2'3'-cyclic dinucleotide

Abstract

The present disclosure relates to 2'3'-cyclic dinucleotides modified with 2'-phosphonoalkyl bonds or 3'-phosphonoalkyl bonds and their derivatives, which can regulate the activity of STING adaptor proteins. The present invention discloses compounds of formula (IA) or formula (IB) or pharmaceutically acceptable salts thereof, wherein L 1 is ‑O‑ or ‑K‑C(R 6 R 7 )‑;L 2 K-C(R 6 R 7 )‑.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 654,054, filed April 6, 2018, and U.S. Provisional Application No. 62 / 737,205, filed September 27, 2018, both of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. This ASCII copy was created on January 23, 2019, is named 052838_540001US_ST25.txt and is 6954 bytes in size. Technical Field

[0005] The present invention relates to novel 2'3'-cyclic dinucleotides, such as those modified with 2'-phosphonoalkyl substituents or 3'-phosphonoalkyl substituents and their derivatives. Such 2'3'-cyclic dinucleotides modulate the activity of the STING adaptor protein (stimulator of interferon genes). Therefore, the 2'3'-cyclic dinucleotides are believed to be useful in treating diseases in which modulation of the STING adaptor protein is beneficial, such as inflammation, allergic and autoimmune diseases, cancer, viral infections caused by viruses such as hepatitis B and human immunodeficiency virus, and in immunogenic compositions or vaccine adjuvants. Background Art

[0006] The innate immune system recognizes the presence of pathogens or the destruction of the host's homeostasis through a series of pattern recognition receptors (PRRs), which detect small ligand sets associated with pathogens or damage. These ligands are generally referred to as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (Takeuchi O et al., Cell, 2010: 140, 805-820). Over the past two decades, a variety of PRRs have been identified, including Toll-like receptors, retinoic acid-inducible gene (RIG-I)-like receptors, nucleotide-binding oligomerization domain-like (NOD) receptors, C-type lectin receptors, and cytoplasmic DNA sensors (Brubaker SW et al., Annu Rev Immunol, 2015: 33, 257-290). PRR recognition of PAMPs and DAMPs ultimately leads to the upregulation of cytokines and chemokines (including interferons), and immune cell recruitment to the site of infection. All these processes slow down pathogen replication and promote the generation of adaptive immunity.

[0007] Cellular DNA is normally confined to the nucleus and mitochondria of healthy cells. Therefore, DNA present in the cytosol represents a signal indicating the presence of pathogens or disruption of host homeostasis. Sensing of exogenous DNA is initiated by several DNA sensors, such as DNA-dependent activator of IRF (DAI) or DEAD box polypeptide 41 (DDX41). These DNA sensors signal by recruiting protein kinase TBK1, which triggers activation of transcription factors NF-κB (nuclear factor κB) and IRF-3 (interferon-regulated activator 3), via the STING adaptor protein (stimulator of interferon genes, also known as STING, STING protein, TMEM173, MITA or ERIS) (Unterholzner L, Immunology, 2013: 218, 1312-1321). Activation of the STING adaptor protein is believed to ultimately lead to the release of type I and type III interferons, as well as a variety of cytokines and chemokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ).

[0008] Alternatively, the STING adaptor protein can be activated by second messenger cyclic dinucleotides (CDNs) (Burdette et al., Nature 2011: 478, 515-518). CDNs with affinity for STING contain two purine nucleotide monophosphates linked to two 3′-5′ (3′3′-CDN), two 2′-5′ (2′2′-CDN), or 2′-5′ and 3′-5′ phosphodiester bonds (2′3′-CDN). The prototype 2′3′-cGAMP (c[G(2′,5′)pA(3′,5′)p]) is the product of activation of the host cGAS protein in the presence of pathogens or self-dsDNA (Zhang et al., Molecular Cell 2013: 51, 226-235).

[0009] Type I interferon (IFN) is an immunomodulatory cytokine that plays a key role in viral immunity. It can induce dendritic cells (DC) and macrophage maturation and activation (Galluci et al., Nat Med, 1999: 5, 1249-1255) and promote T cell and B cell survival, activation and differentiation. In addition, interferon can activate a large number of intracellular pathways that inhibit viral replication. The clinical effectiveness of type I interferon has been demonstrated by its effectiveness in treating chronic hepatitis B and C (Lin and Young, Cytokine Growth Factor Rev, 2014: 25, 369-376).

[0010] In addition, interferon shows effectiveness 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 activation in mice. Animals lacking IFN-α / β receptors in dendritic cells are unable to suppress immunogenic tumors and are defective in cross-presenting antigens 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 capable of inhibiting distant cancer metastasis and providing long-term survival immune memory (Corrales et al., Cell Rep, 2015: 11, 1018-1030).

[0011] It is believed that CDN can promote the activation 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).

[0012] 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.

[0013] The present invention aims to describe novel 2′3′ cyclic phosphonate dinucleotides and their derivatives that bind to and activate the STING adaptor protein, thereby stimulating signal transduction pathways to induce interferon and other cytokines / chemokines. It is believed that one advantage over previously disclosed CDNs arises from the replacement of the phosphate bond with a phosphonoalkyl bond, which is resistant to hydrolysis by phosphodiesterases present in tissues and body fluids. Such compounds may be useful as antiviral or anticancer agents, as vaccine adjuvants, or for the treatment of allergic or other inflammatory diseases. Summary of the Invention

[0014] Provided herein is a compound, namely a cyclic dinucleotide of formula (IA) or formula (IB),

[0015]

[0016]

[0017] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0018] in

[0019] L 1 -O- or -KC(R 6 R 7 )-;

[0020] L 2 -KC(R 6 R 7 )-;

[0021] Y 1 and Y 2 Each is independently -O-, -S- or -CH2-;

[0022] X 1 and X 3 Each independently represents OH, SH, OR 13 SR 13 or N(R 13 )2;

[0023] X 2 and X 4 Each independently is O or S;

[0024] R 1 、R 5 、R 8 and R 12 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13)2, CH2OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, OR 13 SR 13 or N(R 13 )2;

[0025] R 2 、R 3 、R 4 、R 9 、R 10 and R 11 Each independently represents H, OH, F, Cl, Br, I, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, OR 13 SR 13 or N(R 13 )2;

[0026] R 6 and R 7 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、CH2N3、OR 13 SR 13 、N(R 13 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0027] Each R 13 are independently H, -C(=Z)R 14 、-C(=Z)OR 14 、-C(=Z)SR 14 、-C(=Z)N(R 14 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C2-C10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0028] Each R 14 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0029] Each Z is independently O, S or NR 13 ;

[0030] K represents O, S, S(O), S(O)2, NH or NR 13 variables;

[0031] bases 1 and bases 2 Each independently is:

[0032]

[0033] in

[0034] A.A 1 、A 2 、A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH2, OR 13 SR 13 、NHR 13 、N(R 13 )2 or R 14 ;and

[0035] wherein C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Substituted aryl or C2-C 10 The substituted heteroaryl is substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, -SH, -NH2, =O, =NH, =S, ≡N, halogen, -N3, C1-6 Alkyl, C 1-6 Alkoxy, -CN and -COOR p , where R p is hydrogen or C1 to C6 alkyl.

[0036] In some embodiments, the pharmaceutical composition comprises a cyclic dinucleotide of Formula (IA) or (IB) or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0037] In some embodiments, a method of treating a disease or condition, e.g., a method of treating or preventing a viral infection, hepatitis B virus infection, HIV infection, a hyperproliferative disease, or cancer, comprises administering to an individual or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of Formula (IA) or (IB), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

[0038] In some embodiments, a method of enhancing vaccine efficacy comprises administering a therapeutically effective amount of a cyclic dinucleotide of Formula (IA) or (IB) or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

[0039] In some embodiments, a method of modulating the activity of a STING adaptor protein in inducing type I interferon, cytokine and / or chemokine production (dependent on the STING adaptor protein) in a human or animal comprises administering a therapeutically effective amount of a cyclic dinucleotide of Formula (IA) or (IB) or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing. DETAILED DESCRIPTION

[0040] Overview

[0041] Provided herein are novel 2'3'-cyclic dinucleotides comprising at least one phosphonoalkyl group that bind to the STING protein and modulate its activity, eg, activate the STING protein.

[0042] definition

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash preceding or at the end of a chemical group is used for convenience to indicate the point of attachment to the parent group; a chemical group may be depicted with or without one or more dashes without losing its general meaning. Prefixes such as "C u-v ” or “C u -Cv " indicates that the subsequent group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0044] "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, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)2), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)2), 2-methyl-2-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-methyl-3 ... )CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(C H3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0045] "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.

[0046] "Alkenyl" is a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), or 2 to 6 carbon atoms (ie, C 2-6 alkenyl), or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3.

[0047] "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 (ie, 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 .

[0048] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0049] As used herein, "haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halo substituent, which may be the same or different. For example, C 1-4 Haloalkyl is C 1-4 One or more hydrogen atoms of the alkyl group have been replaced by a halogen substituent. 1-4 Examples of haloalkyl include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0050] As used herein, "aryl" refers to a single all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one ring is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) having approximately 9 to 20 carbon atoms, in which at least one ring is aromatic and in which the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) pendant oxy groups on any carbocyclic portion of the polycondensed ring system. The rings of a polycondensed ring system may be connected to each other via fusion, spiro, and bridging bonds, where valence requirements permit. It should also be understood that when referring to a specific atomic range member aryl group (e.g., a 6- to 10-membered aryl group), that atomic range refers to the total ring atoms of the aryl group. For example, a 6-membered aryl group would include phenyl and a 10-membered aryl group would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0051] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, as further described below. Thus, "heteroaryl" includes a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaromatic ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple fused ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a heteroaryl group as defined above is fused with one or more rings selected from the group consisting of heteroaryl (forming, for example, 1,8-naphthyridinyl), heterocycle (forming, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (forming, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (forming, for example, indazolyl) to form a polycondensed ring system. Thus, a heteroaryl group (either a single aromatic ring or a polycondensed ring system) has from about 1 to 20 carbon atoms and from about 1 to 6 heteroatoms within the heteroaryl ring. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) pendant oxy groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of the polycondensed ring systems may be linked to each other via fusion, spirocyclic, and bridging bonds, as valence requirements permit. It should be understood that the individual rings of the polycondensed ring systems may be linked in any order relative to each other. It is understood that the point of attachment of a heteroaryl or heteroaryl polycondensed ring system can be at any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when reference is made to a specific atomic range member aryl (e.g., a 5- to 10-membered heteroaryl), that 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.

[0052] "Cycloalkyl" refers to a single saturated or partially unsaturated all-carbon ring (i.e., C 3-20The term "cycloalkyl" also includes polycondensed, 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 polycondensed ring systems may be connected to each other via fusion, spiro, and bridging bonds when valence requirements permit. Non-limiting examples of monocyclic cycloalkyl groups 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.

[0053] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3-membered, 4-membered, 5-membered, 6-membered, 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. The rings of multiple fused ring systems (e.g., bicyclic heterocyclyl) 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, 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-thiophene, [3.3]hept-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-2-yl, 2-azabicyclo[2.1.1]hexan-2-yl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptan-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-2-yl, 2-azabicyclo[2.1.1]hexan-2-yl, 4-azaspiro[2.4]heptan-6-yl, 5-azaspiro[2.4]heptan-2-yl, and the like.

[0054] As used herein, "oxo" refers to =0.

[0055] As used herein, "substituted" refers to substitution with one or more substituents (e.g., 1, 2, 3, or 4 or more substituents) selected from the group consisting of: -OH, -SH, -NH2, =O, =NH, =S, ≡N, halogen, -N3, C 1-6 Alkyl, C 1-6 Alkoxy, -CN and -COOR p , where R p is hydrogen or C1 to C6 alkyl.

[0056] "Compounds of the present invention" include compounds disclosed herein, for example, compounds of the present invention include compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and (IB-8), including the compounds of the following examples.

[0057] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For the purposes of the present invention, beneficial or desired results include, but are not limited to, relief of symptoms and / or reduction in the severity 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 severity of a disease or condition); b) slowing or curbing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as regression of clinical symptoms, improvement of the disease condition, delaying disease progression, improving quality of life, and / or prolonging survival.

[0058] 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 disease or condition does not develop in the individual.

[0059] As used herein, "prevention (prevent / prevention / preventing)" refers to a therapy that prevents the onset of a disease or disorder so that the clinical symptoms of the disease do not develop. Therefore, "prevention" involves administering treatment (e.g., administering a therapeutic substance) to an individual before signs of disease are detectable in the individual (e.g., administering a therapeutic substance to an individual in the absence of a detectable infectious agent (e.g., a virus) in the individual). An individual may be an individual at risk of developing a disease or disorder, such as an individual with one or more risk factors known to be associated with the development or onset of a disease or disorder. Therefore, 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 receiving anti-HBV prophylactic treatment may be an individual at risk of contracting 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.

[0060] As used herein, "modulation" or "modulating" the activity of a protein (e.g., a STING adaptor protein) refers to changing the activity such that the activity is increased or decreased. In some embodiments, modulation can increase the activity.

[0061] As used herein, the term "viral infection" describes a disease state in which a virus invades a healthy cell, multiplies or replicates using the cell's reproductive machinery, and ultimately lyses the cell, causing cell death, releasing virions, and infecting other cells through the newly produced progeny viruses. Latent infection caused by certain viruses is also a possible outcome of a viral infection.

[0062] As used herein, the term "enhancing" refers to any form of increase in the immunogenic activity of an effective dose of a vaccine resulting from the administration of a therapeutically effective dose of a compound of the present invention (e.g., a cyclic dinucleotide of Formula (Ia), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8)) to an animal or human, wherein the compound is administered at any time prior to, concurrently with, or just after administration of an effective dose of a vaccine to the same animal or human.

[0063] As used herein, "animal" refers to a mammal, eg, a livestock animal such as a pig, cow, horse, dog, cat, rat, or mouse, or a non-human primate such as a macaque or chimpanzee.

[0064] As used herein, "at-risk individual" refers to an individual who is at risk of developing a condition to be treated. An individual "at-risk" may or may not have a detectable disease or condition and may or may not have displayed detectable disease prior to treatment using the methods described herein. "At-risk" indicates that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. An individual who has one or more of these risk factors has a higher probability of developing the disease or condition than an individual who does not have these risk factors.

[0065] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound sufficient to achieve treatment of such disease when administered to a subject for the treatment of a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be in one or more doses, that is, a single dose or multiple doses may be required to achieve the desired therapeutic target. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if a desired or beneficial result can be achieved or has been achieved in combination with one or more other agents. The suitable dosage of any co-administered compound may be reduced as appropriate due to the combined action of the compounds (e.g., additive or synergistic effects).

[0066] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0067] 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 other therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more other 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 other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other 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 other therapeutic agents after a period of time (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound of the invention after a period of time (e.g., 1 to 12 hours). Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to administering a compound disclosed herein and one or more other therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the patient's body.

[0068] 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 preparing pharmaceutical compositions suitable for veterinary or human medical use.

[0069] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or as free bases where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of compounds that possess the pharmacological activity of the desired free base. Such salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates Salts include, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0070] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from appropriate bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl.) Also included are base addition salts such as sodium or potassium salts.

[0071] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase metabolic resistance and, therefore, may be useful for increasing the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, when administered to a mammal. See, for example, 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 employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0072] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Positron-emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) substitutions are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula (IA) or Formula (IB) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples set forth below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

[0073] 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 preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. Where compounds are presented in their chiral form, it is understood that the embodiments encompass, but are not limited to, that specific diastereoisomerism or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiments are directed to that specific diastereoisomerism or enantiomerically enriched form; or racemic or non-racemic mixtures of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers that is not in a 1:1 ratio.

[0074] 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 contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0075] 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 tautomers of any such compounds.

[0076] As used herein, "solvate" refers to the result 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.

[0077] As used herein, "hydrate" refers to a compound of the present invention chemically associated with one or more water molecules.

[0078] As used herein, "prodrug" refers to a derivative of a drug that is converted into the parent drug according to some chemical or enzymatic pathway when administered to the human body.

[0079] Compound

[0080] In some embodiments, the compound, i.e., a cyclic dinucleotide, has the structure of Formula (IA) or Formula (IB)

[0081]

[0082]

[0083] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0084] in

[0085] L 1 -O- or -KC(R 6 R 7 )-;

[0086] L 2 -KC(R 6 R 7 )-;

[0087] Y 1 and Y 2 Each is independently -O-, -S- or -CH2-;

[0088] X 1 and X 3 Each independently represents OH, SH, OR 13 SR 13 or N(R 13 )2;

[0089] X 2 and X 4 Each independently is O or S;

[0090] R 1 、R 5 、R 8 and R 12 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2, CH2OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, OR 13 SR 13 or N(R 13 )2;

[0091] R 2 、R 3 、R 4 、R 9 、R 10 and R11 Each independently represents H, OH, F, Cl, Br, I, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, OR 13 SR 13 or N(R 13 )2;

[0092] R 6 and R 7 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、CH2N3、OR 13 SR 13 、N(R 13 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0093] Each R 13 are independently H, -C(=Z)R 14 、-C(=Z)OR 14 、-C(=Z)SR 14 、-C(=Z)N(R 14 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0094] Each R 14 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C3-C7 cycloalkyl, C2-C10 Heterocycloalkyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C2-C 10 Heteroaryl or C2-C 10 substituted heteroaryl;

[0095] Each Z is independently O, S or NR 13 ;

[0096] K represents O, S, S(O), S(O)2, NH or NR 13 variables;

[0097] bases 1 and bases 2 Each independently is:

[0098]

[0099] in

[0100] A.A 1 、A 2 、A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH2, OR 13 SR 13 、NHR 13 、N(R 13 )2 or R 14 ;and

[0101] wherein C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Substituted aryl or C2-C 10 The substituted heteroaryl is substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, -SH, -NH2, =O, =NH, =S, ≡N, halogen, -N3, C 1-6 Alkyl, C 1-6 Alkoxy, -CN and -COOR p , where R p is hydrogen or C1 to C6 alkyl.

