information. Any natural, synthetic or engineered albumin can be used in the context of the nanoparticle compositions described herein. In some embodiments, the albumin is human serum albumin.

[0318] In some embodiments, the albumin nanoparticles further comprise one or more cell targeting epitopes. In some embodiments, the epitope is covalently linked to or directly conjugated to albumin. In some embodiments, the epitope is 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 contribute to targeting the lymphatic system. In selected embodiments, the albumin nanoparticles further comprise one or more epitopes from a microbial agent (e.g., Clostridioides difficile, Bacillus anthracis, Clostridium botulinum, Heliobacter pylori, Rotavirus sp., Coronaviridae).

[0319] c. Lipophilic preparations

[0320] In some embodiments, the compounds disclosed herein are incorporated into lipophilic compositions comprising liposomes, lipid nanoparticles, micelles, etc. In some embodiments, the disclosed compounds are encapsulated in liposomes, lipid nanoparticles or micelles. As described above, the formulation may also include a pharmaceutically acceptable carrier.

[0321] In some embodiments, the disclosed compounds are incorporated into a lipophilic composition comprising one or more vesicle-forming lipids. The method for preparing a lipophilic composition includes, for example, lipid film hydration, optionally combined with ultrasonic treatment or extrusion, solvent evaporation (e.g., ethanol injection, ether injection or reverse phase evaporation), solvent diffusion method, thermal homogenization process, detergent removal method or a combination thereof. The disclosed compounds can be combined with one or more lipids before vesicle formation (passive loading) or after vesicle formation (active loading). Lipophilic compositions can prolong the in vivo circulation time, increase the stability of the compound, and prevent degradation in the blood. Lipophilic compositions can increase the distribution of compounds in the lungs, breasts, pancreas and spleen.

[0322] Any naturally occurring or synthetic vesicle-forming lipid or combination thereof may be used. One or more vesicle-forming lipids may be selected from di-aliphatic chain lipids, such as phospholipids; diglycerides; di-aliphatic glycolipids; single lipids, such as sphingomyelin or glycosphingolipids; steroidal lipids; lipids derived from hydrophilic polymers; or mixtures thereof.

[0323] The lipophilic compositions of the present disclosure may include 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 include cationic lipids and / or ionizable lipids, neutral or non-cationic lipids, and cholesterol.

[0324] Cationic and / or ionizable lipids include, for example, amine-containing lipids that can be readily protonated and can have a positive or partially positive charge at physiological pH due to pKa values ​​between pH 5 and 8. The polar head groups of the cationic lipids preferably comprise amine derivatives such as primary, secondary and / or tertiary amines, quaternary ammonium, various combinations of amines, amidine salts or guanidine and / or imidazole groups as well as pyridinium, piperazine and amino acid head groups such as 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(tetradecyl)propyl-(2-hydroxyethyl)-dimethylammonium bromide (DMRIE), didodecyl(dimethyl)ammonium bromide (DDAB), 1,2-dioleyloxypropyl-3-dimethyl-hydroxyethylammonium 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).

[0325] In some embodiments, the lipophilic composition comprises polyethylene glycol (PEG)-lipid conjugates. PEG-lipid conjugates may include but are not limited to PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, the PEG lipid can be 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.

[0326] The sterol may include cholesterol, coproposterol, ergosterol, campesterol, sitosterol, stigmasterol, brassicasterol, or a sterol ester such as cholesterol hemisuccinate, cholesterol sulfate, or any other cholesterol derivative.

[0327] Neutral or non-cationic lipids may include one or more phospholipids. Phospholipids include a phospholipid moiety and one or more fatty acid moieties. The phospholipid moiety may include, but is not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine and sphingomyelin. The fatty acid moiety may include, 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.

[0328] Phospholipids suitable for use in the composition may include, but are not limited to, phosphatidylglycerol (PG), including dimyristoylphosphatidylglycerol (DMPG) and 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG); phosphatidylcholine (PC), including egg yolk phosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DPSC ... 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-diundecyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecyl-sn-glycero-3-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-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-di(eicosahexaenoyl)-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine; phosphatidylethanolamine (PE) including 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dialinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-di(eicosahexaenoyl)-sn-glycero-3-phosphoethanolamine; phosphatidic acid (PA); phosphatidylinositol (PI); phosphatidylserine (PS); and sphingomyelin (SM).

[0329] The positively charged lipid structures described herein may also include other components that are typically used to form vesicles (e.g., for stabilization). Examples of such other components include, but are not limited to, fatty alcohols, fatty acids, and / or any other pharmaceutically acceptable excipients that may affect surface charge, membrane fluidity, and facilitate incorporation of lipids into lipid assemblies.

[0330] The lipophilic composition can also be targeted, for example, containing one or more targeting moieties or biodistribution modifiers on its surface. The targeting moiety can be any agent that can specifically bind to or interact with the desired target, and is generally known in the art, for example, ligands such as folic acid, proteins, antibodies or antibody fragments, etc.). In some embodiments, the targeting moiety is an immune cell epitope (e.g., B cell and T cell epitopes). In the embodiment selected, the targeting moiety comprises one or more epitopes from a microbial agent (e.g., Clostridium difficile, Bacillus anthracis, Clostridium botulinum, Helicobacter pylori, rotavirus, Coronavirus family).

[0331] The lipophilic composition can have any structure, for example, a structure having an interior space isolated from the external medium by one or more lipid bilayers, or any microcapsule having a semipermeable membrane having a lipophilic central portion, wherein the membrane isolates the interior. In some embodiments, the lipophilic composition can comprise a unilamellar liposome, having a single lipid layer. The disclosed compound can be located entirely or partially within the interior space of the liposome, or entirely or partially within the bilayer membrane of the liposome. In some embodiments, the lipophilic composition comprises a micelle.

[0332] d. Additional preparations

[0333] In some embodiments, the disclosed compounds are incorporated into formulations comprising PLA and / or PLGA. PLA or PLGA formulations can be prepared by various methods known in the art, such as single / double emulsion solvent evaporation technology, spray drying, spray freeze drying, supercritical fluid drying, and nanoprecipitation.

[0334] In some embodiments, the disclosed compounds are incorporated into polymer drug delivery systems formed from polymers of naturally occurring materials (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), dendrimers, etc.) The formulations can be prepared by various methods known in the art, such as single / double emulsion solvent evaporation technology, spray drying, spray freeze drying, supercritical fluid drying and nanoprecipitation.

[0335] In some embodiments, the disclosed compounds are incorporated into organic nanoparticles formed from peptides, proteins, nucleic acids, or any combination thereof.

[0336] In some embodiments, the disclosed compounds are incorporated into inorganic nanoparticles formed from silica, gold, silver, iron, and the like.

