3'3'-Cyclic dinucleotides and prodrugs thereof

Abstract

The present invention relates to 3'3' cyclic phosphonic acid dinucleotides of general 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 / 815,172, filed on March 7, 2019, and U.S. Provisional Application No. 62 / 862,456, filed on June 17, 2019, which are incorporated herein in their entirety for all purposes. Technical Field

[0003] The present invention relates to 3'3' cyclic dinucleotides and their derivatives, which are suitable for treating diseases that can benefit from modulation of 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 disruption through a series of pattern recognition receptors (PRRs), which detect a small ligand collection 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). In 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 causes the upregulation of cytokines and chemokines (including interferons), and immune cell recruitment to the site of infection. All of these processes slow pathogen replication and promote the generation of adaptive immunity.

[0005] Cellular DNA is usually 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 homeostasis in the host. Sensing of exogenous DNA is initiated by several DNA sensors, such as DNA-dependent activator of IRF (DAI) or DEAD box polypeptide 41 (DDX41). These DNA sensors signal via the STING adapter protein (interferon gene stimulator, also known as STING, STING protein, TMEM173, MITA or ERIS) (Unterholzner L, Immunology, 2013: 218, 1312-1321) by recruiting protein kinase TBK1 that triggers activation of transcription factors NF-κB (nuclear factor κB) and IRF-3 (interferon regulatory factor 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 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 the 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 utility 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 shows efficacy in treating human cancer (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 tumor-initiating T cell priming 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 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 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 ;

[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 Independently for C 1 -C 6 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 for C 1 -C 20 Alkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Alkynyl, -(C 1 -C 6 Alkylene)-(C 3 -C 14 Cycloalkyl) or C 3 -C 20 Cycloalkyl, wherein each R 2a Independently, 1, 2 or 3 R2b replace;

[0022] Each R 2b are independently -OH, -SH, -NH 2 , =O, =NH, =S, halogen, -N 3 、-CN、C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino or C 1 -C 6 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 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkyne or C 7 -C 13 Alkyl arylene;

[0025] L 2 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylidene, C 6 -C 10an arylene group or a 5- to 10-membered heteroarylene group;

[0026] L 3 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 Alkyne;

[0027] R 6 H or C 1 -C 6 alkyl;

[0028] n is 0, 1 or 2;

[0029] Base 1 and bases 2 Each independently

[0030]

[0031] in

[0032] A. A 1 , A 2 , A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH 2 , 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 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -C 10 heteroaryl;

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

[0036] Each R 16 Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -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 for treating a disease or condition, such as a method for treating or preventing a viral infection, a hepatitis B virus infection, an HIV infection, a hyperproliferative disease, or a 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 a human or animal to induce the production of type I interferons, cytokines and / or chemokines (dependent on the STING adaptor protein) (e.g., inducing STING adaptor protein-dependent type I interferons, cytokines or chemokines) 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 one of the foregoing. DETAILED DESCRIPTION

[0041] I. Overview

[0042] Provided herein are novel 3'3'-cyclic dinucleotides comprising at least one phosphonomethoxy group that bind to a STING protein and modulate STING protein activity, e.g., 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 before 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 "C 1 -C 6 "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 may 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 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH (CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, 2-butyl, -CH (CH 3 )CH 2 CH 3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 )、1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 and octyl (-(CH 2 ) 7 CH 3 ). 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 (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ) and -CH 2 -CH=CH-CH 3 The alkenyl group 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 (—CH 2 C≡CH) and -CH 2 -C≡C-CH 3 The alkynyl group 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] Alkylamine is -HNR b Group, where R b It is an alkyl group.

[0053] Alkylthio is -SR b Group, where R b It is an alkyl group.

[0054]

[0046] "Halo" or "halogen" as used herein refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

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

[0056] As used herein, "arylene" refers to a divalent radical on a single aromatic ring or a multi-fused all-carbon ring system (wherein 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 aryl substituents 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, C 7 Alkaryl refers to benzyl, and 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, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and 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, with the proviso that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl or furanyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings), wherein a heteroaryl as defined above is condensed with one or more rings selected from the following: heteroaryl (to form, for example, 1,8-naphthyridinyl), heterocyclic (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocyclic (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 (single aromatic ring or polycondensed ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. Such polycondensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) pendant oxy groups on the carbocyclic or heterocyclic portions of the condensed rings. The rings of the polycondensed ring systems may be connected to each other via fusion, spirocyclic and bridging bonds when valence requirements permit. It should be understood that the individual rings of the polycondensed ring systems may be connected in any order relative to each other. It is understood that the point of attachment of the 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 certain atomic range member heteroaryl (e.g., 5- to 10-membered heteroaryl) is referenced, 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, thianaphthenyl, 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 cycloalkyl group having 3 to 20 ring carbon atoms (i.e., C 3-20The term "cycloalkyl" also includes polyfused saturated and partially unsaturated all-carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to about 20 ring carbon atoms). The rings of polyfused 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. The cycloalkyl group 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 a 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, such as 3 to 12 ring atoms, such as 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 (e.g., bicyclic heterocyclyl) systems may be connected to each other via fusion, spiro and bridging bonds when valence requirements permit. Heterocycles include, but are not limited to, azetidine, aziridine, imidazoline, 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 groups wherein 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, symptom relief and / or reduction in the degree 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 degree of a disease or condition); b) slowing down or curbing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the 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, "prevention (prevent / prevention / preventing)" refers to a therapy that prevents the onset of a disease or disorder so that clinical symptoms of the disease do not develop. Therefore, "prevention" is about administering therapy (e.g., administering a therapeutic substance) to an individual before signs of disease can be detected 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 suffering from a disease or disorder, such as an individual with one or more risk factors known to be associated with the onset or onset of a disease or disorder. Therefore, 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 of an anti-cancer preventive therapy may be an individual at risk of suffering from 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 substance to an individual who does not have a detectable HBV infection. It should be understood that an individual for anti-HBV preventive therapy may be an individual at risk of infection with the HBV virus. 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 (eg, a STING adaptor protein) refers to altering the activity such 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 eventually 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 due to administration of a therapeutically effective dose of a compound of the present invention to an animal or human, 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, e.g., a livestock animal such as a pig, cow, horse, dog, cat, rat, or mouse, or a non-human primate such as a cynomolgus monkey or a 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 show detectable disease prior to treatment with 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 with one or more of these risk factors has a higher chance of developing a disease or condition than an individual without these risk factors.

[0075] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that can effectively induce a desired biological or medical response, including an amount of a compound that is sufficient to achieve such disease treatment when administered to an individual 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 individual 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 treatment endpoint. An effective amount may be considered in the case of administration of 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 or a pharmaceutically acceptable salt thereof provided herein 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 one or more symptoms associated with cancer or hyperproliferative diseases to some extent. 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, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, 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 livestock.

[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 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 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 a unit dose of a compound of the invention within seconds or minutes. In some embodiments, a unit dose of a compound of the invention is administered first, followed by a unit dose of one or more additional therapeutic agents after a period of 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 a unit dose of a compound of the invention after a period of 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 suitable 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 when appropriate. Pharmaceutically acceptable salts are non-toxic salts of free base forms of compounds having 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, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates The invention relates to pharmaceutically acceptable salts of the present invention. The pharmaceutically acceptable salts of the present invention are exemplified in the following examples: 1,2-dihydro-1,4-dioic acid salt, 2,4-dihydro-1,6-dioic acid salt, 2,6-dihydro-1,4-dioic acid salt, 2,6-dihydro-1,4-dioic acid salt, 2,6-dihydro-1,6 ...

[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 N(C 1 -C 4 alkyl) 4 + Base addition salts, such as sodium or potassium salts, are also included.

[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 deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may increase metabolic resistance and, therefore, when administered to mammals, may be useful for extending the half-life of the compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0083] Examples of isotopes that may 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) substitution may be 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 the methods described in the Examples set forth below, using an appropriate isotopically labeled reagent in place of the non-labeled 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 may 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 may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of 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 E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that the embodiments encompass but are not limited to specific diastereoisomers or enantiomerically enriched forms. When chirality is not specified but exists, it is understood that the embodiments are for 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 in a ratio that is not 1:1.

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

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

[0090] III. Compounds

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

[0092]

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

[0094] in

[0095] 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 ;

[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 Independently for C 1 -C 6 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 for C 1 -C 20 Alkyl, C 2 -C 20 Alkenyl, C2 -C 20 Alkynyl, -(C 1 -C 6 Alkylene)-(C 3 -C 14 Cycloalkyl) or C 3 -C 20 Cycloalkyl, wherein each R 2a Independently, 1, 2 or 3 R 2b replace;

[0101] Each R 2b are independently -OH, -SH, -NH 2 , =O, =NH, =S, halogen, -N 3 、-CN、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino or C 1 -C 6 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 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkyne or C 7 -C13 Alkyl arylene;

[0104] L 2 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylidene, C 6 -C 10 an arylene group or a 5- to 10-membered heteroarylene group;

[0105] L 3 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 Alkyne;

[0106] R 6 H or C 1 -C 6 alkyl;

[0107] n is 0, 1 or 2;

[0108] Base 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, NH 2 , 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 )SR16 ,-C(=Z 1 )N(R 16 ) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -C 10 heteroaryl;

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

[0115] Each R 16 Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -C 10 Heteroaryl.

[0116] In one aspect, provided herein is a compound of formula (I):

[0117]

[0118] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0119] in

[0120] 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 ;

[0121] X 2 and X4 Each independently is O or S;

[0122] R 4 and R 10 are each independently H, OH or halogen;

[0123] Each R 1 Independently for C 1 -C 6 Alkyl or -LR 2 ;

[0124] 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 ;

[0125] Each R 2a Independently for C 1 -C 20 Alkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Alkynyl, -(C 1 -C 6 Alkylene)-(C 3 -C 14 Cycloalkyl) or C 3 -C 20 Cycloalkyl, wherein each R 2a Independently, 1, 2 or 3 R 2b replace;

[0126] Each R 2b are independently -OH, -SH, -NH 2 , =O, =NH, =S, halogen, -N 3 、-CN、C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino or C 1 -C 6 Dialkylamino;

[0127] 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 ;

[0128] L 1 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkyne or C 7 -C 13 Alkyl arylene;

[0129] L 2 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylidene, C 6 -C 10 an arylene group or a 5- to 10-membered heteroarylene group;

[0130] L 3 C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 Alkyne;

[0131] R 6 H or C 1 -C 6 alkyl;

[0132] n is 0, 1 or 2;

[0133] Base 1 and bases 2 Each independently

[0134]

[0135] in

[0136] A. A 1 , A 2 , A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH 2 , OR 15 , SR 15 、NHR 15 、N(R 15 ) 2 or R 16 ;

[0137] Each Z is independently O, S or NR 15 ;

[0138] 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 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -C 10 heteroaryl;

[0139] Each Z 1 are independently O or S; and

[0140] Each R 16 Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C2 -C 10 Heteroaryl.

[0141] In some embodiments, A, A 1 , A 2 , A 3 and A 4 Each independently is H, OH or NH 2 In some embodiments, A is NH 2 In some embodiments, A 1 For NH 2 In some embodiments, A 2 For NH 2 In some embodiments, A 3 For NH 2 In some embodiments, A 4 For NH 2 .

[0142] 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 , C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 2 -C 10 Heterocycloalkyl, C 6 -C 10 Aryl or C 2 -C 10 In some embodiments, each R 15 Independently H, C 1 -C 6 Alkyl or C 6 -C 10 Aryl.

[0143] In some embodiments, each R 16 Independently for C 1 -C 6 alkyl.

[0144] In some embodiments, Z is O.

[0145] In some embodiments, Z 1 is O.

[0146] In some embodiments, X 2 and X 4Each 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 is O.

[0147] In some embodiments, the compound of Formula (I) has the structure of Formula (Ia):

[0148]

[0149] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of formula (I) has the structure of formula (II):

[0151]

[0152] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound of formula (I), (Ia) and / or (II) has the structure of formula (IIa):

[0154]

[0155] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0156] In some embodiments of the compounds of Formula (I), (Ia), (II) and / or (IIa), the base 1 and bases 2 Each independently is:

[0157]

[0158] In some embodiments, the base 1 and bases 2 Each independently is:

[0159]

[0160] In some embodiments, the base 1 and bases 2 Each independently is:

[0161]

[0162]

[0163] In some embodiments, the base 1 and bases 2 Each independently

[0164]

[0165] In some embodiments, the base 1 for and

[0166] Base 2 for

[0167]

[0168] In some embodiments, the base 1 for

[0169] and

[0170] Base 2 for

[0171]

[0172] In some embodiments, the base 1 for

[0173] and

[0174] Base 2 for

[0175]

[0176] In some embodiments, the base 1 for

[0177] and

[0178] Base 2 for

[0179]

[0180] In some embodiments, the base 1 and bases 2 Each

[0181]

[0182] In some embodiments of compounds of Formula (I), (Ia), (II) and / or (IIa), A 1 , A 2 , A 3 and A 4 Each independently is H, OH or NH 2In some embodiments, A 1 OH or NH 2 In some embodiments, A 2 H or NH 2 In some embodiments, A 3 H or NH 2 In some embodiments, A 4 For NH 2 .

[0183] In some embodiments of compounds of Formula (I), (Ia), (II) and / or (IIa), A 1 , A 2 and A 3 Each independently is H, OH or NH 2 In some embodiments, A 1 OH or NH 2 In some embodiments, A 2 H or NH 2 In some embodiments, A 3 H or NH 2 .

[0184] In some embodiments, the compound of Formula (I), (Ia), (II) and / or (IIa) has the structure of Formula (III):

[0185]

[0186] or its enantiomer, hydrate, solvate or pharmaceutically acceptable salt, wherein

[0187] A 1 OH or NH 2 ; A 2 H or NH 2 ; and A 3 For H.