[0102] In some embodiments, the compound is of Formula (IA) or Formula (IB):

[0103]

[0104] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0105] in

[0106] L 1 -O- or -KC(R 6 R 7 )-;

[0107] L 2 -KC(R 6 R 7 )-;

[0108] Y 1 and Y 2 Each is independently -O-, -S- or -CH2-;

[0109] X 1 and X 3 Each independently represents OH, SH, OR 13 SR 13 or N(R 13 )2;

[0110] X 2 and X 4 Each independently is O or S;

[0111] R 1 、R 5 、R 8 and R 12 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2, CH2OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR 13 SR 13 or N(R 13 )2;

[0112] R 2 、R 3 、R 4 、R 9 、R 10 and R 11 Each independently represents H, OH, F, Cl, Br, I, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR 13 SR 13 or N(R 13 )2;

[0113] R 6 and R 7Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、CH2N3、OR 13 SR 13 、N(R 13 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 heteroaryl;

[0114] Each R 13 are independently H, -C(=Z)R 14 、-C(=Z)OR 14 、-C(=Z)SR 14 、-C(=Z)N(R 14 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl, or C2-C 10 heteroaryl;

[0115] Each R 14 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 heteroaryl;

[0116] Each Z is independently O, S or NR 13 ;

[0117] K represents O, S, S(O), S(O)2, NH or NR 13 variables;

[0118] bases 1 and bases 2 Each independently is:

[0119]

[0120] in

[0121] A.A 1 、A 2 、A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, NH2, OR 13 SR13 、NHR 13 、N(R 13 )2 or R 14 .

[0122] In some embodiments of compounds of Formula (IA) and / or (IB), C1-C6 substituted alkyl, C2-C6 substituted alkenyl, C2-C6 substituted alkynyl, C2-C 10 Substituted heterocycloalkyl, C6-C 10 Substituted aryl or C2-C 10 Substituted heteroaryl groups contain 1, 2 or 3 substitutions.

[0123] In some embodiments of compounds of Formula (IA) and / or (IB), Y 1 and Y 2 It is O.

[0124] In some embodiments of compounds of Formula (IA) and / or (IB), X 2 and X 4 is O, and X 1 and X 3 Each independently is OH or OR 13 In some embodiments, X 2 and X 4 is O, and X 1 and X 3 For OH.

[0125] In some embodiments of compounds of Formula (IA) and / or (IB), L 1 In some embodiments, L 1 -OC(R 6 R 7 )-. In some embodiments, L 1 It is -O-CH2-.

[0126] In some embodiments of compounds of Formula (IA) and / or (IB), L 2 -OC(R 6 R 7 )-. In some embodiments, L 2 It is -O-CH2-.

[0127] In some embodiments of compounds of Formula (IA) and / or (IB), L 1 -O- or -OC(R 6 R 7 )-, and L 2 -OC(R 6 R 7 )-. In some embodiments, L 1is -O- or -O-CH2-, and L 2 In some embodiments, L 1 is -O-, and L 2 In some embodiments, L 1 is -O-CH2-, and L 2 It is -O-CH2-.

[0128] In some embodiments of compounds of Formula (IA) and / or (IB), R 1 、R 5 、R 8 and R 12 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR 13 SR 13 or N(R 13 ) 2. In some embodiments, R 1 、R 5 、R 8 and R 12 Each independently represents H, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、C 1-3 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR 13 SR 13 or N(R 13 ) 2. In some embodiments, R 1 、R 5 、R 8 and R 12 Each is H.

[0129] In some embodiments of compounds of Formula (IA) and / or (IB), R 2 、R 3 、R 4 、R 9 、R 10 and R 11 Each independently represents H, OH, F, Cl, Br, I, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR 13 SR 13 or N(R 13) 2. In some embodiments, R 2 、R 3 、R 4 、R 9 、R 10 and R 11 Each independently represents H, OH, F, Cl, Br, I, CN, N3, C1-C6 alkyl, OR 13 SR 13 or N(R 13 )2.

[0130] In some embodiments of compounds of Formula (IA) and / or (IB), R 2 、R 4 、R 9 and R 10 Each is independently H, OH, F, Cl, Br, I, CN or N3. In some embodiments, R 2 、R 4 、R 9 and R 10 Each is H.

[0131] In some embodiments of compounds of Formula (IA) and / or (IB), R 6 and R 7 Each independently represents H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、CH2N3、OR 13 SR 13 、N(R 13 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 In some embodiments, R 6 and R 7 Each independently represents H, CN, N3, F, Cl, Br, I, COOR 13 、CON(R 13 )2、CH2OH、CH2N3、OR 13 SR 13 、N(R 13 )2, C1-C3 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 In some embodiments, R 6 and R7 are each independently H, C1-C3 haloalkyl, CN, N3, F, Cl, Br, and I. In some embodiments, R 6 and R 7 are each independently H, CH2F, CHF2, CF3, CN, N3, F, Cl, Br, and I. In some embodiments, R 6 and R 7 Each is H.

[0132] In some embodiments of compounds of Formula (IA) and / or (IB), each R 13 are independently H, -C(=Z)R 14 、-C(=Z)OR 14 、-C(=Z)SR 14 、-C(=Z)N(R 14 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 In some embodiments, each R 13 are independently H or C1-C6 alkyl.

[0133] In some embodiments of compounds of Formula (IA) and / or (IB), each R 14 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C 10 Heterocycloalkyl, C6-C 10 Aryl or C2-C 10 In some embodiments, each R 14 are independently H or C1-C6 alkyl.

[0134] In some embodiments, the compound of Formula (IA) has the structure of Formula (IIA-1):

[0135]

[0136] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound of Formula (IA) has the structure of Formula (IIA-2):

[0138]

[0139] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0140] In some embodiments of compounds of Formula (IA), (IIA-1), and / or (IIA-2), K is a variable representing -O-; R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 12 Each is H; X 2 and X 4 Each is O; Y 1 and Y 2 Each is O.

[0141] In some embodiments, the compound of formula (IA) has the structure of formula (IA-1):

[0142]

[0143] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0144] In some embodiments of compounds of (IA) and / or (IA-1), L 1 -O- or -OC(R 6 R 7 )-, and L 2 -OC(R 6 R 7 )-. In some embodiments, L 1 is -O- or -O-CH2-, and L 2 In some embodiments, L 1 is -O-, and L 2 In some embodiments, L 1 is -O-CH2-, and L 2 It is -O-CH2-.

[0145] In some embodiments, the compound of formula (IA) has the structure of formula (IA-2):

[0146]

[0147] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound of formula (IA) has the structure of formula (IA-3):

[0149]

[0150] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0151] In some embodiments of compounds of Formula (IA-2) and / or (IA-3),

[0152] bases 1 and bases 2 Each independently

[0153] and

[0154] R 3 and R 11 Each independently represents H, F or OH. In some embodiments, R 3 and R 11 are each independently H or F. In some embodiments, R 3 and R 11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11 is H. In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 is F, and R 11 For OH.

[0155] In some embodiments of compounds of Formula (IA-2) and / or (IA-3),

[0156] bases 1 and bases 2 Each independently

[0157] and

[0158] R 3 and R 11 Each independently represents H, F or OH. In some embodiments, R 3 and R 11 are each independently H or F. In some embodiments, R 3 and R11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11 is H. In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 is F, and R 11 For OH.

[0159] In some embodiments of compounds of Formula (IA-2) and / or (IA-3),

[0160] bases 1 for

[0161]

[0162] bases 2 for

[0163] and

[0164] R 3 and R 11 Each is independently H, F or OH. In some embodiments, R 3 and R 11 are each independently H or F. In some embodiments, R 3 and R 11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11is H. In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 is F, and R 11 For OH.

[0165] In some embodiments, the compound of formula (IA) has the structure of formula (IA-4):

[0166]

[0167] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound of formula (IA) has the structure of formula (IA-5):

[0169]

[0170] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the compound of formula (IB) has the structure of formula (IIB-1):

[0172]

[0173] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the compound of formula (IB) has the structure of formula (IIB-2):

[0175]

[0176] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0177] In some embodiments of compounds of Formula (IB), (IIB-1), and / or (IIB-2), K is a variable representing -O-; R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 12 Each is H; X 2 and X 4 Each is O; Y 1 and Y 2 Each is O.

[0178] In some embodiments, the compound of formula (IB) has the structure of formula (IB-1):

[0179]

[0180] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0181] In some embodiments of compounds of Formula (IB) and / or (IB-1), L 1 O- or -C(R 6 R 7 )-O-, and L 2 -C(R 6 R 7 )-O-. In some embodiments, L 1 is -O- or -CH2-O-, and L 2 In some embodiments, L 1 is -O-, and L 2 In some embodiments, L 1 is -CH2-O-, and L 2 It is -CH2-O-.

[0182] In some embodiments, the compound of formula (IB) has the structure of formula (IB-2):

[0183]

[0184] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the compound of formula (IB) has the structure of formula (IB-3):

[0186]

[0187] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0188] In some embodiments of compounds of Formula (IB-2) and / or (IB-3),

[0189] bases 1 and bases 2 Each independently

[0190] and

[0191] R 3 and R 11 Each independently represents H, F or OH. In some embodiments, R 3 and R 11are each independently H or F. In some embodiments, R 3 and R 11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11 is H. In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 is F, and R 11 For OH.

[0192] In some embodiments of compounds of Formula (IB-2) and / or (IB-3),

[0193] bases 1 and bases 2 Each independently

[0194] and

[0195] R 3 and R 11 Each independently represents H, F or OH. In some embodiments, R 3 and R 11 are each independently H or F. In some embodiments, R 3 and R 11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11 is H. In some embodiments, R 3 is H, and R11 In some embodiments, R 3 is F, and R 11 For OH.

[0196] In some embodiments of compounds of Formula (IB-2) and / or (IB-3),

[0197] bases 1 for

[0198]

[0199] bases 2 for

[0200] and

[0201] R 3 and R 11 Each is independently H, F or OH. In some embodiments, R 3 and R 11 are each independently H or F. In some embodiments, R 3 and R 11 Each is F. In some embodiments, R 3 and R 11 Each is H. In some embodiments, R 3 and R 11 In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R 3 is F, and R 11 is H. In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 is F, and R 11 For OH.

[0202] In some embodiments, the compound of formula (IB) has the structure of formula (IB-4):

[0203]

[0204] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the compound of formula (IB) has the structure of formula (IB-5):

[0206]

[0207] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound of formula (IB) has the structure of formula (IB-6):

[0209]

[0210] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the compound of formula (IB) has the structure of formula (IB-7):

[0212]

[0213] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the compound of formula (IB) has the structure of formula (IB-8):

[0215]

[0216] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0217] In some embodiments of structures of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), the base 1 and bases 2 Each independently is:

[0218]

[0219]

[0220] In some embodiments, the base 1 and bases 2 Each independently is:

[0221]

[0222] In some embodiments, the base 1 and bases 2 Each independently is:

[0223]

[0224] In some embodiments, the base 1 and bases 2 Each independently is:

[0225]

[0226] In some embodiments, the base 1 and bases 2 Each independently is:

[0227]

[0228] In some embodiments, the base 1 and bases 2 Each independently is:

[0229]

[0230] In some embodiments, the base 1 for

[0231]

[0232] and base 2 for

[0233]

[0234] In some embodiments, the base 1 for

[0235]

[0236] And base 2 for

[0237]

[0238] In some embodiments, the base 1 and bases 2 Each for

[0239]

[0240] In some embodiments, the base 1 and bases 2 Each for

[0241]

[0242] In some embodiments of the structures of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), A, A 1 、A 2 、A 3 and A 4 Each independently represents H, OH, SH, F, Cl, Br, I, or NH2.

[0243] In some embodiments of the structures of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), A 1 、A 2 and A 3 Each is independently H, OH, SH, F, Cl, Br, I, NH2. In some embodiments, A 1 、A 2 and A 3 Each is independently H, OH and NH2.

[0244] In some embodiments of the structures of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), R 3 and R 11 Each independently represents H, OH, F, Cl, Br, I, CN, N3 or OR 13 In some embodiments, R 3 and R 11 Each independently represents H, OH, F, Cl, Br or OR 13 In some such embodiments, R 13 is a C1-C6 alkyl group. In some embodiments, R 3 and R 11 are each independently H, OH or F. In some embodiments, R 3 is H, and R 11 is F. In some embodiments, R3 is F, and R 11 is H. In some embodiments, R 3 is OH, and R 11 is F. In some embodiments, R 3 is OH, and R 11 is H. In some embodiments, R 3 is F, and R 11 In some embodiments, R 3 is H, and R 11 In some embodiments, R 3 and R 11 In some embodiments, R 3 and R 11 For F.

[0245] In some embodiments, compounds of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8) have the following structure:

[0246]

[0247]

[0248]

[0249]

[0250] or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0252]

[0253] or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0255]

[0256] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0257]

[0258] or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0260]

[0261] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0262]

[0263] or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0265]

[0266] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0267]

[0268] or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0270]

[0271] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0272]

[0273] or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0275]

[0276] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0277]

[0278] or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0280]

[0281] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0282]

[0283] or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0285]

[0286] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0287]

[0288] or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0290]

[0291] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0292]

[0293] or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3) have the following structure:

[0295]

[0296] The presence of a chiral center allows the compound to exist as one of two possible optical isomers ((R)-enantiomers or (S)-enantiomers) or as a racemic mixture of the two. In the presence of substituents that may be attached at different positions in the molecule, all regioisomers and mixtures of regioisomers formed are included within the scope of Formula (IA) or (IB) described herein.

[0297] Compounds of the present invention, such as compounds of Formula (IA), (IIA-1), (IA-1), (IA-2), (IA-3), (IB), (IIB-1), (IB-1), (IB-2), and / or (IB-3), can be depicted in multiple equivalent drawings. For example, compounds of Formula (IB-1) are generally depicted herein as shown below:

[0298]

[0299] The compound of formula (IB-1) above is equivalent to the compound of formula (IB-1) depicted below:

[0300]

[0301] Furthermore, each of the previous drawings is equivalent to the following depiction of a compound of formula (IB-1):

[0302]

[0303] Composition

[0304] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8)), a hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0305] In certain embodiments, pharmaceutical compositions comprise one or more additional therapeutic agents, as described more fully below.

[0306] 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 routine. Tablets may contain excipients including sliding agents, fillers, adhesives and the like. Aqueous compositions can be prepared in a sterile form and are generally isotonic when intended for delivery other than oral administration. All compositions may optionally contain excipients such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like. In certain embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.

[0307] The composition includes compositions suitable for various routes of administration, including those for oral administration. The composition can be present in unit dosage form and can be prepared by any method well known in pharmaceutical technology. Such methods include the step of combining the active ingredient (e.g., a compound of the present invention or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The composition can be prepared by uniformly and tightly combining the active ingredient with a liquid excipient or a finely powdered solid excipient or both, and then shaping the product as needed. Technology and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0308] Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0309] The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients and other therapeutic agents as appropriate. Pharmaceutical compositions containing active ingredients may be in any form suitable for the intended method of administration. When used for example for oral administration, tablets, dragees, buccal lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavorings, coloring agents and preservatives, in order 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. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0310] The amount of active ingredient that can be combined with the inactive ingredient to produce a dosage form can vary depending on the intended subject to be treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material, formulated together with an appropriate and suitable amount of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient ranges from about 5 to about 95% (weight:weight) of the total composition.

[0311] In certain embodiments, a composition comprising a compound of the invention (e.g., a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8)), or a pharmaceutically acceptable salt thereof, in one variation, does not contain an agent that affects the metabolic rate of the active ingredient. Thus, it is understood that a composition comprising a compound of the invention, in one aspect, does not contain an agent that would affect (e.g., slow, hinder, or stop) the metabolism of a compound of the invention or any other active ingredient administered separately, sequentially, or concurrently with a compound of the invention. It is also understood that any of the methods, kits, articles of manufacture, and the like described in detail herein, in one aspect, does not contain an agent that would affect (e.g., slow, hinder, or stop) the metabolism of a compound of the invention or any other active ingredient administered separately, sequentially, or concurrently with a compound of the invention.

[0312] Further described herein are pharmaceutical compositions as described above for modulating STING protein activity to induce STING-dependent production of type I interferons, cytokines, or chemokines.

[0313] Further described herein is 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.

[0314] Further described herein are compounds of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8) for administration 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 the active ingredient with or by mixing with a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient.

[0315] Another possibility is to use compounds of the formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8) as second or further active ingredients having a synergistic effect with other active ingredients in known medicaments, or to administer compounds of the formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8) and such medicaments.

[0316] The compounds of formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8) of the present invention can also be used in the form of prodrugs or other suitable modified forms that release the active ingredient in vivo.

[0317] method

[0318] In one embodiment, provided herein is a method of treating a disease or disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0319] Also provided is a method for modulating the activity of a STING protein, comprising administering a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

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

[0321] Further provided is a method of 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 of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0322] Further provided is a method of inducing STING adaptor protein-dependent type I interferon, cytokine, or chemokine in a human or animal, comprising administering a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

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

[0324] Further provided is a method for treating or preventing a viral infection (e.g., an infection caused by hepatitis B or HIV), comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8), or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

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

[0326] Further provided is a method for treating or preventing a hyperproliferative disease or cancer, comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

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

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

[0329] Further provided is a method for enhancing vaccine efficacy, comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or an enantiomer, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0330] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, which are suitable for use as medicaments in humans or animals.

[0331] Further provided herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use in modulating the activity of a STING protein.

[0332] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates 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 a STING protein.

[0333] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active substances for STING-dependent induction of type I interferons, cytokines or chemokines in humans or animals.

[0334] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active agents in the treatment or prevention of viral infections in humans or animals.

[0335] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active substances in the treatment or prevention of infection caused by hepatitis B virus or HIV in humans or animals.

[0336] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use alone or in combination with one or more therapeutically active agents in the treatment or prevention of a hyperproliferative disease or cancer in humans or animals.

[0337] Further described herein are cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for use in enhancing vaccine efficacy in humans or animals.

[0338] Further described herein is a pharmaceutical composition for modulating STING protein activity to induce STING-dependent production of type I interferons, cytokines, or chemokines in humans or animals.

