Prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenosine nucleosides and methods for their preparation and use

Abstract

To provide methods for treating diseases.SOLUTION: The present disclosure provides prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenosine nucleosides, and compositions, methods and kits thereof. Such compounds can be useful for treating virus infections including human immunodeficiency virus. The compounds have the following formula (I). Provided herein are compounds functioning as antiviral agents (in some embodiments, as anti-HIV agents), pharmaceutical compositions comprising such a compound and optionally in combination with one or more (e.g., two, three or four) additional therapeutic agents, and methods for using such compounds and compositions. Embodiment of every disclosed compound includes pharmaceutically acceptable salts and stereoisomers thereof or a mixture of the stereoisomers.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 992,733, filed March 20, 2020, entitled "PRODRUGS OF 4'-C-SUBSTITUTED-2-HALO-2-DEOXYADENOSINE NUCLEOSIDES AND METHODS OF MAKING AND USING THE SAME," which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to compounds, compositions, and methods for treating viral infections. [Background technology]

[0003] Human immunodeficiency virus (HIV) infection is a serious, life-threatening disease of major public health importance, affecting tens of millions of people worldwide. There is no known cure, and therefore, those affected by HIV may require long-term treatment for the rest of their lives, which may include receiving one or more treatments per day and may result in a variety of side effects. Improved treatments for HIV and other viral infections are desirable. Summary of the Invention [Means for solving the problem]

[0004] Disclosed herein are, for example, compounds of formula (I): [ka] (In the formula, The dashed lines (----), together with the solid line parallel to the dashed lines, represent optional double bonds; X represents a halogen; R 1represents (C1-C6)alkynyl, R 2 is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -P(=O)(OR b )(R c1 ), -P(=O)(R c1 )(R c2 ), -C(= O)(OR d ), -C(=O)(R h ), -C(=O)(OR h ), or -C(=O)(LR h ) and R 3a is H or R e represents R 3b represents H or is absent, R 4 is R d or is absent, R 5 is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -C(=O)(OR d ), -P(=O)(OR b )(R c1 ), -C(=O)(R h ), -C(=O)(OR h ), or -C(=O)(LR h ) and Each R a is (C1~C 25 ) alkyl, which may be the same or different; In addition, each R a is one R b optionally substituted with Each R b represents phenyl or cyclohexyl, In addition, each R b are independently f, -CH2-OC(=O)(R f ), and -OC(=O)(R f Optionally substituted with 1 to 3 groups selected from Each R c1 and R c2 -NH-LC(=O)(OR f ) and -NH-LC(=O)(OR g ), which may be the same or different, Each R d is, independently, [ka] represents R e is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)-LOR f , -C(=O)-LOC(=O)(R f ), -C(=O)-OLC(=O)(OR f ), -C(=O)-LSC(=O)(R f ), -C(=O)(R b ), -C(=O)(OR b ), -C(=O)-OLC(=O)(OR d ), -C(=O)(R d ), -C(=O)(R h ), or -C(=O)(OR h ) and Each R f are independently (C1~C 18 ) alkyl, Each L is independently (C1 to C 18 ) alkylenyl, R g represents cyclohexyl, Each R h are independently a steroid derivative or a bridged, spirocyclic, or fused polycyclic (C7-C 18 ) represents a carbocyclic ring, In addition, the steroid derivative has -OH and (C1-C 12 ) optionally substituted with 1 to 4 groups independently selected from alkyl; R 5 If is H, then R 2 is -P(=O)(OR b )(R c1 ) or -P(=O)(R c1 )(R c2 ) instead of R 3a is H and R 3b is H and R 5 If is H, then R 2 is not H, —C(═O)((C1-C5) alkyl), or —C(═O)(Z-butyl-Z′), Z is a bond, (C1 to C 10 ) alkyl, C(R x )(R z ) and R x and R z are independently H, (C1-C6) alkyl, and (C6-C 10 ) cycloalkyl; R x and R z each is independently optionally substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy; Z' is H, (C1 to C 10 ) alkyl or (C1-C 10 )alkoxy, wherein Z' is optionally substituted with (C1-C6)alkyl, oxo, or (C1-C6)alkoxy; R 3a But R e and R 3b is H, R e is H, or -C(=O)(O-(C1-C6) alkyl) or -C(=O)(C1-C 25 ) alkyl, and R 5 is H or -C(=O)(O-(C1~C 25 ) alkyl), R 2 is -C(=O)(O-(C1~C25 ) alkyl) rather than R 2 is H or -C(=O)(O-(C1-C 10 ) alkyl) R 5 is optionally substituted with —C(═O)(oxo or (C1-C6) alkyl (C1-C 18 ) alkyl), -C(=O)-((C1-C 18 )alkyl), or -C(=O)(phenyl optionally substituted with (C1-C6)alkyl or -OC(=O)((C1-C6)alkyl), R e is (a)H, (b)-C(=O)(O-(C1~C 10 ) alkyl), or (c) -C(=O)((C1-C 15 ) alkyl) compounds, or a pharmaceutically acceptable salt thereof. Also disclosed herein are the sub-formulae Ia and Ib. Also disclosed herein are methods of making and using the same. can be. DETAILED DESCRIPTION OF THE INVENTION

[0005] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed in any way as limiting the scope of the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. I. Definition

[0006] The terms "about" or "approximately" used in connection with a quantity are inclusive of the stated value and have the meaning dictated by the context (e.g., include the degree of error associated with measurement of the particular quantity).

[0007] As used herein, the term "administering" or "administration" typically refers to administration of a composition to a subject to achieve delivery of the composition or an agent contained in the composition to a target site or site to be treated. Those of skill in the art will recognize various routes that may be utilized for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, administration may comprise a single administration. In some embodiments, administration may comprise the application of a fixed number of administrations. In some embodiments, administration may comprise administration that is intermittent (e.g., multiple administrations separated in time) and / or periodic (e.g., individual administrations separated by a common time). In some embodiments, administration may comprise continuous administration (e.g., perfusion application) over at least a selected period of time.

[0008] An "alkyl" is a hydrocarbon containing normal, secondary, or tertiary atoms. For example, an alkyl group can be one to twenty-five carbon atoms (i.e., C1-C 25 ) alkyl), 1 to 10 carbon atoms (i.e., (C1-C 10 (C1-C8) alkyl), 1 to 8 carbon atoms (i.e., (C1-C8) alkyl), or 1 to 6 carbon atoms (i.e., (C1-C6) alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (C1-C6) alkyl, and ethyl (C1-C6) alkyl. Ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl butyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (- CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3 3,3-dimethyl-2-butyl (-CH(CH)C(CH)), and octyl (-(CH)CH). "Alkyl" also refers to a saturated branched or straight-chain hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkyl group can be any group containing 1 to 10 carbon atoms (i.e., (C1-C 10(C1-C6) alkyl), 1 to 6 carbon atoms (i.e., (C1-C6) alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3) alkyl). Typical alkyl radicals include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0009] As used herein, the term "(C 1~n ) alkyl (wherein n is an integer) ("(C1 to C n "(C ) alkyl", alone or in combination with another radical, is intended to mean an acyclic, straight-chain or branched-chain alkyl radical containing 1 to n carbon atoms. 1~6 )Alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (iso-propyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviation Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents a 1-methylethyl group, Bu represents a butyl group, and tBu represents a 1,1-dimethylethyl group.

[0010] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene refers to alkyl groups having 1 to 25 carbon atoms (i.e., C 1~25 alkylene), 1 to 8 carbon atoms (i.e., C 1~8 alkylene), 1 to 6 carbon atoms (i.e., C 1~6 alkylene), or may have 1 to 4 carbon atoms (i.e., C 1~4alkylene). Examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0011] "Alkenyl" refers to an alkyl group containing normal, secondary, or tertiary carbon atoms and at least one site of unsaturation, i.e., carbon-carbon, sp 2 It is a straight or branched chain hydrocarbon having a double bond. For example, an alkenyl group is an alkyl group having 2 to 20 carbon atoms (i.e., C2 to C6). 20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0012] As used herein, "(C 2~n The term "(C )alkenyl" (where n is an integer), alone or in combination with another radical, is intended to mean an unsaturated acyclic straight or branched chain radical containing 2 to n carbon atoms, at least two of which are joined together by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise specified, the term "(C )alkenyl" is intended to mean an unsaturated acyclic straight or branched chain radical containing 2 to n carbon atoms, at least two of which are joined together by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. 2~n The term "(C)alkenyl" is understood to encompass the individual stereoisomers where possible, including, but not limited to, the (E) and (Z) isomers, and mixtures thereof. 2~n) When an alkenyl group is substituted, unless otherwise specified, it is understood to be substituted on any carbon atom that would otherwise carry a hydrogen atom, and it is understood that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0013] "Alkynyl" refers to a straight or branched chain hydrocarbon containing normal, secondary, or tertiary carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. For example, an alkynyl group can be any group containing 2 to 20 carbon atoms (i.e., C2 to C6). 20 The alkynyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkyne), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0014] As used herein, "(C 2~n The term (C)alkynyl" (where n is an integer), alone or in combination with another radical, is intended to mean an unsaturated acyclic straight or branched chain radical containing 2 to n carbon atoms, at least two of which are joined to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. 2~n ) When an alkynyl group is substituted, unless otherwise specified, it is understood to be substituted on any carbon atom that would otherwise carry a hydrogen atom, and it is understood that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0015] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological) that is effective in inhibiting viral formation and / or replication in humans, including, but not limited to, agents that interfere with either host or viral mechanisms necessary for viral formation and / or replication in humans.