[0188] 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 For SR 1 ; and X 3 In some embodiments, X1 is OH; and X 3 For 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 is SH. In some embodiments, X 1 For SR 1 ; and X 3 is SH. In some embodiments, X 1 is SH; and X 3 For SR 1 In some embodiments, X 1 and X 3 Each is SH. In some embodiments, X 1 and X 3 Each is independently SR 1 .

[0189] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), each R 1 Independently -LR 2 .

[0190] In some embodiments of the 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 , L 1-OL 2 , or L 1 -O(C=O)OL 2 In some embodiments, L is L 1 , L 1 -O(C=O)-L 2 or L 1 -OL 2 .

[0191] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), L 1 C 1 -C 6 Alkylene or C 7 -C 13 In some embodiments, L 1 C 1 -C 6 Alkylene, such as -CH 2 -. In some embodiments, L 1 C 7 -C 13 Alkylarylene, such as –CH 2 -Ph-.

[0192] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), L 2 C 1 -C 6 Alkylene, C 6 -C 10 In some embodiments, L 2 C 1 -C 6 Alkylene or C 6 -C 10 In some embodiments, L 2 C 1 -C 6 Alkylene, such as –CH 2 -. In some embodiments, L 2 C 6 -C 10 Arylene groups, such as phenylene groups.

[0193] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa) and / or (III), L is L 1 , L 1 -O(C=O)-L 2 or L 1 -OL 2 ; L1 C 1 -C 6 Alkylene or C 7 -C 13 Alkyl arylene; L 2 C 1 -C 6 Alkylene or C 6 -C 10 Arylene.

[0194] 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 .

[0195] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), R 2a C 1 -C 20 Alkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Alkynyl or -(C 1 -C 6 Alkylene)-(C 3 -C 14 In some embodiments, R 2a C 3 -C 20 Cycloalkyl, such as C 3 -C 16 Cycloalkyl, C 3 -C 10 Cycloalkyl, C 3 -C 8 Cycloalkyl, C 3 -C 7 Cycloalkyl, C 5 -C 8 Cycloalkyl or C 4 -C 7 In some embodiments, R 2a C 1 -C 20 Alkyl or -(C 1 -C 6 Alkylene)-(C 3 -C 14 In some embodiments, R 2a C 1 -C 20 Alkyl or -CH 2 -(C3 -C 14 In some embodiments, R 2a -CH 2 -(C 3 -C 14 Cycloalkyl), such as -CH 2 -(C 3 -C 10 Cycloalkyl), -CH 2 -(C 3 -C 8 Cycloalkyl), -CH 2 -(C 3 -C 7 Cycloalkyl) or -CH 2 -(C 5 -C 8 In some embodiments, R 2a C 1 -C 20 Alkyl groups, such as C 1 -C 16 Alkyl, C 3 -C 20 Alkyl, C 3 -C 18 Alkyl, C 3 -C 16 Alkyl, C 3 -C 14 Alkyl, C 3 -C 12 Alkyl, C 3 -C 10 Alkyl, C 3 -C 8 Alkyl, C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 3 -C 6 alkyl.

[0196] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 1 for

[0197]

[0198]

[0199] In some embodiments, X 1 for

[0200] and

[0201] R2a C 3 -C 20 alkyl.

[0202] In some embodiments, X 1 for

[0203]

[0204] and

[0205] R 2a C 3 -C 20 alkyl.

[0206] In some embodiments, X 1 for

[0207]

[0208] In some embodiments, X 1 for

[0209]

[0210] In some embodiments, X 1 for

[0211]

[0212] In some embodiments, X 1 for

[0213]

[0214] In some embodiments, X 1 for

[0215]

[0216] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 3 for

[0217]

[0218] In some embodiments, X 3 for

[0219] and

[0220] R 2a C 3 -C 20 alkyl.

[0221] In some embodiments, X 3 for

[0222]

[0223] and

[0224] R 2a C 3 -C 20 alkyl.

[0225] In some embodiments, X 3 for

[0226]

[0227] In some embodiments, X 3 for

[0228]

[0229] In some embodiments, X 3 for

[0230]

[0231] In some embodiments, X 3 for

[0232]

[0233] In some embodiments, X 3 for

[0234]

[0235] 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 Through an R 2b replace.

[0236] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), R 2b -OH, halogen, -CN, C 1 -C 6 Alkoxy or C 1 -C 6 In some embodiments, R 2b is a halogen, such as F or Cl.

[0237] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 C 1 -C 6 Alkylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 1 -C 20 In some embodiments, X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 -CH 2 -; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 3 -C 20 alkyl.

[0238] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 C 1 -C 6 Alkylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 1 -C 20 In some embodiments, X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 -CH 2; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 3 -C 20 alkyl.

[0239] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 C 7 -C 13 Alkyl arylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 1 -C 20 In some embodiments, X 1 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 -CH 2 -Ph-;R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 3 -C 20 alkyl.

[0240] In some embodiments of compounds of Formula (I), (Ia), (II), (IIa) and / or (III), X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 C 7 -C 13 Alkyl arylene; R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 1 -C20 In some embodiments, X 3 OR 1 or SR 1 ; R 1 For-LR 2 ; L is L 1 ; L 1 -CH 2 -Ph-;R 2 -O(C=O)-R 2a OR -O(C=O)-OR 2a ; and R 2a C 3 -C 20 alkyl.

[0241] In some embodiments, the compound of formula (III) has the structure of formula (IIIa):

[0242]

[0243] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound of formula (III) has the structure of formula (IIIb):

[0245]

[0246] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of formula (III) has the structure of formula (IIIc):

[0248]

[0249] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the compound of formula (III) has the structure of formula (IIId):

[0251]

[0252] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0253] 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 For NH2 .

[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 For NH 2 .

[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 For NH 2 In some embodiments, A 2 For NH 2 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 10 are 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 an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

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

[0262] In some embodiments of compounds of Formula (IIIe), A 1In some embodiments, A 1 For NH 2 .

[0263] In some embodiments of compounds of Formula (IIIe), A 2 H and A 1 For NH 2 In some embodiments, A 2 For NH 2 And A 1 For OH.

[0264] In some embodiments, the compound is a compound of formula (IIIe), or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments of the compound of formula (IIIe), R 4 and R 10 are 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.

[0266] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), (IIId) and / or (IIIe), R 2a C 2 -C 20 Alkyl groups, such as C 2 -C 16 Alkyl, C 2 -C 14 Alkyl, C 2 -C 12 Alkyl, C 2 -C 8 Alkyl, C 2 -C 6 Alkyl, C 3 -C 16 Alkyl, C 3 -C 14 Alkyl, C 3 -C 12 Alkyl, C 3 -C 8 Alkyl or C 3 -C 6 alkyl.

[0267] In some embodiments, the compounds of the invention have the following structure:

[0268]

[0269]

[0270]

[0271]

[0272] or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compounds of the invention have the following structure:

[0274]

[0275]

[0276] or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the compounds of the invention have the following structure:

[0278]

[0279]

[0280] or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe) have the structure as depicted, or are tautomers, enantiomers, or pharmaceutically acceptable salts thereof.

[0282] Compounds of the invention, e.g., compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), and / or (IIIe) may be shown in several equivalent drawings. For example, compounds of Formula (Ia) are generally depicted herein as shown above, with the 3′-substituents of each nucleoside facing toward each other:

[0283]

[0284] The compound of formula (Ia) above is equivalent to the compound of formula (Ia) as depicted below:

[0285]

[0286] Furthermore, each of the previous drawings is equivalent to the following depiction of a compound of formula (Ia):

[0287]

[0288] Each of the previous drawings is equivalent to the following depiction of a compound of formula (Ia):

[0289]

[0290] The presence of a chiral center allows the compound to exist in the form of one of the two possible optical isomers ((R)-enantiomers or (S)-enantiomers) or in the form of 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 in the present invention.

[0291] The present invention also provides a method for preparing a compound of the present invention, for example a compound of formula (I). The compound can be prepared in a variety of ways, including by the method of example. For example, wherein X 1 and X 3 Each independently is OR 1 or SR 1 Compounds of formula (IIa) can be prepared by combining a suitably protected procompound with a suitable prodrug moiety and then removing the protecting group to provide a compound of formula (IIa).

[0292] In some embodiments, the method for preparing a compound of formula (IV) or a salt thereof:

[0293]

[0294] in

[0295] L is –CH 2 -,

[0296] R 2 -O-(C=O)-R 2a OR –O-(C=O)-OR 2a ,

[0297] R 2a C 1 -C 20 alkyl,

[0298] R 15 =–(C=O)R 16 ,and

[0299] R 16 C 2 -C 6 Alkenyl,

[0300] Comprising a compound of formula (IVa) or a salt thereof:

[0301]

[0302] in

[0303] R 15 =–(C=O)R 16 ,and

[0304] R 16 C 2 -C 6 Alkenyl,

[0305] And the compound of formula (V):

[0306] R 2 -LX 5 (V),

[0307] in

[0308] L is –CH 2 -,

[0309] R 2 -O-(C=O)-R 2a OR –O-(C=O)-OR 2a ,

[0310] R 2a C 1 -C 20 Alkyl, and

[0311] X 5 is Cl, Br or I,

[0312] Under conditions suitable for the formation of a compound of formula (IV).

[0313] In some embodiments of compounds of formula (IV) and / or (V), R 2 -O-(C=O)-R 2a In some embodiments, R 2 -O-(C=O)-OR 2a .

[0314] In some embodiments of compounds of formula (IV) and / or (V), R 2a C 1 -C 20 Alkyl groups, such as C 2 -C 20 Alkyl, C 2 -C 16 Alkyl, C 2 -C 12 Alkyl, C 2 -C 8 Alkyl, C 2 -C 6 Alkyl, C 2 -C 20Alkyl, C 3 -C 16 Alkyl, C 3 -C 12 Alkyl, C 3 -C 8 Alkyl or C 3 -C 6 In some embodiments, R 2a C 4 In some embodiments, R 2a C 3 Alkyl, for example isopropyl.

[0315] In some embodiments of compounds of Formula (IV) and / or (IVa), R 16 C 3 -C 4 Alkenyl, such as C 4 Alkenyl, for example 3-butenyl.

[0316] In some embodiments of compounds of Formula (V), X 5 For I.

[0317] In some embodiments, the method for preparing a compound of formula (IV) comprises a salt of a compound of formula (IV) and / or (IVa). Any salt form of a compound of formula (IV) may be prepared. Suitable salts of a compound of formula (IVa) include basic salts, such as ammonium salts, such as quaternary ammonium salts, such as tetraalkylammonium salts, such as tetramethylammonium, tetraethylammonium, tetrapropylammonium or tetrabutylammonium; aryltrialkylammonium salts, such as phenyltrimethylammonium; or alkylaryltrialkylammonium salts, such as benzyltrimethylammonium or benzyltriethylammonium. In some embodiments, the salt is a tetrabutylammonium salt.

[0318] In some embodiments, the method comprises mixing a compound of formula (IVa) or a salt thereof and a compound of formula (V) in a suitable solvent. The method may use any aprotic solvent. In some embodiments, the suitable solvent is selected from the group consisting of acetonitrile, dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, methyl tert-butyl ether, tetrahydrofuran and tetrahydropyran, and mixtures thereof. In some embodiments, the suitable solvent is acetonitrile.

[0319] The method for preparing formula (IV) compound can carry out any suitable reaction time.For example, the time reaction can be a few minutes, a few hours or a few days.In certain embodiments, the reaction time can be several hours, for example, about 2,3,4,5,6,7,8,9,10,11 or about 12 hours, for example, 2 hours.The reaction mixture can also be in any suitable pressure.For example, the reaction mixture can be in a state below atmospheric pressure, about atmospheric pressure or above atmospheric pressure.In certain embodiments, the reaction mixture can be in a state of about atmospheric pressure.

[0320] The method for preparing the compound of formula (IV) can be carried out at any suitable reaction temperature, for example but not limited to below room temperature, room temperature or above room temperature. In some embodiments, the temperature of the reaction mixture may be from about -20°C to about 100°C, or from about 0°C to about 50°C, or from about 10°C to about 40°C, or from about 10°C to about 30°C. In some embodiments, the temperature of the reaction mixture may be about 20°C.

[0321] The method can prepare formula (IV) compound with any suitable yield. For example, the yield of formula (IV) compound can be at least about 10% from formula (IVa) compound, or at least about 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70% or at least about 75% from formula (IVa) compound. In some embodiments, the yield of formula (IV) can be at least 25% from formula (IVa) compound. In some embodiments, the yield of formula (IV) can be at least 35% from formula (IVa) compound. In some embodiments, the yield of formula (IV) can be at least 50% from formula (IVa) compound. In some embodiments, the yield of formula (IV) can be at least 75% from formula (IVa) compound.

[0322] In some embodiments, a method of preparing a compound of formula (IV) having the following structure:

[0323]

[0324] It includes mixing a salt of a compound of formula (IVa) having the following structure:

[0325]

[0326] and a compound of formula (V) having the following structure:

[0327]

[0328] Under conditions suitable for the formation of a compound of formula (IV).

[0329] In some embodiments, a method of preparing a compound of formula (IV) having the following structure:

[0330]

[0331] It includes mixing a salt of a compound of formula (IVa) having the following structure:

[0332]

[0333] and a compound of formula (V) having the following structure:

[0334]

[0335] Under conditions suitable for the formation of a compound of formula (IV).

[0336] IV. Composition

[0337] 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.

[0338] In certain embodiments, pharmaceutical compositions comprise one or more additional therapeutic agents, as described more fully below.

[0339] Pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts thereof can be prepared with one or more pharmaceutically acceptable excipients that can be selected according to conventional practice. Tablets may contain excipients including glidants, fillers, adhesives and the like. Aqueous compositions can be prepared in sterile form and are generally isotonic when intended for delivery by routes other than oral administration. All compositions may contain excipients as appropriate, 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.

[0340] 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 pharmaceutical technology. 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 closely associating the active ingredient with a liquid excipient or a finely powdered solid excipient or both, and then forming 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.