[0339] Further described herein is a pharmaceutical composition for treating or preventing a viral infection, an infection caused by hepatitis B virus, HIV, a hyperproliferative disease, or cancer in humans or animals.

[0340] Further described herein are the use of cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, for the production of medicaments for the treatment or prevention of infection caused by hepatitis B virus, HIV, a hyperproliferative disease or cancer.

[0341] Application

[0342] The compounds of the present invention (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural), and the like. It will be appreciated that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0343] The compounds of the invention can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about 12 months or longer. In one variation, the compounds are administered daily or on an intermittent schedule for the duration of the individual's life.

[0344] The dosage or frequency of administration of the compounds of the invention may be adjusted during the course of treatment based on the judgment of the administering physician.

[0345] An effective amount of the compound can be administered to an individual (eg, a human). In certain embodiments, the compound is administered once daily.

[0346] The compound can be administered by any applicable route and means, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include about 0.00001 mg per kilogram of body weight per day to about 10 mg per kilogram of body weight per day, such as about 0.0001 mg per kilogram of body weight per day to about 10 mg per kilogram of body weight per day, or such as about 0.001 mg per kilogram of body weight per day to about 1 mg per kilogram of body weight per day, or such as about 0.01 mg per kilogram of body weight per day to about 1 mg per kilogram of body weight per day, or such as about 0.05 mg per kilogram of body weight per day to about 0.5 mg per kilogram of body weight per day, or such as about 0.3 mg to about 30 mg per day, or such as about 30 mg to about 300 mg per day.

[0347] The compounds of this invention can be in the form of any dosage (such as 1mg to 1000mg compound) of the compounds of this invention and one or more other therapeutic agents.Therapeutically effective amount can include per dose about 1mg to per dose about 1000mg, such as per dose about 50mg to per dose about 500mg, or such as per dose about 100mg to per dose about 400mg, or such as per dose about 150mg to per dose about 350mg, or such as per dose about 200mg to per dose about 300mg.Other therapeutically effective amounts of the compounds of this invention are per dose about 100,125,150,175,200,225,250,275,300,325,350,375,400,425,450,475 or about 500mg. Other therapeutically effective amounts of the compounds of the invention are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. Single doses can be administered hourly, daily, or weekly. For example, a single dose can be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose can also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose can also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In certain embodiments, a single dose can be administered every other week. A single dose can also be administered monthly.

[0348] The present invention also includes kits comprising cyclic dinucleotides of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or enantiomers, hydrates, solvates or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing any of the foregoing.

[0349] In one embodiment, kits are provided comprising a combination of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0350] Combination therapy

[0351] 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 the disease is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8)), 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 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) other therapeutic agents.

[0352] In certain embodiments, the present invention provides a method for treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents suitable for treating viral infection. In some embodiments, the viral infection is hepatitis B infection. In some embodiments, the viral infection is HIV infection.

[0353] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more other therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two other therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three other therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0354] Administration of combination therapy

[0355] In certain embodiments, the compounds disclosed herein are administered with one or more other therapeutic agents. Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to administering the compound disclosed herein and the one or more other therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of the compound disclosed herein and the one or more other therapeutic agents is present in the subject. When administered sequentially, the combination can be administered in two or more administrations.

[0356] Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially such that a therapeutically effective amount of each agent is present in the patient's body.

[0357] In certain embodiments, a compound as disclosed herein (e.g., a compound of any of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8)) 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 IA or IB (e.g., 10 mg to 1000 mg of compound).

[0358] Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more other therapeutic agents. The compounds disclosed herein can be administered within seconds, minutes, or hours of administering one or more other therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is first administered, followed by administering a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is first administered, followed by administering a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, followed by administering a unit dose of one or more other therapeutic agents after a period of time (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is first administered, followed by administering a unit dose of a compound disclosed herein after a period of time (e.g., 1 to 12 hours).

[0359] In certain embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents in a single dosage form for simultaneous administration to a subject, eg, in a solid dosage form for oral administration.

[0360] In certain embodiments, the compounds of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8) are formulated as tablets, which may optionally contain one or more additional compounds useful for treating the disease being treated. In certain embodiments, the tablets may contain another active ingredient useful for treating a viral disease, such as hepatitis B virus or HIV.

[0361] In certain embodiments, the tablets are suitable for once-daily administration.

[0362] In one embodiment, a pharmaceutical composition is provided that comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, one to three) other therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0363] 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, or one to three, or one to four) additional therapeutic agents.

[0364] Viral combination therapy

[0365] 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 disoproxildisoproxil), tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof.

[0366] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 10, 5 to 15, 5 to 20, 5 to 25, 25 to 30, 20 to 30, 15 to 30, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. As disclosed herein, a compound (e.g., a compound of Formula (IA) or (IB)) can be combined with an agent provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as is specifically and individually listed for each dose combination.

[0367] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. 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 disoproxil hemifumarate, or tenofovir disoproxil. 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. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. As disclosed herein, a compound (e.g., a compound of formula (IA) or (IB)) can be combined with an agent provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as is specifically and individually listed for each dose combination.

[0368] HIV combination therapy

[0369] In certain embodiments, a method for treating or preventing HIV infection in a human or animal that is infected or at risk of 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) other therapeutic agents. In one embodiment, a method for treating HIV infection in a human or animal that is infected or at risk of 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) other therapeutic agents.

[0370] 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 other therapeutic agents suitable for treating HIV infection.

[0371] In certain embodiments, the compounds disclosed herein are formulated in tablet form, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain another active ingredient useful for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0372] In certain embodiments, the tablets are suitable for once-daily administration.

[0373] In the above embodiments, the other therapeutic agent may be an anti-HIV agent. In some embodiments, the other 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 regulators, gene editing factors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T), latency reversal agents, compounds targeting HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4 / beta-7 antagonists, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, disulfide protein isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, reverse cyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase activation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and other HIV therapeutic agents and combinations thereof.

[0374] 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.

[0375] HIV combination drugs

[0376] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine and rilpivirine), (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (bictegravir, emtricitabine, tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, 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 Pifuroxetine; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, clopinavir + ritonavir, clopinavir + ritonavir + abacavir + lamivudine, clopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, clopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

[0377] HIV protease inhibitors

[0378] 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.

[0379] HIV reverse transcriptase inhibitors

[0380] 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.

[0381] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, 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.

[0382] HIV integrase inhibitors

[0383] 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- 15567, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivative, integrase-LEDGF inhibitor, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, and cabotegravir.

[0384] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0385] HIV entry inhibitors

[0386] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0387] Examples of CCR5 inhibitors include apraviroc, vicriviroc, 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).

[0388] 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.

[0389] Examples of CD4 attachment inhibitors include ibalizumab and CDA analogs.

[0390] Examples of gp120 inhibitors include Radha-108 (receptor) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0391] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (vMIP).

[0392] HIV maturation inhibitors

[0393] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0394] Latency reversal agents

[0395] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberoylanilide hydroxamic acid, or suberoyl, aniline, and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, and GSK-343.

[0396] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0397] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG lactone.

[0398] Capsid inhibitors

[0399] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid dissociation compounds, HIV nucleoprotein capsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

[0400] Immune-based therapies

[0401] 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; progressive cell death protein 1 (Pd-1) modulators; progressive death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; chloroquine (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; Interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103.

[0402] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and modulators disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), U.S. Patent No. 9670205 (Gilead Sciences Inc.), US20160289229 (Gilead Sciences Inc.), U.S. Patent Application No. 15 / 692161 (Gilead Sciences Inc.) and U.S. Patent Application No. 15 / 692,093 (Gilead Sciences Inc.).

[0403] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0404] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, and selenirib. mesylate), rigosertib, regosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-22 69577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV- 1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0405] Alpha-4 / beta-7 antagonists

[0406] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0407] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0408] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include Fab derivatives, bnABs (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), ibalizumab, Immuglo and MB-66.

[0409] 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.

[0410] Pharmacokinetic enhancers

[0411] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0412] HIV vaccine

[0413] 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 adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env evolutionary branch C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccines, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), II-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deleted HCMV vectored HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI.

[0414] Additional HIV treatments

[0415] Examples of other 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), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (GileadSciences) and WO 2013 / 091096(Boehringer Ingelheim).

[0416] 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.

[0417] Gene therapy and cell therapy

[0418] Gene therapy and cell therapy include: genetic modification to silence genes; genetic approaches to directly kill infected cells; infusions of immune cells designed to replace large portions of an individual's own immune system to boost the immune response to infected cells or activate the individual's own immune system to kill infected cells, or to seek out and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

[0419] Examples of dendritic cell therapies include AGS-004.

[0420] gene editing factors

[0421] Examples of gene editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0422] Examples of CRISPR / Cas9 systems targeting HIV include EBT101.

[0423] CAR-T cell therapy

[0424] 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 induction binding sites on gp120, N glycans on gp120, V2 of gp120, and proximal membrane regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+ T cells, CD8+ T cells, or a combination thereof.

[0425] Examples of HIV CAR-T include VC-CAR-T.

[0426] TCR-T cell therapy

[0427] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides on the surface of virus-infected cells.

[0428] Those skilled in the art will appreciate that the above-listed additional therapeutic agents may be included in more than one of the above-listed classes. Specific classes are not intended to limit the functionality of those compounds listed in those classes.

[0429] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitory compound. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0430] In certain embodiments, 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 emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (Bictegravir, Emtricitabine, Tenofovir Elafenamide); Adefovir; Adefovir Dipivoxil; Cobicistat; Emtricitabine; 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; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; pralidin; fosamprenavir; fosamprenavir calcium and efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; dida Novoxin; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (resipitor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; fosfez; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0431] In specific embodiments, 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.

[0432] In specific embodiments, 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.

[0433] 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 bitegravir; and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0434] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent and a second additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bisaclavir, wherein the second additional therapeutic agent is emtricitabine.

[0435] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 10 mg, 5 to 15 mg, 5 to 20 mg, 5 to 25 mg, 25 to 30 mg, 20 to 30 mg, 15 to 30 mg, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. As disclosed herein, a compound (e.g., a compound of Formula (IA) or (IB)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as is specifically and individually listed for each dose combination.

[0436] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 to 250 mg, 200 to 300 mg, 200 to 350 mg, 250 to 350 mg, 250 to 400 mg, 350 to 400 mg, 300 to 400 mg, or 250 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. 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 and 200 mg of emtricitabine. As disclosed herein, a compound (e.g., a compound of Formula (IA) or (IB)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as if each dose combination is specifically and individually listed.

[0437] HBV combination therapy

[0438] In certain embodiments, a method for treating or preventing HBV infection in a human with infection or at risk of 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) other therapeutic agents. In one embodiment, a method for treating HBV infection in a human with infection or at risk of 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) other therapeutic agents.

[0439] 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) other therapeutic agents suitable for treating HBV infection.

[0440] 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 factors (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.

[0441] In certain embodiments, the compound of Formula (IA) or (IB) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, lipoprotein A1 modulators, arginine kinase inhibitors, B lymphocyte and T lymphocyte attenuation 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 modulators, epigenetic modulators, farnesoid X receptor agonists, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBVRNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAPs inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta Receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholate co-transporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nuclear protein inhibitors, nuclear protein modulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidyl cyclohexane 3-kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulators of the interferon gene (STING) promoter, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, Toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

[0442] HBV combination drugs

[0443] Examples of combination drugs used to treat HBV include (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0444] Other HBV drugs

[0445] Examples of other drugs used to treat HBV include α-hydroxyphenol, amdoxovir, β-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 (Ti Fen Tai)), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, and Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N,and compounds disclosed in US20150210682 (Roche), US 2016 / 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). ,

[0446] HBV vaccine

[0447] HBV vaccines include both 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 (Hansen's polymorphic 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 HepB, Comvax, DTP-Hib-HBV Vaccine, DTP-HBV Vaccine, Yi Tai, 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.

[0448] 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.

[0449] HBV DNA polymerase inhibitors

[0450] Examples of HBV DNA polymerase inhibitors include adefovir Emtricitabine Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl, CMX-157, besifovir, entecavir Entecavir maleate, telbivudine Filociril, 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.

[0451] Immunomodulators

[0452] Examples of immunomodulators include retalide, imidol hydrochloride, ingaron, demavir, chloroquine (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, the polymer polyethyleneimine (PEI), Gepon, 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.

[0453] Toll-like receptor (TLR) modulators

[0454] 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, polyICLC, Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1.

[0455] 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).

[0456] Examples of TLR8 modulators include motomod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688, and compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Patent No. 9,670,205, US20160289229, U.S. Patent Application No. 15 / 692,161, and U.S. Patent Application No. 15 / 692,093.

[0457] 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.

[0458] 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 (BristolMyers Squibb), WO201704023 (3MCo),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), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan Kelun Biotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), WO2015023958 (University of Kansas).

[0459] Interferon α receptor ligand

[0460] Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON ), pegylated interferon α-2a Pegylated interferon α-1b, interferon α1b Veldona, Infradure, Interferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeg interferon alpha-2b (YPEG-rhIFNα-2b), MOR-22, peg interferon alpha-2b (PEG- ), 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), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), ropeg interferon alfa-2b, rHSA-IFN alfa-2a (recombinant human serum albumin interferon alfa 2a fusion protein), rHSA-IFN alfa 2b, recombinant human interferon alfa-(1b,2a,2b), peg interferon alfa-2b (Amega), peg interferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, ShangSheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alfa-2b, SFR-9216, and Interapo (Interapa).

[0461] Hyaluronidase inhibitors

[0462] Examples of hyaluronidase inhibitors include astodrimer.

[0463] Hepatitis B surface antigen (HBsAg) inhibitors

[0464] 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 and REP-006, and REP-9AC′.

[0465] Examples of HBsAg secretion inhibitors include BM601.

[0466] Cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors

[0467] Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAb, tremelimumab, and JHL-1155.

[0468] Cyclophilin inhibitors

[0469] 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).

[0470] HBV viral entry inhibitors

[0471] Examples of HBV viral entry inhibitors include Myrcludex B.

[0472] Antisense oligonucleotides targeting viral mRNA

[0473] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

[0474] Short interfering RNA (siRNA) and ddRNAi

[0475] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

[0476] Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

[0477] Endonuclease modulators

[0478] Examples of endonuclease modulators include PGN-514.

[0479] Ribonucleotide reductase inhibitors

[0480] Examples of ribonucleotide reductase inhibitors include Trimidox.

[0481] HBV E antigen inhibitors

[0482] Examples of HBV E antigen inhibitors include wogonin.

[0483] Covalently closed circular DNA (cccDNA) inhibitors

[0484] Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0485] Farnesoid X receptor agonists

[0486] 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.

[0487] HBV antibodies

[0488] Examples of HBV antibodies targeting hepatitis B virus surface antigens include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed).

[0489] Examples of HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include Zutectra, ShangSheng Gan Di, Uman Big (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGamB, igantibe, Niuliva, CT-P24, hepatitis B immune globulin (intravenous, pH 4, HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088).

[0490] Fully human monoclonal antibodies include HBC-34.

[0491] CCR2 chemokine antagonists

[0492] Examples of CCR2 chemokine antagonists include propagermanium.

[0493] Thymosin agonists

[0494] Examples of thymosin agonists include Thymalfasin, recombinant thymosin α1 (GeneScience)

[0495] cytokines

[0496] 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.

[0497] Nuclear protein regulators

[0498] Nucleoprotein modulators can be HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23.

[0499] 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).

[0500] Examples of transcript 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).

[0501] Retinoic acid-inducible gene 1 stimulator

[0502] 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.

[0503] NOD2 stimulators

[0504] Examples of NOD2 stimulators include SB-9200.

[0505] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0506] Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, regolitinib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, , XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotic acid, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, puquitinib mesylate mesylate), SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

[0507] Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

[0508] 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.).

[0509] PD-1 inhibitors

[0510] 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-0 01. Camrelizumab, Sintilimab, tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (epidermal growth factor receptor antagonist; progressive cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-L1 / TGF-β bifunctional fusion protein), Genolizumab, and BMS-936559.

[0511] PD-L1 inhibitors

[0512] 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.

[0513] 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), WO201动205464 (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). ;

[0514] Recombinant Thymosin alpha-1

[0515] Examples of recombinant thymosin α-1 include NL-004 and PEGylated thymosin α-1.

[0516] Bruton's tyrosine kinase (BTK) inhibitors

[0517] Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the BTK inhibitors disclosed in US Pat. No. 20140330015 (Ono- Pharmaceutical), US20130079327 (Ono Pharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0518] KDM inhibitors

[0519] 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).

[0520] Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

[0521] STING agonists

[0522] 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), WO2014179760 (University of California), WO2018098203 (Janssn), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer).

[0523] Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0524] Examples of NNRTIs include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555 (Gilead).

[0525] HBV replication inhibitors

[0526] Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and Xingantie.

[0527] Arginase inhibitors

[0528] Examples of arginase inhibitors include CB-1158, C-201, and ramucirumab.

[0529] Gene therapy and cell therapy

[0530] Gene therapy and cell therapy include genetic modification to silence genes; genetic approaches to directly kill infected cells; infusions of immune cells designed to replace large portions of a patient's own immune system to boost the immune response to infected cells or activate the patient's own immune system to kill infected cells, or to seek out and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

[0531] gene editing factors

[0532] Examples of genome editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system; e.g., 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 gene expression blockade) of the PreC, C, X, PreS1, PreS2, S, P, or SP gene refers to (1) reduction or elimination of PreC, C, X, PreS1, PreS2, S, P, or SP gene expression, (2) interference with the function of the prenuclear 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) reduction or elimination of the intracellular, serum, and / or brain parenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and / or HBSP protein. Blocking gene expression of one or more of the PreC, C, X, PreS1, PreS2, S, P, and / or SP genes is performed by targeting HBV cccDNA and / or genes integrated into HBV DNA.

[0533] CAR-T cell therapy

[0534] 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.

[0535] TCR-T cell therapy

[0536] TCR T cell therapy includes T cells that express HBV-specific T cell receptors. TCR-T cell lines are engineered to target HBV-derived peptides presented on the surface of cells infected with the virus. 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.