[0016] As used herein, the term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl refers to an aromatic ring of about 1 to 2 carbon atoms, in which at least one ring is aromatic (e.g., an aryl ring fused to one or more aryl or carbocyclic rings). These include phenyl radicals or ortho, spiro, or bridged bicyclic or polycyclic radicals having 9 to 14 atoms. Such bicyclic or polycyclic rings may be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the bicyclic or polycyclic ring. It is understood that the point of attachment of the bicyclic or polycyclic radicals defined above may be at any position on the ring, including the aryl or carbocyclic portions of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0017] "Arylalkyl" refers to an alkyl radical, as defined herein, in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical, as described herein (i.e., an aryl-alkyl-moiety). The alkyl group of an "arylalkyl" is typically 1 to 6 carbon atoms (i.e., an aryl(C1-C6)alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, and the like.

[0018] As used herein, "aryl-(C 1~nThe term aryl-(C )alkyl- (where n is an integer), alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above, which is itself substituted with an aryl radical as defined above. 1~n Examples of aryl-(C )alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, and phenylpropyl. 1~n ) When an alkyl-group is substituted, unless otherwise specified, it is understood that substituents may be attached to either the aryl portion or the alkyl portion, or both, and that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0019] The term "carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocyclic or polycyclic ring system. In one embodiment, a carbocycle is a monocyclic ring containing 3 to 6 ring carbons (i.e., (C3-C6)carbocycle). Examples of carbocycles include polycyclic carbocycles having 7 to 12 carbon atoms as bicyclic rings and polycyclic carbocycles having up to about 20 carbon atoms as polycyclic carbocycles, although the maximum single ring of a polycyclic carbocycle is 7 carbon atoms. The term "spirocarbocycle" refers to a carbocyclic ring system in which the rings of the ring system are connected to a single carbon atom (e.g., spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc.). The term "fused carbocycle" refers to a carbocyclic ring system in which the rings of the ring system are connected to two adjacent carbon atoms, such as bicyclo[4,5], [5,5], [5,6], or [6,6] systems, or in which 9-10 ring atoms are arranged as bicyclo[5,6] or [6,6] systems (e.g., decahydronaphthalene, norsabinane, norcarane). The term "bridged carbocycle" refers to a carbocyclic ring system in which the rings of the ring system are connected to two non-adjacent carbons (e.g., norbornane, bicyclo[2.2.2]octane, etc.). A "carbocycle" or "carbocyclyl" can be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups. Non-limiting examples of monocyclic carbocycles 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.

[0020] "Carbocyclylalkyl" refers to an alkyl radical, as defined herein, in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical, as defined herein (i.e., a carbocyclyl-alkyl- moiety). The alkyl group of an "alkyl" is typically 1 to 6 carbon atoms (i.e., carbocyclyl(C1-C6)alkyl). Typical carbocyclylalkyl groups include, but are not limited to, carbocyclyl-CH2-, carbocyclyl-CH(CH3)-, carbocyclyl-CH2CH2-, 2-(carbocyclyl)ethan-1-yl, and the like, and the "carbocyclyl" moiety contains any of the above carbocyclyl groups.

[0021] The term "chiral" refers to molecules that have the property of non-superimposability to their mirror image partners, while the term "achiral" refers to molecules that have the property of non-superimposability to their mirror image partners. - Refers to molecules that can be superimposed on the toner.

[0022] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms having 3 to 15 carbon atoms, and in some embodiments 3 to 10 carbon atoms or 3 to 7 carbon atoms, which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, cycloheptenyl, and cyclooctyl.

[0023] As used herein, "(C 3~m The term ")cycloalkyl" (where m is an integer), alone or in combination with another radical, means a cycloalkyl substituent containing 3 to m carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0024] As used herein, "(C 3~m ) cycloalkyl-(C 1~nThe term (C)alkyl-" (n and m are both integers), alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms, as defined above, which is itself substituted with a cycloalkyl radical containing 3 to m carbon atoms, as defined above. 3~7 ) cycloalkyl-(C 1~6 Examples of )alkyl- include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, and 2-cyclohexylethyl. (C 3~m ) cycloalkyl-(C 1~n ) If an alkyl-group is substituted, unless otherwise specified, it is understood that substituents may be attached to either the cycloalkyl or the alkyl portion thereof, or both, such that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0025] As used herein, "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administration of one or more agents or modalities to a subject receiving other agents or modalities in combination. For clarity, combination therapy does not require that the individual agents be administered together (or necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or active portions thereof may be administered together in a combination composition or even as a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0026] As used herein, the term "equivalent" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to one another, but that are sufficiently similar to permit a comparison thereof such that a person of ordinary skill in the art would understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, equivalent sets of conditions, circumstances, individuals, or populations are characterized by multiple substantially identical characteristics and one or a few different characteristics. A person of ordinary skill in the art will understand what level of identity is necessary in any given situation for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered equivalent in context. For example, a person of ordinary skill in the art will understand that a set of conditions, individuals, or populations is equivalent to one another when the sets are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in outcomes or phenomena obtained in different sets of conditions, individuals, or populations are caused by or indicate differences in variously varying these characteristics.

[0027] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising," are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0028] "Diastereomer" refers to a stereoisomer with two or more centers or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0029] As used herein, the term "dosage form" refers to a physically discrete unit of an active agent (e.g., a therapeutic, prophylactic, or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a unit dose (whole fraction thereof) appropriate to administer according to a dosing regimen determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a prophylactic or therapeutic dosing regimen). One of skill in the art will understand that the total amount of a composition or agent to be administered to a particular subject is determined by one or more attending physicians and may include administration of multiple dosage forms.

[0030] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0031] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0032] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0033] As used herein, the term "HIV replication inhibitor" is intended to mean an agent that is capable of reducing or eliminating the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0034] As used herein, the term "HBV replication inhibitor" refers to an inhibitor of HBV replication in vitro, ex vivo, It is intended to mean an agent that can reduce or eliminate the replicative capacity of HBV in host cells, whether in vivo or in vivo.

[0035] "Mammal" includes both humans and non-domestic animals such as domestic animals, eg, laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and wildlife.

[0036] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical can be substituted or unsubstituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals. When a variable is substituted, for example, as described in the phrase "(C-C)alkyl" alone or as part of a group, "optionally substituted," it is understood that this phrase means that the variable (C-C)alkyl can be substituted when it is alone, and also that it can be substituted when the variable "(C-C)alkyl" is part of a larger group, such as, for example, aryl(C-C)alkyl or -(C-C)alkyl-SO-(C-C)alkyl-(C-C)carbocyclic group. Similarly, when so stated, other variables (e.g., (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, heteroaryl, heterocycle, etc.) can also be substituted "alone or as part of a group."

[0037] As used herein, the term "oxo" is intended to mean an oxygen atom attached to a carbon atom as a substituent by a double bond (=O).

[0038] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, emulsifier, or other pharmacologically inactive substance that can be formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition, is compatible with the other ingredients of the formulation, and is suitable for use in humans or veterinary animals without undue toxicity, irritation, allergic response, etc.

[0039] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + (Wherein, X is C 1~4 Pharmaceutically acceptable salts of a nitrogen atom or amino group include, for example, salts derived from appropriate bases such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, ... Pharmaceutically acceptable salts of hydroxy compounds include salts of organic carboxylic acids such as propionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. + and NX4 + (X is H or C 1~4 and the anion of said compound in combination with a suitable cation such as an alkyl group (independently selected from alkyl groups).

[0040] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable, i.e., salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of the compounds of the embodiments disclosed herein. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

[0041] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to an embodiment disclosed herein. Examples of metal salts prepared in this manner include Li + , Na + , and K + A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0042] Additionally, salts may be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, HSO, HPO, or organic sulfonic acids, to a basic center, typically an amine. Finally, it should be understood that the compositions herein include the non-ionized and zwitterionic forms of the compounds disclosed herein.