[0341] 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 active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0342] The pharmaceutical compositions disclosed herein include one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients and other therapeutic agents selected as appropriate. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration. When used, for example, for oral use, tablets, dragees, 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, flavoring agents, coloring agents and preservatives to provide a palatable preparation. 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.

[0343] The amount of active ingredients that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended treatment of the individual 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 material, formulated with an appropriate and suitable amount of a pharmaceutically acceptable excipient. In certain embodiments, the range of pharmaceutically acceptable excipients is from about 5 to about 95% (weight:weight) of the total composition.

[0344] In certain embodiments, the composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof does not contain, in one variation, an agent that affects the metabolic rate of an active ingredient. Thus, it is understood that a composition comprising a compound of the invention does not contain, in one aspect, 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 do not contain, in one aspect, 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.

[0345] The present invention also includes a pharmaceutical composition as described above, which is used to modulate the activity of the STING protein to induce the STING-dependent production of type I interferons, cytokines or chemokines.

[0346] 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.

[0347] In some embodiments, the pharmaceutical compositions described above are for use in humans or animals.

[0348] 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 by mixing the active ingredient with pharmaceutically acceptable therapeutically inert organic and / or inorganic carriers or excipients.

[0349] In one aspect, provided herein is the use of a compound of the invention as a second or additional active ingredient that has a synergistic effect with other active ingredients in known drugs, or the administration of a compound of the invention together with such drugs.

[0350] The compounds of the present invention may also be used in the form of prodrugs or other appropriately modified forms which release the active ingredient in vivo.

[0351] V. Methods

[0352] In one embodiment, provided herein is a method for treating a disease or disorder, 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.

[0353] Also provided is a method for regulating 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.

[0354] 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 act as a direct cytosolic DNA sensor (CDS) and an adaptor protein for type I interferon signaling via different molecular mechanisms. The STING adaptor protein has been shown to activate downstream transcription factors STAT6 and IRF3 via TBK1, and NF-κB via IKKβ, which can achieve 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.

[0355] Further provided is a method for preventing or treating a disease or condition responsive to modulation of a 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 invention, or an enantiomer or pharmaceutically acceptable salt thereof.

[0356] 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.

[0357] 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. It is believed that activation of the STING adaptor protein ultimately leads to the release of type I and type III interferons and a variety of cytokines and chemokines, such as IL-6, TNF-α, and INF-γ. Therefore, inducing STING adaptor protein-dependent type I interferons, cytokines, or chemokines in a human or animal results in the 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.

[0358] 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 invention, or an enantiomer or a pharmaceutically acceptable salt thereof.

[0359] The viral infection that can be treated or prevented by the method of the present invention can be any infection caused by a virus, such as a virus from the Hepadnaviridae family of viruses, such as hepatitis B; or any retrovirus, such as an alpharetrovirus, such as Rous sarcoma virus; a betaretrovirus, such as a simian retrovirus; a deltaretrovirus, such as a bovine leukemia virus or a human T-lymphotropic virus (HTLV), including HTLV-1, HTLV-2, and HTLV-3; a gammaretrovirus, such as a murine leukemia virus or a feline leukemia virus; or a lentivirus, such as a human immunodeficiency virus (HIV) (including HIV-1 and HIV-2), a simian immunodeficiency virus, an equine infectious anemia virus, a bovine immunodeficiency virus, a rabbit endogenous lentivirus K (RELIK), or a feline immunodeficiency virus.

[0360] 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.

[0361] Hyperproliferative diseases include diseases caused by excessive growth of non-cancerous cells. Such conditions include, but are not limited to, psoriasis, actinic keratosis and seborrheic keratosis, warts, keloids, and eczema.

[0362] Cancers that can be treated or prevented by the methods of the 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.

[0363] 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).

[0364] 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; neuropathy 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, colorectal cancer, penile cancer, vulvar cancer, thyroid cancer, salivary gland cancer, endometrial or uterine cancer, hepatoma, hepatocellular carcinoma, liver cancer, stomach cancer or gastric 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).

[0365] Any of the methods of treatment provided herein can be used to treat cancers at various stages. For example, cancer stages include, but are not limited to, early, advanced, locally advanced, remission, refractory, relapsed after remission, and progressive cancer.

[0366] individual

[0367] Any of the therapeutic 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.

[0368] In some embodiments, the subject may be a human being that exhibits one or more symptoms associated with cancer or a hyperproliferative disease. In some embodiments, the subject may be a human being that exhibits 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.

[0369] In some embodiments, an individual may be a human being who has a risk of suffering from cancer or a hyperproliferative disease or is genetically or otherwise prone (e.g., risk factor) to suffering from 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 with a risk of suffering from cancer. Before the treatment methods described herein are performed, the individual may or may not have a detectable disease, and may or may not show a detectable disease. An individual with risk may have one or more so-called risk factors, which are measurable parameters associated with the development of the cancer described herein. An individual with one or more such risk factors has a higher probability of suffering from 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, individuals with a risk of cancer include individuals whose relatives have experienced the disease, for example, and individuals with risk determined by analysis of genes or biochemical markers.

[0370] In addition, individuality can be the human being who is subjected to one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery or any combination thereof.Therefore, one or more compounds provided herein can be used before, during or after the administration of chemotherapy, radiotherapy, immunotherapy, surgery or its combination.

[0371] In some embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy, or (ii) 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).

[0372] 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.

[0373] 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.

[0374] 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 disorder in a human or animal.

[0375] The present invention further includes the cyclic dinucleotides provided herein, including the compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use in modulating the activity of the STING protein.

[0376] The present invention further includes the cyclic dinucleotides provided herein, including the 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.

[0377] 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 use in STING-dependent induction of type I interferons, cytokines or chemokines in humans or animals.

[0378] 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.

[0379] 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 viral infections in humans or animals, such as viral infections caused by hepatitis B virus or HIV.

[0380] 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.

[0381] The present invention further includes the cyclic dinucleotides provided herein, including the compounds of the present invention, or enantiomers or pharmaceutically acceptable salts thereof, for use in enhancing vaccine efficacy in humans or animals.

[0382] 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.

[0383] 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.

[0384] 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 viral infections (e.g., caused by hepatitis B virus or HIV), hyperproliferative diseases or cancer.

[0385] VI. Application

[0386] The compounds of the 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 should be understood that the preferred route may vary, for example, with the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0387] The compounds of the invention can be administered to individuals for a desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compounds are administered daily or intermittently for the duration of an individual's life.

[0388] The dosage or administration frequency of the compounds of the invention may be adjusted during the course of treatment based on the judgment of the administering physician.

[0389] The compound can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once daily.

[0390] 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 may include about 0.00001 mg per kg of body weight per day to about 10 mg per kg of body weight per day, such as about 0.0001 mg per kg of body weight per day to about 10 mg per kg of body weight per day, or such as about 0.001 mg per kg of body weight per day to about 1 mg per kg of body weight per day, or such as about 0.01 mg per kg of body weight per day to about 1 mg per kg of body weight per day, or such as about 0.05 mg per kg of body weight per day to about 0.5 mg per kg 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.

[0391] 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). The 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 present 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 may be administered hourly, daily or weekly. For example, a single dose may be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours or once every 24 hours. A single dose may also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once every other week. A single dose may also be administered once a month.

[0392] 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 above.

[0393] 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.

[0394] VII. Combination therapy

[0395] 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.

[0396] In certain embodiments, the present invention provides a method for treating a viral infection, comprising administering to an individual 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, which are 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.

[0397] 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 may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0398] Administration of combination therapy

[0399] In certain embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co-administration of compounds disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and the one or more additional therapeutic agents, such that a therapeutically effective amount of the compounds disclosed herein and the one or more additional therapeutic agents is present in the subject. When administered sequentially, the combination may be administered in two or more administrations.

[0400] Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and the 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.

[0401] In certain embodiments, a compound as disclosed herein (e.g., any compound of Formula I) can 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 a compound of Formula I (e.g., 10 mg to 1000 mg of the compound).

[0402] 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 may 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 first administered, followed by 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 first administered, followed by a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, followed by 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 first administered, followed by a unit dose of a compound disclosed herein after a period of several hours (e.g., 1 to 12 hours).

[0403] 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, for example, in a solid dosage form for oral administration.

[0404] In certain embodiments, the compounds of the invention are formulated as tablets, which may optionally contain one or more other compounds useful for treating the disease being treated. In certain embodiments, the tablets may contain another active ingredient useful for treating viral diseases, such as hepatitis B virus or HIV.

[0405] In certain embodiments, such tablets are suitable for once-daily administration.

[0406] In one embodiment, a pharmaceutical composition is provided that includes 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.

[0407] In one embodiment, a kit is provided comprising a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0408] Viral combination therapy

[0409] 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, type I interferon), lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogs, 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.

[0410] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 5-30 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 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 their pharmaceutically acceptable salts are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts 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 any dose of the compound (e.g., 50 mg to 500 mg of the compound) with the agents provided herein, as if each combination of doses is specifically and separately listed.

[0411] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil 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. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 300 mg of tenofovir bisfumarate, tenofovir hemifumarate or tenofovir bisfumarate. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 250 mg of tenofovir bisfumarate, tenofovir hemifumarate or tenofovir bisfumarate. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 150 mg of tenofovir bisfumarate, tenofovir hemifumarate or tenofovir bisfumarate. As disclosed herein, the compounds (e.g., compounds of formula (I)) can be combined with any dose of the compound (e.g., 50 mg to 500 mg of the compound) with the agents provided herein, as if each combination of doses is specifically and separately listed.

[0412] HIV combination therapy

[0413] In certain embodiments, a method for treating or preventing a human or animal having HIV infection or at risk of 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 HIV infection or at risk of 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.

[0414] 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.

[0415] In certain embodiments, the compounds disclosed herein are formulated as tablets, which may optionally contain one or more other compounds suitable for treating HIV. In certain embodiments, the tablets may contain another active ingredient 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 ectopic) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0416] In certain embodiments, such tablets are suitable for once-daily administration.

[0417] 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, TALEN), 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 cell cycle 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.

[0418] 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.

[0419] HIV combination drugs

[0420] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and andrositabine); ( rilpivirine, tenofovir disoproxil fumarate, and andrositabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and andrositabine); (tenofovir disoproxil fumarate and andrositabine; TDF+FTC); (tenofovir alafenamide and andrositabine); (tenofovir alafenamide, andrositabine and rilpivirine), (tenofovir alafenamide, andrositabine, cobicistat, and elvitegravir); (bictegravir, andrositabine, tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate, andrositabine and cobicistat; efavirenz, lamivudine and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and andrositabine; tenofovir alafenamide hemifumarate and andrositabine; tenofovir alafenamide hemifumarate, andrositabine and rilpivirine; tenofovir alafenamide hemifumarate, andrositabine, 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 tenofovir disoproxil fumarate + andrositabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine; tuluravidine + lamivudine, 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.

[0421] HIV protease inhibitors

[0422] 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.

[0423] HIV reverse transcriptase inhibitors

[0424] 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.

[0425] 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.

[0426] HIV integrase inhibitors

[0427] 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 golden tricarboxylic acid, a derivative of a golden tricarboxylic 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 derivatives, integrase-LEDGF inhibitors, 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.

[0428] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0429] HIV entry inhibitors

[0430] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 ligation inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0431] 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).

[0432] 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.

[0433] Examples of CD4 ligand inhibitors include ibalizumab and CADA analogs.

[0434] Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0435] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Hemicept).

[0436] HIV maturation inhibitors

[0437] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0438] Latency reversal agents

[0439] 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, anilide 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.

[0440] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0441] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0442] Capsid inhibitors

[0443] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid cleavage compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and AVI-CAN1-15 series.

[0444] Immune-based therapies

[0445] 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; planned cell death protein 1 (Pd-1) modulators; planned 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; mycophenolic acid ethyl ester (MPA) and its ester derivative mycophenolic acid ethyl ester (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 α-2a, peginterferon α-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators and IR-103.

[0446] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and modulators disclosed in the following documents: 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 (VentirxPharma), 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.). Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0447] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, and selenirib. mesylate), rigosertib, rigosertib 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.

[0448] Alpha-4 / beta-7 antagonists

[0449] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0450] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0451] 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.

[0452] 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.

[0453] Pharmacokinetic enhancers

[0454] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0455] HIV vaccine

[0456] 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 vaccine, 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 vector 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. .

[0457] Additional HIV treatments

[0458] 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).

[0459] 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.

[0460] Gene therapy and cell therapy

[0461] Gene therapy and cell therapy include genetic modification for silencing genes; genetic approaches for directly killing infected cells; infusions of immune cells designed to replace large portions of an individual's own immune system to enhance 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 for modifying cellular activity to further alter endogenous immune responsiveness to infection.

[0462] Examples of dendritic cell therapies include AGS-004.

[0463] Gene editing agents

[0464] Examples of gene editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0465] Examples of CRISPR / Cas9 systems targeting HIV include EBT101.

[0466] CAR-T cell therapy

[0467] CAR-T cell therapy includes a population 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 induced 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.

[0468] Examples of HIV CAR-T include VC-CAR-T.

[0469] TCR-T cell therapy

[0470] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides on the surface of virus-infected cells.

[0471] 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.

[0472] In one embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV non-nucleoside reverse transcriptase inhibitors. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV protease inhibitor compounds. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors and pharmacokinetic enhancers. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0473] 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 andrositabine); ( Rilpivirine, tenofovir disoproxil fumarate, and andrositabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and andrositabine); (tenofovir disoproxil fumarate and andrositabine; TDF+FTC); (tenofovir alafenamide and andrositabine); (tenofovir alafenamide, andrositabine, and rilpivirine); (tenofovir alafenamide, andrositabine, cobicistat, and elvitegravir); (Biclavir, Andrositabine, Tenofovir Elafenamide); Adefovir; Adefovir Dipivoxil; Cobicistat; Andrositabine; Tenofovir; Tenofovir Disoproxil; 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; Dolulavir; Elvitegravir; Ritonavir; Atazanavir sulfate and ritonavir; Darunavir; Lamivudine; Pralastine; Fosamprenavir; Fosamprenavir calcium efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Sita ivudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldescan; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (resipitor); lamivudine and tenofovir disoproxil fumarate; efavirenz; lamivudine and tenofovir disoproxil fumarate; fosfezin; lamivudine; nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0474] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0475] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0476] 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, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bisoprolol; and a second additional therapeutic agent selected from the group consisting of andrositabine and lamivudine.