[0537] In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with: an HBV DNA polymerase inhibitor; one or two additional therapeutic agents selected from the group consisting of: an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody and a bispecific antibody targeting a surface antigen of hepatitis B virus), and an "antibody-like" therapeutic protein (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators; and one or two other therapeutic agents 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 modulators).

[0538] In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one second additional therapeutic agent selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody and a bispecific antibody targeting the surface antigen of hepatitis B virus), and an "antibody-like" therapeutic protein (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginine kinase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators.

[0539] In another 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: an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting a hepatitis B virus surface antigen, an siRNA, an miRNA gene therapy agent, sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (HBV core or capsid protein inhibitor).

[0540] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with compounds and other drugs for the treatment of HBV, and combinations thereof, such as those disclosed in U.S. Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 (Gilead Sciences), and U.S. Patent No. 10,673,667. 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 (ArrayBiopharma), 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. 8,513,184 (Gilead Sciences), U.S. Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO 2013096744(Novira)、US20150225355(Novira)、US20140178337(Novira)、US20150315159(N ovira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20 150132258(Novira)、US9181288(Novira)、WO2014184350(Janssen)、WO2013144129(Roche)、 US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), U.S. Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0217880 (Onopharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals),Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel ), US20140171432, US20140213591(Quanticel), US20160039808(Quanticel), US20140275084(Quanticel), WO2014164708(Quanticel), US9186337B2(Oryzon Genomics).

[0541] Cancer combination therapy

[0542] In one embodiment, the compounds of the present invention can be used in conjunction with other therapeutic approaches for the treatment of cancer. Preferably, combination therapy with chemotherapeutic agents, hormones, antibodies, surgery and / or radiation therapy is contemplated.

[0543] In some embodiments, the additional anti-cancer therapy is surgery and / or radiation therapy.

[0544] In some embodiments, the additional anti-cancer therapy is at least one additional cancer agent.

[0545] In some embodiments, a combination is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one other cancer agent.

[0546] In some embodiments, a combination is provided for use in therapy comprising a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or a pharmaceutically acceptable salt thereof, and at least one other cancer agent.

[0547] In some embodiments, provided is the use of a combination comprising a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7) and / or (IB-8), or a pharmaceutically acceptable salt thereof, and at least one cancer agent, in the manufacture of a medicament for treating cancer.

[0548] Examples of additional cancer agents include intercalating substances such as anthracyclines, doxorubicin, idarubicin, epirubicin, and daunorubicin; topoisomerase inhibitors such as irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticines, and aurintricarboxylic acid; acid; nitrosourea compounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin; nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid, and 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; tetranitrate); microtubule-disrupting drugs such as vinblastine, colcemid, and nocodazole; antifolates such as methotrexate, aminopterin, dichloromethopterin, 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 gestagene, androgene, glucocorticoids, dexamethasone, prednisolone, and prednisone; anticancer antibodies, such as monoclonal antibodies, for example, alemtuzumab, apolizumab, cetuximab, mab), epratuzumab, galiximab, gemtuzumab, ipilimumab, 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.

[0549] In certain embodiments, a method for treating or preventing a hyperproliferative disorder or cancer in a human or animal suffering from or at risk of suffering from a hyperproliferative disorder or cancer comprises administering to the human or animal a therapeutically effective amount of a compound of Formula (IA), (IIA-1), (IIA-2), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IIB-1), (IIB-2), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8) as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating a hyperproliferative disorder or cancer in a human or animal suffering from or at risk of suffering from a hyperproliferative disorder or cancer comprises 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) other therapeutic agents.

[0550] In certain embodiments, the present invention provides a method for treating a hyperproliferative disorder or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the hyperproliferative disorder or cancer.

[0551] 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 regulators or editing factors (such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, engineered T cell receptors (TCR-T) or any combination thereof. Such therapeutic agents may be in the form of compounds, antibodies, polypeptides or polynucleotides. In one embodiment, provided herein is a product comprising compounds described herein and other therapeutic agents in the form of a combination formulation for simultaneous, separate or sequential use in therapy.

[0552] The one or more therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or inhibitors of a gene, ligand, receptor, protein, or factor. Non-limiting examples of other therapeutic agents include: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2B, A2a, A3), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), Aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, α1 adrenergic receptor, α2 adrenergic receptor, α-ketoglutarate dehydrogenase (KGDH), amino Peptidase N, AMP-activated protein kinase, anaplastic 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), argininase (I), arginine deiminase, aromatase, stellate homolog 1 (ASTE1) gene, ataxia telangiectasia, and Rad 3-related (ATR) serine / threonine protein kinase, Aurora kinase (such as 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat-containing 5 (BIRC5) gene, basic immunoglobulin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenergic receptor, beta catenin, B lymphocyte antigen CD19, B lymphocyte antigen CD20, B lymphocyte adhesion molecule, B lymphocyte stimulator ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein White-9 ligand modulator, brachymembrane protein, bradykinin receptor, B-raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and extracellular domain (BET) bromodomain-containing proteins (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), testicular cancer antigen 2, testicular cancer 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), caspases (such as caspases-3, caspases-7, caspases-9), caspases 8 apoptosis-related cysteine ​​peptidase CASP8-FADD class regulators, caspases recruitment domain protein-15, cathepsin G, CCR5 gene, CDK activating kinase (CAK), checkpoint kinases (such as CHK1, CHK2), chemokine (CC main structure) receptors (such as CCR2, CCR4, CCR5), chemokine (CX C main structure) receptors (such as CXCR4, CXCR1 and CXCR2), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), tight junction proteins (such as 6, 18), cluster of differentiation (CD), such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, 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 C3, connective tissue growth factor, COP9 signaling subunit 5, CSF-1 (colony stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T lymphocyte protein 4) receptor, cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs, such as CDK1, CDK1B, CDK2-9), cyclooxygenases (such as 1, 2), CYP2B1 gene, cysteinyl palmitoyltransferase, 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 primase, dUTP pyrophosphatase, L-dopachrome tautomerase, echinoderm tubulin-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulin, endosialin, endostatin, endothelins (such as ET-A, ET-B), enhancer of zeste homolog 2 ( EZH2), ephrelin (EPH) tyrosine kinases (such as Epha3, Ephb4), ephrelin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigenetic factors, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-B2 avian erythroblastic leukemia virus oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen estrogen receptors (such as α, β), estrogen-related receptors, eukaryotic translation initiation factor 5A (EIF5A) gene, nuclear export protein 1, extracellular signal-related kinases (such as 1, 2), extracellular signal-regulated kinases (ERK), factors (such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FG-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, Fms-related tyrosine kinase 3 (Flt 3), focal adhesion kinase (FAK, such as FAK2), folate hydroxylase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folic acid, folate transporter 1, FYN tyrosine kinase, paired alkaline amino acid cleavage enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoids, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK,such as 3-β), phosphatidylinositol proteoglycan 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 (78 kDa glucose-regulated protein) calcium-binding protein, molecular chaperone protein groEL2 gene, heat shock protein (such as 27, 70, 90α, β), heat shock protein gene, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-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 antigens, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (such as E6, E7) protein, hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1α (HIF1α), imprinted human maternally expressed transcript (H19) gene, mitogen-activated protein 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 receptor, immunoglobulin gamma Fc receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (such as 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM-1), interferon (such as α, α2, β, γ), melanoma interferon-inducible protein 2 (AIM2), interferon type I receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK,Such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinase-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-associated protein-1, leukotriene A4 hydroxylase, 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, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylase (such as KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatidate-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, vault protein, MAPK-activated protein kinase (such as MK2), Mas-related G protein-coupled receptor, matrix metalloproteinase (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (such as 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (prostate 6 transmembrane epithelial antigen 1), transferrin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl CoA thiolase, mitogen-activated 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, octadecyl alanine-rich protein kinase C matrix (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NFκB activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB activated NK receptor, norepinephrine transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF) κB, nucleolin, nucleolar phosphatidylcholine, nucleolar phosphatidylcholine-alkynoblastoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptor (such as δ), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4 or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, such as α, δ, γ), P-glycoprotein (such as 1), phosphatase and contraction 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), melanoma preferentially expressed antigen (PRAME) gene, pentenyl binding protein (PrPB), possible transcription factor PML, progesterone receptor, progressive cell death 1 (PD-1), progressive cell death ligand 1 inhibitor (PD-L1), activating protein (PSAP) gene, prostaglandin receptor (EP4), prostate specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyl transferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine-protein kinase (PIM,such as PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-α-reductase, Raf protein kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (such as γ), retinoid X receptor, Rheb (brain-enriched Ras homolog) GTPase, Rho (Ras homolog)-associated protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (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, myoplasmic calcium ATPase, second mitochondrial-derived activator of caspase (SMAC) protein, secreted frizzled-related protein-2, semaphorin-4D, serine proteases, serine / threonine kinases (STKs), serine / threonine-protein kinases (TBKs, such as TBK1), signal transducers and transcription (STATs,such as STAT-1, STAT-3, STAT-5), signaling lymphocytic activation molecule (SLAM) family member 7, 6 transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide co-transporter, sodium phosphate co-transporter 2B, somatostatin receptors (such as 1, 2, 3, 4, 5), sonic hedgehog protein, exchange factor (SOS), specificity protein 1 (Sp1), transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1, 2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small anti-ubiquitin modifier), superoxide dismutase, survivin protein, synapsin 3, syndecan-1, synuclein α, T cell surface glycoprotein CD28, box-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-containing Bletilla striata mucin domain protein 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, T NFSF9 gene, Toll-like receptors (TLRs, such as 1-13), topoisomerases (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-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signaling protein, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, myosin receptor kinase (Trk) receptors (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, tyrosine kinase with immunoglobulin and EGF-like domains (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin conjugating enzyme E2I (UBE2I, UBC9), urease (Urease), urokinase plasminogen activator, uterine globulin Uteroglobin, vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig inhibitor of T cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein kinase, Wilms' tumor antigen 1, Wilms' tumor protein, X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

[0553] Non-limiting examples of other therapeutic agents can be categorized by their mechanism of action into, for example, the following groups:

[0554] Antimetabolites / anticancer agents, such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (lipid cytarabine, daunomycin), and TAS-118;

[0555] Purine analogs, folate antagonists (such as pralatrexate) and related inhibitors;

[0556] Antiproliferative / antimiotic 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);

[0557] DNA-damaging agents, such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, and cyclophosphamide Actinomycin D, daunorubicin, cypermethrin, epirubicin, ifosfamide, melphalan, dichloromethane, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, paclitaxel, Taxotere, teniposide, etoposide, and triethylthiophosphoramide;

[0558] DNA hypomethylating agents, such as guadecitabine (SGI-110), ASTX727;

[0559] Antibiotics, such as actinomycin D, daunomycin, cytoxan, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin);

[0560] Enzymes such as L-asparaginase that systemically metabolize L-asparagine and deprive cells that do not have the ability to synthesize their own asparagine;

[0561] antiplatelet agents;

[0562] DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

[0563] Agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

[0564] Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol;

[0565] pan-Trk, ROS1, and ALK inhibitors, such as entrectinib and TPX-0005;

[0566] ALK inhibitors, such as alectinib and ceritinib;

[0567] Antiproliferative / antimitotic alkylating agents, such as the nitrogen mustards cyclophosphamide and analogs (melphalan, chlorambucil, hexamethylmelamine, and thiotepa), alkylnitrosoureas (carmustine) and analogs, streptozotocin, and triazenes (dacarbazine);

[0568] antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0569] Platinum coordination complexes (cisplatin, oxaliplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

[0570] Hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (letrozole and anastrozole);

[0571] Anticoagulants, such as heparin, synthetic heparin salts, and other thrombin inhibitors;

[0572] Fibrinolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;

[0573] anti-migration agents;

[0574] antisecretory agents (breveldin);

[0575] Immunosuppressants such as tacrolimus, sirolimus, azathioprine, and mycophenolate;

[0576] growth factor inhibitors, and vascular endothelial growth factor inhibitors;

[0577] Fibroblast growth factor inhibitors, such as FPA14;

[0578] Anti-VEGFR antibodies, such as IMC-3C5, GNR-011, and tanibirumab;

[0579] Anti-VEGF / DDL4 antibodies, such as ABT-165;

[0580] Anti-cadherin antibodies, such as HKT-288;

[0581] Anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat-containing 15 (LRRC15) antibodies, such as ABBV-085.ARGX-110;

[0582] angiotensin receptor blockers, nitric oxide donors;

[0583] Antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0584] DNA interfering oligonucleotides, such as PNT2258 and AZD-9150;

[0585] Anti-ANG-2 antibodies, such as MEDI3617 and LY3127804;

[0586] anti-ANG-1 / ANG-2 antibodies, such as AMG-780;

[0587] Anti-MET / EGFR antibodies, such as LY3164530;

[0588] Anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomozuotuximab, ABT-806, vectibix, modotuximab, RM-1929;

[0589] Anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0590] Anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, and ABBV-428;

[0591] anti-endoglin antibodies, such as TRC105 (carotuximab);

[0592] Anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0593] Anti-HER3 antibodies, such as LJM716 and GSK2849330;

[0594] Anti-HER2 antibodies, such as margetuximab, MEDI4276, and BAT-8001;

[0595] anti-HLA-DR antibodies, such as IMMU-114;

[0596] Anti-IL-3 antibodies, such as JNJ-56022473;

[0597] Anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

[0598] Anti-EphA3 antibodies, such as KB-004;

[0599] Anti-CD20 antibodies, such as obinutuzumab and IGN-002;

[0600] anti-CD20 / CD3 antibodies, such as RG7828;

[0601] Anti-CD37 antibodies, such as AGS67E, otlertuzumab (TRU-016);

[0602] anti-ENPP3 antibodies, such as AGS-16C3F;

[0603] Anti-FGFR-3 antibodies, such as LY3076226 and B-701;

[0604] Anti-FGFR-2 antibodies, such as GAL-F2;

[0605] Anti-C5 antibodies, such as ALXN-1210;

[0606] anti-CD27 antibodies, such as varlilumab (CDX-1127);

[0607] Anti-TROP-2 antibodies, such as IMMU-132

[0608] Anti-NKG2a antibodies, such as monalizumab;

[0609] Anti-VISTA antibodies, such as HMBD-002;

[0610] Anti-PVRIG antibodies, such as COM-701;

[0611] anti-EpCAM antibodies, such as VB4-845;

[0612] Anti-BCMA antibodies, such as GSK-2857916

[0613] anti-CEA antibodies, such as RG-7813;

[0614] Anti-cluster of differentiation 3 (CD3) antibodies, such as MGD015;

[0615] Anti-folate receptor alpha antibodies, such as IMGN853;

[0616] MCL-1 inhibitors, such as AMG-176, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037;

[0617] epha2 inhibitors, such as MM-310;

[0618] Anti-LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767;

[0619] Raf kinase / VEGFR inhibitors, such as RAF-265;

[0620] Polycomb (EED) inhibitors, such as MAK683;

[0621] Anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0622] anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0623] Anti-Fucosyl-GM1 antibodies, such as BMS-986012;

[0624] p38 MAP kinase inhibitors, such as ralimetinib;

[0625] PRMT1 inhibitors, such as MS203;

[0626] Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0627] FLT3-ITD inhibitors, such as BCI-332;

[0628] Erythroid cell-derived factor 2 stimulators, such as omaveloxolone (RTA-408);

[0629] Myosin receptor kinase (TRK) inhibitors, such as LOXO-195 and ONO-7579;

[0630] Anti-ICOS antibodies, such as JTX-2011 and GSK3359609;

[0631] Anti-DR5 (TRAIL2) antibodies, such as DS-8273;

[0632] Anti-GD2 antibodies, such as APN-301;

[0633] Anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0634] Anti-carbonic anhydrase IX antibodies, such as TX-250;

[0635] Anti-CD38-atenin, such as TAK573;

[0636] Anti-mucin 1 antibodies, such as gatipotuzumab;

[0637] Mucin 1 inhibitors, such as GO-203-2C;

[0638] MARCKS protein inhibitors, such as BIO-11006;

[0639] Folate antagonists, such as arfolitixorin;

[0640] Galectin-3 inhibitors, such as GR-MD-02;

[0641] Phospho-P68 inhibitors, such as RX-5902;

[0642] CD95 / TNF modulators, such as ofranergene obadenovec;

[0643] PI3K / Akt / mTOR inhibitors, such as ABTL-0812;

[0644] pan-PIM kinase inhibitors, such as INCB-053914;

[0645] IL-12 gene stimulators, such as EGEN-001 and tavokinogene telseplasmid;

[0646] Heat shock protein HSP90 inhibitors, such as TAS-116 and PEN-866;

[0647] VEGF / HGF antagonists, such as MP-0250;

[0648] SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659;

[0649] SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0650] FLT3 tyrosine kinase inhibitors, such as FF-10101;

[0651] FLT3 tyrosine kinase agonists, such as CDX-301;

[0652] FLT3 / MEK1 inhibitors, such as E-6201;

[0653] IL-24 antagonists, such as AD-IL24;

[0654] RIG-I promoters, such as RGT-100;

[0655] Aeromonas lysin stimulants, such as topsalysin;

[0656] P-glycoprotein 1 inhibitors, such as HM-30181A;

[0657] CSF-1 antagonists, such as ARRY-382 and BLZ-945;

[0658] anti-mesothelin antibodies, such as SEL-403;

[0659] Thymidine kinase stimulators, such as aglatimagene besadenovec;

[0660] Polo-like kinase 1 inhibitors, such as PCM-075;

[0661] TLR-7 agonists, such as TMX-101 (imiquimod);

[0662] NEDD8 inhibitors, such as pevonedistat (MLN-4924), TAS-4464;

[0663] Pleiotropic pathway modulators, such as avadomide (CC-122);

[0664] FoxM1 inhibitors, such as thiostrepton;

[0665] anti-MUC1 antibodies, such as Mab-AR-20.5;

[0666] Anti-CD38 antibodies, such as isatuximab and MOR-202;

[0667] UBA1 inhibitors, such as TAK-243;

[0668] Src tyrosine kinase inhibitors, such as VAL-201;

[0669] VDAC / HK inhibitors, such as VDA-1102;

[0670] BRAF / PI3K inhibitors, such as ASN-003;

[0671] Elf4a inhibitors, such as rohinitib and eFT226;