[0043] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a vehicle generally accepted in the art for delivering biologically active compounds to mammals, e.g., humans. Such vehicles include all pharmaceutically acceptable excipients.

[0044] As used herein, "preventing" and "prevent" refer to The term "pre-exposure prophylaxis" refers to administering a compound, composition, or pharmaceutically acceptable salt according to the present disclosure before or after a person is exposed to a virus, but before symptoms of the disease appear and / or before the virus is detected in the blood. In some embodiments, the term refers to preventing symptoms of the disease from appearing and / or preventing the virus from reaching detectable levels in the blood. The term also encompasses administering a compound or composition according to the present embodiments disclosed herein before an individual is exposed to a virus (also called pre-exposure prophylaxis or PrEP (pre-exposure prophylaxis)) to prevent HIV infection from becoming established if the individual is exposed to the virus and / or to prevent the virus from permanently establishing an infection and / or to prevent symptoms of the disease from appearing and / or to prevent the virus from reaching detectable levels in the blood. This use The term includes both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. The term also refers to the prevention of perinatal transmission of HIV from mother to infant by administration to the mother before birth and to the child within the first few days of life. The term also refers to the prevention of HIV infection through blood transfusions.

[0045] "Spirocyclic" as in "spiro" refers to an aryl, carbocyclic, or heterocyclic structure described herein that is connected to an existing ring structure in a compound disclosed herein through a single atom shared by the spiro ring structure and the existing ring structure. For example, the following bicyclic compounds each incorporate a spirocyclopropane (i.e., the cyclopropane ring is spirocyclic relative to the cyclohexane ring), a spiro 1,3-dithiolane (i.e., the 1,3-dithiolane ring is spirocyclic relative to the cycloheptane ring), and a spirocyclopentene (i.e., the cyclopentene ring is spirocyclic relative to the cyclohexene ring): [ka]

[0046] The term "stereoisomer" refers to compounds that have identical chemical constitution but differ with respect to the arrangement of atoms or groups in space. For example, a stereoisomer refers to a compound that is composed of the same atoms bonded by the same bonds as another compound, but the two compounds have different three-dimensional structures that are not interchangeable with one another. The present disclosure contemplates various stereoisomers and mixtures thereof, including diastereomers, enantiomers, and the like. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0047] The term "steroid" refers to a group of radicals, either alone or in combination with another radical, such as -OH and (C1-C 12 ) alkyl, and "steroid" includes, but is not limited to, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, β-sitosterol, campesterol, cholesterol, stigmasterol, stigmastanol, campestanol, brassicasterol, ergosterol, lupeol, cycloartenol.

[0048] As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human). In some embodiments, the subject is suffering from the relevant disease, disorder, or ill health condition. In some embodiments, the human subject is an adult, adolescent, or pediatric subject. In some embodiments, the subject is susceptible to the disease, disorder, or ill health condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or ill health condition. In some embodiments, the subject does not exhibit symptoms or characteristics of the disease, disorder, or ill health condition. In some embodiments, the subject possesses one or more characteristics characteristic of susceptibility or risk of the disease, disorder, or ill health condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or has been administered a diagnostic and / or therapeutic and / or prophylactic agent.

[0049] As used herein, the term "therapeutically effective amount" is the amount that produces the desired effect for which it is administered. In some embodiments, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount that is sufficient when administered to a population suffering from or susceptible to a disease, disorder, and / or ill-health condition in accordance with a therapeutic administration regimen to treat the disease, disorder, and / or ill-health condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of, stabilizes one or more characteristics of, and / or delays the onset of, one or more symptoms of the disease, disorder, and / or ill-health condition. Those skilled in the art will understand that the term "therapeutically effective amount" does not actually require successful treatment to be achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that, when administered to patients in need of such treatment, provides a specific, desired pharmacological response in a significant number of subjects. In some embodiments, reference to a therapeutically effective amount refers to the amount of one or more specific tissues (e.g., tissues affected by a disease, disorder, or ill-health condition). ) or fluid (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of skill in the art will understand that in some embodiments, a therapeutically effective amount may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated and / or administered in multiple doses, for example, as part of a dosing regimen.

[0050] With respect to a disease or poor health condition, the term "treatment" or "treating" includes preventing the disease or poor health condition from occurring, inhibiting the disease or poor health condition, eliminating the disease or poor health condition, and / or alleviating one or more symptoms of the disease or poor health condition.

[0051] The term "treating," in reference to treating a disease state in a patient, includes (i) inhibiting or ameliorating the disease state in the patient, e.g., preventing or slowing its onset, or (ii) palliating the disease state in the patient, i.e., causing regression or cure of the disease state. In the case of HIV, treating includes reducing the level of HIV viral load in the patient.

[0052] As used herein, the term "treatment" is intended to mean administering a compound or composition according to the invention to reduce or eliminate the symptoms of HIV infection and / or to reduce the viral load in a patient. The term "treatment" also encompasses administering a compound or composition according to the invention after an individual has been exposed to the virus but before symptoms of the disease appear and / or before the virus is detectable in the blood, to prevent the onset of disease symptoms and / or the virus from reaching detectable levels in the blood, and administering a compound or composition according to the invention to a mother before birth and to her child within the first few days of life, to prevent perinatal transmission of HIV from mother to infant.

[0053] As used herein, the terms "treating" and "treatment" are intended to mean administering a compound or composition according to embodiments disclosed herein to reduce or eliminate one or more symptoms of HIV or HBV infection and / or to reduce the viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also encompass administering a compound or composition according to embodiments disclosed herein after an individual has been exposed to the virus but before symptoms of the disease appear and / or before the virus is detectable in the blood to prevent symptoms of the disease from appearing and / or to prevent the virus from reaching detectable levels in the blood, as well as administering a compound or composition according to embodiments disclosed herein to a mother before birth and her child within the first few days of life to prevent perinatal transmission of HIV, for example, from mother to infant. The terms "treating" and "treatment" also encompass administering a compound or composition according to embodiments disclosed herein both before and after an individual is exposed to the virus.

[0054] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of the formulas disclosed herein that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively. 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 125In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of compounds, for example, by characterizing their site or mode of action, or binding affinity to a pharmacologically important site of action. Topically labeled compounds, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose because of their ease of incorporation and facile means of detection.

[0055] In some embodiments, deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced required dosage. Thus, in some situations, heavier isotopes may be preferred.

[0056] Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13 N may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the formulae disclosed herein can be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples below, using the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0057] The methods, compositions, kits, and articles of manufacture provided herein employ or include the compounds disclosed herein, or pharmaceutically acceptable salts thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom (where n is the number of hydrogen atoms in the molecule) may be replaced by deuterium atoms or D. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds have increased resistance to metabolism and are therefore useful for increasing the half-life of the compound or its pharmaceutically acceptable salt when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0058] The embodiments disclosed herein are also intended to encompass in vivo metabolic products of the disclosed compounds. EFdA is not intended to be included in the embodiments disclosed herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to an embodiment disclosed herein to a mammal for a period sufficient to yield its metabolic products. Such products are typically identified by administering a detectable dose of a radiolabeled compound according to an embodiment disclosed herein to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0059] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Unless otherwise specified, the present disclosure is meant to include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include: Chiral synthesis from suitable optically pure precursors or racemates using, for example, chiral high-pressure liquid chromatography (HPLC). This includes resolution of the E and Z isomers (or racemates of the salts or derivatives). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. II. Compounds

[0060] Provided herein are compounds that function as antiviral agents (in some embodiments, anti-HIV agents), pharmaceutical compositions containing such compounds, optionally in combination with one or more (e.g., two, three, or four) additional therapeutic agents, and methods of using such compounds and compositions. All compound embodiments described herein include any pharmaceutically acceptable salt thereof, its stereoisomer, or mixture of its stereoisomers.