[0477] 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, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bisoprolol; and a second additional therapeutic agent, wherein the second additional therapeutic agent is andrositabine.

[0478] 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, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of andrositabine. 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 and 200 mg of andrositabine. As disclosed herein, the compounds (e.g., compounds of formula (I)) 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 is specifically and separately listed.

[0479] 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 invention may 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 is specifically and separately listed.

[0480] HBV combination therapy

[0481] In certain embodiments, a method for treating or preventing HBV infection in a human suffering from or at risk of 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 suffering from or at risk of 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.

[0482] 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.

[0483] 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.

[0484] In certain embodiments, the compounds of the invention are formulated as tablets, which may optionally contain one or more other compounds useful in treating HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 regulators, arginase inhibitors, B lymphocyte and T lymphocyte attenuation factor 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 modulators, 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 virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein regulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein regulators, 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, RNase inhibitors, RNADNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, interferon gene stimulator (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) regulators, viral ribonucleotide reductase inhibitors and combinations thereof.

[0485] HBV combination drugs

[0486] 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).

[0487] Other HBV drugs

[0488] 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, IPB-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). ,

[0489] HBV vaccine

[0490] 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.

[0491] 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.

[0492] HBV DNA polymerase inhibitors

[0493] Examples of HBV DNA polymerase inhibitors include adefovir Andrositabine Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, intiv Intifo Maleate, Telbivudine Filocivir, pradefovir, clevudine, ribavirin, lamivudine Phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

[0494] Immunomodulators

[0495] 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, 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.

[0496] Toll-like receptor (TLR) modulators

[0497] 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.

[0498] 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).

[0499] Examples of TLR8 modulators include motomod, resimod, 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 (VentirxPharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (NoviraTherapeutics), US20130251673 (Novira Therapeutics), U.S. Patent No. 9670205, US20160289229, U.S. Patent Application No. 15 / 692161 and U.S. Patent Application No. 15 / 692093.

[0500] 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.

[0501] 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), 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), 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).

[0502] Interferon alpha receptor ligand

[0503] 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 α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), YPEG-rhIFNα-2b, MOR-22, PEGylated interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 Interferon beta-1a Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, interferon alpha-2b (IFN, Laboratorios Bioprofarma), alpha interferon 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon α2a fusion protein), rHSA-IFNα2b, recombinant human interferon α-(1b, 2a, 2b), Pegylated Interferon α-2b (Amega), Pegylated Interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-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).

[0504] Hyaluronidase inhibitors

[0505] Examples of hyaluronidase inhibitors include astodrimer.

[0506] Hepatitis B surface antigen (HBsAg) inhibitors

[0507] 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′.

[0508] Examples of HBsAg secretion inhibitors include BM601.

[0509] Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor

[0510] 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.

[0511] Cyclophilin inhibitors

[0512] 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).

[0513] HBV viral entry inhibitors

[0514] Examples of HBV viral entry inhibitors include Myrcludex B.

[0515] Antisense oligonucleotides targeting viral mRNA

[0516] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

[0517] Short interfering RNA (siRNA) and ddRNAi.

[0518] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

[0519] Examples of DNA-guided RNA interference (ddRNAi) include BB-HB-331.

[0520] Endonuclease modulators

[0521] Examples of endonuclease modulators include PGN-514.

[0522] Ribonucleotide reductase inhibitors

[0523] Examples of ribonucleotide reductase inhibitors include Trimidox.

[0524] HBV E antigen inhibitors

[0525] Examples of HBV E antigen inhibitors include wogonin.

[0526] Covalently closed circular DNA (cccDNA) inhibitors

[0527] Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0528] Farnesoid X receptor agonists

[0529] 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.

[0530] HBV antibodies

[0531] Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed).

[0532] 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).

[0533] Fully human monoclonal antibodies include HBC-34.

[0534] CCR2 chemokine antagonists

[0535] Examples of CCR2 chemokine antagonists include propagermanium.

[0536] Thymosin agonists

[0537] Examples of thymosin agonists include Thymalfasin, recombinant thymosin α1 (GeneScience).

[0538] Cytokines

[0539] 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.

[0540] Nuclear protein regulator

[0541] Nucleoprotein modulators may 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.

[0542] 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).

[0543] 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).

[0544] retinoic acid inducible gene 1 stimulator

[0545] 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.

[0546] NOD2 Stimulator

[0547] Examples of NOD2 stimulators include SB-9200.

[0548] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0549] Examples of PI3K inhibitors include idecoxib, ACP-319, AZD-8186, AZD-8835, buparcoxib, CDZ-173, CLR-457, picoglice, neratinib, regoctibin, regoctibin sodium, EN-3342, TGR-1202, idecoxib, durvicoxib, IPI-549, UCB-5857, tylenicoxib, XL-765, gidacoxib, ME-401, VS-5584, cobancoxib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panucoxib, GSK-2267, 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.

[0550] Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

[0551] 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.).

[0552] PD-1 inhibitors

[0553] 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, BMS-936559.

[0554] PD-L1 inhibitors

[0555] 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.

[0556] 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). ;

[0557] Recombinant Thymosin α-1

[0558] Examples of recombinant thymosin α-1 include NL-004 and pegylated thymosin α-1.

[0559] Bruton's tyrosine kinase (BTK) inhibitors

[0560] 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 Compounds disclosed in US20130079327 (Ono Pharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0561] KDM inhibitors

[0562] 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).

[0563] Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

[0564] STING agonists

[0565] 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).

[0566] Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0567] Examples of NNRTIs include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555 (Gilead).

[0568] HBV replication inhibitors

[0569] Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and Xingantie.

[0570] Arginase inhibitors

[0571] Examples of arginase inhibitors include CB-1158, C-201 and ramustat.

[0572] Gene therapy and cell therapy

[0573] Gene therapy and cell therapy include genetic modification for silencing genes; genetic approaches for directly killing infected cells; infusions of immune cells designed to replace large portions of a patient's own immune system to enhance the immune response to infected cells or to activate a patient's own immune system to kill infected cells or to seek out and kill infected cells; and genetic approaches for modifying cellular activity to further alter endogenous immune responsiveness to infection.

[0574] Gene editing agents

[0575] Examples of genome editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; 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 PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminating the expression of PreC, C, X, PreSI, PreS2, S, P or SP gene; (2) interfering with the function of 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 HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol and / or HBSP protein. 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.

[0576] CAR-T cell therapy

[0577] CAR T cell therapy includes a population 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.

[0578] TCR-T cell therapy

[0579] TCR T cell therapy includes T cells expressing 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.

[0580] 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, a HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, a HBV therapeutic vaccine, HBV antibodies (including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigens), 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, 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).

[0581] In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are 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 a bispecific antibody 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.

[0582] In another specific embodiment, the 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: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

[0583] 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. Pat. No. 8722054 (Gilead 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), 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. 8513184 (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.

[0584] Cancer combination therapy

[0585] In one embodiment, the compounds of the present invention can be used together with other therapeutic methods for cancer treatment. Preferably, combination therapy with chemotherapeutic agents, hormones, antibodies, surgery and / or radiation therapy is contemplated.

[0586] In some embodiments, the other anti-cancer therapy is surgery and / or radiation therapy.

[0587] In some embodiments, the other anti-cancer therapy is at least one additional cancer agent.

[0588] 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.

[0589] In some embodiments, a combination for use in therapy is provided, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other cancer agent.

[0590] In some embodiments, there is provided a 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.

[0591] Examples of other cancer drugs include: intercalating substances such as anthracycline, 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 ene), androgene, glucocorticoids, dexamethasone, prednisolone and prednisone; anti-cancer 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. ;

[0592] In certain embodiments, a method for treating or preventing a hyperproliferative disorder or cancer in a human or animal having or at risk of 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 a hyperproliferative disorder or cancer 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.

[0593] In certain embodiments, the present invention provides a method of treating a hyperproliferative disorder or cancer, the method 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 a hyperproliferative disorder or cancer.

[0594] 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 editors (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, a product is provided herein comprising a compound described herein and an additional therapeutic agent in the form of a combined preparation for simultaneous, separate, or sequential use in therapy.

[0595] Non-limiting examples of additional therapeutic agents include: Abelson murine leukemia virus 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), arginase (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 sequence 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 ligands, bone morphogenetic protein-9 ligand regulator, brachykinin, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and extradomain (BET) bromodomain-containing 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 protease recruitment domain protein-15, cathepsin G, CCR5 gene, CDK activated 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, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 190, 260, 270, 280, 300, 190, 110, 130, 130, 130, 140, 13 ... 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 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulin, endosialin, endostatin, endothelin (such as ET-A, ET-B), enhancer of zeste homolog 2 (EZ H2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigenetic factor, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythrocytic leukemia virus oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β deoxycholate 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 cleavage 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), phosphoinositide 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, heparinase, hepatocyte growth factor, HERV-H LTR-associated 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 kinase kinase kinase kinase kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-κ-B kinase (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 receptors, immunoglobulin gamma Fc receptors (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1 inhibitors, insulin receptors, insulin-like growth factors (such as 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / beta-5, integrin alpha-V / beta-6, intercellular adhesion molecule 1 (ICAM-1), interferon (such as alpha, alpha2, beta, gamma), interferon-induced protein 2 (AIM2) absent in melanoma, type I interferon receptor, interleukin 1 ligand, interleukin 13 receptor alpha 2, 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, kissin (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) gene, 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 (prostatic 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-associated 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 delta), 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, purine 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 (Ras homolog enriched in brain) 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 (Recepteur d′Origine Nantais)) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, endoplasmic 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 transduction and transcription (STAT,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 receptor (such as 1, 2, 3, 4, 5), sonic hedgehog protein, non-seven kinase (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, interferon gene stimulator (STING) receptor, interferon gene stimulator 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 signal transduction 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,Such as 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 cell apoptosis inhibitory protein, zinc finger protein transcription factor, or any combination thereof.

[0596] Non-limiting examples of additional therapeutic agents can be categorized by their mechanism of action into, for example, the following groups:

[0597] - antimetabolites / anticancer agents such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunomycin), and TAS-118;

[0598] -Purine analogs, folate antagonists (such as pralatrexate) and related inhibitors;

[0599] - 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);

[0600] -DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide Actinomycin D, daunomycin, cranberry, epirubicin, ifosfamide, melphalan, dichloromethane, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, paclitaxel, Taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

[0601] - DNA hypomethylating agents such as guadecitabine (SGI-110), ASTX727;

[0602] - antibiotics such as actinomycin D, daunomycin, idarubicin, edamicin, anthracycline, mitoxantrone, bleomycin, plicamycin (mithramycin);

[0603] - enzymes such as L-asparaginase which metabolize L-asparagine systemically and deprive cells that do not have the ability to synthesize their own asparagine;

[0604] - Antiplatelet agents;

[0605] - DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

[0606] -Agents that activate or reactivate latent human immunodeficiency virus (HIV), such as pambinostat and romidepsin;

[0607] -Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol;

[0608] - Pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005;

[0609] - ALK inhibitors, such as alectinib, ceritinib;

[0610] - Antiproliferative / antimitotic alkylating agents such as nitrogen mustard cyclophosphamide and analogs (melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas (carmustine) and analogs, streptozotocin, and triazenes (dacarbazine);

[0611] - Antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0612] - Platinum coordination complexes (cisplatin, oxaliplatin and carboplatin), procarbazine, hydroxyurea, mitotane and aminoglutethimide;

[0613] - Hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide and nilutamide) and aromatase inhibitors (letrozole and anastrozole);

[0614] - anticoagulants, such as heparin, synthetic heparin salts and other thrombin inhibitors;

[0615] - fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

[0616] - Anti-migration agents;

[0617] - Antisecretory agents (breveldin);

[0618] - Immunosuppressants such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil;

[0619] - Growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0620] - Fibroblast growth factor inhibitors, such as FPA14;

[0621] - anti-VEGFR antibodies, such as IMC-3C5, GNR-011, tanibirumab;

[0622] - anti-VEGF / DDL4 antibodies, such as ABT-165;

[0623] - anti-cadherin antibodies, such as HKT-288;

[0624] - anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat 15 (LRRC15) antibodies, such as ABBV-085.ARGX-110;

[0625] - Angiotensin receptor blockers, nitric oxide donors;

[0626] - antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0627] -DNA interfering oligonucleotides, such as PNT2258, AZD-9150;

[0628] - anti-ANG-2 antibodies, such as MEDI3617 and LY3127804;

[0629] - anti-ANG-1 / ANG-2 antibodies, such as AMG-780;

[0630] - anti-MET / EGFR antibodies, such as LY3164530;

[0631] - anti-EGFR antibodies such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomozutuximab, ABT-806, vectibix, modotuximab, RM-1929;

[0632] - anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0633] - anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428;

[0634] - anti-endoglin antibodies, such as TRC105 (carotuximab);

[0635] - anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0636] - Anti-HER3 antibodies, such as LJM716, GSK2849330;

[0637] - anti-HER2 antibodies, such as margetuximab, MEDI4276, BAT-8001;

[0638] - anti-HLA-DR antibodies, such as IMMU-114;

[0639] - anti-IL-3 antibodies, such as JNJ-56022473;

[0640] - anti-OX40 antibodies such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

[0641] - anti-EphA3 antibodies, such as KB-004;

[0642] - anti-CD20 antibodies, such as obinutuzumab, IGN-002;