[0337] e. Additional therapeutic agents

[0338] Any of the above compositions or formulations disclosed herein may also include at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent includes an immunomodulator, a chemotherapeutic agent, a nucleic acid (e.g., mRNA, an aptamer, an antisense oligonucleotide, a ribozyme nucleic acid, an interfering RNA, an antisense and antigenic nucleic acid), a decongestant, a steroid, an analgesic, an antibacterial agent, an immunotherapy or a combination thereof. In some embodiments, 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 I PI3K inhibitor, an isoform-selective PI3K inhibitor).

[0339] Exemplary immunomodulators include: indoleamine 2,3-dioxygenase (IDO) inhibitors and analogs thereof, such as epasta, BMS-986205, indomod, PF-06840003 and analogs thereof; signal transducer and activator of transcription 3 (Stat3) inhibitors and analogs thereof, such as SM-36 and analogs thereof; toll-like receptor (TLR) agonists and analogs thereof, such as imiquimod, resiquimod, segamod, gademod, SM-360320, TMX-101, TMX-202, TMX-302, TMX-306, GSK2245035, CL097, 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, such as atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, mevastatin, pitavastatin, rosuvastatin and their analogs.

[0340] In some embodiments, at least one additional therapeutic agent comprises at least one chemotherapeutic agent. The term "chemotherapeutic agent" or "anticancer agent" as used herein includes any small molecule or other drug used for cancer treatment or prevention. Chemotherapeutic agents include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemaciclib, afinitor (everolimus), alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, and fulvestrant. estrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol acetate, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib.

[0341] In some embodiments, 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 deoxyribonucleic acids (DNA), ribonucleic acids (RNA) (including 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.

[0342] In some embodiments, at least one additional therapeutic agent is RNA. The RNA that can be used in the compositions and methods described herein can be selected from the group consisting of, but not limited to: shortmers, antagomirs, antisense RNAs, ribozymes, small interfering RNAs (siRNAs), asymmetric interfering RNAs (aiRNAs), microRNAs (miRNAs), Dicer substrate RNAs (dsRNAs), small hairpin RNAs (shRNAs), transfer RNAs (tRNAs), messenger RNAs (mRNAs), and mixtures thereof.

[0343] In certain embodiments, at least one additional therapeutic agent is 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 can 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.

[0344] In some embodiments, at least one additional therapeutic agent is siRNA. siRNA may be able to selectively knock down or down-regulate the expression of a gene of interest. For example, after administering a nanoparticle composition comprising siRNA to a subject in need, siRNA may be selected to silence genes associated with a particular disease, disorder or condition. siRNA may comprise a sequence complementary to an mRNA sequence encoding a gene or protein of interest. In some embodiments, siRNA may be an immunomodulatory siRNA.

[0345] In some embodiments, at least one additional therapeutic agent is a shRNA or a vector or plasmid encoding the same shRNA. After the appropriate construct is delivered to the nucleus, the shRNA can be produced in the target cell. The constructs and mechanisms associated with shRNA are well known in the relevant art.

[0346] PI3K inhibitors can target any category of PI3K, including Class I (e.g., IA and IB), Class II or Class III. In some embodiments, PI3K inhibitors are compounds disclosed herein. In some embodiments, PI3K inhibitors include 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 that can be used for the compositions and methods of the present invention include, but are not limited to, IPI-549, idelalis, copanlis, duvelisib, apellis, lanilixibu, erbulis, bupasib, taselixibu, pitilisi, PX-886, pilalisi, BEZ235, GSK2126458, GSK2636771, AZD8186, SAR260301, gidaris, apellis, PQR309, MLN1117, and perifosine.

[0347] f. Vaccine

[0348] The compounds and compositions can also be used in vaccines. Vaccines contain the disclosed compounds or compositions and antigens or nucleic acids encoding them. 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 can be used.

[0349] Depending on the infectious disease, autoimmune disease, disorder, cancer, pathogen, or condition being treated using a given vaccine composition, the antigens may be derived from and / or isolated from essentially any desired source.

[0350] The vaccines described herein may be capable of providing immunity against one or more conditions associated with an infectious disease, including but not limited to influenza, measles, human papillomavirus (HPV), rabies, meningitis, pertussis, tetanus, rubella, hepatitis, and tuberculosis, and may include infectious disease-derived antigens and / or epitopes, or nucleic acids encoding the same.

[0351] The vaccines described herein may also direct an immune response against cancer cells, and may include tumor cell-derived antigens, epitopes and / or new epitopes, or portions thereof, or nucleic acids encoding tumor cell-derived antigens, epitopes and / or new epitopes. Tumor antigens are surface molecules differentially expressed by tumor cells relative to non-tumor tissues. Tumor antigens distinguish tumor cells from normal cells immunologically, and provide diagnostic and therapeutic targets for human cancers. Tumor antigens have been characterized as altered carbohydrate molecules of membrane proteins or glycoproteins or glycolipids on the cell surface. Cancer cells often have unique tumor antigens on their surfaces, such as truncated epidermal growth factor, folate binding protein, epithelial mucin, melanoferrin, carcinoembryonic antigen, prostate-specific membrane antigen, HER2-neu, which are candidates for therapeutic cancer vaccines. Because tumor antigens are normal or associated with normal components of the body, the immune system is usually unable to produce an effective immune response to those antigens to destroy tumor cells. Illustrative cancer types for which this method 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.

[0352] In other embodiments, the antigen present in the vaccine composition is not an exogenous 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, nervous system diseases, rheumatic diseases / connective tissue diseases, autoimmune cytopenias, and related autoimmune diseases. Such conventional organ-specific autoimmunity may include thyroiditis (Graves+Hashimoto's), gastritis, adrenalitis (Addison's), oophoritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, anti-receptor antibody disease, and vitiligo. Such nervous system diseases may include schizophrenia, Alzheimer's disease, depression, hypopituitarism, diabetes insipidus, Sjögren's syndrome, and multiple sclerosis. Such rheumatic diseases / 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 retinitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis and other immune related diseases, as described herein and known in the relevant art.

[0353] In one embodiment, the antigen in the vaccine composition is a peptide, polypeptide or an immunogenic portion thereof. As used herein, an "immunogenic portion" is a protein portion that is recognized (e.g., specifically bound) by a B cell and / or T cell surface antigen receptor. Such an immunogenic portion typically comprises at least 5 amino acid residues of the antigen protein or a variant thereof, more preferably at least 10, and even more preferably at least 20 amino acid residues.

[0354] The immunogenic portion of an antigenic polypeptide can be generally identified using well-known techniques, such as those summarized in Paul, Fundamental Immunology, 3rd edition, 243-247 (Raven Press, 1993) and the references cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, antisera and / or T cell lines or clones. As used herein, if antisera and antibodies specifically bind to an antigen (e.g., they react with proteins in ELISA or other immunoassays, and do not react detectably with unrelated proteins), they are "antigen-specific". Such antisera and antibodies can be prepared using known techniques. The immunogenic portion of a protein is a portion that reacts with such antisera and / or T cells, and its reaction level is not significantly lower than the reactivity of the full-length polypeptide (e.g., in ELISA and / or T cell reactivity assays). Such immunogenic portions can react at a level similar to or higher than the reactivity of the full-length polypeptide in such assays. Such screening can generally be performed using methods well known to those of ordinary 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 can be immobilized on a solid support and contacted with patient serum to allow antibodies in the serum to bind to the immobilized polypeptide. Unbound serum can then be removed and the antibody can be screened using, for example, 125 Bound antibodies were detected by I-labeled protein A.