[0061] In one embodiment, a compound of formula (I): [ka] (In the formula, The dashed lines (----), together with the solid line parallel to the dashed lines, represent optional double bonds; X represents a halogen; R 1 represents (C1-C6)alkynyl, R 2 is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -P(=O)(OR b )(R c1 ), -P(=O)(R c1 )(R c2 ), -C(=O)(OR d ), -C(=O)(R h ), -C(=O)(OR h ), or -C(=O)(LR h ) and R 3a is H or R e represents R 3b represents H or is absent, R 4 is R d or is absent, R 5 is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -C(=O)(OR d ), -P(=O)(OR b )(R c1 ), -C(=O)(R h ), -C(=O)(OR h ), or -C(=O)(LR h ) and Each R a is (C1~C 25 ) alkyl, which may be the same or different; In addition, each R a is one R b optionally substituted with Each Rb represents phenyl or cyclohexyl, In addition, each R b are independently f , -CH2-OC(=O)(R f ), and -OC(=O)(R f Optionally substituted with 1 to 3 groups selected from Each R c1 and R c2 -NH-LC(=O)(OR f ) and -NH-LC(=O)(OR g ), which may be the same or different, Each R d is, independently, [ka] represents R e is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)-LOR f , -C(=O)-LOC(=O)(R f ), -C(=O)-OLC(=O)(OR f ), -C(=O)-LSC(=O)(R f ), -C(=O)(R b ), -C(=O)(OR b ), -C(=O)-OLC(=O)(OR d ), -C(=O)(R d ), -C(=O)(R h ), or -C(=O)(OR h ) and Each R f are independently (C1~C 18 ) alkyl, Each L is independently (C1 to C 18 ) alkylenyl, R g represents cyclohexyl, Each R hare independently a steroid derivative or a bridged, spirocyclic, or fused polycyclic (C7-C 18 ) represents a carbocyclic ring, In addition, the steroid derivative has -OH and (C1-C 12 ) optionally substituted with 1 to 4 groups independently selected from alkyl; R 5 If is H, then R 2 is -P(=O)(OR b )(R c1 ) or -P(=O)(R c1 )(R c2 ) instead of R 3a is H and R 3b is H and R 5 If is H, then R 2 is not H, —C(═O)((C1-C5) alkyl), or —C(═O)(Z-butyl-Z′), Z is a bond, (C1 to C 10 ) alkyl, C(R x )(R z ) and R x and R z are independently H, (C1-C6) alkyl, and (C6-C 10 ) cycloalkyl R x and R z each is independently optionally substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy; and Z' is H, (C1 to C 10 ) alkyl, or (C1-C 10 ) represents alkoxy, wherein Z' is optionally substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy; R 3a But R e and R 3b is H, R e is H, or -C(=O)(O-(C1-C6) alkyl) or -C(=O)(C1-C 25 ) alkyl, R 5 is H or -C(=O)(O-(C1-C 25 ) alkyl), R 2 is -C(=O)(O-(C1~C 25 ) alkyl) rather than R 2 is H or -C(=O)(O-(C1-C 10 ) alkyl) R 5 is optionally substituted with —C(═O)(oxo or (C1-C6) alkyl (C1-C 18 ) alkyl), -C(=O)-((C1-C 18 ) cyclohexyl optionally substituted with alkyl), or —C(═O)((C1-C6) alkyl or —O— C(=O)(phenyl optionally substituted with (C1-C6)alkyl)), R e is (a)H, (b)-C(=O)(O-(C1~C 10 ) alkyl), or (c) -C(=O)((C1-C 15 ) alkyl) compounds, or a pharmaceutically acceptable salt thereof.

[0062] Formula (Ia): [ka] (In the formula, X represents F or Cl; R 2 is H, -C(=O)(R a ), -C(=O)(R b ), or -P(=O)(OR b )(R c1 ) and R 3 is H, -C(=O)(R a ), or -C(=O)(OR a ) and R 5 is H, -C(=O)(R a ), or -P(=O)(ORb )(R c1 ) and Each R a are independently (C1~C 25 ) alkyl, In addition, each R a is independently one R b optionally substituted with Each R b are independently f and -OC(=O)(R f phenyl optionally substituted with 1 to 3 groups independently selected from R c1 is -NH-LC(=O)(OR g ) and Each R f are independently (C1~C 18 ) alkyl, L is (C1~C 18 ) alkylenyl, R g represents cyclohexyl, however, R 5 If H, then R 2 is -P(=O)(OR b )(R c1 ) instead of R 3 and R 5 If H, then R 2 is not H, —C(═O)((C1-C5) alkyl), or —C(═O)(Z-butyl-Z′), Z is a bond, (C1 to C 10 ) alkyl, C(R x )(R z ) and R x and R z are independently H, (C1-C6) alkyl, and (C6-C 10 ) cycloalkyl; In addition, R x and R z each is independently optionally substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy; Z' is H, (C1 to C 10 ) alkyl, or (C1-C 10 )alkoxy, wherein Z' is optionally substituted with (C1-C6)alkyl, oxo, or (C1-C6)alkoxy; R 3 is H, or -C(=O)(O-(C1-C6) alkyl) or -C(=O)(C1-C 25 ) alkyl, and R 5 If is H, then R 2 is -C(=O)(O-(C1~C 25 ) alkyl) rather than R 2 is H, R 5 But -C(=O)((C1~C 18 ) alkyl), R 3 is H, -C(=O)(O-(C1~C 10 ) alkyl)), or -C(=O)((C1-C 15 ) alkyl) compounds, or a pharmaceutically acceptable salt thereof.

[0063] Formula (Ib) below: [ka] (In the formula, X represents F or Cl; R 2 is -C(=O)(R a ) and R 5 is H or -C(=O)(R a ) and Each R a is independently one R b optionally substituted with (C1 to C 25 ) alkyl, Each R b independently represents phenyl optionally substituted with 1 to 3 groups independently selected from —CH3 and —OC(═O)—CH3; however, R5 If H, then R 2 is not —C(═O)(C1-C5 alkyl) or —C(═O)(Z-butyl-Z′), Z is a bond, (C1 to C 10 ) alkyl, C(R x )(R z ) and R x and R z are independently selected from H and (C1-C6) alkyl; R x and R z each is independently optionally substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy; Z' is H, (C1 to C 10 ) alkyl, or (C1-C 10 )alkoxy, and Z' is optionally substituted with (C1-C6)alkyl, oxo, or (C1-C6)alkoxy; or a pharmaceutically acceptable salt thereof.

[0064] The following description applies to one or more of the formulas disclosed herein (Formulas I, Ia, and Ib): X can be selected from halogen. In some embodiments, X is In some embodiments, X is Cl. In some embodiments, X is F. In some embodiments, X is Br. In some embodiments, X is I.

[0065] R 1 may be selected from (C1-C6)alkynyl. In some embodiments, R 1 is ethynyl. In some embodiments, R 1 is propynyl. In some embodiments, R 1 is butynyl. In some embodiments, R 1 is pentynyl. In some embodiments, R 1 is hexynyl.

[0066] R 2is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -P(=O)(OR b )(R c1 ), -P(=O)(R c1 )(R c2 ), -C(=O)(OR d ), -C(=O)(R h ), -C(=O)(OR h ), and -C(=O)(LR h ) can be selected from the nomenclature -P(=O)(R c1 )(R c2 It will be appreciated that groups such as ) can also be represented as: [ka]

[0067] Similarly, those skilled in the art will recognize the nomenclature -P(=O)(OR b )(R c1 It will be appreciated that groups such as: [ka]

[0068] Similarly, those skilled in the art will recognize the nomenclature -C(=O)(R a It will be appreciated that groups such as: [ka]

[0069] Similarly, those skilled in the art will recognize the nomenclature -C(=O)(OR a It will be appreciated that groups such as: [ka]

[0070] In some embodiments, R 2 is H. In some embodiments, R 2 is -C(=O)(R a In some embodiments, R 2 is -C(=O)((C1~C 25 ) alkyl). In some embodiments, R 2 is -C(=O)((C1~C 18 ) alkyl). In some embodiments, R 2 is -C(=O)((C1~C 12 ) alkyl). In some embodiments, R 2 is —C(═O)((C1-C6)alkyl). In some embodiments, R 2 is —C(═O)((C1-C4) alkyl). In some embodiments, R 2 is —C(═O)(methyl). In some embodiments, R 2 is —C(═O)(isopropyl). In some embodiments, R 2 is —C(═O)((C1-C4) alkyl substituted with phenyl. In some embodiments, R 2 is —C(═O)((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with —CH3. In some embodiments, R 2 is —C(═O)((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with acetoxy. In some embodiments, R 2 is —C(═O)((C1-C4) alkyl substituted with phenyl), wherein the phenyl is substituted with —CH3 and acetoxy.

[0071] In some embodiments, R 2 is -C(=O)(OR a In some embodiments, R 2 But -C(=O)((C1~C 16 ) alkoxy). In some embodiments, R 2is -C(=O)((C1~C 12 )alkoxy).