[0643] - anti-CD20 / CD3 antibodies, such as RG7828;

[0644] - anti-CD37 antibodies, such as AGS67E, otlertuzumab (TRU-016);

[0645] - anti-ENPP3 antibodies, such as AGS-16C3F;

[0646] - anti-FGFR-3 antibodies, such as LY3076226, B-701;

[0647] - anti-FGFR-2 antibodies, such as GAL-F2;

[0648] - anti-C5 antibodies, such as ALXN-1210;

[0649] - anti-CD27 antibodies, such as varlilumab (CDX-1127);

[0650] - anti-TROP-2 antibodies, such as IMMU-132;

[0651] - anti-NKG2a antibodies, such as monalizumab;

[0652] -Anti-VISTA antibodies, such as HMBD-002;

[0653] - anti-PVRIG antibodies, such as COM-701;

[0654] - anti-EpCAM antibodies, such as VB4-845;

[0655] - anti-BCMA antibodies, such as GSK-2857916;

[0656] - anti-CEA antibodies, such as RG-7813;

[0657] - anti-cluster of differentiation 3 (CD3) antibodies, such as MGD015;

[0658] - anti-folate receptor alpha antibodies, such as IMGN853;

[0659] - MCL-1 inhibitors, such as AMG-176, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037;

[0660] -epha2 inhibitors, such as MM-310;

[0661] - anti-LAG-3 antibodies such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767;

[0662] -raf kinase / VEGFR inhibitors, such as RAF-265;

[0663] - EEG inhibitors, such as MAK683;

[0664] - anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0665] - anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0666] - anti-Fucoidan-GM1 antibodies, such as BMS-986012;

[0667] - p38 MAP kinase inhibitors, such as ralimetinib;

[0668] -PRMT1 inhibitors, such as MS203;

[0669] - Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0670] - FLT3-ITD inhibitors, such as BCI-332;

[0671] - erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408);

[0672] - Myosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579;

[0673] - Anti-ICOS antibodies, such as JTX-2011, GSK3359609;

[0674] - anti-DR5 (TRAIL2) antibodies, such as DS-8273;

[0675] - anti-GD2 antibodies, such as APN-301;

[0676] - anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0677] - anti-carbonic anhydrase IX antibodies, such as TX-250;

[0678] - anti-CD38 attenukine, such as TAK573;

[0679] - Anti-MUC1 antibodies, such as gatipotuzumab;

[0680] - Mucin 1 inhibitors, such as GO-203-2C;

[0681] - MARCKS protein inhibitors, such as BIO-11006;

[0682] -Folic acid antagonists, such as arfolitixorin;

[0683] -Galectin-3 inhibitors, such as GR-MD-02;

[0684] -Phosphopeptide 68 inhibitors, such as RX-5902;

[0685] -CD95 / TNF modulators, such as ofranergene obadenovec;

[0686] -PI3K / Akt / mTOR inhibitors, such as ABTL-0812;

[0687] - Pan-PIM kinase inhibitors such as INCB-053914;

[0688] - IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid;

[0689] - Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866;

[0690] - VEGF / HGF antagonists, such as MP-0250;

[0691] -SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659;

[0692] -SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0693] - FLT3 tyrosine kinase inhibitors, such as FF-10101;

[0694] - FLT3 tyrosine kinase agonists, such as CDX-301;

[0695] - FLT3 / MEK1 inhibitors, such as E-6201;

[0696] - IL-24 antagonists, such as AD-IL24;

[0697] - RIG-I agonists, such as RGT-100;

[0698] - Aeromonas lysin stimulators, such as topsalysin;

[0699] - P-glycoprotein 1 inhibitors, such as HM-30181A;

[0700] - CSF-1 antagonists, such as ARRY-382, BLZ-945;

[0701] - anti-mesothelin antibodies, such as SEL-403;

[0702] - thymidine kinase stimulators, such as aglatimagene besadenovec;

[0703] - Polo-like kinase 1 inhibitors, such as PCM-075;

[0704] - TLR-7 agonists, such as TMX-101 (imiquimod);

[0705] -NEDD8 inhibitors such as pevonedistat (MLN-4924), TAS-4464;

[0706] - Pleiotropic pathway modulators, such as avadomide (CC-122);

[0707] - FoxM1 inhibitors, such as Thiostephacin;

[0708] - anti-MUC1 antibodies, such as Mab-AR-20.5;

[0709] - anti-CD38 antibodies, such as isatuximab, MOR-202;

[0710] -UBA1 inhibitors, such as TAK-243;

[0711] - Src tyrosine kinase inhibitors, such as VAL-201;

[0712] - VDAC / HK inhibitors, such as VDA-1102;

[0713] -BRAF / PI3K inhibitors, such as ASN-003;

[0714] - Elf4a inhibitors, such as rohinitib, eFT226;

[0715] -TP53 gene stimulators, such as ad-p53;

[0716] -PD-L1 / EGFR inhibitors, such as GNS-1480;

[0717] - Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0718] - SIRT3 inhibitors, such as YC8-02;

[0719] - stromal cell-derived factor 1 ligand inhibitors, such as olaptesedpegol (NOX-A12);

[0720] - IL-4 receptor modulators, such as MDNA-55;

[0721] - arginase-I stimulators, such as pegzilarginase;

[0722] - topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

[0723] - Hypoxia-inducible factor-1α inhibitors, such as PT-2977, PT-2385;

[0724] -CD122 agonists, such as NKTR-214;

[0725] - p53 tumor suppressor protein stimulators, such as kevetrin;

[0726] - Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924;

[0727] - Kinesin spindle protein (KSP) inhibitors, such as filansib (ARRY-520);

[0728] -CD80-fc fusion protein inhibitors, such as FPT-155;

[0729] - multiple endocrine neoplasia protein and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

[0730] - Liver x receptor agonists, such as RGX-104;

[0731] - IL-10 agonists, such as AM-0010;

[0732] - EGFR / ErbB-2 inhibitors, such as varlitinib;

[0733] -VEGFR / PDGFR inhibitors, such as vorolanib;

[0734] - IRAK4 inhibitors, such as CA-4948;

[0735] - anti-TLR-2 antibodies, such as OPN-305;

[0736] - Calmodulin modulators, such as CBP-501;

[0737] - glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0738] - a second mitochondrial-derived SMAC protein inhibitor, such as BI-891065;

[0739] - lactoferrin modulators, such as LTX-315;

[0740] -Kit tyrosine kinase / PDGF receptor alpha antagonists, such as DCC-2618;

[0741] - KIT inhibitors, such as PLX-9486;

[0742] - exportin 1 inhibitors, such as eltanexor;

[0743] - EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib;

[0744] - anti-CD33 antibodies, such as IMGN-779;

[0745] - anti-KMA antibodies, such as MDX-1097;

[0746] - Anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453;

[0747] - anti-CD55 antibodies, such as PAT-SC1;

[0748] - anti-PSMA antibodies, such as ATL-101;

[0749] - anti-CD100 antibodies, such as VX-15;

[0750] - anti-EPHA3 antibodies, such as fibatuzumab;

[0751] - Anti-Erbb antibodies, such as CDX-3379, HLX-02, seribantumab;

[0752] - anti-APRIL antibodies, such as BION-1301;

[0753] - Anti-Tigit antibodies, such as BMS-986207, RG-6058;

[0754] - CHST15 gene inhibitors, such as STNM-01;

[0755] -RAS inhibitors, such as NEO-100;

[0756] - somatostatin receptor antagonists, such as OPS-201;

[0757] -CEBPA gene stimulators, such as MTL-501;

[0758] -DKK3 gene modulators, such as MTG-201;

[0759] - p70s6k inhibitors, such as MSC2363318A;

[0760] - Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202;

[0761] - Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0762] - Anti-programmed 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), pilizumab, 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);

[0763] -PD-L1 / VISTA antagonists, such as CA-170;

[0764] -Anti-PD-L1 / TGFβ antibodies, such as M7824;

[0765] - anti-transferrin antibodies, such as CX-2029;

[0766] - anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0767] - ATM (ataxia telangiectasia) inhibitors, such as AZD0156;

[0768] - CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2);

[0769] - CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-IO;

[0770] - EXH2 inhibitors, such as GSK2816126;

[0771] -HER2 inhibitors, such as neratinib, tucatinib (ONT-380);

[0772] - KDM1 inhibitors such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;

[0773] - CXCR2 antagonists, such as AZD-5069;

[0774] -GM-CSF antibodies, such as lenzilumab;

[0775] - DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01);

[0776] - protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin;

[0777] -Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, elacestrant (RAD-1901), and AZD9496;

[0778] - Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0779] - Selective androgen receptor modulators (SARMs), such as GTX-024, darolutamide;

[0780] - Transforming growth factor-β (TGF-β) kinase antagonists, such as galunisertib;

[0781] - Anti-transforming growth factor-β (TGF-β) antibodies, such as LY3022859, NIS793, XOMA 089;

[0782] - 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);

[0783] - Mutant-selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0784] - 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;

[0785] - anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumab tesirine;

[0786] - anti-clusterin antibodies, such as AB-16B5;

[0787] - anti-ephrin-A4 (EFNA4) antibodies, such as PF-06647263;

[0788] - anti-RANKL antibodies, such as denosumab;

[0789] - anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0790] - anti-sodium phosphate co-transporter 2B (NaP2B) antibodies, such as lifastuzumab;

[0791] - anti-c-Met antibodies, such as ABBV-399;

[0792] - adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509;

[0793] -α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0794] - XPO1 inhibitors, such as selinexor (KPT-330);

[0795] - isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221);

[0796] - IDH1 inhibitors such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;

[0797] - interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0798] - arginine deiminase stimulators, such as polyethylene glycol arginine deiminase (ADI-PEG-20);

[0799] - 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, baunatuzumab vedotin, ABBV-085;

[0800] - claudin-18 inhibitors, such as claudiximab;

[0801] -β-catenin inhibitors, such as CWP-291;

[0802] -Anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179;

[0803] -CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425;

[0804] -CD39 / CD73 antagonists, such as PBF-1662;

[0805] - Chemokine receptor 2 (CCR) inhibitors such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0806] - thymidylate synthase inhibitors, such as ONX-0801;

[0807] -ALK / ROS1 inhibitors, such as lorlatinib;

[0808] - Telomerase inhibitors, such as G007-LK;

[0809] - Mdm2 p53-binding protein inhibitors, such as CMG-097, HDM-201;

[0810] - c-PIM inhibitors, such as PIM447;

[0811] - BRAF inhibitors such as dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394;

[0812] - Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0813] - Cell cycle inhibitors, such as selumetinib (MEK1 / 2) and sapacitabine;

[0814] - AKT inhibitors such as MK-2206, ipatasertib, afuresertib, AZD5363 and ARQ-092, capivasertib, triciribine;

[0815] - anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors such as tremelimumab, AGEN-1884, BMS-986218;

[0816] -c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361;

[0817] -c-Met / VEGFR inhibitors, such as BMS-817378, TAS-115;

[0818] -c-Met / RON inhibitors, such as BMS-777607;

[0819] -BRAF / EGFR inhibitors, such as BGB-283;

[0820] - bcr / abl inhibitors, such as rebastinib, asciminib;

[0821] - MNK1 / MNK2 inhibitors, such as eFT-508;

[0822] - mTOR inhibitors / cytochrome P450 3A4 stimulators, such as TYME-88;

[0823] - Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0824] - Pan-RAF inhibitors such as LY3009120, LXH254, TAK-580;

[0825] - Raf / MEK inhibitors, such as RG7304;

[0826] -CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);

[0827] - kinase inhibitors, such as vandetanib;

[0828] - E-selectin antagonists, such as GMI-1271;

[0829] - Differentiation inducing agents, such as retinoic acid;

[0830] - epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291);

[0831] - topoisomerase inhibitors such as daunorubicin, daunorubicin, actinomycin D, eniposide, epirubicin, etoposide, idarubicin, 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);

[0832] -Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

[0833] - Growth factor signaling kinase inhibitors;

[0834] - Nucleoside analogs, such as DFP-10917;

[0835] - Axl inhibitors such as BGB-324 (bemcentinib), SLC-0211;

[0836] - 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;

[0837] - PARP inhibitors such as olaparib, rucaparib, veliparib, talazoparib, ABT-767, BGB-290;

[0838] -Proteasome inhibitors, such as ixazomib, carfilzomib Marizomib;

[0839] - glutaminase inhibitors, such as CB-839;

[0840] - 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, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVac tm 、STASELL-T、ATASELL-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, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara vaccines expressing p53, such as MVA-p53; DPX-Survivac; BriaVaxTM ;GI-6301;GI-6207;GI-4000;

[0841] - anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab;

[0842] - STAT-3 inhibitors, such as napabucasin (BBI-608);

[0843] - ATPase p97 inhibitors, such as CB-5083;

[0844] - Smoothened (SMO) receptor inhibitors such as (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

[0845] - 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), interferon alpha-2a follow-up biologicals (Biosidus) (Inmuta, Inter 2A), interferon alpha-2b follow-up biologicals (Biosidus-Baifeilong, Citopheron, Ganapar, Beijing Kawin Technology (Kaferon), alfafeldon, pegylated interferon alpha-1b, pegylated interferon alpha-2b follow-on biologic (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon);

[0846] - interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100);

[0847] - IL-6 receptor modulators, such as tocilizumab, siltuximab, AS-101 (CB-06-02, IVX-Q-101);

[0848] - Telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0849] - DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guadacitidine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001 and azacitidine;

[0850] -DNA gyrase inhibitors, such as pyrantelone and sobuzoxan;

[0851] - Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, and AT-101;

[0852] - Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024;

[0853] - anti-myostatin inhibitors, such as landogrozumab;

[0854] - hyaluronidase stimulators, such as PEGPH-20;

[0855] -Wnt pathway inhibitors such as SM-04755, PRI-724, WNT-974;

[0856] -γ-secretase inhibitors such as PF-03084014, MK-0752, RO-4929097;