[0355] Peptide and polypeptide antigens can be prepared using any of a variety of well-known techniques. Recombinant polypeptides encoded by DNA sequences can be easily prepared from isolated DNA sequences using any of a variety of expression vectors known to those of ordinary skill in the art. Expression can be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule encoding the recombinant polypeptide. Suitable host cells include prokaryotes, yeast, and higher eukaryotic cells, such as mammalian cells and plant cells. Preferably, the host cell used is an E. coli, yeast, or mammalian cell line, such as COS or CHO.

[0356] Portions and other variants of protein antigens having less than about 100 amino acids and generally less than about 50 amino acids may also be produced by synthetic methods using techniques well known to those of ordinary skill in the art. For example, such polypeptides may be synthesized using any commercially available solid phase technique (such as the Merrifield solid phase synthesis method, in which amino acids are sequentially added to a growing amino acid chain). See, Merrifield, J. Am. Chem. Soc. 85: 2149-2146, 1963. Equipment for automatic synthesis of polypeptides is commercially available from suppliers such as Perkin Elmer / Applied BioSystems Division (Foster City, Calif.), and may be operated according to the manufacturer's instructions.

[0357] In certain embodiments, the nucleic acid encoding the antigen is DNA. This type of illustrative DNA-based vaccine contains DNA encoding one or more polypeptide antigens so that the antigen is produced in situ. Alternatively, the vaccine can be a vaccine based on RNA. In certain embodiments, the nucleic acid encoding the antigen is mRNA. mRNA can encode any polypeptide antigen of interest, including any natural or non-naturally occurring or otherwise modified polypeptide. The polypeptide encoded by mRNA can be of any size and can have any secondary structure or activity. In some embodiments, the polypeptide encoded by mRNA can stimulate an immune response when expressed in a cell.

[0358] Vaccine compositions of the present disclosure may also contain other compounds, which may be biologically active or inactive. Vaccines or drugs may include adjuvants or immunostimulants, or polynucleotides encoding adjuvants or immunostimulants (e.g., adjuvant polypeptides). Adjuvants and immunostimulants are compounds or compositions that directly or indirectly stimulate the immune system's response to co-administered antigens. In some embodiments, vaccines are non-adjuvanted or self-adjuvanting.

[0359] Suitable adjuvants are commercially available, for example, glucose-based lipid adjuvant (GLA); Pam3CSK4; Freund's incomplete adjuvant 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 such as aluminum hydroxide gel (alum), AlK(SO4)2, AlNa(SO4)2, AlNH4(SO4), and Al(OH)3; calcium salts (e.g., Ca3(PO4)2), iron salts, or zinc salts; insoluble suspensions of acylated tyrosine; acylated sugars; cationic or anionic derivatized polysaccharides; polynucleotides (e.g., polyIC, polyAU, and CpG oligodeoxynucleotides (e.g., class A or class B)); polyphosphazenes; cyanoacrylates; polymerase-(DL-lactide-co-glycoside); bovine serum albumin; diphtheria toxoid; tetanus toxoid; erythrine; keyhole-limpet hemocyanin; Pseudomonas toxin A; cholera toxoid; cholera toxin; pertussis toxin; viral proteins; Quil A; aminoalkylglucosamine phosphate compounds. In addition, adjuvants such as cytokines (e.g., GM-CSF or interleukin-2, -7 or -12), interferons or tumor necrosis factor 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 skilled in the art. When obtained from recombinant sources, the adjuvant may comprise a protein fragment comprising at least the immunostimulatory portion of the molecule.

[0360] Other known immunostimulatory macromolecules that can be used include, but are not limited to, polysaccharides, tRNA, non-metabolizable synthetic polymers such as polyvinylamine, polymethacrylic acid, polyvinylpyrrolidone, mixed condensation polymers of 4',4-diaminodiphenylmethane-3,3'-dicarboxylic acid and 4-nitro-2-aminobenzoic acid (having relatively high molecular weight) (see Sela, M., Science 166: 1365-1374 (1969)), or glycolipids, lipids, or carbohydrates.

[0361] In some embodiments, adjuvant polypeptides include immune activating proteins, such as CD70, CD40 ligands and constitutively active TLR4, or polycationic peptides (e.g., protamine). In some embodiments, the adjuvant polypeptide is a flagellin polypeptide. Commercially available mRNA encoding adjuvant polypeptides can be used as, for example, 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 an anti-Müllerian hormone receptor II extracellular domain (AMHR2-ED), as described above, and the other encoding an adjuvant polypeptide (e.g., a flagellin polypeptide or an immune activating protein).

[0362] Vaccine preparation is a mature art, and general guidance for vaccine preparation and formulation is readily available from any of a variety of sources. One such example is New Trends and Developments in Vaccines, ed. Volier et al. University Park Press, Baltimore, Md., USA 1978. Vaccine compositions can generally be used for both prophylactic and therapeutic purposes.

[0363] The amount of antigen in each dose of vaccine is generally selected to induce an immunoprotective response without significant adverse side effects in typical vaccines. This amount will vary depending on the specific immunogen used and its presentation. Of course, the dose administered may be based on age, body weight, the type of concurrent treatment (if any) and the nature of the antigen administered.

[0364] The immunogenic activity of a given amount of a vaccine composition can be readily determined, for example, by monitoring increases in antibody titers against the antigens used in the vaccine composition (Dalsgaard, K. Acta Veterinia Scandinavica 69: 1-40 (1978)). Another common method involves injecting various amounts of the vaccine composition intradermally into CD-1 mice, after which serum is harvested from the mice and tested, for example, by ELISA, for anti-immunogen antibodies. These and other similar methods will be apparent to those skilled in the art.

[0365] 4. Usage

[0366] The disclosure provides a method for inducing or regulating an immune or inflammatory response. As used herein, the term "regulation" generally refers to the ability to change by increasing or decreasing, such as directly or indirectly promoting / stimulating / upregulating or interfering / suppressing / downregulating (for example, immune or inflammatory response) specific concentration, level, expression, function or behavior. In some embodiments, regulation is relative to a control, or relative to a generally expected average activity level, or relative to a control activity level, increasing and / or reducing a certain concentration, level, activity or function.

[0367] Therefore, in some embodiments, regulating immune or inflammatory response refers to the ability of the compounds of the present invention to change or regulate one or more aspects of immune or inflammatory response. In some embodiments, the method polarizes macrophages. In some embodiments, the method induces interferon response. In some embodiments, the method activates transcription factors (e.g., STAT6, IRF3) of innate immune response.

