2'3'-Cyclic dinucleotides and prodrugs thereof

Abstract

The present invention relates to 2'3' cyclic phosphonic acid dinucleotides of formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations of said substances with other agents or medicines. The present invention also relates to the use of said compounds for treating or preventing diseases or conditions that can be improved by regulating STING proteins, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 815,170, filed on March 7, 2019, and U.S. Provisional Application No. 62 / 862,460, filed on June 17, 2019, which are both incorporated herein in their entirety for all purposes. Technical Field

[0003] The present invention relates to 2'3' cyclic dinucleotides and their derivatives, which are suitable for treating diseases that can benefit from regulating the STING adaptor protein (stimulator of interferon genes), such as inflammatory, allergic and autoimmune diseases, cancer and viral infections such as chronic hepatitis B and human immunodeficiency virus, and for preparing immunogenic compositions or vaccine adjuvants. Background Art

[0004] The innate immune system recognizes the presence of pathogens or the host's homeostasis through a series of pattern recognition receptors (PRRs), which detect a small ligand set associated with pathogens or damage. The ligands are generally referred to as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (Takeuchi O et al., Cell, 2010: 140, 805-820). Over the past two decades, a variety of PRRs have been identified, including Toll-like receptors, retinoic acid-inducible gene (RIG-I)-like receptors, nucleotide-binding oligomerization domain-like (NOD) receptors, C-type lectin receptors, and cytosolic DNA sensors (Brubaker SW et al., Annu Rev Immunol, 2015: 33, 257-290). Recognition of PAMPs and DAMPs by PRRs ultimately leads to the upregulation of cytokines and chemokines (including interferons), and the recruitment of immune cells to the site of infection. All of these processes slow down pathogen replication and promote the generation of adaptive immunity.

[0005] Cellular DNA is normally confined to the nucleus and mitochondria of healthy cells. Therefore, DNA present in the cytosol represents a signal indicating the presence of pathogens or disruption of host homeostasis. Sensing of exogenous DNA is initiated by several DNA sensors, such as the DNA-dependent activator of IRFs (DAI) or DEAD box polypeptide 41 (DDX41). These DNA sensors signal by recruiting the protein kinase TBK1, which triggers activation of the transcription factors NF-κB (nuclear factor κB) and IRF-3 (interferon regulatory factor 3), via the STING adaptor protein (stimulator of interferon genes, also known as STING, STING protein, TMEM173, MITA, or ERIS) (Unterholzner L, Immunology, 2013: 218, 1312-1321). Activation of the STING adaptor protein is believed to ultimately lead to the release of type I and type III interferons, as well as a variety of cytokines and chemokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ).

[0006] Alternatively, the STING adaptor protein can be activated by second messenger cyclic dinucleotides (CDNs) (Burdette et al. Nature 2011: 478, 515-518). CDNs with affinity for STING contain two purine nucleotide monophosphates linked to two 3'-5' (3'3'-CDN), two 2'-5' (2'2'-CDN), or 2'-5' and 3'-5' phosphodiester bonds (2'3'-CDN). The prototype 2'3'-cGAMP (c[G(2',5')pA(3',5')p]) is the product of activation of the host cGAS protein in the presence of pathogens or self-dsDNA (Zhang et al. Molecular Cell 2013: 51, 226-235).

[0007] Type I interferon (IFN) is an immunomodulatory cytokine that plays a key role in viral immunity. It can induce maturation and activation of dendritic cells (DC) and macrophages (Galluci et al., Nat Med, 1999: 5, 1249-1255) and can promote T cell and B cell survival, activation and differentiation. In addition, interferon can activate many intracellular pathways that inhibit viral replication. The clinical effectiveness of type I interferon has been demonstrated by its effectiveness in treating chronic hepatitis B and C (Lin and Young, Cytokine Growth Factor Rev, 2014: 25, 369-376).

[0008] In addition, interferon has shown efficacy in the treatment of human cancers (Cohen et al., N Engl J Med, 2005: 353, 2477-2490, Tsao et al., N Engl J Med, 2004: 351, 998-1012). It can inhibit tumor cell proliferation and can synergize with many approved anticancer agents. In addition, type I IFN can act on immune cells to induce anti-tumor responses (Musella et al., Oncoimmunology 2017: 6: e1314424). Type I IFN signaling has been shown to be crucial in priming tumor-initiating T cells in mice. Animals lacking IFN-α / β receptors in dendritic cells are unable to suppress immunogenic tumors and are defective in antigen cross-presentation to CD8+ T cells (Fuertes et al., J Exp Med, 2011: 208, 2005-2016, Diamond et al., J Exp Med, 2011: 208: 1989-2003). Consistent with these observations, intratumoral injection of STING protein agonists has been shown to induce regression of established tumors in mice and generate substantial systemic immune responses that can inhibit distant cancer metastasis and provide immunological memory for long-term survival (Corrales et al., Cell Rep, 2015: 11, 1018-1030).

[0009] It is believed that CDN can promote the priming of cellular and humoral immunity. For example, CDN has been shown to be an effective adjuvant in animal models (Dubensky et al., Ther Adv Vaccines, 2013: 1, 131-143).

[0010] Patent publications WO 2014 / 093936, WO 2014 / 189805, WO 2013 / 185052, US 2014 / 03441976, WO 2015 / 077354, WO 2015 / 185565, WO 2016 / 145102, WO 2017 / 093933、WO 2017 / 027646、WO 2017 / 027645、WO 2017 / 175156、WO 2017 / 175147、WO 2017 / 123657、WO 2018 / 013908、WO 2018 / 013887, WO2018 / 009652, WO 2018 / 009648 and WO 2018 / 009466 discloses certain CDNs and their use in inducing immune responses.

[0011] There remains a need for novel CDNs that can activate STING. Summary of the Invention

[0012] In one embodiment, the present invention provides a compound of formula (I):

[0013]

[0014] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0015] in

[0016] X 1 and X 3 Each independently represents OH, OR 1 , SH or SR 1 , whose restriction condition is X 1 and X 3 At least one of them is OR 1 , SH or SR 1 ;

[0017] X 2 and X 4 Each independently is O or S;

[0018] R 4 and R 10 are each independently H, OH or halogen;

[0019] Each R 1 are independently C1-C6 alkyl or -LR 2 ;

[0020] Each R 2 are independently -O(C=O)-N(R 2a )2, -O(C=O)-NHR 2a 、-O(C=O)-R 2a or-O(C=O)-OR 2a ;

[0021] Each R 2a Independently C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, -(C1-C6 alkylene)-(C3-C 14 Cycloalkyl) or C3-C 20 Cycloalkyl, wherein each R 2a Independently, as appropriate, through 1, 2 or 3 R 2b replace;

[0022] Each R 2bare independently -OH, -SH, -NH2, =O, =NH, =S, halogen, -N3, -CN, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 dialkylamino;

[0023] L is L 1 、L 1 -O(C=O)-L 2 、L 1 -(C=O)OL 2 、L 1 -OL 2 、L 1 -S(O) n -L 2 、L 1 -O(C=O)OL 2 、L 1 -O(C=O)NR 6 -L 2 、L 1 -NR 6 (C=O)OL 2 or L 1 -O(C=O)-L 2 -OL 3 ;

[0024] L 1 is C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene or C7-C 13 alkylarylene;

[0025] L 2 C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C6-C 10 an arylene group or a 5- to 10-membered heteroarylene group;

[0026] L 3 is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene;

[0027] R 6 is H or C1-C6 alkyl;

[0028] n is 0, 1, or 2;

[0029] bases 1 and bases 2 Each independently

[0030]

[0031] in

[0032] A.A 1 、A 2 、A3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH2, OR 15 SR 15 、NHR 15 、N(R 15 )2 or R 16 ;

[0033] Each Z is independently O, S or NR 15 ;

[0034] Each R 15 are independently H, -C(=Z 1 )R 16 、-C(=Z 1 )OR 16 、-C(=Z 1 )SR 16 、-C(=Z 1 )N(R 16 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 heteroaryl;

[0035] Each Z 1 are independently O or S; and

[0036] Each R 16 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 Heteroaryl.

[0037] In some embodiments, the pharmaceutical composition comprises a cyclic dinucleotide of formula (I) or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient and / or diluent.

[0038] In some embodiments, a method of treating a disease or condition, such as a method of treating or preventing a viral infection, hepatitis B virus infection, HIV infection, a hyperproliferative disease, or cancer, comprises administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of formula (I), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

[0039] In some embodiments, the method of enhancing the efficacy of a vaccine comprises administering a therapeutically effective amount of a cyclic dinucleotide of formula (I), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

[0040] In some embodiments, a method of modulating the activity of a STING adaptor protein in inducing type I interferon, cytokine and / or chemokine production (dependent on the STING adaptor protein) in a human or animal (e.g., inducing STING adaptor protein-dependent type I interferon, cytokine or chemokine) comprises administering a therapeutically effective amount of a cyclic dinucleotide of Formula (I) or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing. DETAILED DESCRIPTION

[0041] I. Overview

[0042] Provided herein are novel 2'3'-cyclic dinucleotides comprising at least one phosphonomethoxy group that bind to a STING protein and modulate STING protein activity, eg, activate a STING protein.

[0043] II. Definitions

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash preceding or at the end of a chemical group is used for convenience to indicate the point of attachment to the parent group; a chemical group may be depicted with or without one or more dashes without losing its general meaning. Prefixes such as "C u-v ” or “C u -C v " indicates that the subsequent group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0045] "Alkyl" is a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2C H3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH( CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3). The alkyl group may be unsubstituted or substituted.

[0046] As used herein, "alkylene" refers to a divalent straight-chain or branched saturated monovalent hydrocarbon radical derived from an alkane by removing two hydrogen atoms from different carbon atoms.

[0047] "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined above. For example, C 1-4 Alkoxy refers to an -O-alkyl group having 1 to 4 carbons.

[0048] "Alkenyl" is a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (ie, C 2-6alkenyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups may be unsubstituted or substituted.

[0049] As used herein, "alkenylene" refers to a divalent straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond, which is derived from an alkene by removing two hydrogen atoms from different carbon atoms.

[0050] "Alkynyl" is a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl) or 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups may be unsubstituted or substituted.

[0051] As used herein, "alkynylene" refers to a divalent straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond, which is derived from an alkyne by removing two hydrogen atoms from different carbon atoms.

[0052] Alkylamino is -HNR b Group, where R b For alkyl.

[0053] Alkylthio is -SR b Group, where R b For alkyl.

[0054]

[0046] "Halo" or "halogen" as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0055] As used herein, "aryl" refers to a single all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one ring is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl. Aryl also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) having approximately 9 to 20 carbon atoms, in which at least one ring is aromatic and in which the other rings may or may not be aromatic (i.e., carbocyclic). Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, or 3) pendant oxy groups on any carbocyclic portion of the polycondensed ring system. The rings of a polycondensed ring system may be connected to each other via fusion, spirocyclic, and bridging bonds when valence requirements permit. It should also be understood that when reference is made to an atomic range member aryl group (e.g., a 6- to 10-membered aryl group), the atomic range refers to the total ring atoms of the aryl group. For example, a 6-membered aryl group would include phenyl, and a 10-membered aryl group would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0056] As used herein, "arylene" refers to a divalent group on a single aromatic ring or a multi-fused all-carbon ring system (in which at least one ring is aromatic) formed by removing two hydrogen atoms from different carbon atoms on the ring or ring system.

[0057] As used herein, "alkaryl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by an aryl substituent which may be the same or different. The alkyl and aryl groups may be any of the alkyl and aryl groups described above. In certain embodiments, the alkaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. An alkaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the combination of the constituent alkyl and aryl groups. For example, a C7 alkaryl group refers to a benzyl group, while a C 11 Alkaryl groups include 1-methylnaphthyl and n-pentylphenyl. Non-limiting examples of alkaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, and the like. Alkaryl groups may be unsubstituted or substituted.

[0058] As used herein, "alkylarylene" refers to a divalent group on a group formed by linking an alkane to an aromatic ring, wherein the group is formed by removing two hydrogen atoms from each of the alkane and the aromatic ring.

[0059] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, as further described below. Thus, "heteroaryl" includes a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) in which a heteroaryl group as defined above is condensed with one or more rings selected from the group consisting of heteroaryl (to form, for example, 1,8-naphthyridinyl), heterocycle (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl) to form a polycondensed ring system. Thus, a heteroaryl group (either a single aromatic ring or a polycondensed ring system) has from about 1 to 20 carbon atoms and from about 1 to 6 heteroatoms within the heteroaryl ring. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) pendant oxy groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of the polycondensed ring system may be linked to each other via fusion, spirocyclic, and bridging bonds, as valence requirements permit. It should be understood that the individual rings of the polycondensed ring system may be linked in any order relative to each other. It is understood that the point of attachment of a heteroaryl or heteroaryl polycondensed ring system can be at any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when a reference is made to a certain atomic range member heteroaryl (e.g., a 5- to 10-membered heteroaryl), the atomic range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include thiazolyl and a 10-membered heteroaryl would include quinolinyl. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thiaindanyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl. The heteroaryl group may be unsubstituted or substituted.

[0060] As used herein, "heteroarylene" refers to a divalent radical on a heteroaromatic ring or ring system, wherein the radical is formed by removing two hydrogen atoms from different carbons.

[0061] "Cycloalkyl" refers to a group having 3 to 20 ring carbon atoms (i.e., C 3-20The term "cycloalkyl" also includes polycyclic carbocyclic rings such as bicyclic carbocyclic rings (e.g., bicyclic carbocyclic rings having about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to about 20 ring carbon atoms). The rings of polycyclic fused ring systems may be connected to each other via fusion, spirocyclic, and bridging bonds when valence requirements permit. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl. Cycloalkyls may be unsubstituted or substituted.

[0062] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a monosaturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes monosaturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The rings of multiple fused ring systems (e.g., bicyclic heterocyclyl) may be connected to each other via fusion, spiro, and bridge bonds when valence requirements permit. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2- thia-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl and the like. The heterocyclyl group may be unsubstituted or substituted.

[0063] As used herein, "oxo" refers to =0.

[0064] As used herein, "substituted" refers to a group in which one or more hydrogen atoms are independently replaced with one or more substituents (eg, 1, 2, 3, or 4 or more) as indicated.

[0065] "Compounds of the present invention" include compounds disclosed herein, for example, compounds of the present invention include compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId) and / or (IIIe), including the compounds of the Examples.

[0066] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For the purposes of the present invention, a beneficial or desired result includes, but is not limited to, relief of symptoms and / or reduction in the extent of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the extent of a disease or condition); b) slowing or curbing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as regression of clinical symptoms, improvement of the disease condition, delaying disease progression, improving quality of life, and / or prolonging survival.

[0067] As used herein, "delay" means to postpone, hinder, slow, arrest, stabilize, and / or delay the development of a disease or condition. This delay can be of varying lengths of time, depending on the disease being treated and / or the individual's medical history. As will be apparent to one skilled in the art, sufficient or significant delay can actually encompass prevention, such that the individual does not develop the disease or condition.

[0068] As used herein, "prevent / prevention / preventing" refers to a therapy that prevents the onset of a disease or condition so that clinical symptoms of the disease do not develop. Thus, "prevention" refers to administering a therapy (e.g., administering a therapeutic substance) to an individual before signs of a disease are detectable in the individual (e.g., administering a therapeutic substance to an individual in the absence of detectable cancer (e.g., hepatocellular carcinoma) in the individual). An individual may be an individual at risk of developing a disease or condition, such as an individual with one or more risk factors known to be associated with the onset or onset of a disease or condition. Thus, in certain embodiments, the term "preventing cancer" refers to administering an anti-cancer therapeutic substance to an individual who does not have detectable cancer. It should be understood that an individual on an anti-cancer preventive therapy may be an individual at risk of developing cancer. It should also be understood that prevention does not require a 100% success rate. In some instances, prevention can be understood as reducing the risk of cancer, rather than completely eliminating the occurrence of cancer.

[0069] In certain embodiments, the term "preventing HBV infection" refers to administering an anti-HBV therapeutic to an individual who does not have detectable HBV infection. It should be understood that individuals receiving anti-HBV prophylactic therapy may be individuals at risk of HBV infection. It should also be understood that prevention does not require a 100% success rate. In some cases, prevention can be understood as reducing the risk of infection, rather than completely eliminating the occurrence of infection.

[0070] As used herein, "modulation" or "modulating" the activity of a protein (e.g., a STING adaptor protein) refers to changing the activity so that the activity is increased or decreased. In some embodiments, modulation increases the activity.

[0071] As used herein, "viral infection" describes a disease state in which a virus invades a healthy cell, uses the cell's reproductive machinery to multiply or replicate, and ultimately lyses the cell, causing cell death, releasing viral particles and infecting other cells through the newly produced progeny viruses. Latent infection with certain viruses is also a possible outcome of a viral infection.

[0072] As used herein, the term "enhancing" refers to any form of increase in the immunogenic activity of an effective dose of a vaccine resulting from administration to an animal or human of a therapeutically effective dose of a compound of the present invention, wherein the compound is administered at any time before, simultaneously with, or immediately after administration of an effective dose of the vaccine to the same animal or human.

[0073] As used herein, "animal" refers to a mammal, eg, a livestock animal such as a pig, cow, horse, dog, cat, rat, or mouse, or a non-human primate such as a cynomolgus macaque or chimpanzee.

[0074] As used herein, "at-risk individual" refers to an individual who is at risk of developing a condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to treatment using the methods described herein. "At-risk" indicates that an individual has one or more so-called risk factors, which are measurable parameters associated with developing a disease or condition and are known in the art. An individual who has one or more of these risk factors has a higher probability of developing the disease or condition than an individual who does not have these risk factors.

[0075] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit a desired biological or medical response, including an amount of a compound that is sufficient to achieve treatment of such a disease when administered to a subject for the treatment of a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be in the form of one or more doses, that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired or beneficial result can be achieved or has been achieved in combination with one or more other agents. The suitable dose of any co-administered compound may be reduced as appropriate due to the combined action of the compounds (e.g., additive or synergistic effects).

[0076] In some embodiments, a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof can (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, suppress, slow down to some extent, and preferably stop the infiltration of diseased cells into peripheral organs; (iv) inhibit (e.g., slow down to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor occurrence and / or recurrence; and / or (vii) alleviate to some extent one or more symptoms associated with cancer or hyperproliferative diseases. In some embodiments, a therapeutically effective amount is sufficient to improve, alleviate, reduce, and / or delay one or more symptoms of cancer or hyperproliferative diseases.

[0077] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0078] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering the one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the invention is administered first, followed by administration of a unit dose of the one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of the one or more additional therapeutic agents is administered first, followed by administration of a unit dose of the compound of the invention within seconds or minutes. In some embodiments, a unit dose of the compound of the invention is administered first, followed by administration of a unit dose of the one or more additional therapeutic agents after a period of several hours (e.g., 1 to 12 hours). In other embodiments, a unit dose of the one or more additional therapeutic agents is administered first, followed by administration of a unit dose of the compound of the invention after a period of several hours (e.g., 1 to 12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject.

[0079] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means that the compounds, salts, compositions, dosage forms, and other materials are suitable for use in the preparation of pharmaceutical compositions for veterinary or human medical use.

[0080] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or as free bases where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that possess the pharmacological activity of the desired free base. Such salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates Pharmaceutically acceptable salts include, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0081] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from appropriate bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl.) Also included are base addition salts such as sodium or potassium salts.

[0082] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase metabolic resistance and, therefore, when administered to a mammal, may be useful for extending the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds may be synthesized by methods well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been deuterated.

[0083] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Positron-emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) substitutions are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples set forth below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0084] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry for amino acids as (R)- or (S)- or (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. Where compounds are expressed in their chiral form, it is understood that the embodiments encompass, but are not limited to, specific diastereoisomers or enantiomerically enriched forms. Where chirality is not specified but is present, it is understood that the embodiments are directed to specific diastereoisomers or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers that is not in a 1:1 ratio.

[0085] As used herein, "stereoisomers" refer to compounds made up of the same atoms bound by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0086] As used herein, "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes any such tautomers of compounds.

[0087] As used herein, "solvate" refers to the product of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0088] As used herein, "hydrate" refers to a compound of the present invention chemically associated with one or more water molecules.

[0089] As used herein, "prodrug" refers to a derivative of a drug that, when administered to a human, is converted to the parent drug according to some chemical or enzymatic pathway. In some embodiments, a prodrug is a biologically inactive derivative of a drug that, after administration to a human, is converted to the biologically active parent drug according to some chemical or enzymatic pathway. Prodrugs of phosphonates and phosphates are known in the art.

[0090] III. Compounds

[0091] In one aspect, provided herein is a compound of formula (I):

[0092]

[0093] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0094] in

[0095] X 1 and X 3 Each independently represents OH, OR 1 , SH or SR 1 , whose restriction condition is X 1 and X 3 At least one of them is OR 1 , SH or SR 1 ;

[0096] X 2 and X 4 Each independently is O or S;

[0097] R 4 and R 10 are each independently H, OH or halogen;

[0098] Each R 1 are independently C1-C6 alkyl or -LR 2 ;

[0099] Each R 2 are independently -O(C=O)-N(R 2a )2, -O(C=O)-NHR 2a 、-O(C=O)-R 2a or-O(C=O)-OR 2a ;

[0100] Each R 2a Independently C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, -(C1-C6 alkylene)-(C3-C 14 Cycloalkyl) or C3-C20 Cycloalkyl, wherein each R 2a Independently, as appropriate, through 1, 2 or 3 R 2b replace;

[0101] Each R 2b are independently -OH, -SH, -NH2, =O, =NH, =S, halogen, -N3, -CN, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 dialkylamino;

[0102] L is L 1 、L 1 -O(C=O)-L 2 、L 1 -(C=O)OL 2 、L 1 -OL 2 、L 1 -S(O) n -L 2 、L 1 -O(C=O)OL 2 、L 1 -O(C=O)NR 6 -L 2 、L 1 -NR 6 (C=O)OL 2 or L 1 -O(C=O)-L 2 -OL 3 ;

[0103] L 1 is C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene or C7-C 13 alkylarylene;

[0104] L 2 C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C6-C 10 an arylene group or a 5- to 10-membered heteroarylene group;

[0105] L 3 is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene;

[0106] R 6 is H or C1-C6 alkyl;

[0107] n is 0, 1, or 2;

[0108] bases 1 and bases 2 Each independently

[0109]

[0110] in

[0111] A.A 1 、A 2 、A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH2, OR 15 SR 15 、NHR 15 、N(R 15 )2 or R 16 ;

[0112] Each Z is independently O, S or NR 15 ;

[0113] Each R 15 are independently H, -C(=Z 1 )R 16 、-C(=Z 1 )OR 16 、-C(=Z 1 )SR 16 、-C(=Z 1 )N(R 16 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 heteroaryl;

[0114] Each Z 1 are independently O or S; and

[0115] Each R 16 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 Heteroaryl.