[0857] - Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0858] -TRAIL pathway inducing compounds, such as ONC201, ABBV-621;

[0859] - Focal adhesion kinase inhibitors such as VS-4718, defactinib, GSK2256098;

[0860] - Hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glaciberib, and vismodegib;

[0861] - Aurora kinase inhibitors such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib, ENMD-2076;

[0862] - HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;

[0863] -ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;

[0864] - mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014), ME-344;

[0865] - mTOR / PI3K inhibitors, such as Gedalis, GSK2141795, Omipalisib, RG6114;

[0866] - Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;

[0867] - Murine dual microoncogene (mdm2) inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);

[0868] - CD137 agonists, such as urelumab, utomilumab (PF-05082566);

[0869] - STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

[0870] - FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0871] - fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0872] - Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

[0873] - Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;

[0874] -CD44 binders, such as A6;

[0875] - Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0876] -CYP17 inhibitors such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0877] -RXR agonists, such as IRX4204;

[0878] - Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib, patidegib;

[0879] - Complement C3 modulators, such as Imprime PGG;

[0880] - IL-15 agonists, such as ALT-803, NKTR-255 and hetIL-15;

[0881] - EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126;

[0882] - 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;

[0883] - DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676);

[0884] - toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and apoptotic protease activators;

[0885] -DNA plasmids, such as BC-819;

[0886] -PLK inhibitors of PLK 1, 2 and 3, such as volasertib (PLK1);

[0887] -WEE1 inhibitors, such as AZD1775 (adavosertib);

[0888] - Rho kinase (ROCK) inhibitors, such as AT13148, KD025;

[0889] -ERK inhibitors such as GDC-0994, LY3214996, MK-8353;

[0890] - IAP inhibitors such as ASTX660, debio-1143, bilinapant, APG-1387, LCL-161;

[0891] - RNA polymerase inhibitors such as lurbinectedin (PM-1183), CX-5461;

[0892] - tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), OXI-4503, fluorapacin (AC-0001) and plinabulin;

[0893] - Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091 and PEPA-10;

[0894] - elongation factor 1α2 inhibitors, such as plitidepsin;

[0895] -CD95 inhibitors, such as APG-101, APO-010, asunercept;

[0896] -WT1 inhibitors, such as DSP-7888;

[0897] - Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0898] - PDGFRα / KIT mutant-specific inhibitors, such as BLU-285;

[0899] - SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550; and

[0900] - Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716.

[0901] 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 having a hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound of the 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 (TKI) and any combination thereof or a pharmaceutically acceptable salt thereof. Non-limiting examples include:

[0902] -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);

[0903] - 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, sepretinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;

[0904] - 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;

[0905] - Cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, 7 and 9, such as abemaciclib, alvocidib (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;

[0906] -Discoid domain receptor (DDR) inhibitors: DDR inhibitors include inhibitors of DDR1 and / or DDR2. Examples of DDR inhibitors include, but are not limited to, inhibitors 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);

[0907] - 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), reminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;

[0908] - 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, Indomed, 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;

[0909] - 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;

[0910] - 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, antibodies described in WO 2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences) and WO 2011 / 097513 (Gilead Biologics);

[0911] - 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 inhibitors described in WO 2012 / 027721 (Gilead Biologics);

[0912] -Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib;

[0913] -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, Bupavicoxib (BKM120), BYL719 (Apovicoxib), CH5132799, Cobancoxib (BAY 80-6946), Duvicoxib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Edesibu 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);

[0914] - 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 US2015 / 0175616;

[0915] - 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, resimod, VTX-1463, and VTX-763;

[0916] - Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, lefitolimod, MGN-1601, and PUL-042; and

[0917] -Tyrosine kinase inhibitors (TKIs): TKIs target the receptors for epidermal growth factor receptor (EGFR) and 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, lestaurine, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, tivoanib and TH-4000, MEDI-575 (anti-PDGFR antibody).

[0918] 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; polyacetylene, especially bullatacin and bullatacinone; camptothecin, including synthetic analogs of topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogs of adozelesin, carzelesin and bizelesin; cryptophycin, especially cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including synthetic analogs KW-2189 and CBI-TMI; 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, chlorambucil ... 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); ), dynemicin including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromophore enediyne antibiotic chromophores, aclacinomycin, actinomycin, authramycin, azoserine, bleomycin, actinomycin C, carabicin, carrninomycin, car zinophilin), chromomycin, actinomycin D, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, cranberries (including N-morpholino-cranberries, cyano-N-morpholino-cranberries, 2-pyrrolino-cranberries and deoxycranberries), 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, thiopurine, 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 antistags such as fentanyl, mitotane, and trilostane; folic acid supplements such as folinic acid;Radiotherapeutic agents, such as radium-223; trichothecenes, especially 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 glycoside; 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; podophyllotoxin; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid acid; trabectedin, triaziquone; 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 (vancristine); vinorelbine Novantrone; teniposide; edatrexate; daunorubicin; aminopterin; xeoloda; ibandronate; CPT-11; 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 above.

[0919] The definition of "chemotherapeutic agent" also includes anti-hormonal 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 above.

[0920] Antihormonal agents

[0921] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX TM ), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene

[0922] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, fenpropimorph, megestrol acetate exemestane, formestane, fadrozole, vorozole Letrozole Anastrozole

[0923] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0924] Examples of progesterone receptor antagonists include onapristone.

[0925] Anti-angiogenic agents

[0926] Anti-angiogenic agents include, but are not limited to, retinoids and their derivatives, 2-methoxyestradiol, regorafenib, necuparanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (paclitaxel bound to albumin), 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′-bipyridyl, β-aminopropionitrile fumarate, 4-propyl-5 -(4-pyridyl)-2(3H)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecanoate, eponemycin, fumacillin, 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, angiogenic inhibitory 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.

[0927] Antifibrotic agents

[0928] Anti-fibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US 4965288 for lysine oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition and US 4997854 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 related 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 related to 2-(1-naphthyloxymethyl)-3-fluoroallylamine; and US 2004-0248871, which are incorporated herein by reference.

[0929] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of the lysine acyl oxidase, and more particularly primary amines that generate a resonance-stabilized product after binding to the carbonyl group, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine and its derivatives; amine ureas and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0930] Other antifibrotic agents are copper chelators that are permeable or non-permeable to cells. Exemplary compounds include indirect inhibitors that block the oxidation of aldehyde derivatives derived from lysine residues and hydroxylysine residues by lysine oxidase to deaminase. Examples include thiolamines (especially D-penicillamine) and analogs thereof, 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.

[0931] Immunotherapeutic agents

[0932] Immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating an individual. Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, baviximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, selenostatin ... umomab), berentuzumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuxim 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, iparibuzumab, MDX-010, BMS-734016 and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lovatumumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, lecitumumab, 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 chemotherapeutic agents is particularly effective.

[0933] Exemplary therapeutic antibodies may be further labeled with or combined with radioactive isotope particles, such as indium-111, yttrium-90 (90Y-xivatumumab), or iodine-131.

[0934] Cancer gene therapy and cell therapy

[0935] 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 responsiveness to cancer.

[0936] Gene editing agents

[0937] Examples of genome editing systems include the CRISPR / Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

[0938] CAR-T cell therapy and TCR-T cell therapy

[0939] 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 may be autologous or allogeneic.

[0940] In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

[0941] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0942] 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.

[0943] In some embodiments, the co-stimulatory 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.

[0944] 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.

[0945] In some embodiments, the antigen binding domain binds a tumor antigen.

[0946] 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 (EGFRvlll); 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 protein 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 (pro, megalin) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100) ; Oncogene fusion protein composed of 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 portion (GloboH); mammary differentiation antigen (NY-BR-1); urine protein 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (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 / testis antigen 1 (NY-ESO-1); cancer / testis 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 testicular antigen-1 (MADCT-1); melanoma cancer testicular antigen-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 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);pre-acrosome binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); kinase anchor 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); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); phosphoinositide protein glycan-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). ;

[0947] 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-Rl (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, tEGFR, tenascin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0948] 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, Aimi Liang Se-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.

[0949] 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-79 6; B7 homolog 6, such as CAR-NKp30 and CAR-B7H6; B lymphocyte antigen CD19, such as TBI-1501, CTL-119huCART-19T cells, JCAR-015US7446190, 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-018WO2016090190; 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; tight junction protein 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, PGN-201; Epstein-Barr virus-specific T lymphocytes, such as TT-10; Erbb2, such as CST-102, CIDeCAR; ganglioside (GD2), such as 4SCAR-GD2; glutamate carboxypeptidase II, such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101; phosphatidylinositol protein glycan-3 (GPC3), such as TT-16, 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-A10TCR; 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. .

[0950] Combination therapy for lymphoma or leukemia

[0951] In some embodiments, the additional therapeutic agent is suitable for treating lymphoma or leukemia. Such agents include aldeselum, 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, cranberry, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), ifosfamide, irinotecan hydrochloride, interferon α-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 cranberry 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 tartrate, SAHA (suberoylanilide hydroxamic acid, or suberoyl, anilide and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[0952] One 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 therapy include, but are not limited to, iodine-131, tositumomab Yttrium-90 ibritumomab tiuxetan as well as and CHOP.

[0953] The above mentioned therapies may be supplemented with stem cell transplantation or treatment or combined with them. 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 under stem cell support, peripheral blood stem cell transplantation treated ex vivo, 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.

[0954] Combination therapy for non-Hodgkin's lymphoma

[0955] In some embodiments, additional therapeutic agents are useful for treating 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 the like), radioimmunotherapy and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0956] 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.

[0957] Examples of experimental antibody agents for treatment of NHL / B cell cancer include ofavumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizumab, apolizumab, milatuzumab, and bevacizumab.

[0958] Examples of standard regimens for chemotherapy for NHL / B cell cancer include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0959] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab Iodine-131 tositumomab

[0960] Combination therapy for mantle cell lymphoma

[0961] 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.

[0962] Other examples of therapeutic agents suitable for treating MCL include:

[0963] - 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;

[0964] - 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;

[0965] - Autologous stem cell transplantation coupled with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib ( or PS-341), or administration of an anti-angiogenic agent, such as thalidomide, particularly in combination with rituximab;

[0966] - Drugs that cause the breakdown of Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents;

[0967] - 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;

[0968] - Other agents, such as flavopiridol, palbociclib (PD0332991), R-rosvetin (Selixib, 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).

[0969] Combination therapy for Waldenstrom's macroglobulinemia

[0970] In some embodiments, additional therapeutic agents are useful for treating Waldenstrom's macroglobulinemia (WM), including aldeselumab, alemtuzumab, acidipine, amifostine trihydrate, aminocamptothecin, anti-sinoplastin A10, anti-sinoplastin AS2-1, anti-thymocyte 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, cranberry hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, 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, pefilgrastim, pegylated liposomal cranberry hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate Simvastatin, sirolimus, tacrolimus, tansimab, 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.

[0971] Other examples of therapeutic procedures used to treat 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 ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0972] Combination therapy for diffuse large B-cell lymphoma

[0973] In some embodiments, additional therapeutic agents are useful for treating diffuse large B-cell lymphoma (DLBCL) and include cyclophosphamide, cytoxan, 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. Combination therapy for chronic lymphocytic leukemia

[0974] In some embodiments, additional therapeutic agents are useful for treating chronic lymphocytic leukemia (CLL) and include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, cranberry, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, as well as combination chemotherapy and chemoimmunotherapy, including the following commonly used combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0975] Combination therapy for myelofibrosis

[0976] In some embodiments, the additional therapeutic agent is suitable for treating myelofibrosis, including hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saredgid and vismodegid.

[0977] Examples of HDAC inhibitors include, but are not limited to, pranosalt and pambinostat.

[0978] Non-limiting examples of tyrosine kinase inhibitors are lestaurinib, bosutinib, imatinib, gilteritinib, radotinib and cabozantinib.

[0979] Combination therapy for hyperproliferative diseases

[0980] In some embodiments, additional therapeutic agents are useful for treating a hyperproliferative disease and include gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel with a JAK inhibitor and / or a PI3Kδ inhibitor.

[0981] Combination therapy for bladder cancer

[0982] In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer and includes atezolizumab, carboplatin, cisplatin, docetaxel, cranberry, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, albumin-bound paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[0983] Breast cancer combination therapy

[0984] 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 paclitaxel, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof.

[0985] Combination therapy for triple-negative breast cancer

[0986] In some embodiments, additional therapeutic agents are useful for treating triple-negative breast cancer and include cyclophosphamide, docetaxel, levofloxacin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[0987] Combination therapy for colorectal cancer

[0988] 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.

[0989] Combination therapy for castration-resistant prostate cancer

[0990] In some embodiments, the additional therapeutic agent is useful for treating castration-resistant prostate cancer and includes abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, cilaxet-T, and any combination thereof.

[0991] Combination therapy for esophageal and esophagogastric junction cancer

[0992] In some embodiments, the 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.

[0993] Combination therapy for gastric cancer

[0994] In some embodiments, the additional therapeutic agent is useful for treating gastric cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0995] Combination therapy for head and neck cancer

[0996] 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.

[0997] Combination therapy for hepatobiliary cancer

[0998] In some embodiments, the additional therapeutic agent is useful for treating hepatobiliary cancer and includes capecitabine, cisplatin, fluoropyrimidines, 5-fluorouracil, gemecitabine, oxaliplatin, sorafenib, and any combination thereof.

[0999] Combination therapy for hepatocellular carcinoma

[1000] In some embodiments, the additional therapeutic agent is useful for treating hepatocellular carcinoma and includes capecitabine, levofloxacin, gemcitabine, sorafenib, and any combination thereof.

[1001] Combination therapy for non-small cell lung cancer

[1002] In some embodiments, the additional therapeutic agent is useful 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.