[0368] The present disclosure also provides methods for treating a disease or disorder comprising administering to a subject in need thereof a compound or composition as disclosed herein. In some embodiments, the subject is a human.

[0369] Diseases or conditions may include cancer, autoimmune diseases, inflammatory diseases, and infectious diseases.

[0370] In some embodiments, the disease or condition is an inflammatory disease or condition. The feature of an inflammatory disease is that the immune system in a tissue or organ is activated to an abnormal level, which may lead to abnormal tissue or organ function and / or disease. Inflammatory diseases and conditions treatable 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, Sjögren's syndrome or Churg-Strauss syndrome.

[0371] In some embodiments, the disease or disorder is an autoimmune disease or disorder.Autoimmune diseases and disorders refer to conditions in a subject characterized by damage to cells, tissues, and / or organs caused by an immune response of the subject to its own cells, tissues, and / or organs. Autoimmune diseases and conditions treatable by the methods of the invention include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, and inflammatory dysregulation of the thyroid gland. Indolent purpura (ITP), irritable bowel syndrome (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 syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, myotonia solium, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis such as dermatitis herpetiformis vasculitis, vitiligo, and Wegener's granulomatosis.

[0372] Some autoimmune disorders are also related to inflammatory conditions. Examples of inflammatory conditions 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), allergic disorders, pulmonary fibrosis, undifferentiated spondyloarthropathies, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation caused by chronic viral or bacterial infections. Examples of psoriasis types 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 related to immune disorders, including, for example, sinopulmonary infections, opportunistic pneumonia, inflammatory bowel disease, autoimmune hepatitis, and juvenile idiopathic arthritis and myelofibrosis.

[0373] In some embodiments, the disease or condition is cancer. In some embodiments, cancer comprises solid tumors. In some embodiments, cancer comprises blood cancer or lymphoma. In some embodiments, cancer is metastatic cancer. In some embodiments, the disclosed compounds, compositions or methods result in the elimination of inhibition of metastasis. 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.

[0374] The compounds and compositions herein can be used to treat various cancers, including carcinomas, sarcomas, lymphomas, leukemias, melanomas, mesotheliomas, multiple myeloma, or seminoma. The cancer can be bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon / rectum cancer, endometrial cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymph node cancer, muscle tissue cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, thyroid cancer, or uterine cancer.

[0375] 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.

[0376] In some embodiments, the disease or condition is an infectious disease. Infectious diseases that can be treated or prevented by the methods of the present invention are caused by infectious sources, including but not limited to viruses, bacteria, fungi, protozoa, worms 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, such as Mycobacterium tuberculosis, Chlamydia, Francisella tularensis; DNA viruses, such as Herpesviridae (Herpes simplex virus-1, Kaposi's sarcoma-associated virus and Epstein-Barr virus), Papillomaviridae (Human papillomavirus), Adenovirus and Hepadnaviridae (Hepatitis B virus) or RNA viruses, such as Retroviridae (Human immunodeficiency virus), Flaviviridae (Dengue virus, Hepatitis C virus), Orthomyxoviridae (Influenza) and Coronaviridae (Human coronavirus and SARS coronavirus).

[0377] The compounds and compositions disclosed herein can be administered to a subject by various methods. In any use or method described herein, the compounds and compositions disclosed herein can be administered by various routes known to those skilled in the art, including but not limited to oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic and / or intraperitoneal administration to a subject in need thereof.

[0378] The amount of the disclosed compound to be used in the disclosed method varies not only with the selected specific compound, but also with the route of administration, the nature and / or symptoms of the disease, and the age and illness of the patient, and will ultimately be determined by the attending physician or clinician. The determination of the effective dose level (i.e., the dose level required to achieve the desired result) can be completed by those skilled in the art using conventional methods (e.g., human clinical trials, in vivo studies, and in vitro studies). For example, a useful dose can be determined by comparing its in vitro activity with the in vivo activity in an animal model.

[0379] The amount and interval of the dosage can be adjusted individually to provide a plasma level of the active part sufficient to maintain the modulatory effect, or the minimum effective concentration (MEC). The MEC of each compound will vary, but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90%, and most preferably between 50-90%. In the case of local administration or selective uptake, the effective local concentration of the drug may be independent of the plasma concentration.

[0380] It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunction. Conversely, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. In the management of the condition of interest, the size of the administered dose will vary with the severity of the symptoms to be treated and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, weight and response of the individual patient. Comparable procedures to those discussed above can be used in veterinary medicine.

[0381] Compounds and compositions disclosed herein can be evaluated for their efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical moieties or their compositions can be determined by determining in vitro toxicity to a cell line (such as a mammalian cell line, and preferably a human cell line). The results of such studies can generally predict toxicity in animals (such as mammals or more specifically humans). Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, dog or monkey model, can be determined using known methods. Several recognized methods can be used to determine the efficacy, such as in vitro methods, animal models or human clinical trials. When selecting a model to determine the efficacy, those skilled in the art can select an appropriate model, dosage, route of administration and / or regimen under the guidance of the prior art.

[0382] A variety of second therapies can be used in combination with the compounds of the present disclosure. The second therapy can be the administration of an additional therapeutic agent, or can be a second therapy unrelated to the administration of another agent. Such second therapies include, but are not limited to, surgery, immunotherapy, radiotherapy.

[0383] The second therapy can be administered simultaneously with the initial therapy, or in the same composition, or in a separate composition that is administered substantially simultaneously with the first composition. In some embodiments, the second therapy can precede or follow treatment with the first therapy with a time interval ranging from a few hours to several months.

[0384] In some embodiments, a therapeutically effective amount of a compound disclosed herein, or a composition thereof, may be administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, effective combination therapy is achieved using a single composition or pharmacological formulation comprising both agents, or using two different compositions or formulations administered simultaneously or separated by a time interval, wherein one composition comprises a compound of the invention and the other composition comprises at least one additional therapeutic agent.

[0385] In some embodiments, the at least one additional therapeutic agent comprises an immunomodulator, a chemotherapeutic agent, a nucleic acid (e.g., an mRNA, an aptamer, an antisense oligonucleotide, a ribozyme nucleic acid, an interfering RNA, an antigen nucleic acid), a decongestant, a steroid, an analgesic, an antibacterial agent, an immunotherapy, or a combination thereof.

[0386] Exemplary immunomodulators include: indoleamine 2,3-dioxygenase (IDO) inhibitors and analogs thereof, such as epasta, BMS-986205, indomod, PF-06840003 and analogs thereof; signal transducer and activator of transcription 3 (Stat3) inhibitors and analogs thereof, such as SM-36 and analogs thereof; toll-like receptor (TLR) agonists and analogs thereof, such as imiquimod, resiquimod, segamod, gademod, SM-360320, TMX-101, TMX-202, TMX-302, TMX-306, GSK2245035, CL097, 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, such as atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, mevastatin, pitavastatin, rosuvastatin and their analogs.