[0116] In some embodiments, A, A 1 、A 2 、A 3 and A 4 Each is independently H, OH or NH2. In some embodiments, A is NH2. In some embodiments, A 1 is NH2. In some embodiments, A 2 is NH2. In some embodiments, A 3 is NH2. In some embodiments, A4 is NH2.

[0117] In some embodiments, each R 15 are independently H, -C(=Z 1 )R 16 、、-C(=Z 1 )OR 16 、-C(=Z 1 )N(R 16 )2, C1-C6 alkyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 In some embodiments, each R 15 are independently H, C1-C6 alkyl or C6-C 10 Aryl.

[0118] In some embodiments, each R 16 are independently C1-C6 alkyl.

[0119] In some embodiments, Z is O.

[0120] In some embodiments, Z 1 It is O.

[0121] In some embodiments, X 2 and X 4 Each is O. In some embodiments, X 2 and X 4 Each is S. In some embodiments, X 2 is O, and X 4 is S. In some embodiments, X 2 is S, and X 4 It is O.

[0122] In some embodiments, the compound of Formula (I) has the structure of Formula (Ia):

[0123]

[0124] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound of formula (I) has the structure of formula (II):

[0126]

[0127] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula (I), (Ia) and / or (II) has the structure of formula (IIa):

[0129]

[0130] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0131] In some embodiments of compounds of Formula (I), (Ia), (II) and / or (IIa), the base 1 and bases 2 Each independently is:

[0132]

[0133] In some embodiments, the base 1 and bases 2 Each independently is:

[0134]

[0135] In some embodiments, the base 1 and bases 2 Each independently is:

[0136]

[0137]

[0138] In some embodiments, the base 1 and bases 2 Each independently

[0139]

[0140] In some embodiments, the base 1 for

[0141] and

[0142] bases 2 for

[0143]

[0144] In some embodiments, the base 1 for

[0145] and

[0146] bases 2 for

[0147]

[0148] In some embodiments, the base 1 for

[0149] and

[0150] bases 2 for

[0151]

[0152] In some embodiments, the base 1 for

[0153] and

[0154] bases 2 for

[0155]

[0156] In some embodiments, the base 1 and bases 2 Each for

[0157]

[0158] In some embodiments of compounds of Formula (I), (Ia), (II) and / or (IIa), A 1 、A 2 、A 3 and A 4 Each is independently H, OH or NH2. In some embodiments, A 1 is OH or NH2. In some embodiments, A 2 is H or NH2. In some embodiments, A 3 is H or NH2. In some embodiments, A 4 is NH2.

[0159] In some embodiments of compounds of Formula (I), (Ia), (II) and / or (IIa), A 1 、A 2 and A 3 Each is independently H, OH or NH2. In some embodiments, A 1 is OH or NH2. In some embodiments, A 2 is H or NH2. In some embodiments, A 3 is H or NH2.

[0160] In some embodiments, the compounds of Formula (I), (Ia), (II) and / or (IIa) have the structure of Formula (III):

[0161]

[0162] or its enantiomer, hydrate, solvate or pharmaceutically acceptable salt, wherein

[0163] A 1 is OH or NH2; A 2 is H or NH2; and A 3 For H.

[0164] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 1 is OH; and X 3 OR 1 In some embodiments, X 1 OR 1 ; and X 3 In some embodiments, X 1 and X 3 Each independently is OR 1 In some embodiments, X 1 SR 1 ; and X 3 In some embodiments, X 1 is OH; and X 3 SR 1 In some embodiments, X 1 and X 3 Each independently selected from the group consisting of OH and SH, wherein X 1 and X 3 In some embodiments, at least one of X is SH. 1 is SH; and X 3 In some embodiments, X 1 is OH; and X 3 In some embodiments, X 1 SR 1 ; and X 3 In some embodiments, X 1 is SH; and X 3 SR 1 In some embodiments, X 1 and X 3 In some embodiments, X 1 and X 3 Each independently SR 1 .

[0165] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), each R 1 Independently -LR 2 .

[0166] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), L is L 1 、L 1 -O(C=O)-L 2 、L 1 -(C=O)OL 2 、L 1 -OL 2 、L 1 -O(C=O)OL 2 、L 1 -O(C=O)NR 6 -L 2 or L 1 -NR 6 (C=O)OL 2 In some embodiments, L is L 1 、L 1 -O(C=O)-L 2 、L 1 -(C=O)OL 2 or L 1 -OL 2 In some embodiments, L is L 1 、L 1 -O(C=O)-L 2 or L 1 -OL 2 .

[0167] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), L 1 is C1-C6 alkylene or C7-C 13 In some embodiments, L 1 is -CH2- or -CH2-Ph-. In some embodiments, L 1 In some embodiments, L 1 C7-C 13 Alkylarylene, such as -CH2-Ph-.

[0168] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), L 2 C1-C6 alkylene, C6-C 10 In some embodiments, L 2 is C1-C6 alkylene or C6-C 10 For example, L 2In some embodiments, L 2 C6-C 10 For example, L 2 It may be a phenylene group.

[0169] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), L 3 is C1-C6 alkylene, for example -CH2-.

[0170] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a .

[0171] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), R 2a C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl or -(C1-C6 alkylene)-(C3-C 14 In some embodiments, R 2a C3-C 20 Cycloalkyl, such as C3-C 16 Cycloalkyl, C3-C 10 In some embodiments, R 2a C1-C 20 Alkyl or -(C1-C6 alkylene)-(C3-C 14 In some embodiments, R 2a C1-C 20 Alkyl or -CH2-(C3-C 14 In some embodiments, R 2a -CH2-(C3-C 14 Cycloalkyl), such as -CH2-(C3-C 10 In some embodiments, R 2a C1-C 20 Alkyl groups, such as C1-C 16 Alkyl, C3-C 20 Alkyl, C3-C 18 Alkyl, C3-C16 Alkyl, C3-C 14 Alkyl, C3-C 12 Alkyl, C3-C 10 C3-C8 alkyl, C2-C8 alkyl, C1-C8 alkyl, C1-C6 alkyl, C2-C6 alkyl or C3-C6 alkyl.

[0172] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 1 for

[0173]

[0174] In some embodiments, X 1 for

[0175] and

[0176] R 2a C3-C 20 alkyl.

[0177] In some embodiments, X 1 for

[0178]

[0179] and

[0180] R 2a C3-C 20 alkyl.

[0181] In some embodiments, X 1 for

[0182]

[0183] In some embodiments, X 1 for

[0184]

[0185] In some embodiments, X 1 for

[0186]

[0187] In some embodiments, X 1 for

[0188]

[0189] In some embodiments, X 1 for

[0190]

[0191] and

[0192] R 2a C3-C 20 alkyl.

[0193] In some embodiments, X 1 for

[0194]

[0195] In some embodiments, X 1 for

[0196]

[0197] In some embodiments, X 1 for

[0198]

[0199] In some embodiments, X 1 for

[0200]

[0201] In some embodiments, X 1 for

[0202]

[0203] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 3 for

[0204]

[0205] In some embodiments, X 3 for

[0206] and

[0207] R 2a C3-C 20 alkyl.

[0208] In some embodiments, X 3 for

[0209]

[0210] and

[0211] R 2aC3-C 20 alkyl.

[0212] In some embodiments, X 3 for

[0213]

[0214] In some embodiments, X 3 for

[0215]

[0216] In some embodiments, X 3 for

[0217]

[0218] In some embodiments, X 3 for

[0219]

[0220] In some embodiments, X 3 for

[0221]

[0222] and

[0223] R 2a C3-C 20 alkyl.

[0224] In some embodiments, X 3 for

[0225]

[0226] In some embodiments, X 1 for

[0227]

[0228] In some embodiments, X 3 for

[0229]

[0230] In some embodiments, X 3 for

[0231]

[0232] In some embodiments, X 3 for

[0233]

[0234] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), R 2a After 1 or 2 R 2b In some embodiments, R 2a After an R 2b replace.

[0235] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), R 2b is -OH, halogen, -CN, C1-C6 alkoxy or C1-C6 alkylthio. In some embodiments, R 2b is a halogen, such as F or Cl.

[0236] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 1 OR 1 or SR 1 ; R 1 -LR 2 ; L is L 1 ;L 1 is C1-C6 alkylene; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C1-C 20 In some embodiments, X 1 OR 1 or SR 1 ; R 1 -LR 2 ; L is -CH2-; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C3-C 20 alkyl.

[0237] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 3 OR 1 or SR 1 ; R 1 -LR 2 ; L is L 1 ;L 1 is C1-C6 alkylene; R 2 -O(C=O)-R 2aor-O(C=O)-OR 2a ; and R 2a C1-C 20 In some embodiments, X 3 OR 1 or SR 1 ; R 1 -LR 2 ; L is -CH2-; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C3-C 20 alkyl.

[0238] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 1 OR 1 or SR 1 ; R 1 -LR 2 ; L is L 1 ;L 1 C7-C 13 Alkylarylene; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C1-C 20 In some embodiments, X 1 OR 1 or SR 1 ;;R 1 -LR 2 ; L is L 1 ;L 1 -CH2-Ph-; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C3-C 20 alkyl.

[0239] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), and / or (III), X 3 OR 1 or SR 1 ; R 1 -LR 2 ; L is L 1 ;L 1 C7-C 13 Alkylarylene; R 2-O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C1-C 20 In some embodiments, X 3 OR 1 or SR 1 ;;R 1 -LR 2 ; L is L 1 ;L 1 -CH2-Ph-; R 2 -O(C=O)-R 2a or-O(C=O)-OR 2a ; and R 2a C3-C 20 alkyl.

[0240] In some embodiments, the compound of formula (III) has the structure of formula (IIIa):

[0241]

[0242] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0243] In some embodiments, the compound of formula (III) has the structure of formula (IIIb):

[0244]

[0245] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0246] In some embodiments, the compound of formula (III) has the structure of formula (IIIc):

[0247]

[0248] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0249] In some embodiments, the compound of formula (III) has the structure of formula (IIId):

[0250]

[0251] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0252] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), and / or (IIId), A 2 is H. In some embodiments, A 2 is NH2.

[0253] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc) and / or (IIId), R 3 C3-C 20 Alkyl or -O-(C3-C 20 In some embodiments, R 3 C1-C 16 Alkyl or -O-(C1-C 16 In some embodiments, R 3 C3-C 16 Alkyl or -O-(C3-C 16 In some embodiments, R 3 is C1-C6 alkyl or -O-(C1-C6 alkyl). In some embodiments, R 3 It is a C1-C6 alkyl group.

[0254] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), and / or (IIId), A 1 In some embodiments, A 1 is NH2.

[0255] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), and / or (IIId), A 2 H and A 1 is NH2. In some embodiments, A 2 is NH2 and A 1 For OH.

[0256] In some embodiments, the compound is a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc) and / or (IIId), or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), and / or (IIId), R 4 and R 10are each independently H or F. In some embodiments, R 4 and R 10 Each is H. In some embodiments, R 4 and R 10 Each is F.

[0258] In some embodiments, the compound of formula (III) has the structure of formula (IIIe):

[0259]

[0260] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0261] In some embodiments of compounds of Formula (IIIe), A 2 is H. In some embodiments, A 2 is NH2.

[0262] In some embodiments of compounds of Formula (IIIe), R 3 C3-C 20 Alkyl or -O-(C3-C 20 In some embodiments, R 3 C1-C 16 Alkyl or -O-(C1-C 16 In some embodiments, R 3 C3-C 16 Alkyl or -O-(C3-C 16 In some embodiments, R 3 is C1-C6 alkyl or -O-(C1-C6 alkyl). In some embodiments, R 3 It is a C1-C6 alkyl group.

[0263] In some embodiments of compounds of Formula (IIIe), A 1 In some embodiments, A 1 is NH2.

[0264] In some embodiments of compounds of Formula (IIIe), A 2 H and A 1 is NH2. In some embodiments, A 2 is NH2 and A 1 For OH.

[0265] In some embodiments, the compound is a compound of formula (IIIe), or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments of compounds of Formula (IIIe), R 4 and R 10are each independently H or F. In some embodiments, R 4 and R 10 Each is H. In some embodiments, R 4 and R 10 Each is F.

[0267] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe), R 2a C2-C 20 Alkyl groups, such as C2-C 16 Alkyl, C2-C 14 Alkyl, C2-C 12 Alkyl, C2-C8 alkyl, C2-C6 alkyl, C3-C 16 Alkyl, C3-C 14 Alkyl, C3-C 12 Alkyl, C3-C8 alkyl or C3-C6 alkyl.

[0268] In some embodiments, the compounds of the present invention have the following structure:

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0279] In some embodiments, the compounds of the present invention have the following structure:

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0289] In some embodiments, the compounds of the present invention have the following structure:

[0290]

[0291] or its enantiomers, hydrates, solvates or pharmaceutically acceptable salts.

[0292] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe) has the structure as depicted, or is a tautomer, enantiomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe), or a pharmaceutically acceptable salt thereof.

[0293] Compounds of the present invention, e.g., compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe), can be depicted in several equivalent drawings. For example, compounds of Formula (Ia) are generally depicted herein as shown above, with the 2'-substituent or 3'-substituent of each nucleoside facing toward each other:

[0294]

[0295] The compound of formula (Ia) above is equivalent to the compound of formula (Ia) as depicted below:

[0296]

[0297] Furthermore, each of the previous drawings is equivalent to the following depiction of a compound of formula (Ia):

[0298]

[0299] Each of the previous drawings is equivalent to the following depiction of a compound of formula (Ia):

[0300]

[0301] The presence of a chiral center allows the compound to exist as one of the two possible optical isomers ((R)-enantiomers or (S)-enantiomers) or as a racemic mixture of the two. In the presence of substituents that may be attached at different positions in the molecule, all regioisomers and mixtures of regioisomers formed are included within the scope of formula (I) described herein.

[0302] IV. Composition

[0303] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0304] In certain embodiments, pharmaceutical compositions comprise one or more additional therapeutic agents, as described more fully below.

[0305] Pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof can be prepared with one or more pharmaceutically acceptable excipients that can be selected according to conventional practice. Tablets may contain excipients including slip agents, fillers, adhesives, and the like. Aqueous compositions can be prepared in a sterile form and can generally be isotonic when intended for delivery by routes other than oral administration. All compositions may optionally contain excipients, such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. In certain embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.

[0306] The composition includes compositions suitable for various routes of administration, including oral administration. The composition can be presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. Such methods include the step of associating the active ingredient (e.g., a compound of the present invention or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The composition can be prepared by uniformly and tightly associating the active ingredient with a liquid excipient or a finely powdered solid excipient or both, and then shaping the product as needed. Technology and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0307] Compositions suitable for oral administration described herein may be presented as discrete units (unit dosage forms), including but not limited to capsules, sachets or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0308] The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients and optionally other therapeutic agents. Pharmaceutical compositions containing active ingredients may be in any form suitable for the intended method of administration. When used for example for oral administration, tablets, dragees, buccal lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavorings, coloring agents, and preservatives to provide a palatable formulation. Tablets containing active ingredients blended with pharmaceutically acceptable non-toxic excipients are acceptable, and such excipients are suitable for making tablets. Such excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated using known techniques (including microencapsulation) to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0309] The amount of active ingredient that can be combined with the inactive ingredient to produce a dosage form can vary depending on the intended subject to be treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of active substance, formulated together with an appropriate and suitable amount of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient ranges from about 5 to about 95% (weight:weight) of the total composition.

[0310] In certain embodiments, the compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, in one variation, do not contain an agent that affects the metabolic rate of an active ingredient. Thus, it is understood that a composition comprising a compound of the invention, in one aspect, does not contain an agent that would affect (e.g., slow, hinder, or stop) the metabolism of a compound of the invention or any other active ingredient administered separately, sequentially, or simultaneously with a compound of the invention. It is also understood that any of the methods, kits, articles of manufacture, and the like described herein, in one aspect, does not contain an agent that would affect (e.g., slow, hinder, or stop) the metabolism of a compound of the invention or any other active ingredient administered separately, sequentially, or simultaneously with a compound of the invention.

[0311] The present invention also includes the pharmaceutical composition described above, which is used to modulate the activity of the STING protein to induce STING-dependent production of type I interferons, cytokines, or chemokines.

[0312] The present invention also includes a pharmaceutical composition as described above for use in treating or preventing a viral infection, an infection caused by hepatitis B virus, HIV, a hyperproliferative disease or cancer.

[0313] In some embodiments, the pharmaceutical compositions described above are for use in humans or animals.

[0314] The present invention further includes the compounds of the present invention administered as the sole active ingredient of a pharmaceutically acceptable composition, which can be prepared by conventional methods known in the art, for example, by combining or mixing the active ingredient with pharmaceutically acceptable therapeutically inert organic and / or inorganic carriers or excipients.

[0315] In one aspect, provided herein are methods for using a compound of the invention as a second or additional active ingredient that has a synergistic effect with other active ingredients in known pharmaceuticals, or for administering a compound of the invention together with such pharmaceuticals.

[0316] The compounds of the present invention may also be used in the form of prodrugs or other appropriately modified forms that release the active ingredient in vivo.

[0317] V. Methods

[0318] In one embodiment, provided herein is a method for treating a disease or condition, comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present invention, including a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId) and / or (IIIe), or an enantiomer or pharmaceutically acceptable salt thereof.

[0319] Also provided is a method for modulating the activity of a STING protein, comprising administering a therapeutically effective amount of a compound of the present invention, or an enantiomer or a pharmaceutically acceptable salt thereof.

[0320] Stimulator of interferon genes adaptor protein (STING), also known as STING, STING protein, transmembrane protein 173 (TMEM173), MPYS, mediator of IRF3 activation (MITA), or endoplasmic reticulum interferon stimulator (ERIS), is a protein encoded by the TMEM173 gene in humans (UniProt code Q86WV6; NCBI reference sequences: NP_938023.1 (isoform 1) and NP_001288667 (isoform 2)). The STING adaptor protein is believed to function as a direct cytosolic DNA sensor (CDS) and an adaptor protein for type I interferon signaling through distinct molecular mechanisms. The STING adaptor protein has been shown to activate the downstream transcription factors STAT6 and IRF3 via TBK1 and NF-κB via IKKβ, which can promote antiviral responses or innate immune responses against intracellular pathogens. When cells are infected by intracellular pathogens such as viruses, mycobacteria, and intracellular parasites, the STING adaptor protein plays a role in innate immunity by inducing the production of type I interferons. Type I interferons mediated by the STING adaptor protein protect infected cells and neighboring cells from local infection through autocrine and paracrine signaling.

[0321] Further provided is a method for preventing or treating a disease or condition responsive to modulation of the STING adaptor protein, comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide provided herein, including a compound of the present invention, or an enantiomer or pharmaceutically acceptable salt thereof.

[0322] Further provided is a method of inducing STING adaptor protein-dependent type I interferon, cytokine, or chemokine in a human or animal, comprising administering a therapeutically effective amount of a cyclic dinucleotide provided herein, including a compound of the present invention, or an enantiomer or pharmaceutically acceptable salt thereof.

[0323] Activation of the STING adaptor protein, in turn, activates the protein kinase TBK1, which subsequently activates the downstream transcription factors NF-κB and IRF-3. Activation of the STING adaptor protein is believed to ultimately lead to the release of type I and type III interferons, as well as a variety of cytokines and chemokines, such as IL-6, TNF-α, and INF-γ. Thus, induction of STING adaptor protein-dependent type I interferons, cytokines, or chemokines in a human or animal results in activation of one or more of NF-κB, IRF-3, type I interferons, type III interferons, IL-6, TNF-α, and INF-γ in the human or animal.

[0324] Further provided is a method for treating or preventing viral infection, such as infection by hepatitis B or HIV, comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present invention, or an enantiomer or pharmaceutically acceptable salt thereof.

[0325] The viral infection that can be treated or prevented by the method of the present invention can be any infection caused by a virus, for example, a virus from the Hepadnaviridae family of viruses, such as hepatitis B; or any retrovirus, for example, an alpharetrovirus, such as Rous sarcoma virus; a betaretrovirus, such as simian retrovirus; a deltaretrovirus, such as bovine leukemia virus or human T-lymphotropic virus (HTLV), including HTLV-1, HTLV-2 and HTLV-3; a gammaretrovirus, such as murine leukemia virus or feline leukemia virus; or a lentivirus, such as human immunodeficiency virus (HIV) (including HIV-1 and HIV-2), simian immunodeficiency virus, equine infectious anemia virus, bovine immunodeficiency virus, rabbit endogenous lentivirus K (RELIK) or feline immunodeficiency virus.

[0326] Further provided is a method for treating or preventing a hyperproliferative disease or cancer, comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present invention, or an enantiomer or a pharmaceutically acceptable salt thereof.

[0327] Hyperproliferative diseases include diseases caused by excessive growth of non-cancerous cells. Such conditions include, but are not limited to, psoriasis, actinic keratoses and seborrheic keratoses, warts, keloids, and eczema.

[0328] Cancers that can be treated or prevented by the methods of the present invention include solid tumors and lymphomas, including but not limited to adrenal cancer, bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, eye cancer, head and neck cancer, kidney cancer such as renal cell carcinoma, liver cancer, lung cancer such as non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer such as squamous cell carcinoma and melanoma, thyroid cancer, uterine cancer, vaginal cancer, and myeloma such as multiple myeloma. The cancer may be untreated, or relapsed and / or refractory.

[0329] In some embodiments, the cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, multiple myeloma (MM), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell ALL, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), mantle cell lymphoma (MCL), follicular lymphoma (FL), Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or marginal zone lymphoma (MZL). In one embodiment, the cancer is minimal residual disease (MRD). In some embodiments, the cancer is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL. In some embodiments, the cancer is indolent non-Hodgkin's lymphoma (iNHL). In some embodiments, the cancer is refractory iNHL. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0330] In some embodiments, the cancer is a solid tumor selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer or renal cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; melanoma; neuroendocrine cancer. Endocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, oligodendritic gliomas multiforme, glioblastoma multiforme in adults, and astrocytomas multiforme in adults; bone cancer; and soft tissue sarcomas, hepatocarcinomas, rectal cancer, penile cancer, vulvar cancer, thyroid cancer, salivary gland cancer, endometrial or uterine cancer, hepatoma, hepatocellular carcinoma, liver cancer, stomach cancer or stomach cancer (including gastrointestinal cancer), peritoneal cancer, squamous cell carcinoma of the lung, gastroesophageal cancer, biliary tract cancer, gallbladder cancer, colorectal / appendix cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma).