[0072] In some embodiments, R 2 is -C(=O)(R b In some embodiments, R 2 is —C(═O)(aryl). In some embodiments, R 2 is —C(═O)(cycloalkyl). In some embodiments, R 2 is —C(═O) (phenyl substituted with (C1-C4) alkyl). In some embodiments, R 2 is —C(═O)(phenyl). In some embodiments, R 2 is —C(═O)(cyclohexyl). In some embodiments, R 2 is —C(═O) (phenyl substituted with an ester). In some embodiments, R 2 is —C(═O)(cyclohexyl substituted with (C1-C4) alkyl). In some embodiments, R 2 is —C(═O)(phenyl substituted with —CH—C(═O)—(C1-C6)alkyl). In some embodiments, R 2 is —C(═O)(phenyl substituted with —CH—C(═O)—(C1-C4) alkyl). In some embodiments, R 2 is —C(═O) (phenyl substituted with an ester). In some embodiments, R 2 is —C(═O) (phenyl substituted with an ester), and the ester moiety is (C1-C 16 ) alkyl esters, (C1-C 12 ) alkyl ester, (C1-C6) alkyl ester, (C6-C 12 ) alkyl ester, or (C 12 ~C 16 ) alkyl esters.

[0073] In some embodiments, R 2 is -C(=O)(OR dIn some embodiments, R 5 is -C(=O)(OR d ) and R d teeth, [ka] In some embodiments, R 2 is -C(=O)(OR d ) and R d teeth, [ka] is.

[0074] In some embodiments, R 2 is -P(=O)(OR b )(R c1 In some embodiments, R 2 is -P(=O)(O-phenyl)(R c1 In some embodiments, R 2 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 2 is -P(=O)(OR b )(—NH—CH(CH)—C(═O)—O—(C1-C6) alkyl). In some embodiments, R 2 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 2 is -P(=O)(OR b )(—NH—CH(CH)—C(═O)—O—(C1-C3) alkyl). In some embodiments, R 2 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C-C) alkyl). In some embodiments, R 2 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C-C)cycloalkyl). In some embodiments, R 2is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-cyclohexyl). In some embodiments, R 2 is -P(=O)(R c1 )(R c2 In some embodiments, R 2 is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C6) alkyl) 2 In some embodiments, R 2 is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C3) alkyl) 2 is.

[0075] In some embodiments, R 2 comprises a phosphate residue. In some embodiments, R 2 comprises a phosphate derivative residue. In some embodiments, R 2 comprises a monophosphate residue. In some embodiments, R 2 comprises a diphosphate residue. In some embodiments, R 2 comprises a triphosphate residue. In some embodiments, R 2 In some embodiments, R 2 comprises a phosphate polyester. In some embodiments, R 2 In some embodiments, R 2 comprises a phosphate triester. In some embodiments, R 2 comprises a phosphate amidate. In some embodiments, R 2 comprises a phosphate monoamidite. In some embodiments, R 2 comprises a diamidate phosphate. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 includes phosphoboranoate.

[0076] In some embodiments, R2 is -C(=O)(R h In some embodiments, R 2 is -C(=O)(OR h In some embodiments, R 2 is -C(=O)((C7~C 10 ) carbocyclic). In some embodiments, R 2 -C(=O)(Bridged-Bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 2 is —C(═O)(bicyclo[2.2.2]octane). In some embodiments, R 2 -C(=O)(spiro-bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 2 is —C(═O)(spiro[5.3]nonane). In some embodiments, R 2 is —C(═O)(spiro[5.3]nonane). In some embodiments, R 2 is —C(═O)(spiro[3.3]heptane). In some embodiments, R 2 -C(=O)(O-bridged-bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 2 is —C(═O)(O-bicyclo[2.2.2]octane). In some embodiments, R 2 -C(=O)(O-spiro-bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 2 is —C(═O)(O-spiro[5.3]nonane). In some embodiments, R 2 is —C(═O)(O-spiro[5.3]nonane). In some embodiments, R 2 is -C(=O) (O-spiro[3.3]heptane).

[0077] In some embodiments, R 2 is -C(=O)(LR h In some embodiments, R 2 teeth, [ka] is.

[0078] In Formula I, R 3a is H and R e may be selected from R 3b represents H or is absent. In some embodiments, R 3a is H. In some embodiments, R 3a is R e In some embodiments, R 3b is H. In some embodiments, R 3b is absent. In some embodiments, R 3a R 3b is R 2 In some embodiments, R 3a R 3b is R 2 In some embodiments, R 3a R 3b is R 2 can be any of the possible substituents listed for

[0079] In some embodiments, R 4 is absent. In some embodiments, R 4 is R d In some embodiments, R 4 is R 3a In some embodiments, R 4 is R 3a In some embodiments, R 4 is R 3a R 3b In some embodiments, R 4 is R 3a R 3b In some embodiments, R 4 is R 3a R 3b can be any of the possible substituents listed for

[0080] R5 is H, -C(=O)(R a ), -C(=O)(OR a ), -C(=O)(R b ), -C(=O)(OR d ), -P(=O)(OR b )(R c1 ), -C(=O)(R h ), -C(=O)(OR h ), or -C(=O)(LR h In some embodiments, R 5 is R 3a R 3b In some embodiments, R 5 is R 3a In some embodiments, R 5 is R 2 In some embodiments, R 5 is R 3a R 3b In some embodiments, R 5 is R 3a In some embodiments, R 5 is R 2 In some embodiments, R 5 is R 2 In some embodiments, R can be any of the possible substituents listed for 5 is R 3a R 3b In some embodiments, R can be any of the possible substituents listed for 5 is R 3a In some embodiments, R can be any of the possible substituents listed for 2 , R 5 , and R 3a R 3b are the same as each other. In some embodiments, R 2 , R 5 , and R 3a are the same as each other. In some embodiments, R 2 , R 5, and R 3a R 3b are not all the same. In some embodiments, R 2 , R 5 , and R 3a is not all the same.

[0081] In some embodiments, R 5 is H. In some embodiments, R 5 is -C(=O)(R a In some embodiments, R 5 is —C(═O)(isopropyl). In some embodiments, R 5 is -C(=O)(OR a In some embodiments, R 5 is -C(=O)(OR a In some embodiments, R 5 is -C(=O)((C1~C 16 ) alkoxy). In some embodiments, R 5 is -C(=O)((C1~C 12 ) alkoxy). In some embodiments, R 5 is —C(═O)((C1-C4)alkoxy). In some embodiments, R 5 is —C(═O)((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with —CH3. In some embodiments, R 5 is —C(═O)((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with acetoxy. In some embodiments, R 5 is —C(═O)((C1-C4) alkyl substituted with phenyl), wherein the phenyl is substituted with —CH3 and acetoxy.

[0082] In some embodiments, R 5 is -C(=O)(R b In some embodiments, R 5is —C(═O)(phenyl substituted with (C1-C4) alkyl). In some embodiments, R 5 is —C(═O)(cyclohexyl substituted with (C1-C4) alkyl). In some embodiments, R 5 is —C(═O)(phenyl substituted with —CH—C(═O)—(C1-C6)alkyl). In some embodiments, R 5 is —C(═O)(phenyl substituted with —CH2—C(═O)—(C1-C4) alkyl).

[0083] In some embodiments, R 5 is -C(=O)(OR d In some embodiments, R 5 is -C(=O)(OR d ) and R d teeth, [ka] In some embodiments, R 5 is -C(=O)(OR d ) and R d teeth, [ka] is.

[0084] In some embodiments, R 5 is -P(=O)(OR b )(R c1 In some embodiments, R 5 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 5 is -P(=O)(OR b )(—NH—CH(CH)—C(═O)—O—(C1-C6) alkyl). In some embodiments, R 5 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R5 is -P(=O)(OR b )(—NH—CH(CH)—C(═O)—O—(C1-C3) alkyl). In some embodiments, R 5 is -P(=O)(O-phenyl)(-NH-CH(CH)-C(=O)-O-(C-C) alkyl). In some embodiments, R 5 is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C6) alkyl) 2 In some embodiments, R 5 is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C3) alkyl) 2 is.

[0085] In some embodiments, R 5 comprises a phosphate residue. In some embodiments, R 5 comprises a phosphate derivative residue. In some embodiments, R 5 comprises a monophosphate residue. In some embodiments, R 5 comprises a diphosphate residue. In some embodiments, R 5 comprises a triphosphate residue. In some embodiments, R 5 In some embodiments, R 5 comprises a phosphate polyester. In some embodiments, R 5 In some embodiments, R 5 comprises a phosphate triester. In some embodiments, R 5 comprises a phosphate amidate. In some embodiments, R 5 comprises a phosphate monoamidite. In some embodiments, R 5 comprises a diamidate phosphate. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 includes phosphoboranoates.