[0672] TP53 gene stimulators, such as ad-p53;

[0673] PD-L1 / EGFR inhibitors, such as GNS-1480;

[0674] Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0675] SIRT3 inhibitors, such as YC8-02;

[0676] Stromal cell-derived factor 1 ligand inhibitors, such as olaptesed pegol (NOX-A12);

[0677] IL-4 receptor modulators, such as MDNA-55;

[0678] Arginase-I stimulators, such as pegzilarginase;

[0679] topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

[0680] Hypoxia-inducible factor-1α inhibitors, such as PT-2977 and PT-2385;

[0681] CD122 agonists, such as NKTR-214;

[0682] p53 tumor suppressor protein stimulators, such as kevetrin;

[0683] Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924;

[0684] Kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520);

[0685] CD80-fc fusion protein inhibitors, such as FPT-155;

[0686] Multiple endocrine neoplasia protein and mixed cell line leukemia (MLL) inhibitors, such as KO-539;

[0687] Liver X receptor agonists, such as RGX-104;

[0688] IL-10 agonists, such as AM-0010;

[0689] EGFR / ErbB-2 inhibitors, such as varlitinib;

[0690] VEGFR / PDGFR inhibitors, such as vorolanib;

[0691] IRAK4 inhibitors, such as CA-4948;

[0692] Anti-TLR-2 antibodies, such as OPN-305;

[0693] Calmodulin modulators, such as CBP-501;

[0694] Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0695] Second mitochondrial-derived activator of caspase (SMAC) protein inhibitors, such as BI-891065;

[0696] Lactoferrin modulators, such as LTX-315;

[0697] Kit tyrosine kinase / PDGF receptor alpha antagonists, such as DCC-2618;

[0698] KIT inhibitors, such as PLX-9486;

[0699] Nuclear exportin 1 inhibitors, such as eltanexor;

[0700] EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib;

[0701] anti-CD33 antibodies, such as IMGN-779;

[0702] Anti-KMA antibodies, such as MDX-1097;

[0703] Anti-TIM-3 antibodies, such as TSR-022, LY-3321367, and MBG-453;

[0704] Anti-CD55 antibodies, such as PAT-SC1;

[0705] Anti-PSMA antibodies, such as ATL-101;

[0706] anti-CD100 antibodies, such as VX-15;

[0707] Anti-EPHA3 antibodies, such as fibatuzumab;

[0708] Anti-Erbb antibodies, such as CDX-3379, HLX-02, and seribantumab;

[0709] Anti-APRIL antibodies, such as BION-1301;

[0710] Anti-Tigit antibodies, such as BMS-986207 and RG-6058;

[0711] CHST15 gene inhibitors, such as STNM-01;

[0712] RAS inhibitors, such as NEO-100;

[0713] Somatostatin receptor antagonists, such as OPS-201;

[0714] CEBPA gene stimulators, such as MTL-501;

[0715] DKK3 gene modulators, such as MTG-201;

[0716] p70s6k inhibitors, such as MSC2363318A;

[0717] Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891 and APL-1202;

[0718] Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0719] Anti-progressive cell death protein 1 (anti-PD-1) antibodies, such as nivolumab ( BMS-936558, MDX-1106), pembrolizumab ( MK-3477, SCH-900475, lambrolizumab (CAS Accession No. 1374853-91-4), pililizumab, PF-06801591, BGB-A317, GLS-010 (WBP-3055), AK-103 (HX-008), MGA-012, BI-754091, REGN-2810 (semipilimumab), AGEN-2034, JS-001, JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-130 6, and anti-progressive death ligand 1 (anti-PD-L1) antibodies, such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), evolocumab, 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);

[0720] PD-L1 / VISTA antagonists, such as CA-170;

[0721] Anti-PD-L1 / TGFβ antibodies, such as M7824;

[0722] Anti-transferrin antibodies, such as CX-2029;

[0723] Anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0724] ATM (ataxia telangiectasia) inhibitors, such as AZD0156;

[0725] CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2);

[0726] CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-10;

[0727] EXH2 inhibitors, such as GSK2816126;

[0728] HER2 inhibitors, such as neratinib and tucatinib (ONT-380);

[0729] KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, and GSK-2879552;

[0730] CXCR2 antagonists, such as AZD-5069;

[0731] GM-CSF antibodies, such as lenzilumab;

[0732] DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01);

[0733] Protein kinase C (PKC) inhibitors, such as LXS-196 and sotrastaurin;

[0734] Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, elacestrant (RAD-1901), and AZD9496;

[0735] Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0736] Selective androgen receptor modulators (SARMs), such as GTX-024 and darolutamide;

[0737] transforming growth factor-beta (TGF-beta) kinase antagonists, such as galunisertib;

[0738] Anti-transforming growth factor-β (TGF-β) antibodies, such as LY3022859, NIS793, XOMA 089;

[0739] 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 (angiogenin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotuzumab (flotet uzumab) (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 / LAG -3), AK-104(CTLA-4 / PD-1), AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), BI-836880(V EFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3);

[0740] Mutant-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0741] 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;

[0742] Anti-delta-like protein ligand 3 (DDL3) antibodies, such as tesinovamab (rovalpituzumab tesirine);

[0743] anti-clusterin antibodies, such as AB-16B5;

[0744] Anti-epinephrine-A4 (EFNA4) antibodies, such as PF-06647263;

[0745] Anti-RANKL antibodies, such as denosumab;

[0746] Anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0747] Anti-sodium phosphate co-transporter 2B (NaP2B) antibodies, such as lifastuzumab;

[0748] anti-c-Met antibodies, such as ABBV-399;

[0749] Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509;

[0750] α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0751] XPO1 inhibitors, such as selinexor (KPT-330);

[0752] Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221);

[0753] IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, and BAY-1436032;

[0754] Interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0755] Arginine deiminase stimulators, such as polyethylene glycol arginine deiminase (ADI-PEG-20);

[0756] 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, polatuzumab vedotin, ABBV-085;

[0757] Claudin-18 inhibitors, such as claudiximab;

[0758] β-catenin inhibitors, such as CWP-291;

[0759] Anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179;

[0760] CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425;

[0761] CD39 / CD73 antagonists, such as PBF-1662;

[0762] Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0763] Thymidylate synthase inhibitors, such as ONX-0801;

[0764] ALK / ROS1 inhibitors, such as lorlatinib;

[0765] Telomerase inhibitors, such as G007-LK;

[0766] Mdm2 p53-binding protein inhibitors, such as CMG-097 and HDM-201;

[0767] c-PIM inhibitors, such as PIM447;

[0768] BRAF inhibitors, such as dabrafenib, vemurafenib, encorafenib (LGX818), and PLX8394;

[0769] Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0770] Cell cycle inhibitors, such as selumetinib (MEK1 / 2) and sapacitabine;

[0771] AKT inhibitors, such as MK-2206, ipatasertib, afuretib, AZD5363, ARQ-092, capivasertib, and triciribine;

[0772] Anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such as tremelimumab, AGEN-1884, and BMS-986218;

[0773] c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, and HQP-8361;

[0774] c-Met / VEGFR inhibitors, such as BMS-817378 and TAS-115;

[0775] c-Met / RON inhibitors, such as BMS-777607;

[0776] BRAF / EGFR inhibitors, such as BGB-283;

[0777] bcr / abl inhibitors, such as rebastinib and asciminib;

[0778] MNK1 / MNK2 inhibitors, such as eFT-508;

[0779] mTOR inhibitors / cytochrome P450 3A4 stimulators, such as TYME-88;

[0780] Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0781] Pan-RAF inhibitors, such as LY3009120, LXH254, and TAK-580;

[0782] Raf / MEK inhibitors, such as RG7304;

[0783] CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);

[0784] kinase inhibitors, such as vandetanib;

[0785] E-selectin antagonists, such as GMI-1271;

[0786] Differentiation-inducing agents, such as retinoic acid;

[0787] Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291);

[0788] topoisomerase inhibitors such as daunorubicin, daunorubicin, actinomycin D, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (lipid irinotecan), vosaroxin, and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), and irofulven (MGI-114);

[0789] Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone;

[0790] Growth factor signaling kinase inhibitors;

[0791] Nucleoside analogs, such as DFP-10917;

[0792] Axl inhibitors such as BGB-324 (bemcentinib), SLC-0211;

[0793] 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;

[0794] PARP inhibitors such as olaparib, veliparib, talazoparib, ABT-767, BGB-290;

[0795] Proteasome inhibitors, such as ixazomib and carfilzomib Marizomib;

[0796] Glutamate inhibitors, such as CB-839;

[0797] vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67 / M57-KLH, IMU-131; bacterial vector vaccines, such as CRS-207 / GVAX: axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofaragene firadenovec); autologous Gp96 vaccines; dendritic cell vaccines such as CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, rocapuldencel-T (AGS-003), DCVAC, CVac tm , stapuldencel-T, eltrapuldencel-T, SL-701, BSK01 TM , ADXS31-142; oncolytic vaccines such as talimogene laherparepvec, 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-enriched cancer vaccine; RNA vaccines, such as CV-9209 and LV-305; DNA vaccines, such as MEDI-0457, MVI-816, and INO-5401; modified varicella virus Ankara vaccines expressing p53, such as MVA-p53; DPX-Survivac; and BriaVax. TM ;GI-6301;GI-6207;GI-4000;

[0798] Anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab;

[0799] STAT-3 inhibitors, such as napabucasin (BBI-608);

[0800] ATPase p97 inhibitors, such as CB-5083;

[0801] Smoothened (SMO) receptor inhibitors, such as (sonidegib, formerly known as LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

[0802] Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), ropeginterferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2B), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), follow-on biologics for interferon alpha-2a (Biosidus) (Inmutag, Inter 2A), follow-on biologics for interferon alpha-2b (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin Technology (Kaferon), Alfaferone, pegylated interferon alfa-1b, follow-on biologics of pegylated interferon alfa-2b (Amega), recombinant human interferon alfa-1b, recombinant human interferon alfa-2a, recombinant human interferon alfa-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alfa-n1 (Humoferon, SM-10500, Sumiferon);

[0803] Interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100);

[0804] IL-6 receptor modulators, such as tocilizumab, siltuximab, and AS-101 (CB-06-02 and IVX-Q-101);

[0805] Telomerase regulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0806] DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine;

[0807] DNA gyrase inhibitors, such as pixantrone and sobuzoxane;

[0808] BCL-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, and AT-101;

[0809] Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024;

[0810] anti-myostatin inhibitors, such as landogrozumab;

[0811] Hyaluronidase stimulators, such as PEGPH-20;

[0812] Wnt pathway inhibitors, such as SM-04755, PRI-724, and WNT-974;

[0813] γ-secretase inhibitors, such as PF-03084014, MK-0752, and RO-4929097;

[0814] Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0815] TRAIL pathway inducing compounds, such as ONC201 and ABBV-621;

[0816] Focal adhesion kinase inhibitors, such as VS-4718, defactinib, and GSK2256098;

[0817] Hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glasdegib, and vismodegib;

[0818] Aurora kinase inhibitors, such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib, ENMD-2076;

[0819] HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine and apatorsen;

[0820] ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib), and VX-970;

[0821] mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014), ME-344;

[0822] mTOR / PI3K inhibitors, such as gedatolisib, GSK2141795, omipalisib, and RG6114;

[0823] Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;

[0824] Murine double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);

[0825] CD137 agonists, such as urelumab and utomilumab (PF-05082566);

[0826] STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

[0827] FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0828] Fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0829] Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

[0830] Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, and inebilizumab;

[0831] CD44 binders, such as A6;

[0832] Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0833] CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0834] RXR agonists, such as IRX4204;

[0835] Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib and patidegib;

[0836] Complement C3 regulators, such as Imprime PGG;

[0837] IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;

[0838] EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126;

[0839] 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;

[0840] DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676);

[0841] Toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators;

[0842] DNA plasmids, such as BC-819

[0843] PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);

[0844] WEE1 inhibitors, such as AZD1775 (adavosertib);

[0845] Rho kinase (ROCK) inhibitors, such as AT13148 and KD025;

[0846] ERK inhibitors, such as GDC-0994, LY3214996, and MK-8353;

[0847] IAP inhibitors such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161;

[0848] RNA polymerase inhibitors, such as lurbinectedin (PM-1183), CX-5461;

[0849] Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), and OXI-4503, fluorapacin (AC-0001), plinabulin;

[0850] Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091, and PEPA-10;

[0851] Elongation factor 1α2 inhibitors, such as plitidepsin;

[0852] CD95 inhibitors, such as APG-101, APO-010, and asunercept;

[0853] WT1 inhibitors, such as DSP-7888;

[0854] Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0855] PDGFRα / KIT mutant-specific inhibitors, such as BLU-285;

[0856] SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550; and

[0857] Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716.

[0858] In some embodiments, provided herein are methods of treating or preventing a hyperproliferative disorder or cancer in a human or animal suffering from or at risk of suffering from a hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound of Formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), (IB-6), (IB-7), and / or (IB-8) as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents selected from the group consisting of an apoptosis signal regulating kinase (ASK) inhibitor; Bruton's tyrosine kinase (BTK) inhibitors; cluster of differentiation 47 (CD47) inhibitors; cyclin-dependent kinase (CDK) inhibitors; discoidin domain receptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors; indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors; Janus kinase (JAK) inhibitors; lysine oxidase-like protein (LOXL) inhibitors; matrix metalloproteinase (MMP) inhibitors; mitogen-activated protein kinase (MEK) inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors; Toll-like receptor 8 (TLR8) inhibitors; Toll-like receptor 9 (TLR9) inhibitors; tyrosine kinase inhibitors (TKIs), and any combination thereof, or pharmaceutically acceptable salts thereof. Non-limiting examples include:

[0859] Apoptosis signal-regulating kinase (ASK) inhibitors: ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences);

[0860] 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, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;

[0861] 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;

[0862] Cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, 7, and 9, such as abemaciclib, alvcidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, and TG-02;

[0863] Discoidin domain receptor (DDR) inhibitors: DDR inhibitors include inhibitors of DDR1 and / or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations);

[0864] 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, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;

[0865] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916;

[0866] 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 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019;

[0867] Lysine acyl oxidase (LOXL) inhibitors: LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and / or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics).

[0868] Matrix metalloproteinase (MMP) inhibitors: MMP inhibitors include inhibitors of MMP1 to MMP10. Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipemastat (Ro32-3555), GS-5745 (andecaliximab), and the inhibitors described in WO 2012 / 027721 (Gilead Biologics);

[0869] 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;

[0870] 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, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib, INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO2005 / 113556 (ICOS), WO Compounds described in WO 2013 / 052699 (Gilead Calistoga), WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences);

[0871] Spleen tyrosine kinase (SYK) inhibitors: Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-N-morpholinylphenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and SYK inhibitors described in US 8450321 (Gilead Connecticut) and SYK inhibitors described in US 2015 / 0175616;

[0872] 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, motolimod, resiquimod, VTX-1463, and VTX-763;

[0873] Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042; and

[0874] Tyrosine kinase inhibitors (TKIs): TKIs target the epidermal growth factor receptor (EGFR) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, and erlotinib. inib), imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, tivoanib, and TH-4000 and MEDI-575 (anti-PDGFR antibody).

[0875] 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, trothamide, triethylethanone phosphoramide, triethylethanone thiophosphoramide and trimethylmelamine; polyacetyl groups, especially bullatacin and bullatacinone; acinone; camptothecin, including its synthetic analogues topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogues adozelesin, carzelesin, and bizelesin; cryptophycin, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin and cyclophosphamide, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, and uracil mustard. mustard); nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin ), dynemicin, including dynemicin A, bisphosphonates such as clodronate, esperamicin, new tumor suppressor protein chromophores and related chromophore enediyne antibiotic chromophores, aclacinomycins, actinomycins, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carcinophilin carzinophilin, chromomycins, actinomycin D, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, cranberries (including morpholino-cranberries, cyanomorpholino-cranberries, 2-pyrrolino-cranberries, and deoxycranberries), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin ns), peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin ), methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, 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;Antiadreners, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; radioactive therapeutic agents, such as radium-223; trichothecenes, particularly T-2 toxin, verracurin A, roridin A, and anguidine; taxoids, such as paclitaxel; Abraxane, docetaxel cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 neplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate acetate; epothilone; etoglucid; nitrates; hydroxyurea; lentinan; leucovorin; lonidamine; maytansines, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folate; podophyllic acid; 2-ethylhydrazide; procarbazine ine); polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tricosporic acid; trabectedin, triaziquone; 2,2′,2″-tricUorotriemylamine; carbamates; vindesine; dacarbazine; mannitol mustard; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil; gemcitabine 6-Thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFIRI (fluorouracil, leucovorin, and irinotecan); and pharmaceutically acceptable salts, acids, or derivatives of any one of the foregoing.

[0876] The definition of "chemotherapeutic agent" also includes antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs) used to modulate or inhibit hormonal effects on tumors, aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

[0877] Antihormonal agents

[0878] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX TM ), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene

[0879] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, fenpropimorph, megestrol acetate Exemestane, formestane, fadrozole, vorozole Letrozole and anastrozole

[0880] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0881] Examples of progesterone receptor antagonists include onapristone.

[0882] Anti-angiogenic agents

[0883] Anti-angiogenic agents include, but are not limited to, retinoids and their derivatives, 2-methoxyestradiol, regorafenib, niculanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (albumin-bound paclitaxel), platelet factor 4, protamine sulfate (herring protamine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,1-3,4-dehydroproline, thioproline), α,α′-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-aminopropionitrile -(4-pyridyl)-2(3H)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecanoate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrine, lobenzarit disodium, n-2-carboxyphenyl-4-chloroaminobenzoic acid disodium or "CCA", thalidomide, angiostatic steroids, carboxyamidoimidazoles, metalloproteinase inhibitors (such as BB-94), inhibitors of S100A9 (such as tasquinimod). Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against such angiogenic growth factors as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0884] Antifibrotic agents

[0885] Anti-fibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), as well as compounds disclosed in US 4965288 relating to inhibitors of lysine oxidase and their use in treating diseases and conditions associated with abnormal deposition of collagen, and compounds disclosed in US 4997854 relating to compounds that inhibit LOX to treat various pathological fibrotic conditions, which applications are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593 relating to compounds such as 2-isobutyl-3-fluoro-allylamine, 2-isobutyl-3-chloro-allylamine, or 2-isobutyl-3-bromo-allylamine; US 5021456, US 5059714, US 5120764, US 5182297, US 5252608 relating to 2-(1-naphthyloxymethyl)-3-fluoroallylamine; and US 2004-0248871, which are incorporated herein by reference.