[0331] Any of the methods of treatment provided herein can be used to treat various stages of cancer. For example, cancer stages include, but are not limited to, early-stage, late-stage, locally advanced, in remission, refractory, relapsed after remission, and progressive cancer.

[0332] individual

[0333] Any of the treatment methods provided herein can be used to treat an individual (eg, a human) who has been diagnosed with or is suspected of having cancer. As used herein, a subject refers to a mammal, including, for example, a human.

[0334] In some embodiments, the subject may be a human exhibiting one or more symptoms associated with cancer or a hyperproliferative disease. In some embodiments, the subject may be a human exhibiting one or more symptoms associated with cancer. In some embodiments, the subject is in an early stage of cancer. In other embodiments, the subject is in an advanced stage of cancer.

[0335] In some embodiments, an individual may be a human being who has a risk of developing cancer or a hyperproliferative disease or is genetically or otherwise predisposed (e.g., a risk factor) to developing cancer or a hyperproliferative disease and has been diagnosed or has not yet been diagnosed. As used herein, an individual "at risk" is an individual at risk of developing cancer. Prior to the treatment methods described herein, the individual may or may not have a detectable disease and may or may not show detectable disease. An individual at risk may have one or more so-called risk factors, which are measurable parameters associated with the development of cancers described herein. An individual with one or more such risk factors has a higher probability of developing cancer than an individual without such risk factors. Such risk factors may include, for example, age, sex, race, diet, history of previous disease, the presence of prodromal disease, genetic (e.g., hereditary) factors, and environmental exposure. In some embodiments, an individual at risk of cancer includes, for example, an individual whose relatives have experienced the disease and an individual at risk determined by analysis of genetic or biochemical markers.

[0336] In addition, individuality can be the human being that undergoes one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery or its any combination.Therefore, one or more compounds provided herein can be used before, during or after the administration of chemotherapy, radiotherapy, immunotherapy, surgery or its combination.

[0337] In some embodiments, the subject may be a human who (i) is substantially refractory to at least one chemotherapy, or (ii) has relapsed after chemotherapy treatment, or both (i) and (ii). In some embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy).

[0338] Further provided is a method of enhancing the efficacy of a vaccine comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide provided herein, including a compound of the present invention, or an enantiomer or pharmaceutically acceptable salt thereof.

[0339] The present invention includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use as medicaments in humans or animals.

[0340] The present invention includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use in treating a disease or condition in a human or animal.

[0341] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use in modulating the activity of a STING protein.

[0342] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention or enantiomers or pharmaceutically acceptable salts thereof, for use in preventing or treating a disease or condition in a human or animal that is responsive to modulation of the STING protein.

[0343] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active substances for STING-dependent induction of type I interferons, cytokines, or chemokines in humans or animals.

[0344] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active agents in treating or preventing viral infections in humans or animals.

[0345] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active substances in the treatment or prevention of infection caused by hepatitis B virus or HIV in humans or animals.

[0346] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active agents in the treatment or prevention of hyperproliferative diseases or cancer in humans or animals.

[0347] The present invention further includes cyclic dinucleotides provided herein, including compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use in enhancing vaccine efficacy in humans or animals.

[0348] The present invention further includes a pharmaceutical composition for modulating STING protein activity to induce STING-dependent production of type I interferons, cytokines, or chemokines in humans or animals.

[0349] The present invention further includes a pharmaceutical composition for treating or preventing viral infections, infections caused by hepatitis B virus, HIV, hyperproliferative diseases or cancer in humans or animals.

[0350] The present invention further includes the use of the cyclic dinucleotides provided herein (including the compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof) for the manufacture of a medicament for treating or preventing infection caused by hepatitis B virus, HIV, hyperproliferative diseases or cancer.

[0351] VI. Application

[0352] The compounds of the present invention (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intratumoral, intradermal, intrathecal, and epidural) and the like. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0353] The compounds of the invention can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about 12 months or longer. In one variation, the compounds are administered daily or on an intermittent schedule for the duration of the individual's life.

[0354] The dosage or frequency of administration of the compounds of the invention may be adjusted over the course of treatment based on the judgment of the administering physician.

[0355] The compound can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once daily.

[0356] The compound can be administered by any applicable route and means, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include about 0.00001 mg per kilogram of body weight per day to about 10 mg per kilogram of body weight per day, such as about 0.0001 mg per kilogram of body weight per day to about 10 mg per kilogram of body weight per day, or such as about 0.001 mg per kilogram of body weight per day to about 1 mg per kilogram of body weight per day, or such as about 0.01 mg per kilogram of body weight per day to about 1 mg per kilogram of body weight per day, or such as about 0.05 mg per kilogram of body weight per day to about 0.5 mg per kilogram of body weight per day, or such as about 0.3 mg to about 30 mg per day, or such as about 30 mg to about 300 mg per day.

[0357] The compounds of the present invention can be combined with one or more additional therapeutic agents at any dose of the compounds of the present invention (e.g., 1 mg to 1000 mg of the compound). A therapeutically effective amount may include about 1 mg per dose to about 1000 mg per dose, such as about 50 mg per dose to about 500 mg per dose, or such as about 100 mg per dose to about 400 mg per dose, or such as about 150 mg per dose to about 350 mg per dose, or such as about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present invention are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the invention are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. Single doses can be administered hourly, daily, or weekly. For example, a single dose can be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose can also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose can also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In certain embodiments, a single dose can be administered every other week. A single dose can also be administered monthly.

[0358] The present invention also includes a kit comprising a compound of the present invention or an enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing.

[0359] In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0360] VII. Combination Therapy

[0361] In certain embodiments, a method for treating or preventing an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease in a human suffering from, or at risk of suffering from, the disease is provided, comprising administering to the human a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease in a human suffering from, or at risk of suffering from the disease is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0362] In certain embodiments, the present invention provides a method for treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents useful for treating the viral infection. In some embodiments, the viral infection is hepatitis B infection. In some embodiments, the viral infection is HIV infection.

[0363] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0364] Administration of combination therapy

[0365] In certain embodiments, the compounds disclosed herein are administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering the compound disclosed herein and the one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of the compound disclosed herein and the one or more additional therapeutic agents is present in the subject. When administered sequentially, the combination can be administered in two or more administrations.

[0366] Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially such that a therapeutically effective amount of each agent is present in the patient's body.

[0367] In certain embodiments, a compound as disclosed herein (e.g., any compound of Formula I) may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of the compound of Formula I (e.g., 10 mg to 1000 mg of the compound).

[0368] Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. The compounds disclosed herein can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administering a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administering a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administering a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administering a unit dose of a compound disclosed herein after a period of several hours (e.g., 1 to 12 hours).

[0369] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a subject, eg, in a solid dosage form for oral administration.

[0370] In certain embodiments, the compounds of the invention are formulated as tablets, which may optionally contain one or more other compounds useful in treating the disease being treated. In certain embodiments, the tablets may contain another active ingredient useful in treating viral diseases, such as hepatitis B virus or HIV.

[0371] In certain embodiments, such tablets are suitable for once-daily administration.

[0372] In one embodiment, a pharmaceutical composition is provided that comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0373] In one embodiment, a kit is provided comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0374] Viral combination therapy

[0375] The compounds described herein can be used or combined with one or more antiviral agents, including abacavir, aciclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, artipla, brivudine, cidofovir, combivir, edoxudin, e), efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine ), imiquimod, indinavir, inosine, integrase inhibitors, interferon (including type III interferon, type II interferon, and type I interferon), lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogs, and oseltamivir oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil fumarate,disoproxil), tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof.

[0376] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The compounds of the present invention can be combined with the agents provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each combination of doses were specifically and separately listed.

[0377] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150, 100-200, 100-250, 100-300, 100-350, 150-200, 150-250, 150-300, 150-350, 150-400, 200-250, 200-300, 200-350, 200-400, 250-350, 250-400, 350-400, or 300-400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate. As disclosed herein, a compound (e.g., a compound of formula (I)) can be combined with an agent provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each combination of doses is specifically and separately listed.

[0378] HIV combination therapy

[0379] In certain embodiments, a method for treating or preventing a human or animal having or at risk of developing an HIV infection is provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating a human or animal having or at risk of developing an HIV infection is provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0380] In certain embodiments, the present invention provides a method for treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating HIV infection.

[0381] In certain embodiments, the compounds disclosed herein are formulated as tablets, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablets may contain another active ingredient useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0382] In certain embodiments, such tablets are suitable for once-daily administration.

[0383] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of: HIV combination drugs, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T), latency reversal agents, compounds targeting HIV capsid (including capsid inhibitors), immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4 / beta-7 antagonists, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, disulfide protein isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, reverse cyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase activation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and other HIV therapeutic agents and combinations thereof.

[0384] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0385] HIV combination drugs

[0386] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and androcitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and andrositabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and androcitabine); (tenofovir disoproxil fumarate and androcitabine; TDF+FTC); (tenofovir alafenamide and andrositabine); (tenofovir alafenamide, andrositabine and rilpivirine), (tenofovir alafenamide, andrositabine, cobicistat, and elvitegravir); (bictegravir, androscitabine, tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate, androscitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and androscitabine; tenofovir alafenamide hemifumarate and androscitabine; tenofovir alafenamide hemifumarate, androscitabine, and rilpivirine; tenofovir alafenamide hemifumarate, androscitabine, cobicistat, and elvitegravir; (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; doravirine, lamivudine and tenofovir disoproxil fumarate dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + andrositabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

[0387] HIV protease inhibitors

[0388] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911.

[0389] HIV reverse transcriptase inhibitors

[0390] Examples of HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

[0391] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, andrositabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and VIDEX (didanosine, DDL), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504, and KP-1461.

[0392] HIV integrase inhibitors

[0393] Examples of HIV integrase inhibitors include elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, a goldenroic acid, a derivative of a goldenroic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine phosphorylation inhibitor, a derivative of a tyrosine phosphorylation inhibitor, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-1 5567, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivative, integrase-LEDGF inhibitor, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, and cabotegravir.

[0394] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0395] HIV entry inhibitors

[0396] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 ligation inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0397] Examples of CCR5 inhibitors include apraviroc, viclaviroc, maraviroc, seneviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0398] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0399] Examples of CD4 ligand inhibitors include ibalizumab and CDA analogs.

[0400] Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0401] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (hemicept).

[0402] HIV maturation inhibitors

[0403] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0404] Latency reversal agents

[0405] Examples of latency reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, aniline and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, and GSK-343.

[0406] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0407] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0408] Capsid inhibitors

[0409] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid dissociation compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series.

[0410] Immune-based therapies

[0411] Examples of immune-based therapies include toll-like receptor modulators, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; Hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, peginterferon alpha-2a, peginterferon alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103.

[0412] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and modulators disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), U.S. Patent No. 9670205 (Gilead Sciences Inc.), US20160289229 (Gilead Sciences Inc.), U.S. Patent Application No. 15 / 692161 (Gilead Sciences Inc.) and U.S. Patent Application No. 15 / 692,093 (Gilead Sciences Inc.).

[0413] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0414] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, and selenirib. mesylate), rigosertib, regosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-22 69577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV- 1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0415] Alpha-4 / beta-7 antagonists

[0416] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0417] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0418] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include Fab derivatives, bnAB (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and antibodies targeting HIV gp120 or gp41, antibody recruitment molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, antibodies targeting gp140, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ilizumab, Immuglo and MB-66.

[0419] Examples of antibodies that target HIV in this manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014, and VRC07. Examples of HIV bispecific antibodies include MGD014.

[0420] Pharmacokinetic enhancers

[0421] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0422] HIV vaccine

[0423] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVINHIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT 4. DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env clade C+Ad4-mGag), EN 41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccines, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), II-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deleted HCMV vectored HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI.

[0424] Additional HIV treatments

[0425] Examples of additional HIV therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0426] Examples of other drugs used to treat HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IM O-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB -9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

[0427] Gene therapy and cell therapy

[0428] Gene therapy and cell therapy include genetic modification to silence genes; genetic approaches to directly kill infected cells; infusions of immune cells designed to replace large portions of an individual's own immune system to boost the immune response to infected cells or to activate an individual's own immune system to kill infected cells or to seek out and kill infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness to infection.

[0429] Examples of dendritic cell therapies include AGS-004.

[0430] gene editing agents

[0431] Examples of gene editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0432] Examples of CRISPR / Cas9 systems targeting HIV include EBT101.

[0433] CAR-T cell therapy

[0434] CAR-T cell therapy includes a colony of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. HIV antigens include HIV envelope proteins or portions thereof, gp120 or portions thereof, CD4 binding sites on gp120, CD4 induction binding sites on gp120, N-glycans on gp120, V2 of gp120, and proximal membrane regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+ T cells, CD8+ T cells, or a combination thereof.

[0435] Examples of HIV CAR-T include VC-CAR-T.

[0436] TCR-T cell therapy

[0437] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides on the surface of virus-infected cells.

[0438] It will be appreciated by those skilled in the art that the additional therapeutic agents listed above may be included in more than one of the above listed classes. The specific classes are not intended to limit the functionality of those compounds listed in those classes.

[0439] In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitory compound. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0440] In a particular embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and androcitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and andrositabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and andrositabine); (tenofovir disoproxil fumarate and androcitabine; TDF+FTC); (tenofovir alafenamide and andrositabine); (tenofovir alafenamide, andrositabine, and rilpivirine); (tenofovir alafenamide, andrositabine, cobicistat, and elvitegravir); (Bictegravir, Andrositabine, Tenofovir Elafenamide); Adefovir; Adefovir Dipivoxil; Cobicistat; Andrositabine; Tenofovir; Tenofovir Disoproxil Fumarate; Tenofovir Elafenamide; Tenofovir Hemifumarate; (durulavir, abacavir, and lamivudine);durulavir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; pralidin; fosamprenavir; fosamprenavir calcium and efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; sitastatin Indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesbevacizumab; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (resipitor); lamivudine and tenofovir disoproxil fumarate; efavirenz; lamivudine and tenofovir disoproxil fumarate; fosfezil; lamivudine; nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0441] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0442] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir hemifumarate, or bictegravir.

[0443] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with: a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bitegravir; and a second additional therapeutic agent selected from the group consisting of andrositabine and lamivudine.

[0444] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with: a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bitegravir; and a second additional therapeutic agent, wherein the second additional therapeutic agent is andrositabine.

[0445] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of andrositabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10 mg, 5-15 mg, 5-20 mg, 5-25 mg, 25-30 mg, 20-30 mg, 15-30 mg, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of andrositabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of andrositabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of andrositabine. As disclosed herein, a compound (e.g., a compound of Formula (I)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as if each combination of doses were specifically and separately listed.

[0446] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate and 200 mg of andrositabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate, or tenofovir disoproxil fumarate and 200 mg of andrositabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200 mg of andrositabine. The compounds of the present invention can be combined with the agents provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as if each combination of doses were specifically and separately listed.

[0447] HBV combination therapy

[0448] In certain embodiments, a method for treating or preventing HBV infection in a human having or at risk of developing HBV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating HBV infection in a human having or at risk of developing HBV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0449] In certain embodiments, the present invention provides a method for treating HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents useful for treating HBV infection.

[0450] The compounds described herein can be used or combined with one or more of the following: chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editing agents (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapies (such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents), or any combination thereof.

[0451] In certain embodiments, the compounds of the invention are formulated as tablets, which may optionally contain one or more other compounds useful in the treatment of HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 regulators, arginine kinase inhibitors, B lymphocyte and T lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric regulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease regulators, epigenetic regulators, farnesoid X receptor agonists, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBVDNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAPs inhibitors, IL-2 agonists, IL-7 Agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators Regulators, ICOS regulators, Mer regulators, NKG2A regulators, NKG2D regulators, OX40 regulators, SIRPα regulators, TIGIT regulators, Tim-4 regulators, Tyro regulators, Na+-taurocholate co-transporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nuclear protein inhibitors, nuclear protein regulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNADNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulator of interferon genes (STING) promoters, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

[0452] HBV combination drugs

[0453] Examples of combination drugs used to treat HBV include (tenofovir disoproxil fumarate and androcitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0454] Other HBV drugs

[0455] Examples of other drugs used to treat HBV include alpha-hydroxytropone, amdoxovir, beta-hydroxycytidine, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin / gentiopicroside, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (TiFen Tai)), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, and Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N,and compounds disclosed in US20150210682 (Roche), US2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). ,

[0456] HBV vaccine

[0457] HBV vaccines include preventive and therapeutic vaccines. Examples of HBV preventive vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, Hepatitis B preventive vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX Recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, YiTai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine.

[0458] Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (εPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccines (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050 and LmHBV.

[0459] HBV DNA polymerase inhibitors

[0460] Examples of HBV DNA polymerase inhibitors include adefovir Andrositabine Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, intivar Intifo maleate, telbivudine Filociril, pradefovir, clevudine, ribavirin, lamivudine Phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and HS-10234.

[0461] Immunomodulators

[0462] Examples of immunomodulators include retalide, imidol hydrochloride, ingaron, demavir, chloroquine (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, the polymer polyethyleneimine (PEI), Gibon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785, RG-7854, AB-506, RO-6871765, AIC-649, and IR-103.

[0463] Toll-like receptor (TLR) modulators

[0464] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include retalide, poly-ICLC, Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1.

[0465] Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, D, telratolimod), SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).

[0466] Examples of TLR8 modulators include motomod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688, and compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Patent No. 9,670,205, US20160289229, U.S. Patent Application No. 15 / 692,161, and U.S. Patent Application No. 15 / 692,093.

[0467] Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, and CYT-003-QbG10.

[0468] Examples of TLR7, TLR8, and TLR9 modulators include compounds disclosed in WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (ROche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai) Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo Dainippon Pharma), WO2016023511 (ChiaTai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (ROche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (BristolMyers Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO2018005586 (BristolMyersSquibb), WO201704023 (3M Co), WO2017163264 (Council of Scientific and Industrial Research (India)), WO2018046460 (GlaxoSmithKline Biologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), WO2017202704 (Roche), WO2018026620 (Bristol Myers Squibb Squibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (ShanghaiDe Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (SichuanKelunBiotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), and WO2015023958 (University of Kansas).

[0469] Interferon α receptor ligand

[0470] Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON ), pegylated interferon α-2a Pegylated interferon α-1b, interferon α1b Veldona, Infradure, Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Y-pegylated interferon alpha-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon alpha-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 Interferon beta-1a Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax alfa, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), interferon alpha 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, Interferon alpha-2b (Amega), Interferon alpha-2b (Virchow), Ropeg interferon alpha-2b, rHSA-IFN alpha-2a (recombinant human serum albumin interferon alpha 2a fusion protein), rHSA-IFN alpha 2b, Recombinant human interferon alpha-(1b, 2a, 2b), Pegylated interferon alpha-2b (Amega), Pegylated interferon alpha-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon alpha-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai (Shang Sheng Lei Tai) Tai), INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa).

[0471] Hyaluronidase inhibitors

[0472] Examples of hyaluronidase inhibitors include astodrimer.

[0473] Hepatitis B surface antigen (HBsAg) inhibitors

[0474] Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006, and REP-9AC'.

[0475] Examples of HBsAg secretion inhibitors include BM601.

[0476] Cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitor

[0477] Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, ProbodymAb, tremelimumab, and JHL-1155.

[0478] Cyclophilin inhibitors

[0479] Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

[0480] HBV viral entry inhibitors

[0481] Examples of HBV viral entry inhibitors include Myrcludex B.

[0482] Antisense oligonucleotides targeting viral mRNA

[0483] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

[0484] Short interfering RNA (siRNA) and ddRNAi.

[0485] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

[0486] Examples of DNA-guided RNA interference (ddRNAi) include BB-HB-331.

[0487] Endonuclease modulators

[0488] Examples of endonuclease modulators include PGN-514.

[0489] Ribonucleotide reductase inhibitors

[0490] Examples of ribonucleotide reductase inhibitors include Trimidox.

[0491] HBV E antigen inhibitors

[0492] Examples of HBV E antigen inhibitors include wogonin.

[0493] Covalently closed circular DNA (cccDNA) inhibitors

[0494] Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0495] Farnesoid X receptor agonists

[0496] Examples of farnesoid X receptor agonists are such as EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670.

[0497] HBV antibodies

[0498] Examples of HBV antibodies targeting hepatitis B virus surface antigens include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed).

[0499] Examples of HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immune globulin (intravenous, pH 4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0500] Fully human monoclonal antibodies include HBC-34.

[0501] CCR2 chemokine antagonists

[0502] Examples of CCR2 chemokine antagonists include propagermanium.

[0503] Thymosin agonists

[0504] Examples of thymosin agonists include Thymalfasin, recombinant thymosin α1 (GeneScience).

[0505] cytokines

[0506] Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin.

[0507] Nuclear protein regulators

[0508] Nucleoprotein modulators can be HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY41-4109, morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23.

[0509] Examples of capsid inhibitors include compounds disclosed in US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janss en), WO2014033167(Janssen), WO2015 / 059212(Janssen), WO2015118057(Janssen), WO2015011281(Janssen), WO2014184365(Janssen), WO2014184350(Janssen), WO 2014161888(Janssen), WO2013096744(Novira), US20150225355(Novira), US20140178337(Novira), US20150315159(Novira), US20150197533(Novira), US20150274 US 20170334882(Novira)、US 20170334898(Roche), WO2017202798(Roche), WO2017214395(Enanta), WO2018001944(Roche), WO2018001952(Roche), WO2018005881(Novira), WO2018005 883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929(Janssen), WO2016168619(Indiana University), WO2016195982(The Penn StateFoundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

[0510] Examples of transcription inhibitors include compounds disclosed in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta), WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

[0511] Retinoic acid-inducible gene 1 stimulator

[0512] Examples of retinoic acid-inducible gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170, RGT-100.

[0513] NOD2 stimulators

[0514] Examples of NOD2 stimulators include SB-9200.

[0515] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0516] Examples of PI3K inhibitors include idelaloxib, ACP-319, AZD-8186, AZD-8835, buparcoxib, CDZ-173, CLR-457, picoxib, neratinib, regolexib, regolexib sodium, EN-3342, TGR-1202, idelaloxib, durvixib, IPI-549, UCB-5857, tylenicib, XL-765, gidacoxib, ME-401, VS-5584, cobancoxib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panucorubicin, GSK-2277, and PD-1 inhibitors. 69557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilacoxib, BAY-1082439, praquintinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonocoxib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

[0517] Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

[0518] Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

[0519] PD-1 inhibitors

[0520] Examples of PD-1 inhibitors include cemiplimab, nivolumab, pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170, durvalumab, atezolizumab, and mDX-400, JS-001, Candida albicans, and PD-1 inhibitors. Camrelizumab, Sintilimab, Sintilimab, Tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (epidermal growth factor receptor antagonist; planned cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-L1 / TGF-β bifunctional fusion protein), Genolizumab, and BMS-936559.