[0086] In some embodiments, R 5 is -C(=O)(R h In some embodiments, R 5 is -C(=O)(OR h In some embodiments, R 5 is -C(=O)(LR h In some embodiments, R 5 -C(=O)(O-spiro-bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 5 is —C(═O)(O-spiro[5.3]nonane). In some embodiments, R 5 is —C(═O)(O-spiro[5.3]nonane). In some embodiments, R 5 is —C(═O)(O-spiro[3.3]heptane). In some embodiments, R 5 is —C(═O)(O-spiro[5.3]nonane). In some embodiments, R 5 -C(=O)(Bridged-Bicyclic (C7-C 10 ) carbocyclic). In some embodiments, R 5 is —C(═O)(bicyclo[2.2.2]octane). In some embodiments, R 5 teeth, [ka] is.

[0087] In some embodiments, at least one R a is (C1~C 25 ) alkyl. In some embodiments, at least one R a is (C1~C 18 ) alkyl. In some embodiments, at least one R a is (C1-C6) alkyl. In some embodiments, at least one R a is (C1-C4) alkyl. In some embodiments, at least one R a is one R bis replaced by .

[0088] In some embodiments, at least one R b is phenyl. In the form, at least one R b is cyclohexyl. In some embodiments, at least one R b is R f In some embodiments, at least one R b is -CH2-OC(=O)(R f In some embodiments, at least one R b is -OC(=O)(R f In some embodiments, at least one R b are two independently selected R f group and one -OC(=O)(R f In some embodiments, at least one R b is phenyl substituted with -CH3, -CH3, and -OC(=O)(CH3).

[0089] In some embodiments, R c1 and R c2 At least one of the groups is -NH-LC(=O)(OR f In some embodiments, at least one R c1 and R c2 is -NH-LC(=O)(OR b In some embodiments, R c1 and R c2 are the same as each other. In some embodiments, R c1 and R c2 are different from each other.

[0090] In some embodiments, at least one R d In some embodiments, R d In some embodiments, R dIn some embodiments, R d includes dioxolane substituted with 1 to 3 additional groups selected from (C1-C6) alkyl and oxo. In some embodiments, R d comprises an oxo-substituted 1,3-dioxolane. In some embodiments, R d includes oxo- and methyl-substituted 1,3-dioxolanes. In some embodiments, R d is -(C1-C6)alkyl-dioxolane. In some embodiments, R d is -CH-dioxolane. In some embodiments, R d is —CH-dioxolane, wherein the dioxolane is substituted with oxo and methyl. In some embodiments, at least one R d teeth, [ka] In some embodiments, at least one R d teeth, [ka] is.

[0091] In some embodiments, R e is H. In some embodiments, R e is -C(=O)(R a In some embodiments, R e is -C(=O)(OR a In some embodiments, R e is -C(=O)-LOR f In some embodiments, R e is -C(=O)-LOC(=O)(R f )

[0092] In some embodiments, R e is -C(=O)-OLC(=O)(OR f In some embodiments, Re is -C(=O)-LSC(=O)(R f In some embodiments, R e is -C(=O)(R b In some embodiments, R e is -C(=O)(OR b )

[0093] In some embodiments, R e is -C(=O)-OLC(=O)(OR d In some embodiments, R e is -C(=O)(R d In some embodiments, R e is -C(=O)(R h In some embodiments, R e teeth,- C(=O)(OR h In some embodiments, R e teeth, [ka] is.

[0094] In some embodiments, R f is (C1-C6) alkyl. In some embodiments, R f is (C1-C3) alkyl.

[0095] In some embodiments, at least one L is (C1-C6) alkylenyl. In some embodiments, at least one L is (C1-C4) alkylenyl. In some embodiments, at least one R h is a spiro-bicyclic (C7-C 10 ) carbocyclic ring. In some embodiments, at least one R h is a bridged bicyclic (C7-C 10 ) carbocyclic ring. In some embodiments, at least one R h is a fused polycyclic carbocycle.

[0096] In some embodiments, at least one R h is -OH and (C1 to C 12 ) alkyl. In some embodiments, R h includes bile acid conjugates. In some embodiments, R h contains sterols.

[0097] In some embodiments, each —C(═O)(R h ) are independently [ka] is selected from.

[0098] In some embodiments, —C(═O)(OR h )teeth, [ka] (wherein R y are independently selected from H, (C1-C8) alkyl, and (C1-C8) alkenyl; each R y are independently optionally substituted with (C1-C6) alkyl).

[0099] In some embodiments, each —C(═O)(LR h ) are independently [ka] is selected from.

[0100] In some embodiments, the compounds disclosed herein have the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and or a pharmaceutically acceptable salt thereof. For compounds described above with the phrase "X=F, Cl," this is intended to be the same as explicitly disclosing each compound individually (one where X=F and a separate one where X=Cl).

[0101] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. III. Pharmaceutical Compositions

[0104] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0105] In some embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as described more fully below.

[0106] Pharmaceutical compositions containing the compounds disclosed herein or pharmaceutically acceptable salts thereof can be prepared with one or more pharmaceutically acceptable excipients, which can be selected according to conventional practice. Tablets may contain excipients, including lubricants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, if intended for delivery by other than oral administration, may generally be isotonic. In some embodiments, the compositions are prepared in accordance with Rowe et al., Handbook The composition may contain excipients such as those described in "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, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form.

[0107] The compositions include those suitable for various routes of administration, including oral administration. The compositions may be prepared by any of the methods known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients, or finely divided solid excipients, or both, and then, if necessary, shaping the product. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0108] Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, sachets or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0109] The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and, optionally, other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These 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 disintegrating agents 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 by 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.

[0110] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended therapeutic subject and mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain about 1 to 1000 mg of active agent, formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients vary from about 5 to about 95% (weight:weight) of the total composition.

[0111] In some embodiments, compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in one variation do not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition comprising a compound of the present disclosure does not contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure. In one aspect, it is also understood that none of the methods, kits, articles of manufacture, etc. detailed herein contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0112] In some embodiments, the pharmaceutical compositions are for human or animal use. That is why.

[0113] The present disclosure further includes compounds of the present disclosure for administration as the sole active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, e.g., by combining or mixing the active ingredient with pharmaceutically acceptable, therapeutically inert organic and / or inorganic carriers or excipients.

[0114] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient that has a synergistic effect with another active ingredient in a known drug, or the co-administration of a compound of the present disclosure with such a drug.

[0115] The compounds of the present disclosure may also be used in the form of prodrugs or other suitably modified forms that release the active ingredient in vivo. IV. Treatment method HIV infection

[0116] The present disclosure provides methods of treating and / or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof. In some embodiments, the method of treating and / or preventing HIV infection in a subject in need thereof comprises administering a composition provided herein to the subject. In some embodiments, the method is for treating and / or preventing HIV-1 infection. In some embodiments, the method is for treating and / or preventing HIV-2 infection.

[0117] In some embodiments, a method for treating an HIV infection in a subject in need thereof comprises administering a composition provided herein to the subject. In some embodiments, the subject is HIV-positive. In some such embodiments, the subject has an unknown HIV status. In some such embodiments, the subject is not HIV-negative.

[0118] In some embodiments, a method for preventing HIV infection in a subject in need thereof comprises administering a composition provided herein to the subject. In some embodiments, the subject is HIV-negative. In some embodiments, the subject is at risk of contracting HIV infection.

[0119] In some embodiments, the present disclosure provides compositions for use in the treatment and / or prevention of HIV infection in a subject.

[0120] In some embodiments, the present disclosure provides compositions for the manufacture of a medicament for treating and / or preventing HIV infection in a subject.

[0121] In some embodiments, the disclosure provides methods for treating and / or preventing HIV infection in a subject in need thereof, the methods comprising administering to the subject a combination therapy comprising a composition provided herein and one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. In some embodiments, methods are provided for treating HIV infection in a human subject having or at risk of having an infection, the methods comprising administering to the human subject a therapeutically effective amount of a compound disclosed herein in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. In some embodiments, the subject is currently receiving or is already receiving one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is selected from the same class of therapeutic agent. In some embodiments, the additional therapeutic agent is selected from a different class of therapeutic agent. In some embodiments, the additional therapeutic agent is suitable for treating and / or preventing HIV infection. In some embodiments, the additional therapeutic agent is not for treating and / or preventing HIV infection.

[0122] In some embodiments, the combination therapy comprises administering a composition provided herein and one, two, three, four, or more additional therapeutic agents. In some embodiments, the combination therapy comprises administering a composition provided herein and two additional therapeutic agents. In some embodiments, the combination therapy comprises administering a composition provided herein and three additional therapeutic agents. In some embodiments, the combination therapy comprises administering a composition provided herein and four additional therapeutic agents.

[0123] The additional therapeutic agent can be any additional therapeutic agent disclosed herein. In some embodiments, the additional therapeutic agent is disclosed in the HIV combination therapy section herein. In some embodiments, the additional therapeutic agent is disclosed in the HBV combination therapy section herein.