[0387] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent.As used herein, the term "chemotherapeutic drug" or "anti-cancer drug" includes any small molecule or other drug used for cancer treatment or prevention. Chemotherapeutic drugs include but are not limited to cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemaciclib, afinitor (everolimus), apellis, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, imatinib, lapatinib, olaparib, megestrol acetate, neratinib, palbociclib, ribociclib, talazopanib, thiotepa, toremifene, methotrexate and tucatinib. In selected embodiments, the chemotherapeutic agent includes paclitaxel.

[0388] In some embodiments of the methods disclosed herein, a compound or composition can be co-administered with an antimicrobial agent (eg, an antiviral agent or a bactericidal agent). In some embodiments, the additional antibacterial agent is an antiviral agent, including but not limited to abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, baloxavir marboxil, bictegravir, boceprevir, bulevirtide, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, doravirine, edoxuridine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunoxuridine, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, iod ...amciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, iodoxuridine, imiquimod, imunoxuridine, imunoxuridine, imunoxuridine, imunoxuridine, imunoxuridine, imun ovir), indinavir, lamivudine, letermovir, lopinavir, loviramide, maraviroc, methisazone, morpholino, nelfinavir, nevirapine, nexavir, nitazoxanide, oseltamivir, penciclovir, peramivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, remdesivir, ribavirin, rilpivirine, rilpivirine, rimantadine, rintatolimod, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, taliverine, telaprevir, telbivudine, tenofovir (e.g., tenofovir alafenamide, alafenamide or tenofovir disoproxil), tipranavir, trifluridine, tromantine, umifenovir, valacyclovir, valganciclovir, vicriviroc, vidarabine, zalcitabine, zanamivir and zidovudine, and any combination thereof.

[0389] In some embodiments, the additional antimicrobial agent is a bactericide. Exemplary bactericides include sulfonamides, amides, spectinomycin, trimethoprim, glycylcyclines, macrolides (e.g., erythromycin, clarithromycin, azithromycin, roxithromycin), oxazolidinones (e.g., linezolid), tetracyclines (e.g., doxycycline, tetracycline, minocycline), beta-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).

[0390] In some embodiments, the second therapy comprises immunotherapy. Immunotherapy includes chimeric antigen receptor (CAR) T cells or T cell transfer therapy, cytokine therapy, immunomodulators, cancer vaccines, or administration of antibodies (e.g., monoclonal antibodies).

[0391] In some embodiments, immunotherapy includes administering antibodies. Antibodies can target 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 known as erbB or EGFR), VEGF, CTLA-4 (also known as CD152), epithelial cell adhesion molecule (EpCAM, also known as 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, etc.). 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 linked to a chemotherapeutic agent. Thus, in some embodiments, the antibody is an antibody-drug conjugate.

[0392] Immunotherapy (e.g., administration of antibodies) can be administered to a subject by a variety of methods. In any of the uses or methods described herein, various routes known to those skilled in the art can be used, including but not limited to oral, inhaled, intravenous, intramuscular, topical, subcutaneous, systemic and / or intraperitoneal administration to a subject in need. Immunotherapy can be administered by parenteral administration (including but not limited to subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac and intraarticular injection). In some embodiments, immunotherapy can be administered in the same or different manner as the compounds or compositions disclosed herein.

[0393] 5. Kit

[0394] In another aspect, the present disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof, and instructions for using the compound or composition.

[0395] Kits may also include other agents and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, doctor, pharmacy, or pharmacist may provide a kit containing a disclosed compound and / or product and another agent for delivery to a patient.

[0396] The kit may also include instructions for using the kit components. Instructions are related materials or methods related to the kit. Materials may include any combination of background information, component lists, brief or detailed schemes for using the composition, problem solving, references, technical support, and any other related documents. Instructions may be provided with the kit or in separate element components (as written or electronic form that can be provided on a computer-readable storage device or downloaded from an Internet website), or in a recorded demonstration.

[0397] It should be understood that the disclosed kits can be used in combination with the disclosed methods. The kits can also include containers or devices for use with the methods or compositions disclosed herein. The kits can optionally provide additional components, such as buffers and disposable equipment (e.g., pipettes, cell culture plates or flasks).

[0398] The kits provided herein are packaged in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, soft packaging, etc. The components of the kit can be physically packaged together or individually.

[0399] 6. Examples

[0400] The abbreviations used in the following schemes and examples are: BOC is tert-butyloxycarbonyl; Boc2O is di-tert-butyl dicarbonate; DCM is dichloromethane; DMAP is 4-dimethylaminopyridine; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq is equivalent; EtOAc is ethyl acetate; MeOH is methanol; RT or rt is room temperature; and THF is tetrahydrofuran.

[0401] All air and moisture sensitive operations were performed under argon or vacuum using standard Schlenk techniques. Anhydrous solvents (Et2O, THF, dioxane, DMSO, DMF, DCM and toluene) were purchased from Fisher Scientific. All chemicals were purchased from Fisher Scientific, Sigma Aldrich, TCI WUXI Apptec and DC Chemicals Europe and used without further purification unless otherwise noted.

[0402] Analytical thin layer chromatography (TLC) was performed using Merck SIL G / UV254 plates. Compounds were visualized by exposure to UV light or immersion of the plates in ninhydrin or potassium permanganate solution followed by heating or staining with iodine vapor in a wide pot chamber. Column chromatography was performed in air using silica gel 60 (Fluka). Column chromatography was performed using Merck Kieselgel 60 (200-500 mm). Solvent systems (s / sv:v) are given.

[0403] NMR spectroscopy 1 H(300MHz), 13 C (75 MHz) were recorded on an ARX 300 or Avance II 500 Bruker spectrometer, respectively. Chemical shifts (δ, ppm) are given with reference to the residual 1H or 13C of the deuterated solvent in the indicated solvent (CDCl3 7.26, 77.00; (CD3)2CO 2.05, 29.84 and 206.26, (CD3)2SO 2.50, 39.52). 1H- and 13C-NMR chemical shifts (δ) are in parts per million (ppm) relative to the TMS scale. Coupling constants J are in Hz. The following abbreviations are used for proton spectral multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, m: multiplet, br.: broad, dd: doublet of doublets, dt: doublet of triplets. Coupling constants (J) are reported in Hertz (Hz). Some unattributable signals will be indicated by ArH (aromatic hydrogen).

[0404] Mass spectra (MS) were recorded using a LCQ-advantage (ThermoFinnigan) mass spectrometer with positive (ESI+) or negative (ESI-) electrospray ionization (ionization tension 4.5 kV, injection temperature 240°C).