[0521] PD-L1 inhibitors

[0522] Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

[0523] Examples of PD-1 inhibitors include the compounds disclosed in the following: WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (Bristol Myers Squibb Co), WO201317322 (Bristol Myers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221 (Incyte Corp), WO2018118848 (Bristol Myers Squibb Co), WO20161266460 (Bristol Myers Squibb Co), WO2017087678 (Bristol Myers Squibb Co), WO2016149351 (Bristol Myers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai Research Institute), WO2017066227 (Bristol Myers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene Discovery Technologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), WO2018085750 (Bristol Myers Squibb Co), WO2015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual;Texas A&M University System)、WO2015160641(BristolMyers Squibb Co)、WO2017079669(Incyte Corp)、WO2015033301(Aurigene Discovery Technologies Ltd)、WO2015034820(BristolMyers Squibb Co)、WO2018073754(Aurigene DiscoveryTechnologies Ltd)、WO2016077518(BristolMyers Squibb Co)、WO2016057624(BristolMyers Squibb Co)、WO2018044783(Incyte Corp)、WO2016100608(BristolMyersSquibb Co)、WO2016100285(BristolMyers Squibb Co)、WO2016039749(BristolMyersSquibb Co)、WO2015019284(Cambridge Enterprise Ltd)、WO2016142894(AurigeneDiscovery Technologies Ltd)、WO2015134605(BristolMyers Squibb Co)、WO2018051255(Aurigene Discovery Technologies Ltd)、WO2018051254(Aurigene DiscoveryTechnologies Ltd)、WO2017222976(Incyte Corp)、WO2017070089(Incyte Corp)、WO2018044963(BristolMyers Squibb Co)、WO2013144704(Aurigene DiscoveryTechnologies Ltd)、WO2018013789(Incyte Corp)、WO2017176608(BristolMyers SquibbCo)、WO2018009505(BristolMyers Squibb Co)、WO2011161699(Aurigene DiscoveryTechnologies Ltd)、WO2015119944(Incyte Corp;Merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd) Ltd), WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971 (Arising International). ;

[0524] Recombinant Thymosin α-1

[0525] Examples of recombinant thymosin α-1 include NL-004 and pegylated thymosin α-1.

[0526] Bruton's tyrosine kinase (BTK) inhibitors

[0527] Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the BTK inhibitors disclosed in US Pat. No. 20140330015 (Ono- Pharmaceutical), US20130079327 (Ono Pharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0528] KDM inhibitors

[0529] Examples of KDM5 inhibitors include compounds disclosed in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).

[0530] Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

[0531] STING agonists

[0532] Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, and compounds disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssn), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer).

[0533] Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0534] Examples of NNRTIs include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555 (Gilead).

[0535] HBV replication inhibitors

[0536] Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and Xingantie.

[0537] Arginase inhibitors

[0538] Examples of arginase inhibitors include CB-1158, C-201, and ramucirumab.

[0539] Gene therapy and cell therapy

[0540] Gene therapy and cell therapy include genetic modification to silence genes; genetic approaches to directly kill infected cells; infusions of immune cells designed to replace large portions of a patient's own immune system to boost the immune response to infected cells or to activate the patient's own immune system to kill infected cells or to seek out and kill infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness to infection.

[0541] gene editing agents

[0542] Examples of genome editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system; for example, cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes. Alteration (e.g., gene knockout and / or blocking of gene expression) of the PreC, C, X, PreS1, PreS2, S, P, or SP gene refers to (1) reducing or eliminating the expression of the PreC, C, X, PreS1, PreS2, S, P, or SP gene; (2) interfering with the function of the precore protein (Precore), core protein (Core), X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or hepatitis B splicing protein (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP); or (3) reducing or eliminating the intracellular, serum, and / or brain parenchymal levels of the HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and / or HBSP proteins. Blocking of gene expression of one or more of the PreC, C, X, PreSI, PreS2, S, P and / or SP genes is performed by targeting genes within HBV cccDNA and / or integrated HBV DNA.

[0543] CAR-T cell therapy

[0544] CAR T cell therapy includes a colony of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HBV antigen binding domain. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic.

[0545] TCR-T cell therapy

[0546] TCR T cell therapy includes T cells that express HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides presented on the surface of virus-infected cells. In certain embodiments, T cells express HBV surface antigen (HBsAg)-specific TCRs. Examples of TCR-T therapies for the treatment of HBV include LTCR-H2-1.

[0547] In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with: an HBV DNA polymerase inhibitor; one or two additional therapeutic agents selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody and a bispecific antibody targeting the surface antigen of hepatitis B virus), and an "antibody-like" therapeutic protein (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators; and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

[0548] In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one second additional therapeutic agent selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody targeting the surface antigen of hepatitis B virus), and bispecific antibodies and "antibody-like" therapeutic proteins (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginine kinase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators.

[0549] In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one second additional therapeutic agent selected from the group consisting of: an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting a surface antigen of hepatitis B virus, an siRNA, an miRNA gene therapy agent, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (HBV core or capsid protein inhibitor).

[0550] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with compounds such as those disclosed in U.S. Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 (Gilead Sciences), Sciences), U.S. Publication No. 2014 / 0045849 (Janssen), U.S. Publication No. 2014 / 0073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), U.S. Publication No. 2014 / 0350031 (Janssen), WO2014 / 023813 (Janssen), U.S. Publication No. 2008 / 0234251 (Array Biopharma), U.S. Publication No. 2008 / 0306050 (Array Biopharma), U.S. Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Publication No. 2011 / 0092485 (Ventirx Pharma) Pharma), US2011 / 0118235 (Ventirx Pharma), U.S. Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO 2013096744(Novira)、US20150225355(Novira)、US20140178337(Novira)、US20150315159(N ovira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20 150132258(Novira)、US9181288(Novira)、WO2014184350(Janssen)、WO2013144129(Roche)、 US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), U.S. Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0217880 (Onopharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals),Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Oryzon Genomics), and other drugs and combinations thereof for the treatment of HBV.

[0551] Cancer combination therapy

[0552] In one embodiment, the compounds of the present invention can be used in conjunction with other therapeutic approaches for the treatment of cancer. Preferably, combination therapy with chemotherapeutic agents, hormones, antibodies, surgery and / or radiation therapy is contemplated.

[0553] In some embodiments, the other anti-cancer therapy is surgery and / or radiation therapy.

[0554] In some embodiments, the other anti-cancer therapy is at least one additional cancer agent.

[0555] In some embodiments, a combination is provided comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other cancer agent.

[0556] In some embodiments, a combination comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one other cancer agent is provided for use in therapy.

[0557] In some embodiments, provided is the use of a combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one cancer agent for the manufacture of a medicament for treating cancer.

[0558] Examples of other cancer drugs include intercalating substances such as anthracyclines, doxorubicin, idarubicin, epirubicin, and daunorubicin; topoisomerase inhibitors such as irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticines, and aurintricarboxylic acid; acid; nitrosourea compounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin; nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid, and isoflavones; Cyclophosphamide (ifosfamide); alkyl sulfonates such as busulfan and treosulfan; alkylating agents such as procarbazin, dacarbazin, temozolomid, and thiotepa; platinum analogs such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate; microtubule-disrupting drugs such as vinblastine, colcemid, and nocodazole;Antifolates such as methotrexate, aminopterin, dichloromethotrexate, pemetrexed, raltitrexed, and pralatrexate; purine analogs such as azathioprine, mercaptopurine, thioguanine, fludarabine, fludarabine phosphate, pentostatin, and cladribine; pyrimidine analogs such as 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine; steroids such as gemcitabine anticancer antibodies, such as monoclonal antibodies, for example, alemtuzumab, apolizumab, cetuximab, epratuzumab, galiximab, gemtuzumab, ipalimumab, labetuzumab, panitumumab, rituximab, trastuzumab, nimotuzumab, mapatumumab, matuzumab, rhMab ICR62 and pertuzumab, radiolabeled antibodies, and antibody-drug conjugates; anticancer peptides, such as radiolabeled peptides and peptide-drug conjugates; and taxanes and taxane analogs, such as paclitaxel and docetaxel.

[0559] In certain embodiments, a method for treating or preventing a hyperproliferative disorder or cancer in a human or animal having, or at risk of having, a hyperproliferative disorder or cancer is provided, comprising administering to the human or animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating a hyperproliferative disorder or cancer in a human or animal having, or at risk of having, a hyperproliferative disorder or cancer is provided, comprising administering to the human or animal a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0560] In certain embodiments, the present invention provides a method of treating a hyperproliferative disorder or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating the hyperproliferative disorder or cancer.

[0561] The compounds described herein can be used or combined with one or more of the following: chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADCs), radiotherapeutics, antitumor agents, antiproliferative agents, oncolytic viruses, gene modifiers or editing agents (such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, engineered T cell receptors (TCR-T), or any combination thereof. Such therapeutic agents may be in the form of compounds, antibodies, polypeptides, or polynucleotides. In one embodiment, provided herein is a product comprising a compound described herein and an additional therapeutic agent in the form of a combined formulation for simultaneous, separate, or sequential use in therapy.

[0562] Non-limiting examples of additional therapeutic agents include: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2B, A2a, A3), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aeromonas lysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha 1 adrenergic receptor, alpha 2 adrenergic receptor, alpha-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP Activated protein kinase, polymorphic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (such as ligand-1, ligand-2), angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein AI (APOA1) gene, apoptosis-inducing factor, apoptosis protein (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1), arginine kinase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad 3-related (ATR) serine / threonine protein kinase, Aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat-containing 5 (BIRC5) gene, basic immunoglobulin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenergic receptor, beta-catenin, B lymphocyte antigen CD19, B lymphocyte antigen CD20, B lymphocyte cell adhesion molecule, B lymphocyte stimulator ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein-9 ligand regulator, brachykinin, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain- and extradomain-containing (BET) bromodomain proteins (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), cancer testicular antigen 2, cancer testicular antigen NY-ESO-1, cancer / testicular antigen 1B (CTAG1) gene, cannabinoid receptors (such as CB1, CB2), carbonic anhydrase, casein kinase (CK,such as CKI, CKII), apoptotic proteases (such as apoptotic proteases-3, apoptotic proteases-7, apoptotic proteases-9), apoptotic proteases 8 apoptosis-related cysteine ​​peptidase CASP8-FADD-like regulator, apoptotic proteases recruitment domain protein-15, cathepsin G, CCR5 gene, CDK activating kinase (CAK), checkpoint kinases (such as CHK1, CHK2), chemokine (CC motif) receptors (such as CCR2, CCR4, CCR5), chemokine ((CXC motif) 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 33, 37, 38, 40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD 47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor) cytotoxic T lymphocyte protein 4), cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs, such as CDK1, CDK1B, CDK2-9), cyclooxygenases (such as 1, 2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine protein, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein-4, DDR2 gene, delta-like protein ligand (such as 3, 4), deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptor (DDR,such as DDR1), DNA binding proteins (such as HU-β), DNA-dependent protein kinases, DNA gyrase, DNA methyltransferase, DNA polymerase (such as α), DNA primers, dUTP pyrophosphatase, L-dopachrome tautomerase, echinoderm tubulin-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulin, endosialin, endostatin, endothelins (such as ET-A, ET-B), enhancer of zeste homolog 2 (EZ H2), ephrin (EPH) tyrosine kinases (such as Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigenetic factors, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythrocytic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β deacetylase Hydrogenase, estrogen receptor (such as α, β), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (such as 1, 2), extracellular signal-regulated kinase (ERK), factor (such as Xa, VIIa), farnesoid X receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, Fms-related tyrosine kinase 3 ( Flt3), focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK,Such as 3-β), phosphatidylinositol protein glycan 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony stimulating factor (GM-CSF) receptor, granulocyte-colony stimulating factor (GCSF) ligand, growth factor receptor binding protein 2 (GRB2), Grp78 (78kDa glucose-regulated protein) calcium binding protein, molecular chaperone protein groEL2 gene, heat shock protein (such as 27, 70, 90α, β), heat shock protein gene, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-HLTR related protein 2, hexokinase, histamine H2 receptor, Histone methyltransferase (DOT1L), histone deacetylase (HDAC, such as 1, 2, 3, 6, 10, 11), histone H1, histone H3, HLA class I antigen (A-2α), HLA class II antigen, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (such as E6, E7) protein, hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1α (HIF1α), imprinted maternal transcript (H19) gene, mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-κ-B kinase enzymes (IKK, such as IKKbe), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (such as G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (such as 1, 2), integrin, Integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM-1), interferons (such as α, α2, β, γ), interferon-inducible protein 2 (AIM2) absent in melanoma, type I interferon receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK,Such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-associated protein-1, leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, dissociation enzyme, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphocyte chemotactic factor kinase, Lyn (Lck / Yes novel type) tyrosine kinase, lysine demethylase (such as KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatidic acid-1 receptor, lysosomal associated membrane protein family (LAMP) genes, lysine oxidase homolog 2, lysine oxidase protein (LOX), lysine oxidase-like protein (LOXL, such as LOXL2), hematopoietic progenitor cell kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (such as MK2), Mas-related G protein-coupled receptor, matrix metalloproteinase (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53 binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (such as 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (prostate six-transmembrane epithelial antigen 1), transferrin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl CoA thiolase, activated mitogen protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase), mTOR complex (such as 1, 2), mucin (such as 1, 5A, 16), mut T homolog (MTH,Such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NFκB activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB activated NK receptor, norepinephrine transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF) κB, nucleolin, nucleolar phosphatidylcholine, nucleolar phosphatidylcholine polymorphic lymphoma kinase (NPM-ALK), 2-hydroxyglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptor (such as δ), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, such as α, δ, γ), P-glycoprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, such as α, δ, γ), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as α, β), platelet-derived growth factor (PDGF, such as α, β), pleiotropic drug resistance transporter, plexin B1, PLK1 gene, polo-like kinase (PLK), Polo-like kinase 1, poly ADP ribose polymerase (PARP, such as PARP1, 2 and 3), antigen preferentially expressed in melanoma (PRAME) gene, prenyl binding protein (PrPB), possible transcription factor PML, progesterone receptor, planned cell death 1 (PD-1), planned cell death ligand 1 inhibitor (PD-L1), saposin precursor (PSAP) gene, prostaglandin receptor (EP4), prostate specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyl transferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine-protein kinase (PIM,such as PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-α-reductase, Raf protein kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (such as γ), retinoid X receptor, Rheb (brain-enriched Ras homolog) GTPase, Rho (Ras homolog)-associated protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Receptor from Nantes) d'Origine Nantais)) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, gamma-secretase, S100 calcium-binding protein A9, sarcoendoplasmic reticulum calcium ATPase, second mitochondrial-derived apoptotic protease activator (SMAC) protein, secretory frizzled-related protein-2, semaphorin-4D, serine proteases, serine / threonine kinases (STKs), serine / threonine-protein kinases (TBKs, such as TBK1), signal transducers and transcription (STATs,such as STAT-1, STAT-3, STAT-5), signaling lymphocytic activation molecule (SLAM) family member 7, six transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptors (such as 1, 2, 3, 4, 5), sonic hedgehog protein, Son of sevenless (SOS), specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1, 2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, survivin protein, synapsin 3, synuclein-1, synuclein α, T cell surface glycoprotein CD28, tank binding kinase (TBK), TATA box binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein ζ chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing 3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase ( TERT) gene, tenascin, TGFβ2 ligand, thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (such as α1), thyroid hormone receptor, thyroid stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-related death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, toll-like receptors (TLRs, such as 1-13), topoisomerase ( Such as I, II, III), transcription factors, transferases, transferrin, transforming growth factor (TGF, such as β) kinase, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related protein, transmembrane glycoprotein NMB, Trop-2 calcium signaling protein, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, myosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF,α, β), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 (TUSC2) gene, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, immunoglobulin-like and EGF-like domain tyrosine kinase (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin conjugating enzyme E2I (UBE2I, UBC9), urease, urokinase plasminogen activator compounds, uteroglobulin, vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig inhibitor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein kinase, Wilms' tumor antigen 1, Wilms' tumor protein, X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

[0563] Non-limiting examples of additional therapeutic agents can be categorized by their mechanism of action into, for example, the following groups:

[0564] - antimetabolites / anticancer agents such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunomycin), and TAS-118;

[0565] -Purine analogs, folic acid antagonists (such as pralatrexate) and related inhibitors;

[0566] - Antiproliferative / antimitotic agents, including natural products such as vinca alkaloids (vinblastine, vincristine) and microtubule disrupting agents such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilone, vinorelbine and epipodophyllotoxins (etoposide, teniposide);

[0567] DNA-damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide Actinomycin D, daunorubicin, cyclophosphamide, epirubicin, ifosfamide, melphalan, dichloromethane, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, paclitaxel, Taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

[0568] - DNA hypomethylating agents such as guadecitabine (SGI-110), ASTX727;

[0569] - antibiotics such as actinomycin D, daunomycin, idarubicin, edamamycin, anthracycline, mitoxantrone, bleomycin, plicamycin (mithramycin);

[0570] - enzymes such as L-asparaginase which metabolize L-asparagine systemically and deprive cells that do not have the ability to synthesize their own asparagine;

[0571] - Antiplatelet agents;

[0572] - DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

[0573] - Agents that activate or reactivate latent human immunodeficiency virus (HIV), such as palbinostat and romidepsin;

[0574] -Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol;

[0575] - Pan-Trk, ROS1, and ALK inhibitors, such as entrectinib and TPX-0005;

[0576] - ALK inhibitors, such as alectinib and ceritinib;

[0577] - Antiproliferative / antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogs (melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkylnitrosoureas (carmustine) and analogs, streptozotocin, and triazenes (dacarbazine);

[0578] - Antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0579] - Platinum coordination complexes (cisplatin, oxaliplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

[0580] - Hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (letrozole and anastrozole);

[0581] - anticoagulants, such as heparin, synthetic heparin salts and other thrombin inhibitors;

[0582] - Fibrinolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;

[0583] - anti-migration agents;

[0584] - Antisecretory agents (breveldin);

[0585] - Immunosuppressants such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil;

[0586] - Growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0587] - Fibroblast growth factor inhibitors, such as FPA14;

[0588] - anti-VEGFR antibodies, such as IMC-3C5, GNR-011, tanibirumab;

[0589] - anti-VEGF / DDL4 antibodies, such as ABT-165;

[0590] - anti-cadherin antibodies, such as HKT-288;

[0591] - anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat 15 (LRRC15) containing antibodies, such as ABBV-085.ARGX-110;

[0592] -Angiotensin receptor blockers, nitric oxide donors;

[0593] - antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0594] -DNA interfering oligonucleotides, such as PNT2258, AZD-9150;

[0595] - anti-ANG-2 antibodies, such as MEDI3617 and LY3127804;

[0596] - anti-ANG-1 / ANG-2 antibodies, such as AMG-780;

[0597] - anti-MET / EGFR antibodies, such as LY3164530;

[0598] - anti-EGFR antibodies such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomozuotuximab, ABT-806, vectibix, modotuximab, RM-1929;

[0599] - anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0600] - anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428;

[0601] - anti-endoglin antibodies, such as TRC105 (carotuximab);

[0602] - anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0603] - anti-HER3 antibodies, such as LJM716, GSK2849330;

[0604] - anti-HER2 antibodies, such as margetuximab, MEDI4276, BAT-8001;

[0605] - anti-HLA-DR antibodies, such as IMMU-114;

[0606] - anti-IL-3 antibodies, such as JNJ-56022473;

[0607] - anti-OX40 antibodies such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

[0608] - anti-EphA3 antibodies, such as KB-004;

[0609] - anti-CD20 antibodies, such as obinutuzumab, IGN-002;

[0610] - anti-CD20 / CD3 antibodies, such as RG7828;

[0611] - anti-CD37 antibodies, such as AGS67E, otlertuzumab (TRU-016);

[0612] - anti-ENPP3 antibodies, such as AGS-16C3F;

[0613] - anti-FGFR-3 antibodies, such as LY3076226, B-701;

[0614] - anti-FGFR-2 antibodies, such as GAL-F2;

[0615] - anti-C5 antibodies, such as ALXN-1210;

[0616] - anti-CD27 antibodies, such as varlilumab (CDX-1127);

[0617] - anti-TROP-2 antibodies, such as IMMU-132;

[0618] - anti-NKG2a antibodies, such as monalizumab;

[0619] -Anti-VISTA antibodies, such as HMBD-002;

[0620] - anti-PVRIG antibodies, such as COM-701;

[0621] - anti-EpCAM antibodies, such as VB4-845;

[0622] - anti-BCMA antibodies, such as GSK-2857916;

[0623] - anti-CEA antibodies, such as RG-7813;

[0624] - anti-cluster of differentiation 3 (CD3) antibodies, such as MGD015;

[0625] - anti-folate receptor alpha antibodies, such as IMGN853;

[0626] - MCL-1 inhibitors such as AMG-176, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037;

[0627] -epha2 inhibitors, such as MM-310;

[0628] - anti-LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767;

[0629] -raf kinase / VEGFR inhibitors, such as RAF-265;

[0630] - Escherichia coli (EED) inhibitors, such as MAK683;

[0631] - anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0632] - anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0633] - anti-Fucoidan-GM1 antibodies, such as BMS-986012;

[0634] - p38 MAP kinase inhibitors, such as ralimetinib;

[0635] -PRMT1 inhibitors, such as MS203;

[0636] - sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0637] - FLT3-ITD inhibitors, such as BCI-332;

[0638] - erythroid cell 2-related factor 2 stimulators, such as omaveloxolone (RTA-408);

[0639] - Myosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579;

[0640] - Anti-ICOS antibodies, such as JTX-2011, GSK3359609;

[0641] - anti-DR5 (TRAIL2) antibodies, such as DS-8273;

[0642] - anti-GD2 antibodies, such as APN-301;

[0643] - anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0644] - anti-carbonic anhydrase IX antibodies, such as TX-250;

[0645] - anti-CD38 attenukine, such as TAK573;

[0646] - Anti-mucin 1 antibodies, such as gatipotuzumab;

[0647] - Mucin 1 inhibitors, such as GO-203-2C;

[0648] - MARCKS protein inhibitors, such as BIO-11006;

[0649] -Folic acid antagonists, such as arfolitixorin;

[0650] -Galectin-3 inhibitors, such as GR-MD-02;

[0651] -P68 phosphorylation inhibitors, such as RX-5902;

[0652] -CD95 / TNF modulators, such as ofranergene obadenovec;

[0653] -PI3K / Akt / mTOR inhibitors, such as ABTL-0812;