[0886] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysine acyl oxidase, and more particularly primary amines that form resonance-stabilized products after binding to the carbonyl group, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine and its derivatives; amine ureas and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0887] Other anti-fibrotic agents are copper chelators that are either cell-permeable or non-permeable. Exemplary compounds include indirect inhibitors that block the oxidative deamination of aldehyde derivatives derived from lysine and hydroxylysine residues by lysine oxidase. Examples include thiolamines (particularly D-penicillamine) and their analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)disulfide)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyldisulfide)butanoic acid, sodium sulfide-4-((p-1-dimethyl-2-amino-2-carboxyethyl)disulfide)butane, 2-acetamidoethyl-2-acetamidoethanethiol sulfonate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0888] Immunotherapeutic agents

[0889] 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, bavituximab, bectumomab, bevacizumab, bivatuzumab, bulimomab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, and figitumumab b), flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (. MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, and novozyme ofetumomab), OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab Rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenamomab

[0014] Rituximab is used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. Combinations of rituximab with chemotherapeutic agents are particularly effective.

[0890] Exemplary therapeutic antibodies can be further labeled with or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y-crivotuzumab), or iodine-131.

[0891] Cancer gene therapy and cell therapy

[0892] Cancer gene therapy and cell therapy include inserting a normal gene into a cancer cell to replace a mutated or altered gene; gene modification to silence mutant genes; genetic approaches to directly kill cancer cells; infusions of immune cells designed to replace a large portion of an individual's own immune system to boost the immune response to cancer cells or to activate an individual's own immune system (T cells or natural killer cells) to kill cancer cells or to seek out and kill cancer cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to cancer.

[0893] gene editing factors

[0894] Examples of genome editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0895] CAR-T cell therapy and TCR-T cell therapy

[0896] 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 present on the surface of tumor cells. The cells can be autologous or allogeneic.

[0897] In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

[0898] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0899] 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.

[0900] In some embodiments, the costimulatory domain comprises one or more functional domains of a protein selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), 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, ITGB 1. CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL1, C D100(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.

[0901] 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, CD3 epsilon, 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, IL2R beta, IL2R gamma, IL7R u, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ld, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB 1. CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

[0902] In some embodiments, the antigen binding domain binds a tumor antigen.

[0903] In some embodiments, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subunit 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); B cell maturation TNF receptor family member (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 CD213A) 2); mesothelin; interleukin 11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testosterone or PRSS21); vascular endothelial growth factor 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 / neu) ; cell surface associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostatic enzyme; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); epinephrine B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (promegaly, megalin) subunit 9 (LMP2); glycoprotein 100 (gp100); by breakpoint cluster Oncogene fusion protein composed of the cytokine receptor (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); tyrosinase; epirelin 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 marker 1 (TEM1 / CD248); related tumor endothelial marker 7 (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; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoH glycosylceramide (GloboH); mammary differentiation antigen (NY-BR-1); urokinase 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 at locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testicular antigen 1 (NY-ESO-1); cancer / testicular antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma antigen-1 (MADCT-1); melanoma 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) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI);CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5); pre-acrosin binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchoring protein 4 (AKAP-4); X-breakpoint synovial sarcoma 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitin 1 (RU1); renal ubiquitin 2 (RU2); legumin; human papillomavirus E6 (HPV E6); 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); Fc fragment of the IgA 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 mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0904] 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 , CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecules (ExoCBM), oncogene products, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrin B2, epithelial tumor antigen, estrogen receptor, embryonic acetylcholine receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tegmented epidermal growth factor receptor (tEGFR), tenascin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0905] Non-limiting examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Aimiliancel-T (Imilecleucel-T), baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, bone marrow stem cell therapy treated with FT-1050, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPCs, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005.

[0906] 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, CD19CAR-CD28-CD3ζ-EGFRt-expressing T cells, CD19 / 4-1BBL shield CAR T cell T 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; caspase 9 suicide gene, such as CaspaCIDe DLI, BPX-501; CCR5, such as SB-728; CDw123, such as MB-102, UCART-123; CD20m, such as CBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1); CD33, such as CIK-CAR.CD33; CD38, such as T-007, UCART-38; CD40 ligand, such as BPX-201; CEACAM protein 4 modulator, such as MG7-CART; Claudin 6, such as CSG-002; EBV-targeted, such as CMD-003; EGFR, such as autologous 4H11-28z / fIL-12 / EFGRt T cells; endonucleases, such as PGN-514 and PGN-201; Epstein-Barr virus-specific T lymphocytes, such as TT-10; ErbB2, such as CST-102 and CIDeCAR; ganglioside (GD2), such as 4SCAR-GD2; glutamate carboxypeptidase II, such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, and P-PSMA-101; phosphatidylinositol protein glycan-3 (GPC3), such as TT-16 and GLYCAR; hemoglobin, 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 Ad5f35-LMPd1-2-transduced autologous dendritic cells; melanoma associated antigen 10, such as MAGE-A10C796T MAGE-A10 TCR; melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6), such as KITE-718; mesothelin, such as CSG-MESO, TC-210; NKG2D, such as NKR-2; Ntrkr1 tyrosine kinase receptor, such as JCAR-024; T cell receptor, such as BPX-701, IMCgp100; T lymphocyte, such as TT-12; tumor infiltrating lymphocyte, such as LN-144, LN-145; and Wilms' tumor protein, such as JTCR-016, WT1-CTL.

[0907] Combination therapy for lymphoma or leukemia

[0908] In some embodiments, other therapeutic agents are suitable for treating lymphoma or leukemia. Such agents include aldesleukin, alvcidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-alexin, BMS-345541, bortezomib, Bortezomib ( PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib Carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, cranberries, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, cranberries, cranberries hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, cranberries, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa alfa), etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, cytarabine, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide ( CC-5013), lymphotrophic hormone-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 lipid dapoxetine hydrochloride, perifosin, prednisolone, prednisone, recombinant flt-3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate citrate), simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine hydrogen tartrate, SAHA (suberoylanilide hydroxamic acid or suberoylanilide and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[0909] 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 therapies include, but are not limited to, iodine-131 tositumomab. Yttrium-90 ibritumomab tiuxetan and With CHOP.

[0910] The above therapies may be supplemented with or combined with stem cell transplantation or therapy. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic technology, low-LET cobalt-60 gamma irradiation therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0911] Combination therapy for non-Hodgkin's lymphoma

[0912] In some embodiments, other 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 approaches (e.g., CHOP, CVP, FCM, MCP and the like), radioimmunotherapy, and combinations thereof, particularly combinations of antibody therapy and chemotherapy.

[0913] 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.

[0914] Examples of experimental antibody agents for the treatment of NHL / B-cell cancer include: ofavumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizumab, apolizumab, milatuzumab, and bevacizumab.

[0915] Examples of standard regimens for chemotherapy for NHL / B-cell cancers include: CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0916] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab and iodine-131 tositumomab

[0917] Combination therapy for mantle cell lymphoma

[0918] In some embodiments, other therapeutic agents are suitable for treating mantle cell lymphoma (MCL), including combination chemotherapy regimens such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of these therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0919] Other examples of therapeutic agents suitable for treating MCL include:

[0920] 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;

[0921] 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;

[0922] Autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib ( or PS-341), or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab;

[0923] Drugs that cause the breakdown of Bcl-2 proteins and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen in combination with other chemotherapeutic agents;

[0924] 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 or other combinations of chemotherapeutic agents;

[0925] Other agents, such as flavopiridol, palbociclib (PD0332991), R-rosvetin (Celixis, CYC202), styrylsulfone, obaclava (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus ( CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide ( CC-5013) and geldanamycin (17-AAG).

[0926] Combination therapy for Waldenstrom's macroglobulinemia

[0927] In some embodiments, other therapeutic agents are suitable for treating Waldenstrom's macroglobulinemia (WM), including aldesleukin, alemtuzumab, flavopiridol, amifostine trihydrate, aminocamptothecin, antisinaplaston A10, antisinaplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-alexin, bortezomib, Bryostatin 1, busulfan, Campas-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin, dexamethasone, docetaxel, dolastatin 10, cypermethrin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-humanized anti-CD22 antibody), etoposide, everolimus, ferritinib, filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphotrophic hormone-activated killer 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 lipid lipocalin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate Simvastatin, sirolimus, tacrolimus, tanespiramycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, vetuzumab, vincristine sulfate, vinorelbine hydrogen tartrate, vorinostat, WT1126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0928] 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 irradiation, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0929] Combination therapy for diffuse large B-cell lymphoma

[0930] In some embodiments, other therapeutic agents are suitable for treating diffuse large B-cell lymphoma (DLBCL) and include cyclophosphamide, vinblastine, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R-ICE.

[0931] Combination therapy for chronic lymphocytic leukemia

[0932] In some embodiments, other 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, and combination chemotherapy and chemoimmunotherapy, including the following commonly used combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0933] Myelofibrosis combination therapy

[0934] In some embodiments, other therapeutic agents suitable for treating myelofibrosis include hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saradegib and vismodegib.

[0935] Examples of HDAC inhibitors include, but are not limited to, pranostat and pabinostat.

[0936] Non-limiting examples of tyrosine kinase inhibitors are lestaurinib, bosutinib, imatinib, gilteritinib, radotinib, and cabozantinib.

[0937] Combination therapy for hyperproliferative diseases

[0938] In some embodiments, additional therapeutic agents are suitable for treating hyperproliferative diseases and include gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel with a JAK inhibitor and / or a PI3Kδ inhibitor.

[0939] Combination therapy for bladder cancer

[0940] In some embodiments, other therapeutic agents suitable for treating bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, cypermethrin, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, albumin-bound paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[0941] Breast cancer combination therapy

[0942] In some embodiments, the additional therapeutic agents are suitable for treating breast cancer and include nab-paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, lipocalin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated lipocalin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof.

[0943] Combination therapy for triple-negative breast cancer

[0944] In some embodiments, other therapeutic agents suitable for treating triple-negative breast cancer include cyclophosphamide, docetaxel, paclitaxel, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[0945] Combination therapy for colorectal cancer

[0946] In some embodiments, the other therapeutic agents are suitable for treating colorectal cancer and include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof.

[0947] Combination therapy for castration-resistant prostate cancer

[0948] In some embodiments, the additional therapeutic agent is suitable for treating castration-resistant prostate cancer and includes abiraterone, cabalitaxel, docetaxel, enzalutamide, prednisone, sipralid-T, and any combination thereof.

[0949] Combination therapy for esophageal and esophagogastric junction cancer

[0950] In some embodiments, other therapeutic agents are suitable 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.

[0951] Combination therapy for gastric cancer

[0952] In some embodiments, the other therapeutic agents are suitable for treating gastric cancer and include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0953] Combination therapy for head and neck cancer

[0954] In some embodiments, the other therapeutic agents are suitable for treating head and neck cancer and include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0955] Combination therapy for hepatobiliary cancer

[0956] In some embodiments, other therapeutic agents suitable for treating hepatobiliary cancer include capecitabine, cisplatin, fluoropyrimidines, 5-fluorouracil, gemecitabine, oxaliplatin, sorafenib, and any combination thereof.

[0957] Combination therapy for hepatocellular carcinoma

[0958] In some embodiments, other therapeutic agents suitable for treating hepatocellular carcinoma include capecitabine, ricinus, gemcitabine, sorafenib, and any combination thereof.

[0959] Combination therapy for non-small cell lung cancer

[0960] In some embodiments, the additional therapeutic agents are suitable for treating non-small cell lung cancer (NSCLC) and include 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.

[0961] Combination therapy for small cell lung cancer

[0962] In some embodiments, other therapeutic agents suitable for treating small cell lung cancer (SCLC) include bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, paclitaxel, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

[0963] Melanoma combination therapy

[0964] In some embodiments, the other therapeutic agents are suitable for treating melanoma and include nab-paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon alfa-2b, ipelizumab, nitrosoureas, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof.

[0965] Ovarian cancer combination therapy

[0966] In some embodiments, other therapeutic agents are suitable for treating ovarian cancer and include 5-fluorouracil, albumin-bound paclitaxel, altretinoin, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, cranberry, etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, lipid cranberry, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0967] Pancreatic cancer combination therapy

[0968] In some embodiments, other therapeutic agents are suitable for treating pancreatic cancer and include 5-fluorouracil, nab-paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, a fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

[0969] Combination therapy for renal cell carcinoma

[0970] In some embodiments, other therapeutic agents are suitable for treating renal cell carcinoma and include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

[0971] Set

[0972] The present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, for example, in treating viral infections. Instructions are typically written, but electronic storage media containing instructions (e.g., magnetic or optical disks) are also acceptable.

[0973] The present invention also provides a pharmaceutical kit comprising one or more containers containing a compound of the present invention or a pharmaceutically acceptable salt thereof. Associated with these containers, as appropriate, may be precautions in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceutical products, which reflect approval by the agency for manufacture, use, or sale for human administration. Each component (if more than one component is present) may be packaged in a separate container, or some components may be combined in a single container if cross-reactivity and shelf life permit. The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or sub-unit doses. The kit may also include multiple unit doses of the compound and instructions for use, and be packaged in sufficient quantity for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0974] Also provided are articles of manufacture comprising a unit dose of a compound of the invention or a pharmaceutically acceptable salt thereof, packaged for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The articles of manufacture may further be sterilized and / or sealed.

[0975] Examples

[0976] The embodiments also relate to methods and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

[0977] Numerous general references are available that provide commonly known chemical synthesis schemes and conditions suitable for synthesizing the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013.)

[0978] Compounds as described herein can be purified by any means 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 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.

[0979] The compounds were characterized using standard instrumental methods. 1 H, 600.13 MHz) and a Bruker AVANCE-500 instrument with a cryogenic probe ( 31 P, 202.4MHz, 19 NMR spectra were measured at 470.4 MHz (F, 470.4 MHz). Mass spectra were obtained in electrospray ionization (ESI) mode on a Waters Q-Tof Micro. HPLC analysis was performed on a Waters LC-MS instrument (Waters 600 controller, Waters 3100 mass detector, Waters photodiode array detector) using a Luna C18 column (Phenomenex, 5 μm, 150 × 4.6 mm) and a Zic-Hilic column (SeQuant, 5 μm, 100 × 4.6 mm).

[0980] During any process for preparing a target compound, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved. This can be achieved with the aid of conventional protecting groups, as described in standard texts such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 4th edition, Wiley, New York 2006. Protecting groups can be removed at a suitable subsequent stage using methods known in the art.

[0981] Exemplary chemical entities suitable for use in the methods of the embodiments will now be described with reference to illustrative synthetic schemes with respect to their general preparation herein and subsequent specific examples. One skilled in the art will recognize that to obtain the various compounds herein, the starting materials can be appropriately selected so that the desired substituents will be carried through the reaction process with or without protection as needed to produce the desired products. Alternatively, it may be necessary or desirable to utilize a suitable group that can be carried through the reaction process and, when appropriate, replaced by the desired substituent in the position of the final desired substituent. In addition, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups. Each reaction depicted in the general scheme is preferably run at a temperature of about 0°C to the reflux temperature of the organic solvent used.

[0982] 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 in the next synthesis step.

[0983] In the following example descriptions, specific embodiments are described. These embodiments are described in sufficient detail to enable one skilled in the art to practice certain embodiments of the present invention. Other embodiments may be used, 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.

[0984] The methods described herein generally provide specific enantiomers or diastereomers as desired products, but the stereochemistry of the enantiomers or diastereomers is not determined in all cases. When the stereochemistry of a specific stereocenter among enantiomers or diastereomers is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0985] Representative syntheses of compounds of the invention are described in the following schemes and in the specific examples that follow. Compounds are named using Marvin Sketch (ChemAxon, Budapest, Hungary).

[0986] Example 1. General Synthesis Method

[0987] The specific 2'3'-cyclic dinucleotides described in detail in the Examples were synthesized according to the general synthetic methods described below.

[0988] List of abbreviations:

[0989] ACN acetonitrile

[0990] BOMOM Benzoyloxymethoxymethyl

[0991] BSA bovine serum albumin

[0992] Bz benzoyl

[0993] CPG controlled pore glass

[0994] CSO (-)-(8,8-Dichlorocamphorylsulfonyl)-oxaziridine

[0995] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0996] DCA dichloroacetic acid

[0997] DCM dichloromethane

[0998] DMAM Dimethylaminomethylene

[0999] DMF dimethylformamide

[1000] DMOCP 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide

[1001] DMSO dimethyl sulfoxide

[1002] DMTr 4,4-dimethoxytrityl

[1003] EtOH

[1004] ESI-MS Electrospray Ionization Mass Spectrometry

[1005] ETT ethylthiotetrazolyl

[1006] FBS fetal bovine serum

[1007] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[1008] HPLC high performance liquid chromatography

[1009] Hpx Hypoxanthine

[1010] HRMS High Resolution Mass Spectrometry

[1011] iBu isobutyl

[1012] iPr Isopropyl

[1013] LCAA long chain aminoalkyl

[1014] MeIm 1-methylimidazole

[1015] MeOH methanol

[1016] MOP 4-methoxy-1-oxo-2-pyridylmethyl

[1017] MOP-OH 4-methoxy-1-oxo-2-pyridylmethanol

[1018] MPNO 4-methoxypyridine-1-oxide

[1019] NMR Nuclear Magnetic Resonance

[1020] Pic 4-methoxy-2-pyridinylmethyl

[1021] Pic-OH 4-methoxy-2-pyridinylmethanol

[1022] Py pyridine

[1023] TBDMS tert-butyldimethylsilyl

[1024] TBDMSCl tert-Butyldimethylsilyl chloride

[1025] tBuOOH tert-butyl peroxide

[1026] TEA triethylamine

[1027] TEAB triethylammonium bicarbonate

[1028] THF Tetrahydrofuran

[1029] TIPSCl triisopropylbenzenesulfonyl chloride

[1030] Ts p-Toluenesulfonyl

[1031] Tzol Tetrazol

[1032] Preparation of monomers derived from nucleoside-2′-phosphonic acid methyl ester and nucleoside-3′-phosphonic acid methyl ester

[1033] According to Páv,O; I.;Barvík,I.;Pohl,R.; M.; Rosenberg, I. Synthesis of oligoribonucleotides with phosphonate-modified linkages. Org. Biomol. Chem. 2011, 9, 6120-6126 and Páv, O.; Panova, N.; J.; Zborníková, E.; Rosenberg I. Activation of human RNase L by 2′- and 5′-O-methylphosphonate-modified oligoadenylates. Bioorg. Med. Chem. Lett. 2012, 22, 181-185. Preparation of phosphonate and aminophosphonate monomers. 2′-Deoxy-2′-fluoro and 3′-deoxy-3′-fluorophosphonate and phosphoramidate monomers were also prepared using the known precursor protocols mentioned above (Kovacs T., Van Aerschot A., Herdewijn P., Torrence PF Nucleosides, Nucleotides & Nucleic Acids 1995, 14:6, 1259-1267; Van Aerschot A., Herdewijn P., Janssen G., Cools M., DeClercq E. Antiviral Research 1989, 12, 133-150). Alternatively, the precursors can be purchased from Carbosynth.