[0124] In some embodiments, the additional therapeutic agent is an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, an HIV Tat or Rev inhibitor, an immunomodulatory agent, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editor (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), a cell therapy (chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, etc.), a latent infection reactivator, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe inhibitor is selected from POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0125] In some embodiments, the additional therapeutic agent is a combination drug for treating and / or preventing HIV infection, another HIV therapeutic agent, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry (fusion) inhibitor, an HIV maturation inhibitor, a latency reactivator, a capsid inhibitor, an immune system therapeutic agent, a PI3K inhibitor, an HIV antibody, and a bispecific antibody, and an "antibody" "antibody-like" therapeutic proteins, and combinations thereof.

[0126] In some embodiments, the additional therapeutic agent is a combination medication for treating and / or preventing HIV infection. Examples of combination medications for treating and / or preventing HIV infection include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine), COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, and emtricitabine); xylofumarate and emtricitabine; TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir diazepam Soproxil 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; COMBIVIR® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM (Registered) Trademarks) (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO, TRIZIVIR® (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; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine +abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine; cabotegravir + rilpivirine; elpida (elsulfavirine; VM-1500; VM-1500A);

[0127] In some embodiments, the additional therapeutic agent is a drug that treats and / or prevents HIV infection. Examples of other drugs for treating and / or preventing HIV infection include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkephalin, 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, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040, PGN -007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

[0128] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. 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, MK-8122, TMB-607, and TMC-310911.

[0129] In some embodiments, the additional therapeutic agent is a reverse transcriptase inhibitor. The reverse transcriptase inhibitor can be a non-nucleoside / non-nucleotide inhibitor or a nucleoside / nucleotide inhibitor.

[0130] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide reverse transcriptase inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500).

[0131] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide reverse transcriptase inhibitor. Examples of nucleoside or nucleotide inhibitors of reverse transcriptase that can be combined with the agents of the present disclosure include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (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, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-8583, VM-2500, and KP-1461.

[0132] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, and dolutegravir. , JTK-351, bictegravir, AVX-15567, diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, 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, VM-3500, and cabotegravir.

[0133] In some embodiments, the HIV integrase inhibitor is a non-catalytic site (i.e., allosteric) integrase inhibitor (NCINI). Examples of NCINIs include CX-05045, CX-05168, and CX-1442.

[0134] In some embodiments, the additional therapeutic agent is an HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[0135] In some embodiments, the additional therapeutic agent is a CCR5 inhibitor. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (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).

[0136] In some embodiments, the additional therapeutic agent is a gp41 inhibitor. 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.

[0137] In some embodiments, the additional therapeutic agent is a CD4 binding inhibitor. Examples of CD4 binding inhibitors include ibalizumab and CADA analogs.

[0138] In some embodiments, the additional therapeutic agent is a gp120 inhibitor. Examples of gp120 inhibitors include Radha-108 (receptor) 3B3-PE38, BanLec, bentonite-based nanopharmaceuticals, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0139] In some embodiments, the additional therapeutic agent is a CXCR4 inhibitor. Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0140] In some embodiments, the additional therapeutic agent is an HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232.

[0141] In some embodiments, the additional therapeutic agent is a latent infection reactivator. Examples of latent infection reactivators include toll-like receptor (TLR) agonists ( TLR7 agonists, including GS-9620, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, such as Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387 and LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, and AT-406), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfide These include ram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343.

[0142] In some embodiments, the additional therapeutic agent is an inhibitor of HDAC (e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR, Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, These include CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat.

[0143] In some embodiments, the additional therapeutic agent is a PKC activator. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0144] In some embodiments, the additional therapeutic agent is a capsid inhibitor. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, and compounds described in this patent (GSK WO 2019 / 087016).

[0145] In some embodiments, the additional therapeutic agent is selected from one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in treating infectious diseases. In various embodiments, the immune checkpoint protein or receptor regulates T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (reviewed, e.g., in Davis, et al., Semin Immunol. (2017) 31:64-75, and Chiossone, et al. Nat Rev Immunol. (2018) 18(11):671-688).

[0146] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, O X40; TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated, BTLA); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (Poliovirus receptor, PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL1 6-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F);Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0147] In some embodiments, the additional therapeutic agent is a blocker or inhibitor of one or more T cell inhibitory immune checkpoint proteins or receptors. Examples of T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, agents as described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0148] In some embodiments, the additional therapeutic agent is a blocker or inhibitor of one or more NK cell inhibitory immune checkpoint proteins or receptors. Examples of NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0149] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is GS-4224, GS-4416, INCB0865 50, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0150] In some embodiments, the additional therapeutic agent is a CTLA4 inhibitor. Examples of CTLA4 inhibitors include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, These include PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0151] In some embodiments, the additional therapeutic agent is an inhibitor of PD-L1 (CD274) or PD-1 (PDCD1).Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, and BI-7540. 91, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-31 55, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), and FS-118 (LAG-3 / PD-L1). These include MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0152] In some embodiments, the additional therapeutic agent is an anti-TIGIT antibody. Examples of anti-TIGIT antibodies include BMS-986207, RG-6058, and AGEN-1307.

[0153] In some embodiments, the additional therapeutic agent is an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 729 3), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS; NCBI gene ID: 355), TNFRSF7 (CD27; NCBI gene ID: 939), TNFRSF8 (CD30; NCBI gene ID: 943), TNFRSF9 (4-1BB; CD137; NCBI gene ID: 3604), TNFRSF10A (CD261; DR4; TRAILR1; NCBI gene ID: 8797), TNFRSF10B (CD262; DR5; TRAILR2; NCBI gene ID: 8795), TNFRSF10C (CD263; TRAILR3; NCBI gene ID: 8794), TNFRSF10D (CD264; TRAILR4; NCBI gene ID: 8793), TNFRSF11A (CD265; RANK; NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF1 7 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0154] In some embodiments, the additional therapeutic agent is an anti-TNFRSF4 (OX40) antibody. Examples of anti-TNFRSF4 (OX40) antibodies include MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, P F-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO 2016 / 179517, WO 2017 / 096179, WO 2017 / 096182, WO 2017 / 096281, and WO 2018 / 089628.

[0155] In some embodiments, the additional therapeutic agent is an anti-TNFRSF5 (CD40) antibody. Examples of anti-TNFRSF5 (CD40) antibodies include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0156] In some embodiments, the additional therapeutic agent is an anti-TNFRSF7 (CD27) antibody. An example of an anti-TNFRSF7 (CD27) antibody is varlilumab (CDX-1127).

[0157] In some embodiments, the additional therapeutic agent is an anti-TNFRSF9 (4-1BB, CD137) antibody. Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies include urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0158] In some embodiments, the additional therapeutic agent is an anti-TNFRSF18 (GITR) antibody. Examples of anti-TNFRSF18 (GITR) antibodies include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628.

[0159] In some embodiments, the additional therapeutic agent is an antibody or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR). Such antibodies can be used, for example, It is described in WO 2017 / 096179 and WO 2018 / 089628.

[0160] In some embodiments, the additional therapeutic agent is a bispecific NK cell inducer (BiKE) or trispecific NK cell inducer (TriKE) (e.g., without Fc), or a bispecific antibody (e.g., with Fc) against an NK cell-activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Optionally, the anti-CD16-binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell inducers include those that target CD16 and one or more HIV-associated antigens. BiKE and TriKE are described, for example, in Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKE) include OXS-3550 and CD16-IL-15-B7H3 TriKe.

[0161] In some embodiments, the additional therapeutic agent is an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1, NCBI gene ID: 3620). Examples of IDO1 inhibitors include 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.

[0162] In some embodiments, the additional therapeutic agent is an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Exemplary TLR7 agonists include AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), and U.S. Patent Application Publication No. 2012 / 0098249 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array B iopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics). Examples of TLR7 / TLR8 agonists include NKTR-262, Telratolimod, and BDB-001.Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and those disclosed in U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 ( Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx. No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics). Exemplary TLR9 agonists include AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

[0163] In some embodiments, the additional therapeutic agent is a stimulator of interferon genes (STING) agonist or activator. Examples of STING receptor agonists or activators include ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP.

[0164] In some embodiments, the additional therapeutic agent is a RIG-I modulator, such as RGT-100, or a NOD2 modulator, such as SB-9200, and IR-103.

[0165] In some embodiments, the additional therapeutic agent is an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0166] In some embodiments, the additional therapeutic agent is an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385.

[0167] In some embodiments, the additional therapeutic agent is an interleukin agonist, such as an IL-2, IL-7, IL-15, IL-10, or IL-12 agonist; examples of IL-2 agonists include Proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldsulkin, AIC-284, and ALKS-423. 0, CUI-101, Neo-2 / 15; examples of IL-15 agonists include ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 agonists include CYT-107.