[0654] - Pan-PIM kinase inhibitors, such as INCB-053914;

[0655] - IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid;

[0656] - Heat shock protein HSP90 inhibitors, such as TAS-116 and PEN-866;

[0657] - VEGF / HGF antagonists, such as MP-0250;

[0658] -SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659;

[0659] -SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0660] - FLT3 tyrosine kinase inhibitors, such as FF-10101;

[0661] - FLT3 tyrosine kinase agonists, such as CDX-301;

[0662] - FLT3 / MEK1 inhibitors, such as E-6201;

[0663] - IL-24 antagonists, such as AD-IL24;

[0664] -RIG-I agonists, such as RGT-100;

[0665] - Aeromonas lysin stimulants, such as topsalysin;

[0666] - P-glycoprotein 1 inhibitors, such as HM-30181A;

[0667] - CSF-1 antagonists, such as ARRY-382, BLZ-945;

[0668] - anti-mesothelin antibodies, such as SEL-403;

[0669] - thymidine kinase stimulators, such as aglatimagene besadenovec;

[0670] - Polo-like kinase 1 inhibitors, such as PCM-075;

[0671] - TLR-7 agonists, such as TMX-101 (imiquimod);

[0672] - NEDD8 inhibitors, such as pevonedistat (MLN-4924), TAS-4464;

[0673] - Pleiotropic pathway modulators, such as avadomide (CC-122);

[0674] -FoxM1 inhibitors, such as Thiostreptomyces;

[0675] - anti-MUC1 antibodies, such as Mab-AR-20.5;

[0676] - anti-CD38 antibodies, such as isatuximab, MOR-202;

[0677] -UBA1 inhibitors, such as TAK-243;

[0678] - Src tyrosine kinase inhibitors, such as VAL-201;

[0679] - VDAC / HK inhibitors, such as VDA-1102;

[0680] -BRAF / PI3K inhibitors, such as ASN-003;

[0681] - Elf4a inhibitors, such as rohinitib, eFT226;

[0682] -TP53 gene stimulators, such as ad-p53;

[0683] -PD-L1 / EGFR inhibitors, such as GNS-1480;

[0684] - retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0685] - SIRT3 inhibitors, such as YC8-02;

[0686] - stromal cell-derived factor 1 ligand inhibitors, such as olaptesedpegol (NOX-A12);

[0687] - IL-4 receptor modulators, such as MDNA-55;

[0688] - Arginase-I stimulators, such as pegzilarginase;

[0689] - topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

[0690] - Hypoxia-inducible factor-1α inhibitors, such as PT-2977, PT-2385;

[0691] -CD122 agonists, such as NKTR-214;

[0692] - p53 tumor suppressor protein stimulators, such as kevetrin;

[0693] - Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924;

[0694] Kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520);

[0695] -CD80-fc fusion protein inhibitors, such as FPT-155;

[0696] Multiple endocrine neoplasia protein and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

[0697] - liver x receptor agonists, such as RGX-104;

[0698] - IL-10 agonists, such as AM-0010;

[0699] -EGFR / ErbB-2 inhibitors, such as varlitinib;

[0700] - VEGFR / PDGFR inhibitors, such as vorolanib;

[0701] - IRAK4 inhibitors, such as CA-4948;

[0702] - anti-TLR-2 antibodies, such as OPN-305;

[0703] - calmodulin modulators, such as CBP-501;

[0704] - glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0705] - Second mitochondrial-derived activator of apoptosis proteinase (SMAC) protein inhibitors, such as BI-891065;

[0706] - lactoferrin modulators, such as LTX-315;

[0707] -Kit tyrosine kinase / PDGF receptor alpha antagonists, such as DCC-2618;

[0708] - KIT inhibitors, such as PLX-9486;

[0709] - exportin 1 inhibitors, such as eltanexor;

[0710] -EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib;

[0711] - anti-CD33 antibodies, such as IMGN-779;

[0712] - anti-KMA antibodies, such as MDX-1097;

[0713] - anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453;

[0714] - anti-CD55 antibodies, such as PAT-SC1;

[0715] - anti-PSMA antibodies, such as ATL-101;

[0716] - anti-CD100 antibodies, such as VX-15;

[0717] - anti-EPHA3 antibodies, such as fibatuzumab;

[0718] - anti-Erbb antibodies, such as CDX-3379, HLX-02, seribantumab;

[0719] - anti-APRIL antibodies, such as BION-1301;

[0720] - Anti-Tigit antibodies, such as BMS-986207, RG-6058;

[0721] - CHST15 gene inhibitors, such as STNM-01;

[0722] -RAS inhibitors, such as NEO-100;

[0723] - somatostatin receptor antagonists, such as OPS-201;

[0724] - CEBPA gene stimulators, such as MTL-501;

[0725] - DKK3 gene modulators, such as MTG-201;

[0726] - p70s6k inhibitors, such as MSC2363318A;

[0727] -Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202;

[0728] - Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0729] - Anti-planned cell death protein 1 (anti-PD-1) antibodies, such as nivolumab ( BMS-936558, MDX-1106), pembrolizumab ( MK-3477, SCH-900475, lambrolizumab (CAS Reg. No. 1374853-91-4), pililizumab, PF-06801591, BGB-A317, GLS-010 (WBP-3055), AK-103 (HX-008), MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS-001, JNJ-63723283, genolizumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306, and anti-programmed death ligand 1 (anti-PD-L1) antibodies, such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, CK-301 (MSB0010718C), MEDI0680, CX-072, CBT-502, PDR-001 (spartalizumab), TSR-042 (dostarlimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308, FAZ-053, and MDX1105-01);

[0730] -PD-L1 / VISTA antagonists, such as CA-170;

[0731] - anti-PD-L1 / TGFβ antibodies, such as M7824;

[0732] - anti-transferrin antibodies, such as CX-2029;

[0733] - anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0734] - ATM (ataxia telangiectasia) inhibitors, such as AZD0156;

[0735] - CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2);

[0736] - CXCR4 antagonists such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-10;

[0737] - EXH2 inhibitors, such as GSK2816126;

[0738] -HER2 inhibitors, such as neratinib, tucatinib (ONT-380);

[0739] - KDM1 inhibitors such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;

[0740] - CXCR2 antagonists, such as AZD-5069;

[0741] -GM-CSF antibodies, such as lenzilumab;

[0742] DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01);

[0743] - protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin;

[0744] -Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, elacestrant (RAD-1901), and AZD9496;

[0745] - Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0746] - Selective androgen receptor modulators (SARMs), such as GTX-024 and darolutamide;

[0747] - Transforming growth factor-beta (TGF-β) kinase antagonists, such as galunisertib;

[0748] - anti-transforming growth factor-β (TGF-β) antibodies, such as LY3022859, NIS793, XOMA 089;

[0749] - Bispecific antibodies, such as MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotozumab (floto tuzumab) (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-117 (CD3 / CLEC12A), MCLA-128 (HER2 / HER3), JNJ-0819, JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1 / LA G-3), AK-104(CTLA-4 / PD-1), AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), BI-836880( VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3);

[0750] - mutant-selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0751] - anti-GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) antibodies, such as MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323;

[0752] - anti-delta-like protein ligand 3 (DDL3) antibodies, such as tesinovamab (rovalpituzumab tesirine);

[0753] - anti-clusterin antibodies, such as AB-16B5;

[0754] - anti-ephrin-A4 (EFNA4) antibodies, such as PF-06647263;

[0755] - anti-RANKL antibodies, such as denosumab;

[0756] - anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0757] - anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab;

[0758] - anti-c-Met antibodies, such as ABBV-399;

[0759] - adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509;

[0760] -α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0761] - XPO1 inhibitors, such as selinexor (KPT-330);

[0762] - Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221);

[0763] - IDH1 inhibitors such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;

[0764] - interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0765] - arginine deiminase stimulators, such as polyethylene glycol arginine deiminase (ADI-PEG-20);

[0766] - Antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylate cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla), milatuzumab-hCD74-DOX, brentuximab vedotin, DCDT2980S, polatuzumab vedotin, SGN-CD70A, SGN-CD19A, inotuzumab bozogamicin, lorvotuzumab mertansine, SAR3419, isactuzumab govitecan, enfortumab vedotin, vedotin)(ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab ravtansine, CX-2009, SAR-566658, W-0101, baunavir vedotin, ABBV-085;

[0767] - Claudin-18 inhibitors, such as claudiximab;

[0768] -β-catenin inhibitors, such as CWP-291;

[0769] - anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179;

[0770] -CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425;

[0771] -CD39 / CD73 antagonists, such as PBF-1662;

[0772] - Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0773] - thymidylate synthase inhibitors, such as ONX-0801;

[0774] -ALK / ROS1 inhibitors, such as lorlatinib;

[0775] - telomerase inhibitors, such as G007-LK;

[0776] - Mdm2 p53-binding protein inhibitors, such as CMG-097, HDM-201;

[0777] -c-PIM inhibitors, such as PIM447;

[0778] -BRAF inhibitors such as dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394;

[0779] - Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0780] -Cell cycle inhibitors, such as selumetinib (MEK1 / 2) and sapacitabine;

[0781] - AKT inhibitors such as MK-2206, ipatasertib, afuretib, AZD5363 and ARQ-092, capivasertib, triciribine;

[0782] - anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such as tremelimumab, AGEN-1884, BMS-986218;

[0783] c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, and HQP-8361;

[0784] -c-Met / VEGFR inhibitors, such as BMS-817378 and TAS-115;

[0785] -c-Met / RON inhibitors, such as BMS-777607;

[0786] -BRAF / EGFR inhibitors, such as BGB-283;

[0787] - bcr / abl inhibitors, such as rebastinib and asciminib;

[0788] - MNK1 / MNK2 inhibitors, such as eFT-508;

[0789] - mTOR inhibitors / cytochrome P450 3A4 stimulators, such as TYME-88;

[0790] - lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0791] - Pan-RAF inhibitors such as LY3009120, LXH254, TAK-580;

[0792] - Raf / MEK inhibitors, such as RG7304;

[0793] -CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);

[0794] - kinase inhibitors, such as vandetanib;

[0795] - E-selectin antagonists, such as GMI-1271;

[0796] - Differentiation-inducing agents, such as retinoic acid;

[0797] - epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291);

[0798] - topoisomerase inhibitors such as daunorubicin, daunorubicin, actinomycin D, eniposide, epirubicin, etoposide, edamycin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114);

[0799] -Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

[0800] - Growth factor signaling kinase inhibitors;

[0801] - Nucleoside analogs, such as DFP-10917;

[0802] - Axl inhibitors such as BGB-324 (bemcentinib), SLC-0211;

[0803] - BET inhibitors such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;

[0804] - PARP inhibitors such as olaparib, rucaparib, veliparib, talazoparib, ABT-767, BGB-290;

[0805] -Proteasome inhibitors, such as ixazomib and carfilzomib Marizomib;

[0806] - glutaminase inhibitors, such as CB-839;

[0807] vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67 / M57-KLH, IMU-131; bacterial vector vaccines, such as CRS-207 / GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofaragene firadenovec); autologous Gp96 vaccines; dendritic cell vaccines such as CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, rocapuldencel-T (AGS-003), DCVAC, CVac tm 、STASEL-T、ATASEL-T、SL-701、BSK01 TM , ADXS31-142; oncolytic vaccines such as talimogenelaherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines such as CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax TM ; Tumor cell vaccines, such as (IND-14205), Oncoquest-L vaccine; live attenuated, recombinant, serotype 1 poliovirus vaccines, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457; DPV-001, a tumor-derived, autophagosome-enriching cancer vaccine; RNA vaccines, such as CV-9209 and LV-305; DNA vaccines, such as MEDI-0457, MVI-816, and INO-5401; modified vaccinia virus Ankara vaccines expressing p53, such as MVA-p53; DPX-Survivac; and BriaVax.TM ;GI-6301;GI-6207;GI-4000;

[0808] - anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab;

[0809] - STAT-3 inhibitors, such as napabucasin (BBI-608);

[0810] - ATPase p97 inhibitors, such as CB-5083;

[0811] - Smoothened (SMO) receptor inhibitors, such as (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

[0812] - Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), ropeginterferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), follow-on biologics to interferon alpha-2a (Biosidus) (Inmuta, Inter 2A), follow-on biologics to interferon alpha-2b (Biosidus-Baifeilong, Citopheron, Ganapar, Beijing Kawin) Technology (Kaferon), alfafelton, pegylated interferon alfa-1b, follow-on biologics of pegylated interferon alfa-2b (Amega), recombinant human interferon alfa-1b, recombinant human interferon alfa-2a, recombinant human interferon alfa-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alfa-n1 (Humoferon, SM-10500, Sumiferon);

[0813] - interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100);

[0814] - IL-6 receptor modulators, such as tocilizumab, siltuximab, AS-101 (CB-06-02, IVX-Q-101);

[0815] Telomerase regulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0816] DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guadacitidine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine;

[0817] -DNA gyrase inhibitors, such as pyrantelone and sobuzoxan;

[0818] - Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, and AT-101;

[0819] - Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024;

[0820] - anti-myostatin inhibitors, such as landogrozumab;

[0821] - Hyaluronidase stimulators, such as PEGPH-20;

[0822] - Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974;

[0823] -γ-secretase inhibitors such as PF-03084014, MK-0752, RO-4929097;

[0824] - Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0825] -TRAIL pathway inducing compounds, such as ONC201 and ABBV-621;

[0826] - Focal adhesion kinase inhibitors, such as VS-4718, defactinib, GSK2256098;

[0827] - Hedgehog inhibitors, such as saridegib, sonidegib (LDE225), gradigib, and vismodegib;

[0828] - Aurora kinase inhibitors, such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib, ENMD-2076;

[0829] - HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;

[0830] -ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;

[0831] - mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014), ME-344;

[0832] - mTOR / PI3K inhibitors, such as GSK2141795, Omipalisib, and RG6114;

[0833] - Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;

[0834] - murine dual microoncogene (mdm2) inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);

[0835] -CD137 agonists, such as urelumab, utomilumab (PF-05082566);

[0836] - STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

[0837] - FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0838] - fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0839] - anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

[0840] -antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;

[0841] -CD44 binders, such as A6;

[0842] - Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0843] -CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0844] - RXR agonists, such as IRX4204;

[0845] - Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib and patidegib;

[0846] - Complement C3 modulators, such as Imprime PGG;

[0847] - IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;

[0848] - EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126;

[0849] - Oncolytic viruses such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301;

[0850] - DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676);

[0851] - toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and apoptotic protease activators;

[0852] -DNA plasmids, such as BC-819;

[0853] -PLK inhibitors of PLK 1, 2 and 3, such as volasertib (PLK1);

[0854] -WEE1 inhibitors, such as AZD1775 (adavosertib);

[0855] - Rho kinase (ROCK) inhibitors, such as AT13148, KD025;

[0856] -ERK inhibitors such as GDC-0994, LY3214996, MK-8353;

[0857] - IAP inhibitors such as ASTX660, debio-1143, bilinapant, APG-1387, LCL-161;

[0858] - RNA polymerase inhibitors, such as lurbinectedin (PM-1183), CX-5461;

[0859] - tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), OXI-4503, fluorapacin (AC-0001), and plinabulin;

[0860] - Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091 and PEPA-10;

[0861] - elongation factor 1α2 inhibitors, such as plitidepsin;

[0862] -CD95 inhibitors, such as APG-101, APO-010, asunercept;

[0863] -WT1 inhibitors, such as DSP-7888;

[0864] - Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0865] - PDGFRα / KIT mutant-specific inhibitors, such as BLU-285;

[0866] - SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550; and

[0867] - Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716.

[0868] In some embodiments, provided herein are methods of treating or preventing a hyperproliferative disorder or cancer in a human or animal having or at risk of a hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents selected from the group consisting of: an apoptosis signal-regulating kinase (ASK) inhibitor; a Bruton's tyrosine kinase (BTK) inhibitor; a cluster of differentiation 47 (CD47) inhibitor; a cyclin-dependent kinase (CDK) inhibitor; Discoidin domain receptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors; indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors; Janus kinase (JAK) inhibitors; lysine oxidase-like protein (LOXL) inhibitors; matrix metalloproteinase (MMP) inhibitors; mitogen-activated protein kinase (MEK) inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors; toll-like receptor 8 (TLR8) inhibitors; toll-like receptor 9 (TLR9) inhibitors; tyrosine kinase inhibitors (TKIs) and any combination thereof or pharmaceutically acceptable salts thereof. Non-limiting examples include:

[0869] - Apoptosis signal-regulating kinase (ASK) inhibitors: ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, inhibitors described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences);

[0870] - Bruton's tyrosine kinase (BTK) inhibitors: Examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, septinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;

[0871] - Cluster of differentiation 47 (CD47) inhibitors: Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621;

[0872] - Cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, 7, and 9, such as abemaciclib, alvcidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, regolitinib, cilinostat, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, and TG-02;

[0873] -Discoid domain receptor (DDR) inhibitors: DDR inhibitors include inhibitors of DDR1 and / or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations);

[0874] - Histone deacetylase (HDAC) inhibitors: Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, pabinostat, pracinostat, quisinostat (JNJ-26481585), ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;

[0875] - Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, Epasta, F-001287, GBV-1012, GBV-1028, GDC-0919, Indomide, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), Reminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916;

[0876] - Janus kinase (JAK) inhibitors: JAK inhibitors inhibit JAK1, JAK2, and / or JAK3. Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019;

[0877] - Lisamine oxidase-like protein (LOXL) inhibitors: LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and / or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics);

[0878] -Matrix metalloproteinase (MMP) inhibitors: MMP inhibitors include inhibitors of MMP1 to MMP10. Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipemastat (Ro32-3555), GS-5745 (andecaliximab), and the inhibitors described in WO2012 / 027721 (Gilead Biologics);

[0879] -Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib;

[0880] - Phosphatidylinositol 3-kinase (PI3K) inhibitors: PI3K inhibitors include inhibitors of PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα and / or pan-PI3K. Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, Bupiracil (BKM120), BYL719 (Irepacil), CH5132799, Cobancoxib (BAY 80-6946), Duvixib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, and Edesib. INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, regolitinib, RP5090, RP6530, SRX3177, tenisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO 2005 / 113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO Compounds described in WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences);

[0881] - Spleen tyrosine kinase (SYK) inhibitors: Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-N-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and SYK inhibitors described in US 8450321 (Gilead Connecticut) and SYK inhibitors described in US 2015 / 0175616;

[0882] - Toll-like receptor 8 (TLR8) inhibitors: Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motomod, resiquimod, VTX-1463, and VTX-763;

[0883] - Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, litenmod, MGN-1601, and PUL-042; and

[0884] -Tyrosine kinase inhibitors (TKIs): TKIs target the epidermal growth factor receptor (EGFR) as well as the receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, Ek Icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, tivoanib, and TH-4000 and MEDI-575 (anti-PDGFR antibodies).

[0885] As used herein, the term "chemotherapeutic agent" or "chemotherapy" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to encompass any non-protein (i.e., non-peptide) compound useful for treating cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide. Alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; polyacetyls, especially bullatacin and bullatacinone; camptothecin, These include synthetic analogs of topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogs of adozelesin, carzelesin, and bizelesin; cryptophycin, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including its synthetic analogs KW-2189 and CBI-TMI; and eleu therobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, methyldi(chloroethyl)amine, methyldi(chloroethyl)amine oxide hydrochloride, melphalan, novembichin, benzyl alcohol, benzophenone ... phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin gamma II); ), dynemycins including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromophores, enediyne antibiotic plastids, aclacinomycin, actinomycin, authramycin, azoserine, bleomycin, actinomycin C, carabicin, carrninomycin, car zinophilin), chromomycin, actinomycin D, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, cypermethrin (including N-morpholino-cypermethrin, cyano-N-morpholino-cypermethrin, 2-pyrrolino-cypermethrin, and deoxycypermethrin), epirubicin, esorubicin, edamycin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin in), peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demoline purine analogs such as fludarabine, 6-mercaptopurine, thiabendine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; adrenal antidepressants such as fentanyl, mitotane, and trilostane; and folic acid supplements such as folinic acid;Radiotherapeutic agents, such as radium-223; trichothecenes, particularly T-2 toxin, verracurin A, roridin A, and anguidine; taxoids, such as paclitaxel; Albumin-bound paclitaxel (abraxane), docetaxel Cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acetylglucosyl esters; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; colchicine; diaziquone; elformthine; elliptinium acetate acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; Lentinan; leucovorin; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folate; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid acid; trabectedin, triaziquone; 2,2',2"-tricUorotriemylamine; carbamate; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Novantrone; teniposide; edatrexate; daunorubicin; aminopterin; xeoloda; ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFIRI (fluorouracil, leucovorin, and irinotecan); and pharmaceutically acceptable salts, acids, or derivatives of any one of the foregoing.

[0886] The definition of "chemotherapeutic agent" also includes antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs) used to modulate or inhibit hormonal effects on tumors, aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

[0887] Antihormonal agents

[0888] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX TM ), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene

[0889] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, fenpropimorph, megestrol acetate Exemestane, formestane, fadrozole, vorozole Letrozole and anastrozole

[0890] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0891] Examples of progesterone receptor antagonists include onapristone.

[0892] Anti-angiogenic agents

[0893] Anti-angiogenic agents include, but are not limited to, retinoids and their derivatives, 2-methoxyestradiol, regorafenib, nicuparanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (albumin-bound paclitaxel), platelet factor 4, protamine sulfate (herring protamine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,1-3,4-dehydroproline, thioproline), α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-aminopropionitrile -(4-pyridyl)-2(3H)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecanoate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrine, lobenzarit disodium, n-2-carboxyphenyl-4-chloroaminobenzoic acid disodium or "CCA", thalidomide, angiostatic steroids, carboxyamidoimidazoles, metalloproteinase inhibitors (such as BB-94), inhibitors of S100A9 (such as tasquinimod). Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies to such angiogenic growth factors as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0894] Antifibrotic agents

[0895] Anti-fibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in U.S. Pat. No. 4,965,288 for lysine oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Pat. No. 4,997,854 for compounds that inhibit LOX to treat various pathological fibrotic states, which applications are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593 relating to compounds such as 2-isobutyl-3-fluoro-allylamine, 2-isobutyl-3-chloro-allylamine, or 2-isobutyl-3-bromo-allylamine; US 5021456, US 5059714, US 5120764, US 5182297, US 5252608 relating to 2-(1-naphthyloxymethyl)-3-fluoroallylamine; and US 2004-0248871, which are incorporated herein by reference.