[0405] Example 1

[0406] Compound synthesis

[0407] General procedure 1: Esterification

[0408] Under nitrogen atmosphere, a solution of carboxylic acid derivative (1eq), EDC hydrochloride (1eq) and DMAP (0.5eq) in anhydrous THF (0.1M) was stirred at 0°C for 0.5h. A solution of alcohol (1eq) in anhydrous THF (0.1M) was then added. The solution was stirred at 0°C to rt for 16h. The reaction progress was monitored by TLC using CH2Cl2-MeOH 10:1 mixture as eluent and using ARX300Brucker spectrometer1H NMR. After the reaction was completed, the mixture was extracted with dichloromethane (3x). The organic layer was merged and 0.2M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine washing were used respectively. Then, the solid residue was purified by manual column chromatography using CH2Cl2-EtOAc or CH2Cl2-MeOH step gradient solvent system as eluent to obtain the title product.

[0409] The synthesis of the bifunctional compounds used the general esterification procedure described above, as described in the following steps.

[0410] 3-((1-methyl-L-tryptophanyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thien-2-yl)-4-oxobutyrate

[0411]

[0412] Step 1: N α -(tert-Butyloxycarbonyl)-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 RT for 16 h. The mixture was washed with 1N aqueous HCl and brine to give the desired product.

[0413] Step 2: 3-Hydroxypropyl N α (tert-Butyloxycarbonyl)-1-methyl-D-tryptophanate. According to General Procedure 1, at room temperature, a mixture of N α The title compound was synthesized from -(tert-Butyloxycarbonyl)-1-methyl-D-tryptophan (1 eq), 1,2-tetradecanediol (1.2 eq), EDC.hydrochloride (1 eq), DMAP (0.5 eq) in anhydrous THF (0.1 M) over 4 h.

[0414] Step 3: 3-((N α -(tert-Butyloxycarbonyl)-1-methyl-D-tryptophanyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate. According to General Procedure 1, 3-hydroxypropyl N αThe title compound was synthesized from (tert-Butyloxycarbonyl)-1-methyl-D-tryptophanate (1 eq), 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (1 eq), EDC hydrochloride (1 eq), DMAP (0.5 eq) in anhydrous THF (0.1 M) over 4 h.

[0415] Step 4: 3-((1-methyl-D-tryptophanyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thien-2-yl)-4-oxobutanoate was prepared from a stirred solution of 3-((N α The title compound was synthesized from a solution of -(tert-butoxycarbonyl)-1-methyl-(D-tryptophanyl)oxy)propyl 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (1 eq) in dioxane HCl (HCl 4M in dioxane) over 5 h.

[0416] (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)

[0417]

[0418] 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 CH2Cl2 (3 mL) was added CuI.A-21 catalyst (16.5 mg, 10 mol%). The reaction mixture was sonicated for 1 h and stirred at room temperature overnight. After completion of the reaction, the catalyst was filtered off using CH2Cl2, and the solvent was evaporated in vacuo. The crude product was then purified by column chromatography to provide compound DMA01-148 (95 mg, 80% yield). 1HNMR(500MHz, CDCl3)δ8.44(dd,J=23.4,5.4Hz,2H),8.03–7.83(m,2H),7.74(d,J=7.4Hz,1H),7.62(t,J=7.7Hz,1H),7.54–7.35(m,5 H), 6.80 (dd, J = 6.5, 4.4Hz, 1H), 6.71 (s, 1H), 4.80 (p, J = 6.8Hz, 1H), 4.46–4.25 (m, 2H), 3.89 (t, J = 4.9Hz, 2H), 1.41 (d, J = 6.8Hz, 3H).

[0419] Synthesis (esterification) of DMA01-166: A solution of 4-(5,6-dimethoxybenzo[b]thiophene-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, then at room temperature for 48 h. After the reaction was completed, the reaction mixture was diluted in CH2Cl2 and washed with saturated NaHCO3 aqueous solution, water and brine, respectively. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. Purification by column chromatography provided compound DMA01-166 (90 mg, 74% yield). 1 H NMR (500MHz, CDCl3) δ8.48–8.39(m,2H),8.09(s,1H),7.95(d,J=7.0Hz,1H),7.87(dd,J=7.5,1.4Hz ,1H),7.82(s,1H),7.61(t,J=7.7Hz,1H),7.53–7.36(m,5H),7.22(s,1H),7.18(s,1H),6.81(dd,J=6 .7,4.4Hz,1H),6.69(s,1H),4.80(p,J=6.8Hz,1H),4.59(dd,J=5.8,4.3Hz,2H),4.49(t,J=5.1Hz,2 H), 3.97 (s, 3H), 3.92 (s, 3H), 3.26–3.03 (m, 2H), 2.64 (td, J = 6.6, 1.8Hz, 2H), 1.40 (d, J = 6.8Hz, 3H).

[0420] 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)-octadecane-9,12-dienoate (DMA01-170)

[0421]

[0422] Synthesis of DMA01-170: According to the above esterification method, compound DMA01-170 was obtained from DMA01-148 and linoleic acid.

[0423] 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)

[0424]

[0425] Synthesis of DMA01-173: According to the above esterification method and the deprotection of Boc with dioxane containing HCl, DMA01-148 and N α -(tert-Butyloxycarbonyl)-1-methyl-D-tryptophan to obtain compound DMA01-173.

[0426] (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)

[0427]

[0428] Synthesis of DMA01-132: DMSO (0.9 mL, 0.4 M) containing (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 azidoacetate (25% in toluene, 180 μL, 0.35 mmol, 1 eq) and CuI (8 mg, 10 mol%) was triturated in an ultrasonic bath for 0.5 h, then heated at 60 °C overnight, followed by column purification (SiO2, CH2Cl2-MeOH 97:3) to give the desired product (150 mg, 75% yield) as an off-white solid. 1H NMR(300MHz,MeOD)δ8.66(dd,J=6.8,1.6Hz,1H),8.49(dd,J=4.5,1.6Hz,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=6.8Hz,1H),4.21(q,J=7.1Hz,2H),1.45(d,J=6.8Hz,3H),1.25(t,J=7.1Hz,3H).

[0429] Synthesis of DMA01-143: THF (1 mL) containing DMA01-132 (31 mg, 0.05 mmol, 1 eq) was treated with an aqueous solution of LiOH (2 mg 0.08 mmol, 1.5 eq) and NaCl (5 mg, 0.081 mmol, 1.5 eq) in 0.3 mL of H O. Methanol (0.3 mL) was added to the mixture, and the reaction was stirred at room temperature overnight, followed by pTLC purification (SiO, CHCl-MeOH 9: 1, duration: 18 h) to give the desired product (5 mg, 17% yield) as an off-white solid. 1 H NMR(300MHz,MeOD)δ8.70(dd,J=6.7,1.7Hz,1H),8.51(dd,J=4.5,1.6Hz,1H),8.21(d,J=7.0Hz,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=6.9Hz,1H),1.47(d,J=6.7Hz,3H).