[1003] Combination therapy for small cell lung cancer

[1004] In some embodiments, the additional therapeutic agent is useful for treating small cell lung cancer (SCLC) and includes bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, cranberry, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

[1005] Combination therapy for melanoma

[1006] In some embodiments, the additional therapeutic agent is useful for treating melanoma and includes nab-paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon alpha-2b, ipelizumab, nitrosoureas, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof.

[1007] Combination therapy for ovarian cancer

[1008] In some embodiments, the additional therapeutic agent is useful for treating ovarian cancer and includes 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, cranberry, etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal cranberry, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[1009] Combination therapy for pancreatic cancer

[1010] 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.

[1011] Combination therapy for renal cell carcinoma

[1012] In some embodiments, the additional therapeutic agent is useful for treating renal cell carcinoma and includes axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

[1013] VIII. Set

[1014] 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, for treating viral infections. The instructions for use are generally written instructions, but electronic storage media (e.g., magnetic disks or optical disks) containing the instructions are also acceptable.

[1015] The present invention also provides a pharmaceutical kit, which includes one or more containers containing a compound of the present invention or a pharmaceutically acceptable salt thereof. Associated with such a container may be precautions in the form prescribed by a governmental agency that manages the manufacture, use or sale of pharmaceutical products, which reflect the approval of the manufacturing, use or sales agency for human administration. Various components (if there is more than one component) may be packaged in separate containers, or some components may be combined in one container if cross-reactivity and storage period permit. The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging) or sub-unit dosage. The kit may also include multiple unit doses of compounds and instructions for use, and is packaged in an amount sufficient for storage and use by pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[1016] Also provided are articles of manufacture comprising a unit dose of a compound of the invention or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packages, and the like. The articles of manufacture may further be sterilized and / or sealed.

[1017] IX. Examples

[1018] The embodiments also relate to methods and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

[1019] Numerous general references are available that provide commonly known chemical synthesis schemes and conditions suitable for synthesizing the disclosed compounds (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013).

[1020] 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.

[1021] 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 was obtained on a Waters LC-MS instrument (Waters 600 controller, Waters 3100 mass detector, Waters photodiode array detector) on a Luna C18 column (Phenomenex, 5 μm, 150×4.6 mm) and a Zic-Hilic column (SeQuant, 5 μm, 100×4.6 mm).

[1022] During any process for the preparation of 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 works 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.

[1023] Exemplary chemical entities suitable for the methods of the embodiments will now be described with reference to illustrative synthetic schemes regarding their general preparation and subsequent specific examples herein. It should be appreciated by those skilled in the art that, in order 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 in the presence or absence of protective measures as required. Alternatively, it may be necessary or desirable to utilize a suitable group that can be carried through the reaction process and replaced by the desired substituent when appropriate in the position of the final desired substituent. In addition, it should be appreciated by those skilled in the art that the transformations shown in the following process can be performed in any order compatible with the functionality of the particular side group. Each reaction depicted in the general process is preferably operated at a temperature of about 0°C to the reflux temperature of the organic solvent used.

[1024] 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.

[1025] 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.

[1026] 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, although the compound may be substantially enantiomerically or diastereomerically pure.

[1027] Representative syntheses of compounds of the invention are described in the following schemes and in the specific examples that follow.

[1028] 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).

[1029] Abbreviations used in the examples presented below include the following:

[1030]

[1031]

[1032] Example 1. Preparation of nucleotide monomers

[1033] Process 1

[1034]

[1035] 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 on 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 CHCl 3 solution (100 mL) and thereafter with 10% EtOH in CHCl 3 The intermediate 2 was washed with 50% MeOH in H 2 O solution (500 mL) was washed off the column, 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 O 6 N 5 FNaP(M+Na) + The calculated value is 474.09492, the experimental value is 474.09485; 1 H NMR (MeOD-d 4 )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-d 4 )δ18.79; 19 F NMR (MeOD-d 4 )δ-203.85.

[1036] 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. Phosphonic acid tosyl ester (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 (gradient elution with 0-10% ethanol / chloroform): HRMS (ESI) C 45 H 49 O 9 N 5 FNaP(M+Na) + The calculated value is 876.31441, the experimental value is 876.31425; 1 H NMR (DMSO-d 6 )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-d 6 )δ18.96; 19F NMR (DMSO-d 6 )δ-199.06.

[1037] 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.

[1038] 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 above 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 2M TEAB (20 mL), and evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with 0.2M TEAB (3×100 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 directly purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate / ethanol / acetone / water 4:1:1:1 in ethyl acetate (SiO 2 Purification by TEA buffer) and lyophilization from dioxane gave intermediate 4: HRMS (ESI) C 46 H 43 O 10 N 6 FP(MH) - The calculated value is 889.27678, the experimental value is 889.27583; 1 H NMR (DMSO-d 6)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-d 6 )δ12.48; 19 F NMR (DMSO-d 6 )δ-199.61.

[1039] Preparation of Monomer 5: Phosphonate 4 (1.3 g, 1.5 mmol) was loaded onto a silica gel column in DCM (10 mL). The column was washed with DCA (10 mL, 3% DCM solution) and allowed to stand at rt for 15 min. The column was then washed with DCA (25 mL, 3% DCM solution) / 10% EtOH in CHCl 3 solution (25 mL) and thereafter with 10% EtOH in CHCl 3 The crude product was washed with 50% MeOH in H 2 O solution (100 mL) was washed off the column, evaporated and purified by preparative HPLC (gradient elution with 0-50% methanol in water). The residue was freeze-dried from water to give intermediate 5: HRMS (ESI) C 25 H 25 O 8 N 6 FP(MH) - The calculated value is 587.14610, the experimental value is 587.14561; 1H NMR (DMSO-d 6 )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-d 6 )δ13.65; 19 F NMR (DMSO-d 6 )δ-198.08.

[1040] Example 2. Preparation of phosphorothioate cyclic dinucleotides

[1041] Process 3

[1042]

[1043] DMOCP (0.48 g; 2.5 mmol) was added to a solution of phosphonate monomer 4 (0.55 g; 0.62 mmol) and nucleoside 8 (0.5 g; 0.74 mmol) in pyridine (20 mL). The reaction mixture was stirred at rt for 3 h, quenched by 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 42 H 39 F 2 N 11 O 11 P(MH) - The calculated value is 942.3, and the experimental value is 942.3.

[1044] Linear dimer 9 was co-evaporated with DCM-dioxane 1:1 (3×10 mL), dissolved in DCM (25 mL), and TEA (0.13 mL; 0.9 mmol) was added. HFIPP was added portionwise to the mixture every 15 min (5×30 μL; 0.09 mmol (0.15 mL; 0.46 mmol; total amount)). After 1.5 h at rt, 0.1 M aqueous TEAB (5 mL) was added, and the mixture was rigorously stirred for 30 min at rt. The mixture was evaporated, and the linear H-phosphonate dimer 10 was used without further purification: ESI-MS ((intermediate 10) C 42 H 40 F 2 N 11 O 13 P 2 (MH) - The calculated value is 1006.2, and the experimental value is 1006.2.

[1045] DMOCP (0.2 g; 1.1 mmol) was added to a solution of linear H-phosphonate dimer 10 (0.21 g; 0.21 mmol) in pyridine (40 mL), and the reaction mixture was stirred at rt for 3 hours. Thereafter, sulfur (67 mg; 2.1 mmol) was added. After stirring at rt for 1 hour, water (20 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 5 hours and evaporated. The mixture of two diastereoisomers was separated into HPLC faster eluting isomer compound 11a and slower eluting isomer compound 11b in an approximately 1:2 ratio using preparative C18 HPLC. The 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 / H 2 O, mobile phase B: 50% ACN / 0.1M TEAB / H 2 O. HPLC method: isocratic elution of A (10 min), followed by linear gradient A-40% B (60 min). Retention time (min): 39.1 (compound 11a) and 43.5 (compound 11b). Diastereomers were prepared using DOWEX Na + Conversion to the sodium salt and freeze-drying from water gave Compound 11a and Compound 11b.

[1046] Compound 11a: ESI-MS C 21 H 23 F2 N 10 O 9 P 2 S(MH) - The calculated value is 691.1, the experimental value is 691.1; 1 H NMR (D 2 O)δ8.51(s,1H),8.28(s,1H),8.19(s,1H),8.17(s,1H),6.40(d,J=15.0Hz,1H),6.34(d, J=15.7Hz,1H),5.61(dd,J=51.3,3.6Hz,1H),5.54(dd,J=51.6,3.6Hz,1H),4.92(dtd,J=2 5.2,9.3,3.6Hz,1H),4.57-4.55(m,4H),4.51(m,1H),4.33(dt,J=12.3,1.7Hz,1H),4.25( ddd,J=11.8,2.8,1.5Hz,1H),4.09(dd,J=15.2,5.7Hz,1H),3.87(dd,J=15.2,7.0Hz,1H); 31 P NMR (D 2 O)δ53.97,20.33; 19 F NMR (D 2 O)δ-198.48,-199.00.

[1047] Compound 11b: ESI-MS C 21 H 23 F 2 N 10 O 9 P 2 S(MH) - The calculated value is 691.1, the experimental value is 691.1; 1 H NMR (D 2O)δ8.32(s,1H),8.30(s,1H),8.07(s,1H),7.99(s,1H),6.34(d,J=15.1Hz,1H),6.31(d,J=15.8Hz, 1H),5.56(dd,J=51.5,3.6Hz,1H),5.52(dd,J=51.5,3.9Hz,1H),4.97(dddd,J=24.1,9.2,8.3,3.9H z,1H),4.60(m,1H),4.58(m,1H),4.56(m,1H),4.55(m,1H),4.53(m,1H),4.35(dt,J=12.4,1.7Hz,1 H),4.19(ddd,J=12.1,4.0,1.5Hz,1H),4.13(dd,J=14.9,4.6Hz,1H),3.81(dd,J=14.9,9.3Hz,1H); 31 P NMR (D 2 O)δ54.61,19.74; 19 F NMR (D 2 O)δ-198.46,-199.48.

[1048] Process 4

[1049]

[1050] ETT (0.26 g; 2.0 mmol) was added to a solution of intermediate 2 (0.17 g; 0.36 mmol) and phosphoramidite 12 (0.35 g; 0.4 mmol; Metkinen Chemistry, Kuopio, Finland, Cat. No. 203-51) in DCM (10 mL) (Scheme 4). The reaction mixture was stirred at room temperature under argon for 2 hours. Thereafter, DDTT (81 mg; 0.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. Methanol (5 mL) was then added and the resulting solution was evaporated. The residue was dissolved in 80% acetic acid in water (10 mL) and stirred at room temperature for 2 hours. The solution was directly loaded on a C18 column and intermediate 13 was separated using a linear gradient of acetonitrile in water: ESI-MS C 38 H 36 F 2 N 11 O 11 P 2 S(MH) + The calculated value is 954.2, and the experimental value is 954.2.

[1051] DMOCP (0.19 g; 1.0 mmol) was added to a solution of intermediate 13 (0.2 g; 0.2 mmol) in pyridine (50 mL), and the reaction mixture was stirred at room temperature for 3.0 hours. Thereafter, sulfur (59 mg; 1.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, water (1 mL) was added and the mixture was concentrated. The residue was co-evaporated with methanol (2x10 mL) and acetonitrile (2x10 mL), then treated with 10% DEA in ACN solution for 2 h at room temperature and evaporated. The residue was dissolved in an aqueous solution (10 mL) of 50% ACN and an ethanol solution (5 mL) of 33% methylamine was added. The mixture was stirred for 3 hours and evaporated. The mixture was separated into three peaks using preparative C18 HPLC: compounds 14a-14c. The 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 / H 2 O, mobile phase B: 50% ACN / 0.1M TEAB / H 2 O. HPLC method: isocratic elution of A (10 min), followed by a linear gradient of A-40% B (60 min), followed by isocratic 40% B (10 min). The peaks were separated using DOWEX Na + Converted to sodium salt and freeze-dried from water. 1 H. 19 F and 31 P NMR data at 25 °C in D 2 Collected in O.

[1052] Compound 14a: retention time (min): 42.0; ESI-MS C 21 H 23 F 2 N 10 O 8 P 2 S 2 (MH) - The calculated value is 707.1, the experimental value is 707.1; 1H NMRδ8.47(s,1H),8.37(s,1H),8.19(s,1H),8.14(s,1H),6.34(d,J=14.1Hz,1H),6.30 (d,J=15.1Hz,1H),5.56(dd,J=51.2,3.4Hz,1H),5.50(dd,J=51.5,3.1Hz,1H),4.80(m ,1H),4.76(m,1H),4.59(m,2H),4.55(m,1H),4.51(m,1H),4.28(dt,J=12.0,1.4Hz,1H ),4.27(ddd,J=11.7,2.4,1.2Hz,1H),4.22(d,J=15.4Hz,1H),4.00(d,J=15.4Hz,1H); 19 F NMRδ-198.96,-199.12; 31 P NMR δ 74.58, 53.41.

[1053] Compound 14b: retention time (min): 45.2; ESI-MS C 21 H 23 F 2 N 10 O 8 P 2 S 2 (MH) - The calculated value is 707.1, the experimental value is 707.1; 1 H NMRδ8.38(s,1H),8.28(s,1H),8.10(s,1H),8.05(s,1H),6.28(d,J=14.3Hz,1H),6.27(d,J=15.4Hz,1 H),5.54(dd,J=51.3,3.7Hz,1H),5.44(dd,J=51.3,3.6Hz,1H),4.85(dddd,J=25.6,9.5,8.5,3.6Hz,1 H),4.73(ddd,J=12.1,7.8,1.8Hz,1H),4.60-4.59(m,2H),4.54(m,1H),4.51(m,1H),4.26(d,J=15.2H z,1H),4.25(dt,J=12.1,1.4Hz,1H),4.23(ddd,J=11.8,3.2,1.0Hz,1H),3.95(dd,J=15.2,2.7Hz,1H); 19 F NMRδ-198.90,-199.16; 31 P NMR δ 73.97, 54.44.