[0896] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysine acyl oxidase, and more particularly primary amines that form resonance-stabilized products after binding to the carbonyl group, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine and their derivatives; amine ureas and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0897] Other anti-fibrotic agents are copper chelators that are either permeable or non-permeable to cells. Exemplary compounds include indirect inhibitors that block the oxidation of aldehyde derivatives derived from lysine and hydroxylysine residues by lysine oxidase to deamination. Examples include thiolamines (especially D-penicillamine) and their analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)disulfide)butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl)disulfide)butyric acid, sodium sulfide-4-((p-1-dimethyl-2-amino-2-carboxyethyl)disulfide)butane, 2-acetamidoethyl-2-acetamidoethanethiol sulfonate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0898] Immunotherapeutic agents

[0899] Immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating a subject. Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, baviximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, and selegiline. umomab), berentuzumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab ab), drozitumab, duligotumab, dusigitumab, ecoromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figimab tumumab), flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipelimumab MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lovatumumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, lecithin, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, okaraizumab ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab Rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, stuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, vetuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0900] Exemplary therapeutic antibodies can be further labeled with or combined with radioactive isotope particles, such as indium-111, yttrium-90 (90Y-xivatumumab), or iodine-131.

[0901] Cancer gene therapy and cell therapy

[0902] Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic methods to directly kill cancer cells; including infusions of immune cells designed to replace large parts of an individual's own immune system to enhance the immune response to cancer cells, or activate an individual's own immune system (T cells or natural killer cells) to kill cancer cells, or to detect and kill cancer cells; genetic methods to modify cell activity to further alter endogenous immune reactivity against cancer.

[0903] gene editing agents

[0904] Examples of genome editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0905] CAR-T cell therapy and TCR-T cell therapy

[0906] CAR-T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain. The immune effector cells are T cells or NK cells. TCR-T cell therapy includes TCR-T cells engineered to target tumor-derived peptides on the surface of tumor cells. The cells can be autologous or allogeneic.

[0907] In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

[0908] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0909] In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of: CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0910] In some embodiments, the costimulatory domain comprises one or more functional domains of a protein selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL 1. CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46 and NKG2D.

[0911] In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: the alpha, beta or zeta chain of a T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R u, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1ld, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSG L1, CD100(SEMA4D), SLAMF6(NTB-A, Ly108), SLAM(SLAMF1, CD150, IPO-3), BLAME(SLAMF8), SELPLG(CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

[0912] In some embodiments, the antigen binding domain binds a tumor antigen.

[0913] In some embodiments, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subclass 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2) ); mesothelin; interleukin 11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testosterone or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine kinase, ERBB2 (Her2 / n eu); mucin 1, cell surface-associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostatic enzyme; prostatic acid phosphatase (PAP); elongation factor 2, mutant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); proteasome (progenitor, megalin) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100) Oncogene fusion protein composed of the breakpoint cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA);o-Acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial cell marker 1 (TEM1 / CD248); tumor endothelial cell marker 7-related (TEM7R); six-transmembrane epithelial antigen of the prostate 1 (STEAP1); tight junction protein 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; C D179a; pleomorphic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); globoH glycosylceramide hexasaccharide moiety (GloboH); mammary gland differentiation antigen (NY-BR-1); urokinase 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); olfactory receptor 51E2 (ORSIE2); TCRγ alternative reading frame protein (TARP); Wilms' tumor protein (WT1); cancer / testicular antigen 1 (NY-ESO-1); cancer / testicular antigen 2 (LAGE-la); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer antigen testis-1 (MADCT-1); melanoma cancer antigen testis-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutants; prostate protein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma Tumor inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (BORIS or brother of imprinting site regulator protein), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5);Preacrosome-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); kinase anchoring protein 4 (AKAP-4); synovial sarcoma, breakpoint X 2 (SSX2); receptor for advanced glycation end products (RAGE-I); kidney ubiquitous protein 1 (RUI); kidney ubiquitous protein 2 (RU2); legumin; human papillomavirus E6 (HPVE6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; mutant heat shock protein 70-2 (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); IgA Fc fragment receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A, member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12, member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); mucin-like hormone receptor-like 2 with an EGF-like module (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0914] In some embodiments, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG 4. ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecules (ExoCBM), oncogene products, antifolate receptor, c-Met, Carcinoembryonic antigen (CEA), cyclin D1, ephrin B2, epithelial tumor antigen, estrogen receptor, embryonic acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double microglobulin 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tegmented epidermal growth factor receptor (tEGFR), tenascin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0915] Non-limiting examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Aimiliancel-T Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, bone marrow stem cell therapy treated with FT-1050, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPCs, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005.

[0916] In some embodiments, tumor targeting antigens include: alpha-fetoprotein, such as ET-1402 and AFP-TCR; anthrax toxin receptor 1, such as anti-TEM8 CAR T cell therapy; B cell maturation antigen (BCMA), such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR); anti-CLL-1 antibodies, such as KITE-796; B7 homolog 6, such as CAR-NKp30 and CAR-B7H6; B lymphocyte antigen CD19, such as TBI-1501, CTL-119 huCART-19 T cells, JCAR-015 US7446190, JCAR-014, JCAR-017, WO2016196388, WO2016033570, WO2015157386), axicabtagene ciloleucel (KTE-C19), US7741465, US6319494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), WO2012079000, WO2017049166, T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζT cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T; B lymphocyte antigen CD20, such as ATTCK-20; B lymphocyte cell adhesion, such as UCART-22, JCAR-018 WO2016090190; NY-ESO-1, such as GSK-3377794, TBI-1301; carbonic anhydrase, such as DC-Ad-GMCAIX; apoptotic proteinase 9 suicide gene, such as CaspaCIDe DLI, BPX-501; CCR5, such as SB-728; CDw123, such as MB-102, UCART-123; CD20m, such as CBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1; CD33, such as CIK-CAR.CD33; CD38, such as T-007, UCART-38; CD40 ligand, such as BPX-201; CEACAM protein 4 modulator, such as MG7-CART; Claudin 6, such as CSG-002; EBV targeting, such as CMD-003; EGFR, such as autologous 4H11-28z / fIL-12 / EFGRt T cells; endonucleases, such as PGN-514 and PGN-201; Epstein-Barr virus-specific T lymphocytes, such as TT-10; Erbb2, such as CST-102 and CIDeCAR; ganglioside (GD2), such as 4SCAR-GD2; glutamate carboxypeptidase II, such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, and P-PSMA-101; phosphatidylinositol protein glycan-3 (GPC3), such as TT-16 and GLYCAR; heme, such as PGN-236; hepatocyte growth factor receptor, such as anti-cMet RNA CAR T; human papillomavirus E7 protein, such as KITE-439; immunoglobulin gamma Fc receptor III, such as ACTR087; IL-12, such as DC-RTS-IL-12; IL-12 agonist / mucin 16, such as JCAR-020; IL-13α2, such as MB-101; IL-2, such as CST-101; K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy; neural cell adhesion molecule L1 L1CAM (CD171), such as JCAR-023; latent membrane protein 1 / latent membrane protein 2, such as autologous dendritic cells transduced with Ad5f35-LMPd1-2; melanoma associated antigen 10, such as MAGE-A10C796TMAGE-A10 TCR; melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6), such as KITE-718; mesothelin, such as CSG-MESO, TC-210; NKG2D, such as NKR-2; Ntrkr1 tyrosine kinase receptor, such as JCAR-024; T cell receptor, such as BPX-701, IMCgp100; T lymphocyte, such as TT-12; tumor infiltrating lymphocyte, such as LN-144, LN-145; and Wilms' tumor protein, such as JTCR-016, WT1-CTL.

[0917] Combination therapy for lymphoma or leukemia

[0918] In some embodiments, the additional therapeutic agent is suitable for treating lymphoma or leukemia. Such agents include aldesleyne, acidipine, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib, Bortezomib ( PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib Carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, cranberries, cranberries hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, cranberries, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa alfa), etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, cytarabine, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide ( CC-5013), lymphomediator-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate acetate), omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal dapoxetine hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, Rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate citrate), simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine hydrogen tartrate, SAHA (suberoylanilide hydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[0919] An improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab. Yttrium-90 ibritumomab tiuxetan as well as and CHOP.

[0920] The therapies mentioned above may be supplemented with or combined with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0921] Combination therapy for non-Hodgkin's lymphoma

[0922] In some embodiments, additional therapeutic agents are useful for the treatment of non-Hodgkin's lymphoma (NHL), particularly non-Hodgkin's lymphoma of B-cell origin, including monoclonal antibodies, standard chemotherapy methods (e.g., CHOP, CVP, FCM, MCP and their analogs), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0923] Examples of unconjugated monoclonal antibodies for the treatment of NHL / B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0924] Examples of experimental antibody agents for the treatment of NHL / B-cell cancer include ofavumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizumab, apolizumab, milatuzumab, and bevacizumab.

[0925] Examples of standard regimens for chemotherapy for NHL / B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0926] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab and iodine-131 tositumomab

[0927] Combination therapy for mantle cell lymphoma

[0928] In some embodiments, additional therapeutic agents are suitable for treating mantle cell lymphoma (MCL), including combination chemotherapy such as CHOP, hyperCVAD, and FCM. This regimen can also be supplemented with the monoclonal antibody rituximab to form the combination therapy R-CHOP, hyperCVAD-R, and R-FCM. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0929] Other examples of therapeutic agents suitable for treating MCL include:

[0930] - Immunotherapies, such as monoclonal antibodies (e.g., rituximab) and cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual's tumor;

[0931] - Radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab Yttrium-90 Ibritumomab Tiuxetan and Used sequentially with CHOP for treatment;

[0932] - Autologous stem cell transplantation coupled with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib ( or PS-341), or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab;

[0933] - Drugs that cause the breakdown of Bcl-2 proteins and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents;

[0934] - mTOR inhibitors, which can cause inhibition of cell growth and even cell death. Non-limiting examples are sirolimus, temsirolimus ( CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus and or other chemotherapeutic agent combinations;

[0935] - Other agents, such as flavopiridol, palbociclib (PD0332991), R-rosvetine (Celixis, CYC202), styrylsulfone, obaclava (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus ( CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide ( CC-5013) and geldanamycin (17-AAG).

[0936] Combination therapy for Waldenstrom's macroglobulinemia

[0937] In some embodiments, additional therapeutic agents are useful for treating Waldenstrom's macroglobulinemia (WM) and include aldesleukin, alemtuzumab, acidipine, amifostine trihydrate, aminocamptothecin, antisinaplaston A10, antisinaplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-alexin, bortezomib, Bryostatin 1, busulfan, Campas-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin Diftos, dexamethasone, docetaxel, dolastatin 10, cypermethrin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, ferritinib, filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphotrophic hormone-activated killer cell cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tesazinol-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pefiragliflozin, pegylated liposomal dapoxetine hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate Simvastatin, sirolimus, tacrolimus, tanespiramycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, vetuzumab, vincristine sulfate, vinorelbine hydrogen tartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0938] Other examples of therapeutic procedures for treating WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 gamma irradiation, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0939] Combination therapy for diffuse large B-cell lymphoma

[0940] In some embodiments, additional therapeutic agents are useful for treating diffuse large B-cell lymphoma (DLBCL) and include cyclophosphamide, vinblastine, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R-ICE.

[0941] Combination therapy for chronic lymphocytic leukemia

[0942] In some embodiments, additional therapeutic agents are useful for treating chronic lymphocytic leukemia (CLL) and include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, vinblastine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following commonly used combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0943] Myelofibrosis combination therapy

[0944] In some embodiments, additional therapeutic agents are suitable for treating myelofibrosis, including hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saradegib and vismodegib.

[0945] Examples of HDAC inhibitors include, but are not limited to, pranosastat and pabinostat.

[0946] Non-limiting examples of tyrosine kinase inhibitors are lestaurinib, bosutinib, imatinib, gilteritinib, radotinib, and cabozantinib.

[0947] Combination therapy for hyperproliferative diseases

[0948] In some embodiments, additional therapeutic agents are useful for treating hyperproliferative diseases and include gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel with a JAK inhibitor and / or a PI3Kδ inhibitor.

[0949] Combination therapy for bladder cancer

[0950] In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer and includes atezolizumab, carboplatin, cisplatin, docetaxel, cypermethrin, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, albumin-bound paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[0951] Breast cancer combination therapy

[0952] In some embodiments, the additional therapeutic agent is suitable for treating breast cancer and includes nab-paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, nab-paclitaxel, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal nab-paclitaxel, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof.

[0953] Combination therapy for triple-negative breast cancer

[0954] In some embodiments, additional therapeutic agents are useful for treating triple-negative breast cancer and include cyclophosphamide, docetaxel, paclitaxel, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[0955] Combination therapy for colorectal cancer

[0956] In some embodiments, the additional therapeutic agent is useful for treating colorectal cancer and includes bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof.

[0957] Combination therapy for castration-resistant prostate cancer

[0958] In some embodiments, the additional therapeutic agent is useful for treating castration-resistant prostate cancer and includes abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, sipralid-T, and any combination thereof.

[0959] Combination therapy for esophageal and esophagogastric junction cancer

[0960] In some embodiments, additional therapeutic agents are useful for treating esophageal and esophagogastric junction cancer and include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0961] Combination therapy for gastric cancer

[0962] In some embodiments, the additional therapeutic agent is suitable for treating gastric cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0963] Combination therapy for head and neck cancer

[0964] In some embodiments, the additional therapeutic agent is useful for treating head and neck cancer and includes afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0965] Combination therapy for hepatobiliary cancer

[0966] In some embodiments, additional therapeutic agents are useful in treating hepatobiliary cancer and include capecitabine, cisplatin, a fluoropyrimidine, 5-fluorouracil, gemecitabine, oxaliplatin, sorafenib, and any combination thereof.

[0967] Combination therapy for hepatocellular carcinoma

[0968] In some embodiments, additional therapeutic agents are useful in treating hepatocellular carcinoma and include capecitabine, ricinus, gemcitabine, sorafenib, and any combination thereof.

[0969] Combination therapy for non-small cell lung cancer

[0970] In some embodiments, the additional therapeutic agent is suitable for treating non-small cell lung cancer (NSCLC) and includes afatinib, nab-paclitaxel, alectinib, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof.

[0971] Combination therapy for small cell lung cancer

[0972] In some embodiments, additional therapeutic agents are useful for treating small cell lung cancer (SCLC) and include bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, cytoxan, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

[0973] Melanoma combination therapy

[0974] In some embodiments, the additional therapeutic agent is suitable for treating melanoma and includes nab-paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon alfa-2b, ipelimab, nitrosoureas, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof.

[0975] Ovarian cancer combination therapy

[0976] In some embodiments, the additional therapeutic agents are useful for treating ovarian cancer and include 5-fluorouracil, albumin-bound paclitaxel, altretinoin, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, cyprodinil, etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal cyprodinil, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0977] Pancreatic cancer combination therapy

[0978] In some embodiments, the additional therapeutic agent is useful for treating pancreatic cancer and includes 5-fluorouracil, nab-paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, a fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

[0979] Combination therapy for renal cell carcinoma

[0980] In some embodiments, additional therapeutic agents are useful for treating renal cell carcinoma and include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

[0981] VIII. Set

[0982] The present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, for example, in treating viral infections. Instructions are typically written, but electronic storage media containing instructions (e.g., a magnetic or optical disk) are also acceptable.

[0983] The present invention also provides a pharmaceutical kit comprising one or more containers comprising a compound of the present invention or a pharmaceutically acceptable salt thereof. Associated with such a container, as appropriate, may be a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceutical products, which notice reflects approval by the manufacturing, use, or sale agency for human administration. The various components (if more than one component is present) may be packaged in separate containers, or some components may be combined in one container if cross-reactivity and shelf life permit. The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or sub-unit dose. The kit may also include multiple unit doses of the compound and instructions for use, and packaged in an amount sufficient for storage and use by a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0984] Also provided are articles of manufacture comprising a unit dose of a compound of the invention or a pharmaceutically acceptable salt thereof, suitably packaged for use in the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The articles of manufacture may further be sterilized and / or sealed.

[0985] IX. Examples

[0986] The embodiments also relate to methods and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

[0987] Numerous general references are available that provide commonly known chemical synthesis schemes and conditions suitable for synthesizing the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013).

[0988] Compounds as described herein can be purified by any method known in the art, including chromatography, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. The disclosed compounds are most commonly purified via silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd edition, LRSnyder and JJKirkland, eds., John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0989] Compounds were characterized using standard instrumental methods. Unless otherwise stated, 1 H. 19 F and 31 P NMR spectra were obtained on a Bruker Avance™ III HD 400 MHz NMR. Mass spectra were obtained in electrospray ionization (ESI) mode on a Waters Q-Tof Micro. HPLC analysis was performed on a Waters LC-MS instrument (Waters 600 controller, Waters 3100 mass detector, Waters photodiode array detector) using a Luna C18 column (Phenomenex, 5 μm, 150 × 4.6 mm) and a Zic-Hilic column (SeQuant, 5 μm, 100 × 4.6 mm).

[0990] During any process for preparing a target compound, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved. This can be achieved with the aid of conventional protecting groups, as described in standard texts such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 4th edition, Wiley, New York 2006. The protecting groups may be removed at a suitable subsequent stage using methods known in the art.

[0991] Exemplary chemical entities suitable for use in the methods of the embodiments will now be described with reference to illustrative synthetic schemes with respect to their general preparation herein and subsequent specific examples. One skilled in the art will recognize that to obtain the various compounds herein, the starting materials may be appropriately selected so that the desired product is obtained by carrying the final desired substituent through the reaction process with or without protective measures as needed. Alternatively, it may be necessary or desirable to utilize a suitable group that can be carried through the reaction process and, when appropriate, replaced by the desired substituent in the position of the final desired substituent. In addition, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups. Each reaction depicted in the general scheme is preferably operated at a temperature of about 0°C to the reflux temperature of the organic solvent used.

[0992] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that independent batches of compounds can be combined and then continued for use in the next synthesis step.

[0993] In the following example descriptions, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present invention. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present invention. Therefore, the following description is not intended to limit the scope of the present invention.

[0994] The methods of the present invention generally provide specific enantiomers or diastereomers as desired products, but the stereochemistry of the enantiomers or diastereomers is not determined in all cases. When the stereochemistry of a specific stereocenter among enantiomers or diastereomers is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0995] Representative syntheses of compounds of the invention are described in the following schemes and the specific examples that follow.

[0996] The specific 2'3'-cyclic dinucleotides described in detail in the Examples were synthesized according to the general synthetic method described below. Unless otherwise indicated, compounds are named using ChemAxon (Budapest, Hungary).

[0997] Abbreviations used in the examples presented below include the following:

[0998]

[0999]

[1000] Example 1. Preparation of nucleotide monomers

[1001] Process 1

[1002]

[1003] H-phosphinic acid 2: To a stirred solution of intermediate 1 (5 g, 7.4 mmol) in DMF (75 mL) was added sodium hydride (900 mg, 22.2 mmol) (Scheme 1) at 4 ° C under argon. The reaction mixture was stirred for another 60 minutes at 4 ° C under argon. H-phosphinic acid tosyl ester (3.05 g, 11.1 mmol) was added to the reaction mixture under argon. The reaction mixture was stirred for another 16 hours at room temperature under argon. Thereafter, glacial acetic acid (1.27 mL, 22.2 mmol) in DMF (10 mL) was added dropwise to the reaction mixture at 4 ° C, and the reaction mixture was evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with sodium bicarbonate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude H-phosphinic acid 2 was loaded onto a silica gel column in DCM (50 mL). The column was washed with dichloroacetic acid (DCA, 50 mL, 3% DCM solution) and allowed to stand at room temperature for 15 minutes. The column was then washed with DCA (100 mL, 3% DCM solution) / 10% EtOH in CHCl3 solution (100 mL) and thereafter with 10% EtOH in CHCl3 solution (500 mL). Intermediate 2 was washed off the column with 50% MeOH in H2O solution (500 mL), evaporated, purified by preparative HPLC (gradient elution with 0-50% methanol in water) and freeze-dried from water to give a lyophilizate: HRMS (ESI) C 18 H 19 O6N5FNaP(M+Na) + The calculated value is 474.09492, the experimental value is 474.09485; 1 H NMR(MeOD-d4)δ8.74(s,2H),8.09(m,2H),7.66(m,1H),7.56(m,2H),7.10(ddd,J=508.5,2.9,1 .2Hz,1H),6.46(dd,J=16.0,2.6Hz,1H),5.69(ddd,J=52.2,4.2,2.6Hz,1H),4.60(ddd,J=17.4 ,6.9,4.2Hz,1H),4.27(dddd,J=6.9,3.0,2.4,1.1Hz,1H),3.96(dd,J=12.8,2.4Hz,1H),3.86( dd,J=12.8,3.0Hz,1H),3.80(ddd,J=13.3,5.7,1.2Hz,1H),3.64(ddd,J=13.3,9.3,2.9Hz,1H); 31 P NMR (MeOD-d4) δ 18.79; 19 F NMR (MeOD-d4) δ -203.85.

[1004] Preparation of phosphonate 3: Sodium hydride (720 mg, 18 mmol) was added to a stirred solution of intermediate 1 (4 g, 6 mmol) in DMF (60 mL) at 4 ° C under argon. The reaction mixture was stirred for another 60 minutes at 4 ° C under argon. Tosyl phosphonate (3.144 g, 9 mmol) was added to the reaction mixture under argon. The reaction mixture was stirred for another 16 hours at rt under argon. Thereafter, glacial AcOH (1.03 mL, 18 mmol) in DMF (10 mL) was added dropwise to the reaction mixture at 4 ° C. The reaction mixture was evaporated and the phosphonate 3 was purified by silica gel chromatography (eluting with a gradient of 0-10% ethanol / chloroform): HRMS (ESI) C 45 H 49 O9N5FNaP(M+Na) + The calculated value is 876.31441, the experimental value is 876.31425; 1 H NMR(DMSO-d6)δ11.28(br s,1H),8.72(s,1H),8.59(s,1H),8.04(m,2H),7.65(m,1H),7.55(m,2H),7.31(m,2H),7.22(m,2H),7.18(m,5H),6.80(m,4H) ,6.48(dd,J=19.5,1.6Hz,1H),5.98(ddd,J=51.9,4.2,1.6Hz,1H),4.81(ddd,J=20.7,8.1,4.2Hz,1H),4.54(m,2H),4.25(dd d,J=8.1,5.6,2.5Hz,1H),3.96(dd,J=13.7,8.8Hz,1H),3.89(dd,J=13.7,9.2Hz,1H),3.74(dd,J=10.9,5.6Hz,1H),3.70(s, 6H), 3.24 (dd, J = 10.9, 2.5Hz, 1H), 1.21 (d, J = 6.2Hz, 3H), 1.18 (d, J = 6.2Hz, 3H), 1.16 (d, J = 6.2Hz, 3H), 1.14 (d, J = 6.2Hz, 3H); 31 P NMR (DMSO-d6) δ 18.96; 19 F NMR (DMSO-d6) δ-199.06.