[0430] 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)

[0431]

[0432] SH-233 was synthesized by a method similar to the synthesis method of DMA01-166 described above, using 2-azidopropan-1-ol instead of 2-azidoethanol. 1H NMR(500MHz,cdcl3)δ8.44(dd,J=14.6,5.7Hz,2H),8.15–7.57(m,5H),7.54–7.32(m,7H), 7.25–7.10(m,3H),6.81(t,J=5.7Hz,1H),6.67(t,J=6.1Hz,1H),5.57(s,2H),4.83–4.74(m ,1H),4.40(dd,J=14.6,6.6Hz,1H),4.00–3.95(m,3H),3.95–3.90(m,3H),3.64(s,1H),3.3 6(d,J=12.3Hz,1H),3.12–2.99(m,1H),2.60(q,J=6.8Hz,1H),1.39(dd,J=9.6,7.0Hz,6H).

[0433] Example 2

[0434] STING activation by dual-function NCEs.

[0435] The THP-1 ISG Blue cell assay is a standard assay for testing STING activation in vitro. DMA01-166 showed enhanced interferon signaling 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.

[0436] Example 3

[0437] Activation of bone marrow dendritic cells (BMDCs) by dual-functional NCEs.

[0438] STING activation induces BMDC activation. To test the ability of DMA01-166 to activate BMDC, BMDC activation was measured by flow cytometry based on upregulation of CD80 and CD86. 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).

[0439] Example 4

[0440] Dual-function NCE induced by mIFNβ secretion.

[0441] STING activation in BMDCs leads to mIFNβ secretion. DMA01-166 showed higher mIFNβ secretion compared with MSA-2 ( Figure 6 ). In contrast, DMA01-173 could not enhance mIFNβ secretion. Figure 7 ) were incubated with BMDC cells for 24 hours. DMA01-166 showed a dose-independent BMDC activation effect.

[0442] Example 5

[0443] Macrophage polarization by dual-function NCEs.

[0444] Both STING activation and PI3K inhibition induced macrophage polarization from the M2 to the M1 phenotype for higher TNFα secretion compared to IPI-549, MSA-2, ADU, and cGAMP, four compounds that have been well studied for their effectiveness on macrophage polarization ( Figure 8 DMA01-173 and DMA01-170 also showed macrophage polarization effects compared to the M2 control group ( Figure 8 The macrophage polarization effect of dual-function NCEs was further tested by first inducing RAW264.7 cells into M2 macrophages and then treating them with different 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 a slight effect on increasing the percentage of M1 ( Fig. 9 DMA01-166 showed a dose-independent macrophage polarization effect ( Fig.10 ).

[0445] Example 6

[0446] PI3K inhibition by dual-function NCEs.

[0447] PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ binding assay kits were obtained from BPS Bioscience (SanDiego, CA, USA). The assay was performed in a 96-well microplate according to the manufacturer's protocol. In short, 5 μL PI3K lipid substrates were added to all wells. Then 5 μL of IPI-549, DMA01-148, 143, 132 or 166 of different concentrations were added, followed by 5 μL ATP (12.5 μM). 10 μL PI3Kα (0.5 ng / μL, PI3Kβ 4 ng / μL, PI3Kγ 4 ng / μL or PI3Kδ 13 ng / μL) were added to start the reaction. The plate was carefully shaken, and the reaction mixture was incubated at 30 ° C for 40 minutes. Then 25 μL ADP-Glo ​​reagent (Promega, Madison, WI, USA) was added to each well, and the reaction was carried out in the dark for 45 minutes. 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 minutes. The luminescence of the reaction mixture was read on a Synergy 2 microplate reader (Biotek).

[0448] IPI-549, DMA01-148, DMA01-143, DMA01-132, DMA01-166, DMA01-170, DMA01-173 were tested for their inhibition of different isoforms of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ ( Fig.11 ). IC50 of compounds for different PI3K isoforms were calculated using Prism 8 (Table 1). DMA01-148 selectively inhibited PI3Kγ with similar efficacy compared to IPI-549. DMA01-143 and DMA01-132 both inhibited PI3Kγ and PI3Kδ. DMA01-166 had no effect on PI3Kα and PI3Kβ, but inhibited PI3Kγ at 349 nM.

[0449] Table 1: In vitro inhibitory activity (IC50) of IPI-549, DMA01-148, 143, 132, and 166 against different isoforms of PI3K

[0450]

[0451] Example 7

[0452] DMA01-166 nanoparticles

[0453] DMA01-166 was dissolved in 1 mL of chloroform (organic phase) and then added dropwise to human serum albumin (66 kDa) dissolved in 20 mL of Milli Q water (aqueous phase) to produce a milky emulsion using a rotor-stator homogenizer. A crude Nano-166 emulsion was obtained after 6 cycles of low pressure (20,000 psi) on a high pressure homogenizer (Nano DeBEE). The organic solvent was removed by rotary evaporation at 25°C. After filtering through a 0.22 μm filter, the resulting Nano-PI suspension was lyophilized to obtain a dry powder for long-term storage at -20°C. As tested by dynamic light scattering (DLS), the size of Nano-166 is approximately 120 nm with a PDI of less than 0.2. The size measured by TEM is less than 100 nm. Nano-166 is stable after dilution 10,000 times ( Fig.12 ).

[0454] The in vivo efficacy of DMA01-166 and its albumin nanoformulation was tested on the KPC transgenic model. DMA01-166 plus PD-1 antibody (D166+PD-1) showed a longer median survival of 185.5 days compared to DMA01-166 (D166 157.5 days) or PD-1 alone (PD-1 132.5 days). Nano-D plus PD-1 antibody (Nano-D+PD-1) showed the longest median survival (185.5 days). Adding paclitaxel albumin nanoformulation (Nano-P) did not change the median survival time ( Fig.13 ).

[0455] It should be understood that the foregoing detailed description and the accompanying examples are merely illustrative and should not be taken as limiting the scope of the present disclosure, which is defined solely by the appended claims and their equivalents.