[1034] Process 1

[1035]

[1036] Compound characterization was consistent with literature values. Exemplary data are shown in the table below.

[1037]

[1038] Representative syntheses of intermediate 6 containing adenine (A) and intermediate 14 containing guanine (G) are described below.

[1039] Intermediate 6 was prepared by adding sodium hydride (0.72 g, 18.0 mmol) to a stirred solution of intermediate 2 (4 g, 6 mmol) in DMF (60 mL) at 4°C under argon (Scheme 1). The reaction mixture was stirred at 4°C for an additional 60 min. Diisopropyltoluenesulfonyloxymethyl phosphonate (3.1 g, 9.0 mmol) was added to the reaction mixture, which was stirred at room temperature under argon for an additional 16 h, at which time glacial AcOH (1.0 mL, 18.0 mmol) in DMF (10 mL) was added dropwise to the reaction mixture at 4°C. The subsequent mixture was evaporated and the crude phosphonate was purified by silica gel chromatography (eluting with a gradient of 0% to 10% ethanol in chloroform) to give 3.5 g (69%) of: C 45 H 49 O9N5FNaP(M+Na) +HRMS (ESI) calculated value 876.31441, experimental value 876.31425.

[1040] Bromotrimethylsilane (2.2 mL; 16.4 mmol) was added to a solution of diisopropyl phosphonate (3.5 g; 4.1 mmol) and 2,6-lutidine (3.8 mL; 32.8 mmol) prepared above in ACN (45 mL). The reaction mixture was stirred at room temperature for 16 hours 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.

[1041] DMOCP (3.8 g; 20.5 mmol) was added to a solution of the nucleoside phosphonic acid prepared above, MOP-OH (1.9 g; 12.3 mmol), and MPNO (2.6 g; 20.5 mmol) in pyridine (45 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched by the addition of 2 M TEAB (20 mL), and evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with 0.2 M TEAB (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, evaporated, and co-evaporated with dioxane to give the crude diMOP phosphonate, which was used without further purification.

[1042] The above diMOP phosphonate was treated with thiophenol (6 mL) and TEA (8.4 mL) in dioxane (45 mL) at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and directly purified by silica gel chromatography (eluting with a gradient of 0% to 100% ethyl acetate / ethanol / acetone / water 4:1:1:1 in ethyl acetate) (TEA-buffered SiO2). The resulting intermediate 6 was lyophilized from dioxane: C 46 H 43 FN6O 11 HRMS of P(MH) - : Calculated value 905.27115, experimental value 905.27039; 1H NMR(DMSO-d6)δ11.25(br s,1H),8.74(s,1H),8.67(s,1H),8.12(d,J=7.2Hz,1H),8.04(m,2H),7.64(m,1H),7.55(m,2H),7.27(m,2H),7.19(m,2H),7.14(m, 4H),7.135(m,1H),7.12(d,J=3.6Hz,1H),6.94(dd,J=7.2,3.6Hz,1H),6.77(m,4H),6.43(dd,J=18.7,1.6Hz,1H),6.01(ddd,J=52. 0,4.0,1.6Hz,1H),4.91(ddd,J=22.2,8.1,4.0Hz,1H),4.87(dd,J=17.2,8.0Hz,1H),4.83(dd,J=17.2,8.2Hz,1H),4.19(ddd,J=8. 1,4.8,2.5Hz,1H),3.76(s,3H),3.68(s,3H),3.67(s,3H),3.62(m,2H),3.29(dd,J=10.9,2.5Hz,1H),3.22(dd,J=10.9,4.8Hz,1H); 31 P NMR (DMSO-d6) δ 12.53; 19 F NMR (DMSO-d6) δ-199.74.

[1043] Preparation of intermediate 14: ACN (14.4 mL, 6.5 mmol) containing 0.45 M tetrazole was added to a stirred solution of intermediate 10 (1.4 g, 2.2 mmol) and N,N,N′,N′-tetraisopropylphosphonomethyl diamidoester (1.8 mL, 6.5 mmol) in DCM (20 mL) under argon (Scheme 1). The reaction mixture was stirred at room temperature under argon for 2 h. The reaction mixture was diluted with DCM (300 mL) and extracted with a saturated solution of sodium bicarbonate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in toluene (5 mL) and added dropwise to hexane (300 mL). The precipitate was collected and lyophilized from benzene to give 1.3 (72%): 31 P NMR (C6D6) δ 155.69 (d, J = 4.8 Hz), 155.27 (d, J = 5.8 Hz).

[1044] Process 2

[1045]

[1046] Preparation of Intermediate 16: Sodium hydride (0.72 g, 18.0 mmol) was added to a stirred solution of Intermediate 2 (4 g, 6 mmol) in DMF (60 mL) at 4°C under argon (Scheme 2). The reaction mixture was stirred at 4°C for an additional 60 min. Diisopropyltoluenesulfonyloxymethyl phosphonate (3.1 g, 9.0 mmol) was added to the reaction mixture, which was stirred at room temperature under argon for an additional 16 h, at which time glacial AcOH (1.0 mL, 18.0 mmol) in DMF (10 mL) was added dropwise to the reaction mixture at 4°C. The subsequent mixture was evaporated and the crude phosphonate was purified by silica gel chromatography (eluting with a gradient of 0% to 10% ethanol in chloroform) to give 3.5 g (69%) of: C 45 H 49 O9N5FNaP(M+Na) + HRMS (ESI) calculated value 876.31441, experimental value 876.31425.

[1047] Bromotrimethylsilane (2.2 mL; 16.4 mmol) was added to a solution of diisopropyl phosphonate (3.5 g; 4.1 mmol) and 2,6-lutidine (3.8 mL; 32.8 mmol) prepared above in ACN (45 mL). The reaction mixture was stirred at room temperature for 16 hours 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.

[1048] DMOCP (3.8 g; 20.5 mmol) was added to a solution of the nucleoside phosphonic acid prepared above, Pic-OH (1.9 g; 12.3 mmol), and MPNO (2.6 g; 20.5 mmol) in pyridine (45 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched by the addition of 2 M TEAB (20 mL), and evaporated. The residue was dissolved in chloroform (0.5 L) and extracted with 0.2 M TEAB (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, evaporated, and co-evaporated with dioxane to give the crude diPic phosphonate, which was used without further purification.

[1049] The diPic phosphonate prepared above was treated with thiophenol (6 mL) and TEA (8.4 mL) in dioxane (45 mL) at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and directly purified by silica gel chromatography (eluting with a gradient of 0% to 100% ethyl acetate / ethanol / acetone / water 4:1:1:1 in ethyl acetate) (TEA-buffered SiO2). Intermediate 16 was lyophilized from dioxane to give 2.4 g (66%) of: C46 H 43 FN6O 10 P(MH) - HRMS (ESI) calculated value 889.27623, experimental value 889.27583; 1 H NMR(DMSO-d6)δ11.25(br s,1H),8.74(s,1H),8.67(s,1H),8.26(d,J=5.7Hz,1H),8.04(m,2H),7.64(m,1H),7.54(m,2H),7.27(m,2H),7.19(m,2H),7 .14(m,5H),7.04(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),3.77(s,3H),3.67(s,6H),3.64(m,2H),3.31(dd,J=11.0,2.5Hz,1H),3.22(dd,J=11.0,5.0Hz,1H); 31 P NMR (DMSO-d6) δ 12.48; 19 F NMR (DMSO-d6) δ-199.61.

[1050] Preparation of intermediate 17: Phosphonate 16 (1.3 g, 1.5 mmol) was loaded onto a silica gel column in DCM (10 mL) (Scheme 2). The column was washed with DCA (10 mL, 3% in DCM) and aged at room temperature for 15 min, whereupon it was then washed with a mixture of DCA (25 mL, 3% in DCM) / 10% EtOH / CHCl (25 mL), and thereafter with 10% EtOH / CHCl (100 mL). The crude product 17 was washed off the column with 50% MeOH / H2O (100 mL), evaporated, purified by preparative HPLC (eluting with a gradient of 0 to 50% methanol in water), and lyophilized from water to give 0.54 g (63%) of: C 25 H 25 FN6O8P(MH) - HRMS (ESI) calculated value 587.14555, found value 587.14561; 1H NMR(DMSO-d6)δ11.23(br s,1H),8.82(s,1H),8.76(s,1H),8.26(d,J=5.6Hz,1H),8.05(m,2H),7.64(m,1H),7.55(m,2H),7.11(d,J=2.6Hz ,1H),6.81(dd,J=5.6,2.6Hz,1H),6.36(d,J=16.1Hz,1H),5.55(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=9.2,2.1Hz,1H),3.82(s,3H),3 .82(dd,J=13.2,2.1,1H), 3.78(dd,J=13.2,2.1,1H), 3.64(dd,J=14.2,8.0Hz,1H), 3.60(dd,J=14.2,3.5Hz,1H); 31 P NMR (DMSO-d6) δ 13.65; 19 F NMR (DMSO-d6) δ -198.08.

[1051] Preparation of modified solid support CE-CPG

[1052] according to O. et al. (2008). Collection of Czechoslovak Chemical Communications 73(1):32-43. Preparation of solid support (LCAA-CPG) modified with 12-cyano-13-[(4,4′-dimethoxytrityl)oxy]-3,6,9-trioxatridecane hydrosuccinate (CE-CPG).

[1053] CE-CPG

[1054]

[1055] Synthesis of dinucleotides derived from nucleoside-2′-phosphonic acid methyl esters and nucleoside-3′-phosphonic acid methyl esters

[1056] Dinucleotides were synthesized from CE-CPG (20 mg) in the 5'→2'(3') direction using the "trityl off" method at a scale of 1 μmol per column, see Scheme 1. Synthesis schemes for the phosphotriester and phosphamidon methods are shown in Table 1. Typically, six columns were used to prepare CDNs. Synthesis was performed on a MOS oligonucleotide synthesizer (IOCB Prague, Czech Republic). In many cases, the end-capping step was optional. The average yield of the coupling step was in the range of 93 to 95% (conductivity detector, DMTr + ).

[1057] Table 1. Protocols for dinucleotide synthesis

[1058]

[1059]

[1060] Cyclization, deprotection and purification of dinucleotides

[1061] To the CE-CPG solid support with the bound linear dimer was added a 10% Et2NH in ACN solution (500 μl) and the heterogeneous mixture was shaken at room temperature for 2 h using an Eppendorf Thermomixer Comfort shaker. The solvent was evaporated and a solution of DMOCP (18 mg) in pyridine (400 μl) was added. The heterogeneous mixture was shaken at room temperature for 2 h. 10 μl of Et3N and 266 μl of water were then added to the reaction mixture and shaking was continued at 65°C for 16 h. The reaction mixture was evaporated.

[1062] To the reaction mixture was added 50% aqueous MeOH (600 μl) and the solid support was separated from the solution by decantation and washed with 50% aqueous MeOH (3×200 μl). To the methanol solution was added 33% MeNH 2 in EtOH (600 μl) and the mixture was shaken at room temperature for 8 hours. The solvent was then evaporated. The residue was dissolved in 0.1 mol.l -1 The 5-mer was dissolved in TEAB (1.5 ml) and applied to a semi-preparative C18 column (Luna 5 μm C18 250×10 mm). Cyclic dinucleotides were separated by reverse phase chromatography.

[1063] In the case of TBDMS protected CDN, the protocol after MeNH2 treatment and evaporation was as follows modified from the above procedure. The residue was dissolved in 20% ACN / 0.1 mol.l -1 TEAB (1.5 ml) and loaded on a SEP-PAK column. -1The column was washed with TEAB (5 ml). The product was then eluted with 80% ACN / water solution (5 ml). The eluent was evaporated and the residue was co-distilled with iPrOH (3×200 μl). The silylated dinucleotide was dissolved in a mixture of DMSO (115 μl), Et3N (60 μl) and Et3N·3HF (75 μl) and the reaction mixture was heated at 65° C. for 3 h. The solution was washed with 0.1 mol·l - 1 TEAB (3 mL) was diluted and loaded onto a semi-preparative C18 column (Luna 5 μm C18 250×10 mm). Cyclic dinucleotides were separated by reverse phase chromatography.

[1064] The preparative HPLC conditions used for purification were as follows: Luna C18 (5 μm, 250×10 mm, Phenomenex); flow rate 3 mL / min; mobile phase A: 0.1 M TEAB / H 2 O, mobile phase B: 50% ACN / 0.1 M TEAB / H 2 O; HPLC method 1: isocratic elution of A (15 min) followed by a linear gradient of A to 30% B (35 min); HPLC method 2: isocratic elution of A (15 min) followed by a linear gradient of A to 20% B (35 min).

[1065] Scheme 3. Exemplary Synthesis of CND Derived from Nucleoside-2′-Methyl Phosphonate and Nucleoside-3′-Methyl Phosphonate

[1066]

[1067] Example 3

[1068] Example 2. (1R,6R,8R,9R,10S,16R,18R,19R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-18-(6-amino-9H-purin-9-yl)-3,9,13,19-tetrahydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1069]

[1070] The solid phase product was prepared according to the above method without the end-capping step.

[1071] C 21 H 25 N 10 O 13 ESI-MS of P2 (MH)- Calculated value: 687.1; Found value: 687.1; HPLC method 1, retention time (min) = 33.3. 1 H and 31 P NMR data:

[1072]

[1073] Example 3. (1R,6S,7R,8R,10R,16R,17R,19R)-17-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-4,7,13,19-tetrahydroxy-3,5,9,12,15,18-hexaoxa-4λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-4,13-dione

[1074]

[1075] The solid phase product was prepared according to the above method without the end-capping step.

[1076] C 21 H 25 N 10 O 13 ESI-MS of P2 (MH) - Calculated value: 687.1; Found: 687.1; HPLC method 1, retention time (min) = 35.2.

[1077] Example 4. (1R,6R,7R,8R,10R,16R,17R,19R)-17-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-7-fluoro-4,13,19-trihydroxy-3,5,9,12,15,18-hexaoxa-4λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-4,13-dione

[1078]

[1079] The solid phase product was prepared according to the above method without the end-capping step.

[1080] C 21 H 24 FN 10 O12 ESI-MS of P2 (MH) - Calculated value: 689.1; Found: 689.1; HPLC method 1, retention time (min) = 33.6.

[1081] At 25℃ in D2O 1 H. 19 F and 31 P NMR data:

[1082]

[1083] Example 5. (1R,6R,8R,9R,10S,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-3,9,13,19-tetrahydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1084]

[1085] The solid phase product was prepared according to the above method without the end-capping step.

[1086] C 21 H 25 N 10 O 13 ESI-MS of P2 (MH) - Calculated value: 687.1; Exp. value: 687.1; HPLC method 1, retention time (min) = 35.6. 1 H and 31 P NMR data:

[1087]

[1088] Example 6. (1R,6S,7R,8R,10R,16R,17R,19R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-4,7,13,19-tetrahydroxy-3,5,9,12,15,18-hexaoxa-4λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-4,13-dione

[1089]

[1090] The solid phase product was prepared according to the above method without the end-capping step.

[1091] C 21 H 25 N 10 O 13 ESI-MS of P2 (MH) - Calculated value: 687.1; Found: 687.1; HPLC method 1, retention time (min) = 34.6.

[1092] Example 7. (1R,6R,7R,8R,10R,16R,17R,19R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-7-fluoro-4,13,19-trihydroxy-3,5,9,12,15,18-hexaoxa-4λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-4,13-dione

[1093]

[1094] The solid phase product was prepared according to the above method without the end-capping step.

[1095] C 21 H 24 FN 10 O 12 ESI-MS of P2 (MH) - Calculated value: 689.1; Found: 689.1; HPLC method 1, retention time (min) = 35.8.

[1096] Example 8. (1R,6R,8R,9R,10S,16R,18R,19R)-8,18-bis(6-amino-9H-purin-9-yl)-3,9,13,19-tetrahydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1097]

[1098] The solid phase product was prepared according to the above method without the end-capping step.

[1099] C 21 H 25 N 10 O 12 ESI-MS of P2 (MH) - Calculated value: 671.1; Found: 671.1; HPLC method 1, retention time (min) = 33.5.

[1100] Example 9. (1R,7R,9R,10R,11S,17R,19R,20R)-9,19-bis(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-4,10,14,20-tetrahydroxy-2,5,8,12,15,18-hexaoxa-4λ 5 ,14λ 5 -diphosphatricyclic [15.2.1.0 7 , 11 ]Eicosane-4,14-dione

[1101]

[1102] The solid phase product was prepared according to the above method without the end-capping step.

[1103] C 22 H 27 N 10 O 14 ESI-MS of P2 (MH) - Calculated value: 717.1; Found: 717.1; HPLC method 1, retention time (min) = 31.5.