[1005] Preparation of Monomer 4: Bromotrimethylsilane (2.164 mL; 16.4 mmol) was added to a solution of diethyl phosphonate (3.5 g; 4.1 mmol) and 2,6-lutidine (3.82 mL; 32.8 mmol) in ACN (45 mL). The reaction mixture was stirred at rt for 16 h and evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with 0.2 M TEAB (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, evaporated, and co-evaporated with dioxane and pyridine. The crude nucleoside phosphonic acid was used without further purification.

[1006] 2-Chloro-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide (DMOCP) (3.772 g; 20.5 mmol) was added to a solution of the crude nucleoside phosphonic acid, 4-methoxy-2-pyridylmethanol (Pic-OH) (1.712 g; 12.3 mmol), and 4-methoxypyridine-N-oxide (MPNO) (2.564 g; 20.5 mmol) in pyridine (45 mL). The reaction mixture was stirred at rt for 16 h, quenched by the addition of 2 M TEAB (20 mL), and evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with 0.2 M TEAB (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, evaporated, and co-evaporated with dioxane. The crude product was treated with thiophenol (6 mL) and TEA (8.4 mL) in dioxane (45 mL) at rt for 6 h. The subsequent reaction mixture was diluted with ethyl acetate and purified directly by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate / ethanol / acetone / water 4:1:1:1 in ethyl acetate (SiO2 buffered with TEA) and lyophilized from dioxane to give intermediate 4: HRMS (ESI) C 46 H 43 O 10 N6FP(MH) - The calculated value is 889.27678, the experimental value is 889.27583; 1H NMR(DMSO-d6)δ11.25(br s,1H),8.74(s,1H),8.67(s,1H),8.26(d,J=5.7Hz,1H),8.04(m,2H),7.64(m,1H),7.54(m,2H),7.27(m,2H),7.19(m,2H),7.14(m,5H),7.0 4(d,J=2.6Hz,1H),6.81(dd,J=5.7,2.6Hz,1H),6.76(m,4H),6.43(dd,J=18.6,1.6Hz,1H),6.01(ddd,J=51.8,4.0,1.6Hz,1H),4.90(ddd,J =22.3,8.1,4.0Hz,1H),4.80(dd,J=14.3,7.5Hz,1H),4.78(dd,J=14.3,7.5Hz,1H),4.20(ddd,J=8.1,5.0,2.5Hz,1H),3.96(dd,J=13.7,8. 8Hz,1H),3.89(dd,J=13.7,9.2Hz,1H),3.77(s,3H),3.67(s,6H),3.64(m,2H),3.31(dd,J=11.0,2.5Hz,1H),3.22(dd,J=11.0,5.0Hz,1H); 31 P NMR (DMSO-d6) δ 12.48; 19 F NMR (DMSO-d6) δ-199.61.

[1007] Preparation of monomer 5: phosphonate 4 (1.3 g, 1.5 mmol) is loaded onto a silica gel column in DCM (10 mL). The column is washed with DCA (10 mL, 3% DCM solution) and allowed to stand at rt for 15 minutes. The column is subsequently washed with a CHCl solution (25 mL) of DCA (25 mL, 3% DCM solution) / 10% EtOH and thereafter with a CHCl solution (100 mL) of 10% EtOH. The crude product 5 is washed out of the column with a H2O solution (100 mL) of 50% MeOH, evaporated, and purified by preparative HPLC (gradient elution with an aqueous solution of 0-50% methanol) using DOWEX TM The Na+ was converted to sodium salt and freeze-dried from water to give intermediate 5: HRMS (ESI) C 25 H 25 O8N6FP(MH) - The calculated value is 587.14610, the experimental value is 587.14561; 1H NMR(DMSO-d6)δ11.23(br s,1H),8.82(s,1H),8.76(s,1H),8.26(d,J=5.6Hz,1H),8.05(m,2H),7.64(m, 1H),7.55(m,2H),7.11(d,J=2.6Hz,1H),6.81(dd,J=5.6,2.6Hz,1H),6.36(br d,J=16.1Hz,1H),5.55(br dd,J=53.1,3.7Hz,1H),4.82(ddd,J=26.5,9.2,3.7Hz,1H),4.82(dd,J=14.5,7.7Hz,1H),4.80(dd,J=14.5,7.7Hz,1H),4.00(dt,J=9.2,2.1 Hz,1H),3.82(s,3H),3.82(dd,J=13.2,2.1Hz,1H),3.78(dd,J=13.2,2.1Hz,1H),3.64(dd,J=14.2,8.0Hz,1H),3.60(dd,J=14.2,3.5Hz,1H); 31 P NMR (DMSO-d6) δ 13.65; 19 F NMR (DMSO-d6) δ -198.08.

[1008] Process 2

[1009]

[1010] Iminophosphonates were prepared using standard protocols according to the following: Páv, O; I.; I.;Pohl,R.; M.; Rosenberg, I. Synthesis of oligoribonucleotides with phosphonate-modified linkages. Org. Biomol. Chem. 2011,, 9, 6120-6126 and Páv, O.; Panova, N.; J.; E.; Rosenberg I. Activation of human RNase L by2'-and 5'-O-methylphosphonate-modified oligoadenylates. Bioorg. Med. Chem. Lett. 2012, 22, 181-185 (Process 2).

[1011] Exemplary Preparation of Iminophosphate Monomer 6-CTo a stirred solution of intermediate 6-B (1.4 g, 2.2 mmol) and N, N, N', N'-tetraisopropylphosphonomethyl diamido ester (1.8 mL, 6.5 mmol) in DCM (20 mL) was added 0.45 M tetrazole (14.4 mL, 6.5 mmol) in ACN under argon. The reaction mixture was stirred at rt under argon for 2 hours, whereupon the mixture was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in toluene (5 mL) and added dropwise to hexane (300 mL) to form a solid precipitate. The precipitate was collected and freeze-dried from benzene to give intermediate 6-C: 31 P NMR (C6D6) δ 155.69 (d, J = 4.8 Hz), 155.27 (d, J = 5.8 Hz).

[1012] Intermediate 7-C was prepared from Intermediate 7-B in a similar manner to the scheme described above.

[1013] intermediates NMR data 7-C <![CDATA[ 31 P NMR(C6D6)δ155.13(d,J=4.0Hz),154.76(d,J=8.0Hz)。]]>

[1014] Example 2. Preparation of phosphorothioate cyclic dinucleotides

[1015] Process 3

[1016]

[1017] DMOCP (0.66 g; 3.6 mmol) was added to a solution of phosphonate monomer 4 (0.8 g; 0.9 mmol) and nucleoside 8 (0.7 g; 1.1 mmol) in pyridine (20 mL) (Scheme 3). The reaction mixture was stirred at rt for 2 h, quenched by the addition of methanol (5 mL), evaporated, and co-evaporated with methanol (3×10 mL). The residue was treated with 80% acetic acid in water (10 mL) at rt for 16 h. The solution was directly loaded onto a C18 column, and the linear dimer 9 was separated using a linear gradient of acetonitrile in water: ESI-MS (Intermediate 9) C 39 H 41 F2N 11 O 12 P(MH) - The calculated value is 924.3, and the experimental value is 924.3.

[1018] The linear dimer 9 was co-evaporated with DCM-dioxane 1:1 (3×10 mL), dissolved in DCM (50 mL), and TEA (0.25 mL; 1.8 mmol) was added. Tris(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite was added portionwise to the mixture every 15 minutes (6×48 μL; 0.15 mmol (0.29 mL; 0.9 mmol; total amount)). After 1.5 hours at rt, 0.1 M aqueous TEAB solution (10 mL) was added, and the mixture was stirred vigorously at rt for 30 minutes. The mixture was evaporated, and the linear H-phosphonate dimer 10 was used without further purification: ESI-MS ((Intermediate 10) C 39 H 42 F2N 11 O 14 P2(MH) - The calculated value is 988.2, and the experimental value is 988.3.

[1019] DMOCP (0.22 g; 1.2 mmol) was added to a solution of linear H-phosphonate dimer 10 (0.23 g; 0.23 mmol) in pyridine (60 mL), and the reaction mixture was stirred at rt for 2.5 hours. Thereafter, sulfur (73 mg; 2.3 mmol) was added. After stirring at rt for 1 hour, water (40 mL) was added and the mixture was stirred at 65 ° C for 4 hours, evaporated, and co-evaporated with methanol (3×10 mL). The mixture was dissolved in 50% ACN in water (10 mL) and 33% methylamine in ethanol (5 mL) was added. The mixture was stirred for 7 hours and evaporated. The mixture of two diastereomers was separated using preparative C18 HPLC in an approximately 3:2 ratio into the HPLC faster eluting isomer compound 11a and the slower eluting isomer compound 11b. Preparative HPLC conditions for purification were as follows: Luna C18 (5 μm, 250 × 21.2 mm, Phenomenex); flow rate 10 mL / min; mobile phase A: 0.1 M TEAB / H₂O, mobile phase B: 50% ACN / 0.1 M TEAB / H₂O. HPLC method: isocratic elution of A (10 minutes), followed by a linear gradient from A to 40% B (60 minutes). Retention times (min): 35.4 (Compound 11a) and 55.3 (Compound 11b).

[1020] Diastereomers were prepared using DOWEX Na + Converted to sodium salt and freeze-dried from water to give compound 11a and compound 11b.

[1021] Compound 11a: ESI-MS C 21 H 23 F2N10 O 10 P2S(MH) - The calculated value is 707.1, the experimental value is 707.1; 1 H NMR(D2O)δ8.32(s,1H),8.26(s,1H),8.08(s,1H),6.45(d,J=17.4Hz,1H),6.15(d, J=8.2Hz,1H),5.75(dd,J=51.8,4.0Hz,1H),5.45(dd,J=53.5,4.1Hz,1H),5.32(ddd d,J=24.8,13.1,8.2,4.1Hz,1H),4.82(m,2H),4.49(ddd,J=8.2,5.0,2.7Hz,1H),4. 29(m,2H),4.12(m,2H),4.01(dd,J=13.7,9.2Hz,1H),3.96(dd,J=13.7,9.0Hz,1H); 19 F NMR(D2O)δ-192.90,-199.21; 32 P NMR (D2O) δ 59.07, 17.67.

[1022] Compound 11b: ESI-MS C 21 H 23 F2N 10 O 10 P2S(MH) - The calculated value is 707.1, the experimental value is 707.1; 1 H NMR(D2O)δ8.26(s,1H),8.21(s,1H),8.03(s,1H),6.44(d,J=17.9Hz,1H),6.15(d,J=8.3Hz,1H),5.70(dd,J=52.0,3.8Hz ,1H),5.53(dd,J=53.3,4.0Hz,1H),5.26(dddd,J=24.8,11.3,8.3,4.0Hz,1H),4.75(ddd,J=9.0,2.4,2.1Hz,1H),4.69(dd d,J=25.2,9.1,3.8Hz,1H),4.55(m,1H),4.35(ddd,J=11.9,4.5,3.5Hz,1H),4.27(ddd,J=11.6,5.5,2.4Hz,1H),4.14(ddd ,J=11.9,4.8,2.5Hz,1H),4.10(ddt,J=11.6,3.2,2.1Hz,1H),4.06(dd,J=14.0,8.5Hz,1H),3.91(dd,J=14.0,9.2Hz,1H);19 F NMR(D2O)δ-193.23,-199.04; 32 P NMR (D2O) δ 54.70, 17.85.

[1023] Process 4

[1024]

[1025] ETT (0.47 g; 3.7 mmol) was added to a solution of 5 (0.39 g; 0.66 mmol) and imidophosphonate 7-C (0.54 g; 0.73 mmol) in DCM (20 mL). The reaction mixture was stirred at rt under argon for 2.5 hours. Thereafter, DDTT (0.29 g; 1.4 mmol) was added and the mixture was stirred at rt for 1 hour. The reaction mixture was evaporated. The residue was treated with 80% acetic acid in water (10 mL) at rt for 2 hours. The solution was directly loaded onto a C18 column and the linear phosphonate dimer 12 was separated using a linear gradient of acetonitrile / 5 mM ammonium bicarbonate: ESI-MS (intermediate 12) C 36 H 37 F2N 10 O 13 P2S(MH) - The calculated value is 949.2, and the experimental value is 949.4.

[1026] 5,5-Dimethyl-2-oxo-2-chloro-1,3,2-dioxaphosphacyclohexane (DMOCP, 0.48 g; 2.5 mmol) was added to a solution of linear phosphonate dimer 12 (0.18 g; 0.2 mmol) in pyridine (10 mL), and the reaction mixture was stirred at rt for 3.0 hours. Water (5 mL) was then added and the mixture was stirred at 65 ° C for 4 hours, evaporated, and co-evaporated with methanol (3×10 mL). The mixture was dissolved in 50% ACN in water (10 mL) and 33% methylamine in ethanol (5 mL) was added. The mixture was stirred for 4 hours and evaporated. The mixture of two diastereomers was separated into the HPLC faster eluting isomer compound 13a and the slower eluting isomer compound 13b in a ratio of approximately 1:2 using preparative C18 HPLC. Preparative HPLC conditions for purification were as follows: Luna C18 (5 μm, 250 x 21.2 mm, Phenomenex); flow rate 10 mL / min; mobile phase A: 0.1 M TEAB / H₂O, mobile phase B: 50% ACN / 0.1 M TEAB / H₂O. HPLC method: isocratic elution of A (10 minutes), followed by a linear gradient from A to 40% B (60 minutes). Retention times (min): 38.1 (Compound 13a) and 58.3 (Compound 13b).

[1027] Diastereomers were prepared using DOWEX Na + Conversion to the sodium salt and freeze-drying from water gave Compound 13a and Compound 13b.

[1028] Compound 13a: ESI-MS C 21 H 22 F2N9O 10 P2S(MH) - The calculated value is 692.1, the experimental value is 692.3; 1H NMR(D2O)δ8.41(s,1H),8.31(s,1H),8.26(s,1H),8.12(s,1H),6.46(dd,J=17.1,0.8Hz,1H),6.35(d,J=8.1Hz,1H),5.74( ddd,J=52.0,3.8,0.8Hz,1H),5.48(dd,J=53.4,4.1Hz,1H),5.41(dddd,J=24.7,13.2,8.1,4.1Hz,1H),4.80-4.76(m,2H), 4.51(ddd,J=8.5,4.6,2.6Hz,1H), 4.31(ddd,J=11.4,5.7,4.6Hz,1H), 4.30(ddd,J=11.5,5.2,2.7Hz,1H), 4.17(dddd,J=1 1.5,3.9,2.6,1.6Hz,1H),4.12(ddd,J=11.4,4.1,2.6Hz,1H),4.01(dd,J=13.6,8.8Hz,1H),3.96(dd,J=13.6,10.1Hz,1H); 19 F NMR(D2O)δ-193.25,-199.71; 32 P NMR (D2O) δ 58.60, 17.95.

[1029] Compound 13b: ESI-MS C 21 H 22 F2N9O 10 P2S(MH) - The calculated value is 692.1, the experimental value is 692.2; 1H NMR(D2O)δ8.36(s,1H),8.26(s,1H),8.19(s,1H),8.11(s,1H),6.45(d,J=17.5Hz,1H),6.34(d,J=8.2Hz,1H),5.69(dd,J=51.9 ,3.7Hz,1H),5.55(dd,J=53.2,4.1Hz,1H),5.39(dddd,J=24.6,11.2,8.2,4.1Hz,1H),4.79(m,1H),4.65(dddd,J=25.2,9.2,3.7 Hz,1H),4.56(ddd,J=9.2,3.0,2.4Hz,1H),4.36(ddd,J=11.9,4.3,3.0Hz,1H),4.28(ddd,J=11.5,5.5,2.6Hz,1H),4.13(dddd, J=11.5,3.5,2.3,1.9Hz,1H),4.12(ddd,J=11.9,4.8,2.4Hz,1H),4.05(dd,J=13.7,8.0Hz,1H),3.91(dd,J=13.7,10.6Hz,1H); 19 F NMR(D2O)δ-193.49,-199.51; 32 P NMR (D2O) δ 54.67, 18.09.

[1030] Example 3. Preparation of thiophosphonate cyclic dinucleotide

[1031] Process 5

[1032]

[1033] ETT (0.56 g; 4.3 mmol) was added to a solution of H-phosphinate 2 (0.4 g; 0.85 mmol) and imidophosphinate 6-C (0.7 g; 0.85 mmol) in DCM (15 mL). The reaction mixture was stirred at rt under argon for 2 hours. Thereafter, (-)-(8,8-dichlorocamphorylsulfonyl)-oxaziridine (CSO) (0.7 g; 2.6 mmol) was added and the mixture was stirred at rt for 1 hour. The solution was then treated with methanol (15 mL) and the mixture was stirred at rt for 1 hour, causing cleavage of the DMTr group. The solution was evaporated and the linear H-phosphinate dimer 14 was separated on a C18 reverse phase using a linear gradient of acetonitrile / 5 mM ammonium bicarbonate: ESI-MS (intermediate 14) C 33 H 37 F2N 10 O 13 P2(MH) -The calculated value is 881.2, and the experimental value is 881.2.

[1034] DMOCP (0.18 g; 1.0 mmol) was added to a solution of linear H-phosphinate dimer 14 (0.18 g; 0.2 mmol) in pyridine (60 mL), and the reaction mixture was stirred at rt for 3.0 hours. Thereafter, sulfur (63 mg; 2.0 mmol) was added. After stirring at rt for 1 hour, water (40 mL) was added and the mixture was stirred at 65 ° C for 4 hours, evaporated, and co-evaporated with methanol (3×10 mL). The mixture was dissolved in 50% ACN in water (10 mL) and 33% methylamine in ethanol (5 mL) was added. The mixture was stirred for 7 hours and evaporated. The mixture of two diastereomers was separated using preparative C18 HPLC in an approximately 2:1 ratio into the HPLC faster eluting isomer compound 15a and the slower eluting isomer compound 15b. Preparative HPLC conditions for purification were as follows: Luna C18 (5 μm, 250 x 21.2 mm, Phenomenex); flow rate 10 mL / min; mobile phase A: 0.1 M TEAB / H₂O, mobile phase B: 50% ACN / 0.1 M TEAB / H₂O. HPLC method: isocratic elution of A (10 min), followed by a linear gradient from A to 40% B (60 min). Retention times (min): 42.0 (Compound 15a) and 55.1 (Compound 15b).

[1035] Diastereomers were prepared using DOWEX Na + Conversion to the sodium salt and freeze-drying from water gave Compound 15a and Compound 15b.

[1036] Compound 15a: ESI-MS C 21 H 23 F2N 10 O 10 P2S(MH) - The calculated value is 707.1, the experimental value is 707.1; 1H NMR(D2O)δ8.24(s,1H),8.15(s,1H),8.07(s,1H),6.41(d,J=17.3Hz,1H),6.16(d,J=8.0Hz,1H),5.68(dd,J=51.9, 3.7Hz,1H),5.50(dd,J=52.9,3.9Hz,1H),5.02(dtd,J=24.8,8.2,3.9Hz,1H),4.82(m,1H),4.61(ddd,J=25.1,9.2,3 .7Hz,1H),4.51(dq,J=9.2,2.7Hz,1H),4.31(ddt,J=11.6,3.8,2.6Hz,1H),4.29(dt,J=11.8,3.0Hz,1H),4.22(dd,J =13.6,2.8Hz,1H),4.17(ddd,J=11.6,3.5,2.2Hz,1H),4.165(dt,J=11.8,2.3Hz,1H),3.96(dd,J=13.6,6.2Hz,1H); 19 F NMR(D2O)δ-193.20,-199.43; 32 P NMR (D2O) δ 69.17, -1.06.

[1037] Compound 15b: ESI-MS C 21 H 23 F2N 10 O 10 P2S(MH) - The calculated value is 707.1, the experimental value is 707.1; 1H NMR(D2O)δ8.24(s,1H),8.18(s,1H),8.01(s,1H),6.42(d,J=17.8Hz,1H),6.15(d,J=8.1Hz,1H),5.69(dd,J=51.9,3. 8Hz,1H),5.43(dd,J=53.3,4.1Hz,1H),5.02(dddd,J=24.5,8.8,8.1,4.1Hz,1H),4.78(m,1H),4.66(ddd,J=25.5,9.3 ,3.8Hz,1H),4.52(dq,J=9.3,2.6Hz,1H),4.48(ddd,J=11.8,7.8,2.1Hz,1H),4.29(dt,J=11.9,3.0Hz,1H),4.16(ddd ,J=11.9,3.8,2.6Hz,1H),4.09(dd,J=13.2,1.5Hz,1H),4.06(dt,J=11.8,2.1Hz,1H),3.99(dd,J=13.2,10.7Hz,1H); 19 F NMR(D2O)δ-193.42,-198.95; 32 P NMR (D2O) δ72.25, -1.02.

[1038] Example 4. Preparation of phosphorothioate-phosphonothioate cyclic dinucleotides

[1039] Process 6

[1040]

[1041] ETT (0.26 g; 2.0 mmol) was added to a solution of H-phosphinate 2 (0.17 g; 0.36 mmol) and imidophosphinate 6-C (0.32 g; 0.4 mmol) in DCM (10 mL). The reaction mixture was stirred at rt under argon for 2 hours. Thereafter, DDTT (81 mg; 0.4 mmol) was added and the mixture was stirred at rt for 1 hour. The solution was then treated with methanol (10 mL) and the mixture was stirred at rt for 1 hour, causing cleavage of the DMTr group. The solution was evaporated and the linear H-phosphinate dimer 16 was purified by silica gel chromatography (gradient elution with 0-50% methanol / chloroform): ESI-MS (intermediate 16) C 33 H 37 F2N 10 O 12 P2S(MH) - The calculated value is 897.2, and the experimental value is 897.2.

[1042] DMOCP (0.17 g; 0.9 mmol) was added to a solution of linear H-phosphinate dimer 16 (0.17 g; 0.18 mmol) in pyridine (60 mL), and the reaction mixture was stirred at rt for 3.0 hours. Thereafter, sulfur (59 mg; 1.8 mmol) was added. After stirring at rt for 1 hour, water (40 mL) was added and the mixture was stirred at 65 ° C for 4 hours, evaporated, and co-evaporated with methanol (3×10 mL). The mixture was dissolved in 50% ACN in water (10 mL) and 33% methylamine in ethanol (5 mL) was added. The mixture was stirred for 6 hours and evaporated. The mixture of four diastereomers was separated using preparative C18 HPLC in an approximate ratio of 3:1:9:4 as the fastest to slowest eluting isomers 17a-17d. (Compound 17b was not separated into pure diastereomers.) Preparative HPLC conditions for purification were as follows: Luna C18 (5 μm, 250 × 21.2 mm, Phenomenex); flow rate 10 mL / min; mobile phase A: 0.1 M TEAB / H₂O, mobile phase B: 50% ACN / 0.1 M TEAB / H₂O. HPLC method: isocratic elution of A (10 minutes), followed by a linear gradient from A to 40% B (60 minutes), followed by an isocratic gradient of 40% B (10 minutes). Retention times (min): 46.0 (Compound 17a), 57.1 (Compound 17c), and 73.2 (Compound 17d).