[0456] Various changes and modifications to the disclosed embodiment will become apparent to those skilled in the art and can be made without departing from the spirit and scope thereof.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 Selected from O, NR w , S and key; R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, halo-C1-C4-alkyl, amino-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, halo, hydroxy, amino, C1-C4-alkylamino, di-C1-C4-alkylamino and cyano; wherein R 1a and R 1b , or R 1a and R 2a , or R 2a and R 2b optionally taken together with the carbon atom to which it is attached to 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; R 3 , R 4 , R 5 , R 6 and R 7 each independently selected from hydrogen, 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y 2. -SO2R z , oligoethylene glycol chains or polyethylene glycol chains and groups -YR 8 ; where R 4 and R 5 , R 5 and R 6 or R 6 and R 7 optionally taken together with the carbon atom to which it is attached to form an optionally substituted 5- or 6-membered ring; Y is selected from -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 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and halo-C1-C6-alkyl; L is a connector; and Z is a moiety of formula (a) or formula (b): Where R 10 is hydrogen or C1-C6 alkyl; in: Q is CH or N; A is aryl or a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O, S and P; R 20 Selected from 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 , where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 and R a7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl; R 21 Selected from hydrogen and the group -L 21 -E, where: 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, or wherein L 21 Combinations comprising any two of such groups; E is a bicyclic heterocyclyl or a bicyclic heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6-cycloalkyl-C 1-4 -alkyl, C1-C4 haloalkyl, oxo, -OR b1 , -N(R b2 )(R b3 ),-SO2R b4 、-SO2N(R b5 )(R b6 ) and -NHSO2R b7 Substituents, where R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl; L b For –(CR c1 R c2 ) m -G b -,in: R c1 and R c2 independently selected from hydrogen and C1-C4 alkyl; m is 0, 1 or 2; and G b is a bond, -NHC(O)-, -NH-, -O-, or -S-; and B is a bicyclic heteroaryl or a bicyclic heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from 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 Substituents, where R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 Each is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

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

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

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 For hydrogen.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 5 and R 6 Each is independently selected from 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, di-C1-C4-alkylamino, cyano, -COOR x 、-CON(R y )2 and -SO2R z .

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 5 and R 6 Each is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C6 alkylthio, halo-C1-C4-alkyl, halo-C1-C4-alkoxy, hydroxy, halo and C1-C4-alkylamino.

7. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R 5 and R 6 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 5 and R 6 Each is independently selected from C1-C4 alkoxy.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 7 For hydrogen.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl and hydroxy.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1a , R 1b , R 2a and R 2b Each is independently selected from hydrogen and C1-C4 alkyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 1b , R 2a and R 2b is hydrogen, and R 1a Selected from hydrogen and C1-C4 alkyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1a and R 2a is hydrogen, and R 1b and R 2b Together with the carbon atom to which it is attached, it forms a 3-membered ring.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 3 is selected from hydrogen and halo.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 3 For hydrogen.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the compound is a compound of formula (Ia):

17. A compound as claimed in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z is a moiety of formula (a).

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 10 It's methyl.

19. A compound as claimed in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z is a moiety of formula (b).

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the moiety of formula (b) is a moiety of formula (bi):

21. The compound or pharmaceutically acceptable salt thereof according to claim 19 or 20, wherein A is phenyl.

22. A compound according to any one of claims 19 to 21 or a pharmaceutically acceptable salt thereof, wherein R 20 For hydrogen.

23. The compound of any one of claims 19 to 22, or a pharmaceutically acceptable salt thereof, wherein Q is CH.

24. A compound as described in any one of claims 19 to 23, or a pharmaceutically acceptable salt thereof, wherein R 21 A group selected from hydrogen and the following formula:

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 19 to 24, wherein the moiety of formula (b) is:

26. A compound as described in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein L comprises one or more groups independently selected from -C(R')2-, -CH=CH-, -C≡C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene and heterocyclylene, wherein each R' is independently selected from hydrogen, C1-C 80 Alkyl, C2-C 80 Alkenyl, C2-C 80 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, and wherein each alkyl, arylene, heteroarylene, cycloalkylene and heterocyclylene is independently unsubstituted or substituted with 1, 2 or 3 substituents.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein L comprises one or more groups independently selected from -C(R')2-, -C≡C-, -O-, -NH-, -C(O)-, and heteroarylene, wherein each R' is independently selected from hydrogen, C1-C 40 Alkyl, phenyl and -CH2-heterocyclyl (e.g., wherein the heterocyclyl is a 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S), wherein the phenyl and the heterocyclyl are each independently unsubstituted or substituted with 1 or 2 substituents.

28. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

29. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, wherein the composition comprises albumin nanoparticles, liposomes, micelles or lipid nanoparticles.

31. The pharmaceutical composition of claim 30, wherein the composition further comprises albumin nanoparticles.

32. The pharmaceutical composition of claim 31, wherein the albumin is human serum albumin or albumin from an animal species.

33. The composition of any one of claims 29 to 32, wherein the composition further comprises at least one additional therapeutic agent.

34. The composition of claim 33, wherein the at least one additional therapeutic agent comprises an immunomodulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antibacterial agent, an immunotherapy, or a combination thereof.

35. The composition of claim 33 or 34, wherein the at least one additional therapeutic agent comprises an RNA selected from the group consisting of small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), micro RNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA), and mixtures thereof.

36. The composition of claim 33 or 34, wherein 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.

37. A composition as described in any one of claims 29 to 36, further comprising one or more cell targeting epitopes.

38. The composition of claim 37, wherein the one or more cell targeting epitopes are covalently linked or directly conjugated to albumin.

39. The composition of claim 37 or 38, wherein the cell targeting epitope comprises an immune cell epitope.

40. A composition as described in claim 37 or 38, further comprising one or more epi-topes from a microbial agent.

41. A vaccine comprising an effective amount of A compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 29 to 40; as well as Antigen or nucleic acid encoding the same.

42. The vaccine of claim 41, wherein the antigen is a tumor antigen, an autoantigen, or an infectious disease-derived antigen.

43. The vaccine of claim 41 or 42, wherein the nucleic acid is messenger RNA (mRNA).

44. A method of treating or preventing a disease or disorder comprising administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, a composition as described in any one of claims 29 to 40, or a vaccine as described in any one of claims 41 to 43.

45. The method of claim 44, wherein the disease or condition comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease.

46. ​​The method of claim 44 or 45, wherein the disease or condition is cancer.

47. The method of claim 46, wherein the subject has cancer, has had cancer, is susceptible to cancer, or has a family history of cancer.

48. The method of any one of claims 45 to 47, wherein the cancer comprises a solid tumor or a hematological cancer.

49. The method of any one of claims 45 to 48, wherein the cancer is a metastatic cancer.

50. The method of any one of claims 45 to 49, wherein the method inhibits or eliminates cancer metastasis, reduces tumor growth, prevents tumor recurrence, or any combination thereof.

51. The method of any one of claims 44 to 50, wherein the administration comprises a primary immunization and at least one subsequent immunization.

52. A method of inducing or modulating an immune or inflammatory response in a subject, comprising administering to a subject in need thereof a compound as described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, a composition as described in any one of claims 29 to 40, or a vaccine as described in any one of claims 41 to 43.

53. The method of any one of claims 44 to 52, wherein the subject is a human.

54. The method of any one of claims 44 to 53, further comprising administering at least one additional therapeutic agent.

55. The method of claim 54, wherein the at least one additional therapeutic agent comprises an immunomodulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antimicrobial agent, an immunotherapy, or a combination thereof.

56. Use of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 28 or a composition as described in any one of claims 29 to 40 in the manufacture of a medicament for treating or preventing a disease or condition.

57. The use of claim 56, wherein the disease or condition comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease.

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