[1104] Example 10. (1R,6R,8R,9R,10R,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-9-fluoro-3,13,19-trihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1105]

[1106] The solid phase product was prepared according to the above method without the end-capping step.

[1107] C 21 H 24 FN 10 O12 ESI-MS of P2 (MH) - Calculated value: 689.1; Found value: 689.1; HPLC method 2, retention time (min) = 46.4. 1 H. 19 F and 31 P NMR data:

[1108]

[1109] Example 11. (1R,6R,8R,9S,10S,16R,18R,19R)-8,18-bis(6-amino-9H-purin-9-yl)-3,9,13,19-tetrahydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1110]

[1111] The solid phase product was prepared according to the above method without the end-capping step.

[1112] C 21 H 25 N 10 O 12 ESI-MS of P2 (MH) - Calculated value: 671.1; Found: 671.1; HPLC method 1, retention time (min) = 28.9.

[1113] Example 12. (1R,7R,9R,10R,11R,17R,19R,20S)-9,19-bis(6-amino-9H-purin-9-yl)-4,10,14,20-tetrahydroxy-2,5,8,12,15,18-hexaoxa-4λ 5 ,14λ 5 -diphosphatricyclic [15.2.1.0 7 , 11 ]Eicosane-4,14-dione

[1114]

[1115] The solid phase product was prepared according to the above method without the end-capping step.

[1116] C 22 H 27 N 10 O 12ESI-MS of P2 (MH) - Calculated value: 685.1; Found: 685.1; HPLC method 1, retention time (min) = 30.9.

[1117] Example 13. (1S,7R,9R,10S,11S,17R,19R,20R)-9,19-bis(6-amino-9H-purin-9-yl)-4,10,14,20-tetrahydroxy-2,5,8,12,15,18-hexaoxa-4λ 5 ,14λ 5 -diphosphatricyclic [15.2.1.0 7 , 11 ]Eicosane-4,14-dione

[1118]

[1119] The solid phase product was prepared according to the above method without the end-capping step.

[1120] C 22 H 27 N 10 O 12 ESI-MS of P2 (MH) - Calculated value: 685.1; Found: 685.1; HPLC method 1, retention time (min) = 29.9.

[1121] Example 14. (1R,6R,8R,9R,10R,16R,18R,19R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-18-(6-amino-9H-purin-9-yl)-9-fluoro-3,13,19-trihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1122]

[1123] The solid phase product was prepared according to the above method without the end-capping step.

[1124] C 21 H 24 FN 10 O 12 ESI-MS of P(MH) - Calculated value: 689.1, experimental value: 689.1; HPLC method 2, retention time (min) = 40.7; 1H NMR(D2O)δ8.39(s,1H),8.17(s,1H),7.83(s,1H),6.27(d,J=8.1Hz,1H),6.26(d,J=19.4Hz,1H),5.70( dd,J=52.1,4.0Hz,1H),5.33(ddd,J=9.2,8.1,4.7Hz,1H),4.85(ddd,J=20.7,8.8,4.0Hz,1H),4.70(d, J=4.7Hz,1H),4.50(dd,J=3.7,2.6Hz,1H),4.43(m,1H),4.22(dt,J=11.8,3.2Hz,1H),4.20(ddd,J=11. 4,5.4,2.6Hz,1H),4.15(ddd,J=11.4,3.7,2.5Hz,1H),4.08(ddd,J=11.8,4.1,2.7Hz,1H),4.04(m,2H); 19 F NMR (D2O) δ-198.4; 31 P NMR (D2O) δ 17.9, -0.7.

[1125] Example 15. (1R,6R,8R,10S,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-3,13,19-trihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1126]

[1127] The solid phase product was prepared according to the above method without the end-capping step.

[1128] C 21 H 25 N 10 O 12 ESI-MS of P2 (MH) - Calculated value: 671.1; Found value: 671.1; HPLC method 2, retention time (min) = 39.2; 1H NMR(D2O)δ8.28(s,1H),8.24(s,1H),8.08(s,1H),6.43(dd,J=6.7,5.4Hz,1H),6.09(d,J=7.9Hz,1H),5.06(ddd,J= 8.8,7,9,4.6Hz,1H),4.67(d,J=4.6Hz,1H),4.60(m,1H),4.49(m,1H),4.30(ddd,J=7.4,3.7,3.5Hz,1H),4.20(ddd ,J=11.5,5.2,2.3Hz,1H),4.11(ddd,J=11.5,3.3,2.5Hz,1H),4.06(ddd,J=11.1,5.8,3.7Hz,1H),3.93(dd,J=13.9 ,7.8Hz,1H),3.78(dd,J=13.9,10.0Hz,1H),2.84(ddd,J=14.2,6.9,5.4Hz,1H),2.77(ddd,J=14.2,6.7,5.5Hz,1H); 31 P NMR (D2O) δ 18.9, -0.3.

[1129] Example 16. (1R,6R,8R,9S,10S,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-3,9,13,19-tetrahydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1130]

[1131] The solid phase product was prepared according to the above method without the end-capping step.

[1132] C 21 H 25 N 10 O 13 ESI-MS of P2 (MH) - Calculated value: 687.1; Found value: 687.1; HPLC method 2, retention time (min) = 38.6; 1H NMR (D2O) δ8.31 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 6.38 (d, J = 5.4Hz, 1H), 6.10 (d, J = 8.1Hz, 1H), 5.06 (dd d,J=9.0,8.1,4.7Hz,1H),4.82(m,1H),4.66(d,J=4.7Hz,1H),4.48(ddd,J=3.5,2.5,2.0Hz,1H),4.34(d d,J=6.3,4.9Hz,1H),4.27(td,J=6.3,3.6Hz,1H),4.21(ddd,J=11.3,5.2,2.5Hz,1H),4.15(ddd,J=11.3 ,5.7,3.6Hz,1H),4.12(dd,J=13.6,7.7Hz,1H),4.10(m,1H),4.07(m,1H),3.90(dd,J=13.6,11.4Hz,1H); 31 P NMR (D2O) δ 18.4, -0.4.

[1133] Example 17. (1S,6R,8R,9R,10R,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-9,19-difluoro-3,13-dihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1134]

[1135] The solid phase product was prepared according to the above method without the end-capping step.

[1136] Alternatively, the compound is prepared in solution according to the sequence shown below. ETT (0.1 g; 0.82 mmol) is added to a solution of phosphonate intermediate 17 (0.1 g; 0.17 mmol) and phosphonamidate intermediate 14 (0.16 g; 0.20 mmol) in DCM (10 mL). The reaction mixture is stirred at room temperature under argon for 3 h. Thereafter, CSO (0.15 g; 0.56 mmol) is added and the mixture is stirred at room temperature for 1 h. The reaction mixture 1 is treated with methanol (10 mL) at room temperature and evaporated. The residue is treated with 80% acetic acid / water (10 mL) at room temperature for 2 h. The solution is directly loaded onto a C18 column and the linear phosphonate dimer 18:C is separated using a linear gradient of acetonitrile in 5 mM ammonium bicarbonate.40 H 44 F2N 11 O 15 P2(MH) - ESI-MS (intermediate 18) calcd. 1018.2, found 1018.2.

[1137]

[1138] To DMOCP (0.16 g; 0.85 mmol) was added a solution of linear phosphonate dimer 18 in pyridine (10 mL), and the reaction mixture was stirred at room temperature for 4.0 h. Thereafter, water (5 mL) was added and the mixture was stirred at 65 ° C for 3 h, evaporated and co-evaporated with methanol (3×10 mL). The cyclic dinucleotides were separated using a linear gradient of acetonitrile in 5 mM ammonium bicarbonate and evaporated. The residue was dissolved in 50% ACN / water (10 mL) and 33% methylamine / ethanol (5 mL) was added. The mixture was stirred for 6 h and evaporated. The product was purified using preparative C18 HPLC (eluting with a linear gradient of acetonitrile in 0.1 M TEAB). DOWEX Na + The desired product was converted into the sodium salt and lyophilized from water; C 21 H 23 F2N 10 O 11 ESI-MS of P2 (MH) - Calculated value: 691.1; Found value: 691.1; HPLC method 2, retention time (min) = 48.9; 1 H NMR(D2O)δ8.25(s,1H),8.20(s,1H),8.02(s,1H),6.44(d,J=17.9Hz,1H),6.16(dd,J=15.6,8.2Hz,1H),5.69(dd,J =52.2,3.8Hz,1H),5.48(dq,J=53.4,4.0Hz,1H),5.14(dddd,J=24.6,9.4,8.2,4.0Hz,1H),4.74(m,1H),4.66(ddd, J=25.5,9.3,3.8Hz,1H),4.51(m,1H),4.29(dt,J=12.0,3.1Hz,1H),4.27(ddd,J=11.6,5.6,2.4Hz,1H),4.16(ddd, J=12.0,4.0,2.5Hz,1H),4.10(dt,J=11.6,2.1Hz,1H),4.06(dd,J=14.0,8.2Hz,1H),3.90(dd,J=14.0,9.4Hz,1H); 19F NMR (D2O) δ -193.9, -199.3; 31 P NMR (D2O) δ 17.9, -0.7.

[1139] Example 18. (1R,6R,8R,9R,10R,16S,18R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-9-fluoro-3,13-dihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1140]

[1141] The solid phase product was prepared according to the above method without the end-capping step.

[1142] C 21 H 24 FN 10 O 11 ESI-MS of P2 (MH) - Calculated value: 673.1; Found value: 673.1; HPLC method 2, retention time (min) = 42.6; 1 H NMR(D2O)δ8.27(s,1H),8.26(s,1H),7.98(s,1H),6.46(d,J=17.6Hz,1H),6.01(d,J=4.7Hz,1H),5.66(dd,J= 52.1,3.6Hz,1H),5.14(dq,J=6.4,4.7Hz,1H),4.59(ddd,J=25.1,9.2,3.6Hz,1H),4.67(m,1H),4.52(m,1H), 4.35(ddd,J=12.0,2.5,2.0Hz,1H),4.19(ddd,J=11.4,7.8,3.2Hz,1H),4.15(ddd,J=12.0,3.5,2.2Hz,1H),4 .05(ddd,J=11.4,6.2,4.7Hz,1H),4.01(dd,J=13.4,7.8Hz,1H),3.84(dd,J=13.4,11.4Hz,1H),2.59(m,2H); 19 F NMR (D2O) δ-199.5; 31 P NMR (D2O) δ17.9, -0.9.

[1143] Example 19. (1S,6R,8R,9R,10S,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-19-fluoro-3,9,13-trihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1144]

[1145] The solid phase product was prepared according to the above method without the end-capping step.

[1146] C 21 H 24 FN 10 O 12 ESI-MS of P2 (MH) - Calculated value: 689.1; Found value: 689.1; HPLC method 2, retention time (min) = 44.6; 1 H NMR(D2O)δ8.25(s,1H),8.22(s,1H),8.02(s,1H),6.16(d,J=8.2Hz,1H),6.14(d,J=1.5Hz,1H) ,5.50(dd,J=53.2,3.9Hz,1H),5.12(dddd,J=24.7,9.2,8.2,3.9Hz,1H),4.82(m,1H),4.76(ddd ,J=3.2,2.5,2.3Hz,1H),4.46(m,2H),4.27(ddd,J=11.6,5.3,2.5Hz,1H),4.25(m,1H),4.14(m, 1H), 4.12 (dt, J=11.6, 2.3Hz, 1H), 4.04 (dd, J=14.1, 7.3Hz, 1H), 3.83 (dd, J=14.1, 10.0Hz, 1H); 19 F NMR (D2O) δ-194.0; 31 P NMR (D2O) δ 18.5, -0.7.

[1147] Example 20. (1S,6R,8R,10S,16R,18R,19R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-19-fluoro-3,13-dihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1148]

[1149] The solid phase product was prepared according to the above method without the end-capping step.

[1150] C 21 H 24 FN 10 O 11 ESI-MS of P2 (MH) - Calculated value: 673.1; Found value: 673.1; HPLC method 2, retention time (min) = 45.4; 1 H NMR(D2O)δ8.27(s,1H),8.24(s,1H),8.07(s,1H),6.43(dd,J=6.7,5.4Hz,1H),6.15(d,J=8.2Hz,1H),5.48(dd,J=53.4,4.0Hz,1H), 5.12(dddd,J=24.9,8.7,8.2,4.0Hz,1H),4.77(dt,J=25.0,2.3Hz,1H),4.59(dddd,J=6.7,5.6,4.9Hz,1H),4.31(m,1H),4.27(ddd,J =11.6,5.2,2.5Hz,1H),4.14(ddt,J=11.6,3.1,2.3Hz,1H),4.09(ddd,J=11.1,5.8,3.5Hz,1H),3.95(dd,J=14.0,7.7Hz,1H),3.91( ddd,J=11.1,7.8,7.2Hz,1H),3.77(dd,J=14.0,10.0Hz,1H),2.84(ddd,J=14.0,6.7,5.4Hz,1H),2.77(ddd,J=14.0,6.7,5.6Hz,1H); 19 F NMR (D2O) δ-193.9; 31 P NMR (D2O) δ 19.3, -0.2.

[1151] Example 21. (1R,6R,8R,9R,10S,16S,18R)-18-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-3,9,13-trihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5-diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1152]

[1153] The solid phase product was prepared according to the above method without the end-capping step.

[1154] C 21 H 25 N 10 O 12 ESI-MS of P2 (MH) - Calculated value: 671.1; Found value: 671.1; HPLC method 2, retention time (min) = 42.6; 1 H NMR(D2O)δ8.30(s,1H),8.25(s,1H),7.97(s,1H),6.17(d,J=1.5Hz,1H),6.01(d,J=4.5Hz,1H),5.13(dq,J=6.2,4.5Hz,1H) ,4.80(dd,J=4.5,1.5Hz,1H),4.67(m,1H),4.47(dq,J=8.5,2.6Hz,1H),4.42(dd,J=8.5,4.5Hz,1H),4.31(dt,J=12.2,4.0, 2.5Hz,1H),4.19(ddd,J=11.2,7.7,2.8Hz,1H),4.14(ddd,J=12.2,4.0,2.5Hz,1H),4.07(ddd,J=11.2,6.4,4.7Hz,1H),3.9 8(dd,J=13.7,7.4Hz,1H),3.78(dd,J=13.7,11.2Hz,1H),2.61(ddd,J=13.5,7.4,6.3Hz,1H),2.57(dt,J=13.5,6.1Hz,1H); 31 P NMR (D2O) δ18.4, -0.8.

[1155] Example 22. (1S,6R,8R,9R,10R,16R,18R,19R)-8,18-bis(6-amino-9H-purin-9-yl)-9,19-difluoro-3,13-dihydroxy-2,4,7,11,14,17-hexaoxa-3λ 5 ,13λ 5 -diphosphatricyclic [14.2.1.0 6 , 10 ]nonadecane-3,13-dione

[1156]

[1157] The solid phase product was prepared according to the above method without the end-capping step.

[1158] Alternatively, the compound is prepared in solution according to the sequence shown above. ETT (35 mg; 0.28 mmol) is added to a solution of phosphonate intermediate 17 (29 mg; 0.050 mmol) and aminophosphoric acid ester intermediate 12 (46 mg; 0.055 mmol) in DCM (4 mL). The reaction...

Claims

1. A compound of formula (IA): Or a compound of formula (IB): or a pharmaceutically acceptable salt thereof, in L 1 is -O- or -O-CH2-, wherein the CH2 group is attached to the phosphorus atom; L 2 is -O-CH2-, wherein the CH2 group is attached to the phosphorus atom; Y 1 and Y 2 Each is -O-; X 1 and X 3 Each independently is OR 13 or SR 13 ; X 2 and X 4 Each independently is O or S; R 1 , R 5 , R 8 , R 2 , R 4 , R 9 , R 10 and R 12 Each is H; R 3 and R 11 Each independently is H, OH or F; Each R 13 are independently H or C1-C6 alkyl; Base 1 and bases 2 Each independently is:

2. The compound according to claim 1, wherein X 2 and X 4 is O, and X 1 and X 3 Each independently is OR 13 .

3. The compound according to claim 1, wherein the compound of formula (IA) has the structure of formula (IA-1): or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound of formula (IA) has the structure of formula (IA-2): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound of formula (IA) has the structure of formula (IA-3): or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound of formula (IA) has the structure of formula (IA-4): or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound of formula (IA) has the structure of formula (IA-5): or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-1): or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-2): or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-3): or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-4): or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-5): or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-6): or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-7): or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound of formula (IB) has the structure of formula (IB-8): or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein Base 1 and bases 2 Each independently is:

17. The compound according to claim 1, wherein the compound of formula (IA) or formula (IB) has the following structure: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. Use of the pharmaceutical composition according to claim 18 for the preparation of a medicament for activating a STING adaptor protein and inducing the production of type I interferons, cytokines and / or chemokines that are dependent on the STING adaptor protein.

20. Use of the pharmaceutical composition according to claim 18 for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is used to treat or prevent viral infection, hyperproliferative disease or cancer in humans or animals.

21. Use of the pharmaceutical composition according to claim 18 for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is used to treat or prevent hepatitis B virus infection or HIV infection in humans or animals.

22. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for activating a STING adaptor protein.

23. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease or condition responsive to activation of a STING adaptor protein in a human or animal in need thereof.

24. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is for treating or preventing a viral infection in a human or animal in need thereof.

25. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is used to treat or prevent hepatitis B virus infection or HIV infection in a human or animal in need thereof.

26. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is for treating or preventing a hyperproliferative disease or cancer in a human or animal in need thereof.

27. Use according to any one of claims 22 to 26, wherein the compound is administered together with another therapeutically active agent.

28. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutically active agents for the preparation of a medicament for treating or preventing a disease or condition responsive to activation of a STING adaptor protein in humans or animals.

29. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutically active agents for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is for treating or preventing a viral infection in a human or animal.

30. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutically active agents for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is for the treatment or prevention of hepatitis B virus infection or HIV infection in humans or animals.

31. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutically active agents for the preparation of a medicament for activating a STING adaptor protein, wherein the medicament is for the treatment or prevention of a hyperproliferative disease or cancer in humans or animals.

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