[1043] Diastereomers were prepared using DOWEX Na + The resulting products were converted to sodium salts and freeze-dried from water to afford Compound 17a, Compound 17c, and Compound 17d.

[1044] Compound 17a: ESI-MS C 21 H 23 F2N 10 O9P2S2(MH) - The calculated value is 723.1, the experimental value is 723.1; 1H NMR(D2O)δ8.32(s,1H),8.26(s,1H),8.17(s,1H),6.44(dd,J=16.7,1.1Hz,1H),6.16(d,J=8.1Hz,1H),5.78(ddd, J=51.8,3.8,1.1Hz,1H),5.47(dd,J=53.0,4.0Hz,1H),5.28(dddd,J=25.3,12.8,8.1,4.0Hz,1H),4.94(dddd,J=23 .4,8.4,3.8Hz,1H),4.82(m,1H),4.50(m,1H),4.29(ddd,J=11.4,6.3,5.3Hz,1H),4.29(m,1H),4.20(ddd,J=11.4 ,5.2,2.6Hz,1H),4.18(dd,J=13.6,4.5Hz,1H),4.11(ddd,J=11.3,4.0,2.8Hz,1H),4.05(dd,J=13.6,4.6Hz,1H); 19 F NMR(D2O)δ-192.92,-200.10; 32 P NMR (D2O) δ 69.07, 58.84.

[1045] Compound 17c: ESI-MS C 21 H 23 F2N 10 O9P2S2(MH) - The calculated value is 723.1, the experimental value is 723.1; 1H NMR(D2O)δ8.26(s,1H),8.17(s,1H),8.08(s,1H),6.42(d,J=17.4Hz,1H),6.16(d,J=8.1Hz,1H),5.70(dd,J=51.9,3.8Hz ,1H),5.61(dd,J=53.0,3.9Hz,1H),5.16(dddd,J=25.0,10.7,8.1,3.9Hz,1H),4.82(m,1H),4.69(ddd,J=24.8,9.0,3.8Hz ,1H),4.57(ddt,J=9.0,3.5,2.5Hz,1H),4.33(ddd,J=11.9,4.7,3.5Hz,1H),4.28(ddt,J=11.5,3.5,2.6Hz,1H),4.21(dd, J=13.7,3.4Hz,1H),4.18(ddd,J=11.5,5.4,2.2Hz,1H),4.16(ddd,J=11.9,4.8,2.5Hz,1H),4.00(dd,J=13.7,5.6Hz,1H); 19 F NMR(D2O)δ-192.79,-199.30; 32 P NMR (D2O) δ 69.18, 54.27.

[1046] Compound 17d: ESI-MS C 21 H 23 F2N 10 O9P2S2(MH) - The calculated value is 723.1, the experimental value is 723.1; 1H NMR(D2O)δ8.26(s,1H),8.19(s,1H),8.02(s,1H),6.44(d,J=17.9Hz,1H),6.14(d,J=8.2Hz,1H),5.69(dd,J=52.0,3.8 Hz,1H),5.51(dd,J=53.3,4.0Hz,1H),5.15(dddd,J=24.6,10.9,8.2,4.0Hz,1H),4.78(m,1H),4.69(ddd,J=25.1,9.1,3 .8Hz,1H),4.56(dq,J=9.0,2.6Hz,1H),4.48(ddd,J=11.9,8.0,2.2Hz,1H),4.34(ddd,J=11.9,4.7,2.8Hz,1H),4.15(d dd,J=11.9,4.7,2.5Hz,1H),4.09(dd,J=13.2,2.1Hz,1H),4.05(dq,J=11.9,2.2Hz,1H),4.02(dd,J=13.2,10.2Hz,1H); 19 F NMR(D2O)δ-192.86,-198.54; 32 P NMR (D2O) δ 72.21, 54.35.

[1047] Example 5. Preparation of methylphosphonate cyclic dinucleotide

[1048] Process 7

[1049]

[1050] DIAD (0.7 mL; 3.4 mmol) was added to a solution of intermediate 7-B (1.0 g; 1.7 mmol), benzyl alcohol (0.4 mL; 3.4 mmol) and triphenylphosphine (0.9 g; 3.4 mmol) in THF (20 mL) (Scheme 7). The reaction mixture was stirred at room temperature for 16 hours, whereupon the mixture was diluted with DCM (300 mL), washed with water (3×100 ml), and the organic layer was concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of 0-10% ethanol / chloroform) to give intermediate 18: ESI-MSC 38 H 36 FN4O6(M+H) + The calculated value is 663.3, the experimental value is 663.3; 1H NMR(DMSO-d6)δ8.47(s,1H),8.25(s,1H),7.35-7.17(m,11H),6.85(m,4H),5.91(d,J =7.5Hz,1H),5..25(d,J=14.5Hz,1H),5.20(d,J=14.5Hz,1H),5.11(ddd,J=54.2,4.3 ,1.6Hz,1H),4.99(dddd,J=23.8,7.3,6.3,4.3Hz,1H),4.34(dddd,J=26.3,5.6,4.4, 1.6Hz, 1H), 3.72 (s, 6H), 3.33 (dd, J=10.5, 5.6Hz, 1H), 3.25 (dd, J=10.5, 4.5Hz, 1H).

[1051] To a stirred solution of intermediate 18 (0.7 g, 1.1 mmol) and N,N,N′,N′-tetraisopropylphosphonomethyl diamidoester (0.9 mL, 3.3 mmol) in DCM (10 mL) was added 0.45 M tetrazole (7.2 mL, 3.3 mmol) in acetonitrile under argon. The reaction mixture was stirred at room temperature under argon for 2 hours, whereupon the mixture was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (eluting with a gradient of 0-50% ethyl acetate / toluene). The product was evaporated and freeze-dried from benzene to give intermediate 19: 31 P NMR (C6D6) δ 155.08 (d, J = 4.7 Hz), 154.73 (d, J = 6.1 Hz).

[1052] Process 8

[1053]

[1054] ETT (52 mg; 0.4 mmol) was added to a solution of intermediate 5 (50 mg; 0.09 mmol) and intermediate 19 (83 mg; 0.1 mmol) in DCM (20 mL) (Scheme 8). The reaction mixture was stirred at room temperature under argon for 2 hours. Thereafter, CSO (75 mg; 0.25 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated. The residue was treated with 80% acetic acid in water (10 mL) at room temperature for 2 hours. The solution was directly loaded onto a C18 column and the linear phosphonate dimer 20 was separated using a linear gradient of acetonitrile / 5 mM ammonium bicarbonate: ESI-MS C 43 H 45 F2N 10 O 14P2(M+H) + The calculated value is 1025.3, and the experimental value is 1025.5.

[1055] 5,5-Dimethyl-2-oxo-2-chloro-1,3,2-dioxaphosphaninane (DMOCP, 81 mg; 0.44 mmol) was added to a solution of intermediate 20 (90 mg; 0.09 mmol) in pyridine (6 mL), and the reaction mixture was stirred at room temperature for 4 hours. Water (4 mL) was then added, and the mixture was stirred at 65°C for 3 hours, evaporated, and co-evaporated with methanol (3×10 mL). The nucleobase-protected CDN was separated using preparative C18 HPLC. The preparative HPLC conditions used for purification were as follows: Luna C18 (15 μm, 200×40 mm, Phenomenex); flow rate 20 mL / min; mobile phase A: 5 mM ammonium bicarbonate / HO. Mobile phase B: ACN. HPLC method: isocratic elution with water (10 minutes), followed by isocratic elution with A (10 minutes), and then a linear gradient from A to 75% B (60 minutes). The fraction containing the nucleobase-protected CDN was evaporated and treated with a 3:1 mixture of aqueous ammonia and ethanol at room temperature for 16 hours. The mixture was evaporated and compound 21 was isolated using preparative C18 HPLC. The preparative HPLC conditions used for purification were as follows: Luna C18 (5 μm, 250 × 21.2 mm, Phenomenex); flow rate 10 mL / min; mobile phase A: 0.1 M TEAB / H2O, mobile phase B: 50% ACN / 0.1 M TEAB / H2O. HPLC method: isocratic elution A (10 minutes), followed by a linear gradient AB (50 minutes), retention time (min): 51.4.

[1056] Products using DOWEX Na + Converted to sodium salt and freeze-dried from water to give compound 21: ESI-MSC 28 H 30 F2N9O 11 P2(M+H) + The calculated value is 768.1, the experimental value is 768.1; 1H NMR(D2O)δ8.51(s,1H),8.24(s,1H),8.21(s,1H),8.08(s,1H),7.47(m, 2H),7.42(m,2H),7.38(m,1H),6.39(d,J=16.7Hz,1H),6.39(d,J=8.0Hz ,1H),5.67(dd,J=51.5,3.6Hz,1H),5.63(d,J=12.4Hz,1H),5.56(d,J=12.4Hz,1H),5.53(dd,J=52.3,4.0Hz,1H),5.49(dtd,J=25.3,8.0,4.0Hz ,1H),4.80(m,1H),4.62(ddd,J=25.8,9.3,3.6Hz,1H),4.51(dq,J=9.3,2.5Hz,1H),4.26(ddd,J=11.5,5.1,2.6Hz,1H),4.23(dt,J=11.8,2.8Hz ,1H),4.15(ddd,J=11.8,3.7,2.0Hz,1H),4.14(dddd,J=11.5,3.0,2.4,2.1Hz,1H),4.07(dd,J=13.6,6.8Hz,1H),3.95(dd,J=13.6,12.0Hz,1H); 31 P NMR (D2O) δ18.36, -1.23; 19 F NMR(D2O)δ-193.93,-199.77.

[1057] Compound 21 (10 mg, 0.013 mmol) was dissolved in 50% ethanol-water (5 mL), 10% palladium / activated charcoal (5 mg) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 3 hours. The reaction mixture was filtered through a nylon syringe filter, and the filtrate was evaporated. The product was purified using preparative C18 HPLC (preparative HPLC conditions for purification were as follows: Luna C18 (5 μm, 250 × 10 mm, Phenomenex); flow rate 3 mL / min; mobile phase A: 0.1 M TEAB / H2O, mobile phase B: 50% ACN / 0.1 M TEAB / H2O; isocratic elution of A (15 min), followed by a linear gradient from A to 20% B (35 min), retention time (min) = 49.8). The desired compound (1S,6R,8R,9R,10R,16R,18R,19R)-8-(6-amino-9H-purin-9-yl)-9,19-difluoro-3,13-dihydroxy-18-(6-oxo-6,9-dihydro-1H-purin-9-yl)-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ5 -diphosphatricyclic [14.2.1.0 6,10 ] Nonadecane-3,13-dione (22) was prepared using DOWEX Na + Converted to sodium salt and freeze-dried from water: ESI-MS (MH) - C 21 H 22 F2N9O 11 Calculated value of P2: 676.1; Found: 676.1. 1 H. 19 F and 31 P NMR data: 1 HNMRδ8.35(s,1H),8.18(s,1H),8.08(s,1H),8.06(s,1H),6.45(d,J=17.3Hz,1H),6.35(d,J=8.2Hz,1H),5.68(dd,J=51. 9,3.6Hz,1H),5.51(dd,J=53.2,4.0Hz,1H),5.29(dddd,J=24.5,9.3,8.2,4.0Hz,1H),4.80(m,1H),4.62(dddd,J=25.4,9. 2,3.6Hz,1H),4.52(dq,J=9.2,2.6Hz,1H),4.30(dt,J=12.0,2.8Hz,1H),4.28(ddd,J=11.5,5.4,2.6Hz,1H),4.15(ddd,J =12.0,3.8,2.4Hz,1H),4.13(ddt,J=11.5,3.6,2.0Hz,1H),4.05(dd,J=13.7,7.7Hz,1H),3.90(dd,J=13.7,11.0Hz,1H); 19 F NMRδ-193.47,-193.81; 31 P NMRδ18.14,-0.88.

[1058] Process 9

[1059]

[1060] Phosphonate 4 (2.2 g; 2.5 mmol) was dissolved in methanol (20 mL) and treated with 33% MeNH in ethanol (10 mL) at room temperature for 2 hours (Scheme 9). The reaction mixture was concentrated and co-evaporated with pyridine (30 mL). The residue was dissolved in pyridine, and 4-pentenoic anhydride (1.8 mL; 10 mmol) and DMAP (76 mg; 0.5 mmol) were added. The reaction mixture was stirred at 50° C. for 24 hours, whereupon water (10 mL) was added and heating at 60° C. was continued for 3 hours. The reaction mixture was concentrated. The subsequent residue was dissolved in chloroform (0.5 L) and washed with 10% citric acid (3×100 mL) and then with 0.2 M TEAB (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was treated with 80% acetic acid in water at room temperature for 2 hours, and the solution was directly loaded onto a C18 column. Intermediate 23 was separated using a linear gradient of acetonitrile in water and the DOWEX TM Na+ was converted to sodium salt and freeze-dried from dioxane-water: ESI-MS C 23 H 27 FN6O8P(MH) - The calculated value is 565.2, the experimental value is 565.2; 1 H NMR(DMSO-d6)δ10.76(s,1H),8.70(s,1H),8.66(s,1H),8.47(d,J=6.1Hz,1H),7.25(d,J=2.6Hz,1H),7.09(dd,J=6.1,2.6Hz,1H),6.34(dd,J =16.4,2.0Hz,1H),5.87(ddt,J=17.2,10.2,6.4Hz,1H),5.66(ddt,J=52.6,4.0,2.0Hz,1H),5.08(ddt,J=17.2,,2.0,1.6Hz,1H),5.04(d,J=9 .2Hz,2H),4.99(ddt,J=10.2,2.0,1.3Hz,1H),4.60(ddd,J=20.8,7.6,4.0Hz,1H),4.07(dddd,J=7.6,3.1,2.5,0.7Hz,1H),3.91(s,3H),3.90 (dd,J=13.9,8.6Hz,1H),3.86(dd,J=13.9,7.2Hz,1H),3.77(dd,J=12.7,2.5Hz,1H),3.66(dd,J=12.7,3.1Hz,1H),2.68(m,2H),2.36(m,2H); 19 F NMR (DMSO-d6) δ-200.01; 31P NMR (DMSO-d6) δ 17.65.

[1061] Process 10

[1062]

[1063] TBDMS-Cl (0.7 g; 4.5 mmol) was added to a solution of intermediate 24 (2.0 g; 3.0 mmol; Carbosynth, catalog number NB63548) and imidazole (0.3 g; 4.5 mmol) in DMF (30 mL) (Scheme 10). The reaction mixture was stirred at room temperature for 16 hours and then quenched by the addition of methanol (5 mL). The mixture was concentrated, then diluted with DCM (300 mL), washed with saturated sodium bicarbonate solution (3×100 ml) and evaporated. The residue was dissolved in methanol (20 mL) and treated with 33% MeNH2 in ethanol (10 mL) at room temperature for 2 hours. The reaction mixture was evaporated and co-evaporated with pyridine. The residue was dissolved in pyridine (30 mL) and 4-pentenoic anhydride (2.3 mL; 12 mmol) and DMAP (91 mg; 0.6 mmol) were added. The reaction mixture was stirred at 50° C. for 24 hours. After this time, water (10 mL) was added and heating was continued at 60° C. for 3 hours. The reaction mixture was evaporated and the residue was dissolved in chloroform (0.5 L) and washed with 10% citric acid (3×100 ml) and then with 0.2 M TEAB (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, evaporated, and co-evaporated with toluene. The residue was dissolved in THF (24 mL) and treated with 0.5 M TBAF (12 mL) at room temperature for 16 hours. The solution was diluted with diethyl ether (200 mL), washed with 10% ammonium chloride solution (3×100 ml), and evaporated. The residue was purified by silica gel chromatography (eluting with a gradient of 0-50% acetone / toluene) to give intermediate 25: ESI-MS C 36 H 37 FN5O6(M+H) + The calculated value is 654.3, the experimental value is 654.3; 1HNMR(DMSO-d6)δ10.76(s,1H),8.60(s,1H),8.52(s,1H),7.40-7.36(m,2H),7..30-7.17(m,7 H),6.90-6.80(m,4H),6.05(d,J=6.4Hz,2H),5.88(ddt,J=16.8,10.3,6.4Hz,1H),5.29-5.16 (m,1H),5.09(dq,J=17.2,1.7Hz,1H),5.04-4.95(m,1H),4.47-4.33(m,1H),3.734(s,3H),3. 732(s,3H),3.41-3.25(m,2H),2.69(dd,J=8.0,6.9Hz,2H),2.37(ddt,J=7.7,6.4,1.4Hz,2H).

[1064] To a stirred solution of intermediate 25 (0.7 g, 1.1 mmol) and N,N,N',N'-tetraisopropylphosphonomethyl diamidoester (0.9 mL, 3.3 mmol) in DCM (10 mL) was added 0.45 M tetrazole (7.2 mL, 3.3 mmol) in ACN under argon. The reaction mixture was stirred at room temperature under argon for 2 hours, whereupon the mixture was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (eluting with a gradient of 0-50% ethyl acetate / toluene). The product was evaporated and freeze-dried from benzene to give intermediate 26: 31 P NMR (C6D6) δ 155.18 (d, J = 4.4Hz), 154.91 (d, = 6.7Hz).

[1065] Process 11

[1066]

[1067] ETT (0.66 g; 5.5 mmol) was added to a solution of phosphonate 23 (0.5 g; 0.88 mmol) and imidophosphonate 26 (0.9 g; 1.1 mmol) in DCM (35 mL). The reaction mixture was stirred at room temperature under argon for 1 hour. Thereafter, CSO (0.9 g; 3.3 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solution was ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in X 1 and X 3 Each independently is OH, OR 1 , SH or SR 1 , whose restriction condition is X 1 and X 3 At least one of them is OR 1 , SH or SR 1 ; X 2 and X 4 Each is O; R 4 and R 10 Each is F; Each R 1 are independently methyl or -LR 2 ; Each R 2 are independently -O(C=O)-R 2a OR -O(C=O)-OR 2a ; Each R 2a Independently C1-C 20 alkyl; L is L 1 , L 1 -O(C=O)-L 2 , L 1 -OL 2 or L 1 -O(C=O)-L 2 -OL 3 , where L 1 Connected to O or S atom, L 2 or L 3 Connect to R 2 ; L 1 is C1-C6 alkylene or C7-C 13 Alkyl arylene; L 2 is C1-C6 alkylene or C6-C 10 arylene; L 3 is C1-C6 alkylene; Base 1 and bases 2 Each independently 2. The compound according to claim 1, which has the structure of formula (Ia): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which has the structure of formula (IIa): or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein X 1 is OH; and X 3 is OR 1 .

5. The compound as claimed in claim 1, wherein X 1 OR 1 ;and X 3 For OH.

6. The compound of claim 1, wherein X 1 and X 3 Each independently is OR 1 .

7. The compound of claim 1, wherein X 1 is OH; and X 3 For SR 1 .

8. The compound of claim 1, wherein X 1 For SR 1 ;and X 3 For OH.

9. The compound of claim 1, wherein X 1 OR 1 ;and X 3 For SR 1 .

10. The compound of claim 1, wherein X 1 For SR 1 ;and X 3 is OR 1 .

11. The compound of claim 1, wherein X 1 and X 3 Each is independently SR 1 .

12. A compound as described in any one of claims 1 to 11, wherein each R 1 Independently -LR 2 .

13. The compound of claim 1, wherein L is L 1 , L 1 -O(C=O)-L 2 or L 1 -OL 2 ; L 1 is C1-C6 alkylene or C7-C 13 an alkylarylene group; and L 2 is C1-C6 alkylene or C6-C 10 Arylene.

14. The compound of claim 1, wherein X 1 for 15. The compound of claim 1, wherein X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 is C1-C6 alkylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ;and R 2a C1-C 20 alkyl.

16. The compound of claim 14 or 15, wherein X 1 for And R 2a C3-C 20 alkyl.

17. The compound of claim 1, wherein X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 For C7-C 13 Alkyl arylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ;and R 2a C1-C 20 alkyl.

18. The compound of claim 14, wherein X 1 for And R 2a C3-C 20 alkyl.

19. The compound of claim 1, wherein X 3 for 20. The compound of claim 1, wherein X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 is C1-C6 alkylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ;and R 2a C1-C 20 alkyl.

21. The compound of claim 19 or 20, wherein X 3 for And R 2a C3-C 20 alkyl.

22. The compound of claim 1, wherein X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 For C7-C 13 Alkyl arylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ;and R 2a C1-C 20 alkyl.

23. The compound of claim 19, wherein X 3 for and R 2a C3-C 20 alkyl.

24. The compound of claim 1, wherein X 1 and X 3 Each independently selected from the group consisting of OH and SH, wherein X 1 and X 3 At least one of 25. The compound of claim 1, wherein R 2a C3-C 16 alkyl.

26. The compound of claim 1 having the following structure: or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 having the following structure: or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient and / or diluent.

29. Use of the pharmaceutical composition according to claim 28 for the preparation of a medicament for modulating the activity of a STING adaptor protein to induce the production of STING adaptor protein-dependent type I interferons, cytokines and / or chemokines.

30. Use of the pharmaceutical composition of claim 28 for the preparation of a medicament for treating or preventing viral infection, hyperproliferative disease or cancer in humans or animals that is responsive to modulation of the activity of the STING adaptor protein.

31. The use according to claim 30, wherein the viral infection is hepatitis B virus infection or HIV infection.

32. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for modulating the activity of a STING adaptor protein.

33. Use of a compound as claimed in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease or disorder responsive to modulation of a STING adaptor protein in a human or animal in need thereof.

34. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inducing STING adaptor protein-dependent type I interferon, cytokine or chemokine in a human or animal in need thereof.

35. Use of a compound as claimed in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a viral infection responsive to modulation of the activity of a STING adaptor protein in a human or animal in need thereof.

36. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing hepatitis B virus infection or HIV infection responsive to modulation of the activity of the STING adaptor protein in a human or animal in need thereof.

37. Use of a compound as claimed in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a hyperproliferative disease or cancer responsive to modulation of the activity of a STING adaptor protein in a human or animal in need thereof.

38. The use of any one of claims 32 to 37, wherein the compound is administered together with another therapeutically active agent.

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