[1054] Compound 14c: retention time (min): 59.1; ESI-MS C 21 H 23 F 2 N 10 O 8 P 2 S 2 (MH) - The calculated value is 707.1, the experimental value is 707.1; 1 H NMRδ8.38(s,1H),8.35(s,1H),8.13(s,1H),8.05(s,1H),6.35(d,J=14.7Hz,1H),6. 32(d,J=15.5Hz,1H),5.50(dd,J=51.8,3.7Hz,1H),5.41(dd,J=51.2,3.6Hz,1H),4.9 1(dtd,J=25.0,9.0,3.6Hz,1H),4.59(m,1H),4.56(m,1H),4.55(m,1H),4.53(m,3H) ,4.30(dd,J=11.4,3.5Hz,1H),4.07(d,J=14.6Hz,1H),3.96(dd,J=14.6,8.1Hz,1H); 19 F NMRδ-198.58,-198.99; 31 P NMR δ 75.74, 53.98.

[1055] Example 3. Preparation of methylphosphonic acid cyclic dinucleotide

[1056] Process 5

[1057]

[1058] Phosphonate 4 (2.2 g; 2.5 mmol) was dissolved in methanol (20 mL) and heated at room temperature with 33% MeNH 2ethanol solution (10 mL) for 2 hours (Scheme 5). 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, then water (10 mL) was added, and heating was continued at 60°C 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 an aqueous solution of 80% acetic acid at room temperature for 2 hours, and the solution was directly loaded on a C18 column. Intermediate 15 was separated using a linear gradient of acetonitrile in water using DOWEX TM Na+ was converted to sodium salt and freeze-dried from dioxane-water: ESI-MS C 23 H 27 FN 6 O 8 P(MH) - The calculated value is 565.2, the experimental value is 565.2; 1 H NMR (DMSO-d 6 )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,2 H),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-d 6 )δ-200.01; 31P NMR (DMSO-d 6 )δ17.65.

[1059] Process 6

[1060]

[1061] TBDMS-Cl (0.7 g; 4.5 mmol) was added to a solution of intermediate 16 (2.0 g; 3.0 mmol; Carbosynth, catalog number NB08366) and imidazole (0.3 g; 4.5 mmol) in DMF (30 mL) (Scheme 6). 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 washed with 33% MeNH at room temperature. 2 ethanol solution (10 mL) 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. Thereafter, 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 MTEAB (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 17: ESI-MS C 36 H 37 FN 5 O 6 (M+H) + The calculated value is 654.3, the experimental value is 654.3; 1 HNMR (DMSO-d 6)δ10.77(s,1H),8.63(s,1H),8.59(s,1H),7.28(m,2H),7.20(m,2H),7.16(m,5H),6.79(m,2H),6.77(m,2H),6.39( dd,J=20.0,1.4Hz,1H),5.86(ddt,J=17.0,10.3,6.5Hz,1H),5.66(ddd,J=52.0,4.4,1.4Hz,1H),5.07(ddt,J=17.0 ,2.0,1.6Hz,1H),4.98(ddt,J=10.3,2.0,1.3Hz,1H),4.84(dddd,J=23.1,8.4,6.8,4.4Hz,1H),4.11(ddd,J=8.4,5 .2,2.5Hz,1H),3.70(s,6H),3.27(dd,J=10.8,2.5Hz,1H),3.21(dd,J=10.8,5.2Hz,1H),2.67(m,2H),2.35(m,2H).

[1062] To a stirred solution of intermediate 17 (0.7 g, 1.1 mmol) and N,N,N′,N′-tetraisopropylphosphonomethyl diamidoester (0.9 mL, 3.3 mmol) in DCM (10 mL) under argon was added 0.45 M tetrazole (7.2 mL, 3.3 mmol) in ACN. 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 18: 31 P NMR (C 6 D 6 ) δ154.59 (d, J = 6.9 Hz), 153.73 (d, J = 9.6 Hz).

[1063] Process 7

[1064]

[1065] ETT (0.66 g; 5.5 mmol) was added to a solution of phosphonate 15 (0.5 g; 0.88 mmol) and imidophosphonate 18 (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 then treated with methanol (5 mL) and evaporated. The residue was treated with 80% acetic acid in water (10 mL) at room temperature for 2 hours, and thereafter the solution was directly loaded on a C18 column and the linear dimer 19 was separated using a linear gradient of acetonitrile in water: ESI-MS C 39 H 46 F 2 N 11 O 14 P 2 (MH) - The calculated value is 992.3, and the experimental value is 992.3.

[1066] DMOCP (0.66 g; 3.5 mmol) was added to a solution of intermediate 19 (0.7 g; 0.7 mmol) in pyridine (70 mL), and the reaction mixture was stirred at room temperature for 2.5 hours. Afterwards, water (30 mL) was added and the mixture was stirred at 60° C. for 3 hours, evaporated, and co-evaporated with acetonitrile (3×50 mL). Compound 20 was isolated using preparative C18 HPLC. The preparative HPLC conditions for purification were as follows: Luna C18 (15 μm, 200×55 mm, Phenomenex); flow rate 30 mL / min; mobile phase A: H 2 O, mobile phase B: ACN. HPLC method: isocratic elution of A (10 minutes), followed by a linear gradient of A-50% B (60 minutes). The product was purified by DOWEX Na + Conversion to sodium salt and freeze drying from dioxane-water gave compound 20: ESI-MSC 31 H 35 F 2 N 10 O 12 P 2 (MH) - Calculated value: 839.2, experimental value: 839.3; residence time (min): 35.6. 1 H NMR (D 2O)δ8.64(s,1H),8.61(s,1H),8.59(s,1H),8.56(s,1H),6.56(dd,J=15.0,0 .6Hz,1H),6.53(dd,J=15.5,0.6Hz,1H),5.92(ddt,J=17.3,10.2,6.4Hz,1H) ,5.64(ddd,J=51.5,4.0,0.6Hz,2H),5.12(dq,J=17.3,1.5Hz,1H),5.03(dq ,J=10.2,1.5Hz,1H),4.95(dddd,J=22.3,8.8,6.9,4.1Hz,1H),4.60(dddd,J= 23.3,9.0,3.9Hz,1H),4.56(dq,J=8.8,2.0Hz,1H),4.52(ddd,J=12.0,4.2, 2.1Hz,1H),4.49(ddt,J=9.0,2.8,2.0Hz,1H),4.43(dt,J=11.8,2.1Hz,1H), 4.25(dt,J=12.0,1.8Hz,1H),4.17(ddd,J=11.8,3.4,1.7Hz,1H),4.07(dd,J =14.2,4.6Hz,1H),3.79(dd,J=14.2,10.8Hz,1H),2.69(m,2H),2.46(m,2H); 19 F NMR (D 2 O)δ-198.70,-199.53; 31 P NMR (D 2 O)δ18.92,-1.15.

[1067] Compound 20 (0.1 g, 0.12 mmol) was dissolved in 50% ACN in water (10 mL), and 33% methylamine in ethanol (5 mL) was added. The mixture was stirred for 2 hours and 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 10 mL / min; mobile phase A: 0.1 M TEAB / H 2 O, mobile phase B: 50% ACN / 0.1M TEAB / H 2O; isocratic elution of A (15 minutes), followed by a linear gradient of A-20% B (35 minutes). Retention time (min) = 44.0. The desired compound (2R,3R,3aR,7aR,9R,10R,10aR,15aR)-2,9-bis(6-amino-9H-purin-9-yl)-3,10-difluoro-5,13-dihydroxydecahydro-2H-difluoro[3,2-d:3′,2′-k][1,3,7,10]tetraoxa[2,8]diphosphocyclotridecane 5,13-dioxide (21) was prepared using DOWEX Na + Converted to sodium salt and freeze-dried from water: ESI-MS (MH) - C 21 H 23 F 2 N 10 O 10 P 2 Calculated value: 675.1; experimental value: 675.1. At 25°C in D 2 O to obtain 1H, 19F and 31P NMR data: 1H NMR δ8.36 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.38 (d, J = 15.3 Hz, 1H), 5.54 (dd, J = 51.4, 3.8 Hz, 1H), 5.44 (dd, J = 51.8, 3.7 Hz, 1H), 4.86 (m, 1H), 4.56 (m, 1H), 4.56 (ddd, J =9.0,2.2,1.6Hz,1H),4.53(m,1H),4.49(m,1H),4.47(dt,J=12.0,2.2Hz,1H),4.33(dt,J=11.8,1.6H z,1H),4.24(ddd,J=12.0,3.4,1.6Hz,1H),4.09(dd,J=14.9,5.4Hz,1H),3.84(dd,J=14.9,8.4Hz,1H); 19 F NMRδ-198.64,-199.19; 31 P NMRδ19.46,-2.05.

[1068] Example 4. Preparation of prodrugs

[1069] Method A: Cyclic dinucleotide (1 μmol, Et 3 NH + Or Na +Salts) were treated with the appropriate alkyl iodide (10 μmol diluted in 10 μL ACN) overnight. (Alkyl iodides were prepared according to literature methods: benzyl-type alkyl iodides were prepared according to Gollnest, T. et al. Nat. Commun. 2015, 6: 8716 and Alvarez-Manzaneda, EJ et al. Tetrahedron Lett. 2005, 46, 3755-3759; and POM-like alkyl iodides were prepared according to Ellis, EE et al. ChemBioChem. 2013, 14, 1134-1144 and Yang, Y. et al. Helv. Chim. Acta 2006, 89, 404-415. POC-like alkyl iodides were prepared according to US 2011 / 166128 and Yang, Y. et al. Helv. Chim. Acta 2006, 89, 404-415.) The reaction mixture was diluted with water (3 mL) and applied directly to an HPLC column and purified using HPLC method 1. The fractions containing the product were freeze-dried.

[1070] HPLC Method 1

[1071]

[1072]

[1073] Preparative HPLC purification was performed on a column packed with C18 reverse phase resin ( The chromatography was performed on a Waters Delta 600 chromatography system using a preparative RP18 column, 5 μm, 10×100 mm. In all methods, linear gradients were used.

[1074] Method B: Cyclic dinucleotide (1 μmol, Et 3 NH + Or Na + Salt) was treated with alkyl iodide (10 μmol diluted in 10 μL DMF) overnight. The reaction mixture was diluted with water (3 mL) and applied directly to an HPLC column and purified using HPLC Method 2. Fractions containing the product were freeze dried.

[1075] HPLC Method 2

[1076] Time (minutes) Flow rate (ml / min) <![CDATA[H 2 O(%)]]> <![CDATA[1:1H 2 O / ACN(%)]]> ACN (%) 0 3 80 20 - 10 3 80 20 - 30 3 - 100 - 50 3 - 50 50 60 3 - - 100

[1077] Preparative HPLC purification was performed on a column packed with C18 reverse phase resin ( The chromatography was performed on a Waters Delta 600 chromatography system using a preparative RP18 column, 5 μm, 10×100 mm. In all methods, linear gradients were used.

[1078] Method C: Heat H at room temperature 2 Cyclic dinucleotides (1 μmol, Et 3 NH + Or Na + Salt) was treated with appropriate alkyl iodide (10 μmol) overnight to form the corresponding prodrug. The reaction mixture was diluted with water (3 mL) and applied directly to an HPLC column and purified using HPLC Method 3 or HPLC Method 4. The fractions containing the product were freeze-dried.

[1079] HPLC Method 3

[1080]

[1081]

[1082] Preparative HPLC purification was performed on a column packed with C18 reverse phase resin ( The chromatography was performed on a Waters Delta 600 chromatography system (preparative RP18 column, 5 μm, 10×100 mm). In all methods, linear gradients were used.

[1083] HPLC Method 4

[1084] Time (minutes) Flow rate (ml / min) <![CDATA[H 2 O(%)]]> <![CDATA[1:1H 2 O / ACN(%)]]> ACN (%) 0 3 50 50 - 10 3 50 50 - 20 3 - 100 - 30 3 - - 100 60 3 - - 100

[1085] Preparative HPLC purification was performed on a column packed with C18 reverse phase resin ( The chromatography was performed on a Waters Delta 600 chromatography system using a preparative RP18 column, 5 μm, 10×100 mm. In all methods, linear gradients were used.

[1086] Method D: Cyclic dinucleotide (1 μmol, Et 3 NH +) was dissolved in methanol (200 μL) and passed through a column of DOWEX 50 tetrabutylammonium salt (1 mL). The resin was washed with methanol (3×1 mL) and the solution was evaporated. The residue was co-evaporated with dioxane (3×1 mL) and acetonitrile (3×1 mL). The ...

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 Independently -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, -(C1-C6 alkylene)-(C3-C 14 Cycloalkyl) or C3-C 20 Cycloalkyl; 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 Directly connected to O or S atoms, 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 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 OR 1 ;and X 3 For SR 1 .

9. The compound of claim 1, wherein X 1 For SR 1 ;and X 3 is OR 1 .

10. The compound of claim 1, wherein X 1 For SR 1 ;and X 3 For OH.

11. The compound of claim 1, wherein X 1 and X 3 Each is independently SR 1 .

12. The compound of claim 1, wherein Each R 2a Independently C1-C 20 Alkyl or -(C1-C6 alkylene)-(C3-C 14 cycloalkyl).

13. The compound according to any one of claims 1 to 12, 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 13, 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 15, wherein X 1 for And R 2a C3-C 20 alkyl.

17. The compound of claim 13, wherein X 3 for 18. 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.

19. The compound of claim 18, wherein X 3 for And R 2a C3-C 20 alkyl.

20. 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.

21. The compound of claim 14, wherein X 1 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 17, 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 them is SH.

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, hepatitis B virus infection, HIV infection, hyperproliferative disease or cancer in humans or animals that is responsive to modulation of the activity of the STING adaptor protein.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

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 a hyperproliferative disease or cancer responsive to modulation of the activity of a STING adaptor protein in a human or animal in need thereof.

37. The use of any one of claims 31 to 36, wherein the compound is administered together with another therapeutically active agent.

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