[0168] In some embodiments, the additional therapeutic agent is an immune-based therapy selected from the following: interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; Flt3 agonist; gepon; nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and RPI-MN.

[0169] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, bupallisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, puquinitib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, 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.

[0170] In some embodiments, the additional therapeutic agent is an integrin alpha-4 / beta-7 antagonist. Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0171] In some embodiments, the additional therapeutic agent is an HIV antibody, a bispecific antibody, or an "antibody-like" therapeutic protein. Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, and the like. These include antibodies, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, and those targeting HIV gp120 or gp41, antibody recruiting 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, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, and MB-66.

[0172] In some embodiments, the additional therapeutic agent is a bNAb, examples of which include those described in U.S. Patent No. 8,673,307, U.S. Patent No. 9,493,549, U.S. Patent No. 9,783,594, WO 2014 / 063059, WO 2012 / 158948, WO 2015 / 117008, and International Application Nos. PCT / US2015 / 41272 and WO 2017 / 096221, specifically antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, and 8ANC195. 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include Klein et al., Nature,492(7427):118-22(2012), Horwitz et al., Proc Natl Acad Sci USA,110(41):16538-43(2013), Scheid,et al.,Science,333:1633-1637(2011), Scheid,et al. al., Nature, 458:636-640 (2009), Eroshkin et al, Nucleic Acids Res., 42 (database issue): Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(l):225-44(2013), for example, 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to outer domain glycans); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0173] In some embodiments, the additional therapeutic agent is a broadly neutralizing antibody, such as those described in, e.g., U.S. Pat. No. 8,673,307, U.S. Pat. No. 9,493,549, and U.S. Pat. No. 9,783,594, as well as WO 2012 / 154312, WO 2012 / 158948; WO 2013 / 086533, WO 2013 / 142324, WO 2014 / 063059; WO 2014 / 089152; WO 2014 / 089152; Examples of such techniques include those described in International Publication No. WO 2015 / 048462, International Publication No. WO 2015 / 103549, International Publication No. WO 2015 / 117008, International Publication No. WO 2016 / 014484, International Publication No. WO 2016 / 154003, International Publication No. WO 2016 / 196975, International Publication No. WO 2016 / 149710, International Publication No. WO 2017 / 096221, and International Publication No. WO 2017 / 133639 and International Publication No. WO 2017 / 133640, all of which are incorporated herein by reference in their entirety for all purposes. Additional examples include Sajadi, et al.,Cell.(2018)173(7):1783-1795;Sajadi,et al.,J Infect Dis.(2016)213(1):156-64;Klein et al.,Nature,492(7427):118-22(2012), Horwitz et al.,Proc. Natl Acad Sci USA,110(41):16538-43(2013), Scheid,et al.,Science,333: 1633-1637 (2011), Scheid, et al., Nature, 458:636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42 (Database Issue): D1 133-9 (2014), Mascola et al., Immunol Rev., 254(1):225-44 (2013) (e.g., 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, and LN01 (all of which bind to the MPER of gp41).

[0174] Examples of additional antibodies that can be used as additional therapeutic agents include bavituximab, UB-421, BF520.1, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, and PGT-123. , PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX0 10 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080- 00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.Examples include 11P, 2F5, 7b2, and LN01.

[0175] Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, TMB bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01.

[0176] Examples of bnabs delivered in vivo are, for example, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically engineered B cells encoding 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301).

[0177] In some embodiments, the additional therapeutic agent is a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0178] Examples of additional HIV treatments include those described in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), ces), 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), U.S. Patent Application Publication No. 2013 / 0165489 (University of Pennsylvania), U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 2014 / 0221356 (Gilead Sciences), U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0179] In some embodiments, the additional therapeutic agent is an HIV vaccine. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus macaque, i.e., rhAD), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enteric virus-based vaccines, gorilla adenovirus vaccines, lentivirus-based vaccines, arenavirus vaccines (e.g., vaccines based on viruses, such as LCMV and Pichinde, two-segment or three-segment arenavirus vaccines, measles virus vaccines, flavivirus vector-based vaccines, tobacco mosaic virus vector-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (such as modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines, such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (Lauer, Clinical and Vaccine Immunology, 2017, DOI:10.1128 / CVI.00298-16); LNP-combined mRNA-based therapeutic vaccines; and LNP-combined self-replicating RNA / self-amplifying RNA vaccines.

[0180] Examples of vaccines include 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, multiclad DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V 2.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 Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 Virus-like particle vaccines such as gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines (e.g., DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclad Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA HIV vaccine, and MVA.These include HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980;eOD-GT8 60mer vaccine, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccine, gp120(A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccine, and TBL-1203HI.

[0181] In some embodiments, the additional therapeutic agent is birth control (i.e., contraception). Examples of birth control agents include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norregestromin, norethindrone, nortinodrel, norgestimate, ormeloxifene, segestrel acetate, ulipristal acetate, and any combination thereof.

[0182] In some embodiments, provided compositions include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); Licitabine; TDF + FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; Raltegral; Raltegravir and lamivudine; Maraviroc; Enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®) Trademark); Abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (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; Prolastin; Fosamprenavir; Fosamprenavir calcium effluvium Virenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide;in combination with one, two, three, four or more additional therapeutic agents selected from lamivudine, nevirapine, and zidovudine; abacavir, and abacavir sulfate;

[0183] In some embodiments, the compositions provided are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0184] In some embodiments, provided compositions are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0185] In some embodiments, provided compositions are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0186] In some embodiments, provided compositions comprise abacavir sulfate, tenofovir, tenofovir, It is combined with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0187] In some embodiments, provided compositions are combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0188] In some embodiments, provided compositions are combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0189] In some embodiments, the additional therapeutic agent is gene therapy or cell therapy. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness to infection. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1. In some embodiments, C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells are co-administered with one or more multispecific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0190] In some embodiments, the additional therapeutic agent is a gene editor (e.g., an HIV-targeted gene editor). In some embodiments, the genome editing system is selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV targets for the CRISPR / Cas9 system include, but are not limited to, EBT-101.

[0191] In some embodiments, the additional therapeutic agent is a CAR-T cell therapy. CAR-T cell therapy includes a population of immune effector cells genetically engineered to express a chimeric antigen receptor (CAR), where the CAR includes an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. 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 can be autologous or allogeneic. Examples of HIV CAR-T include VC-CAR-T, CMV-N6-CART, anti-CD4 CAR cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, and autologous hematopoietic stem cells engineered to express CD4 CAR and C46 peptide. Examples include cells.

[0192] In some embodiments, the additional therapeutic agent is a TCR-T cell therapy, which comprises TCR-T cells genetically engineered to target an HIV-derived protein (e.g., ImmTAV) present on the surface of virally infected cells.

[0193] In some embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells engineered to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019).

[0194] HBV infection The present disclosure provides a method for treating hepatitis B virus (HBV) infection in a patient requiring the treatment. In some embodiments, the method of treating and / or preventing HBV infection in a subject in need thereof comprises administering to the subject a composition provided herein.

[0195] In some embodiments, a method of treating an HBV infection in a subject in need thereof comprises administering to the subject a composition provided herein.

[0196] In some embodiments, a method for preventing HBV infection in a subject in need thereof comprises administering a composition provided herein to the subject. In some embodiments, the subject is at risk of contracting HBV infection.

[0197] In some embodiments, the present disclosure provides compositions for use in treating and / or preventing HBV infection in a subject.

[0198] In some embodiments, the present disclosure provides compositions for the manufacture of a medicament for treating and / or preventing HBV infection in a subject.

[0199] In some embodiments, the present disclosure provides methods for treating and / or preventing HBV infection in a subject in need thereof, the methods comprising administering to the subject a combination therapy comprising a composition provided herein and one or more additional therapeutic agents. In some embodiments, the subject is currently receiving or has already received one or more additional therapeutic agents. In some embodiments, the additional therapeutic agents are selected from the same class of therapeutic agents. In some embodiments, the additional therapeutic agents are selected from a different class of therapeutic agents. In some embodiments, the additional therapeutic agents are for treating and / or preventing HBV infection. In some embodiments, the additional therapeutic agents are not for treating and / or preventing HBV infection.

[0200] In some embodiments, the present disclosure provides methods for treating HBV infection, the methods comprising administering to a subject in need of treatment a therapeutically effective amount of a composition disclosed herein in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents suitable for treating HBV infection.

[0201] In some embodiments, the compositions disclosed herein are combined with one, two, three, four, or more additional therapeutic agents. The compositions disclosed herein are combined with two or more additional therapeutic agents. In some embodiments, the compositions disclosed herein are combined with three additional therapeutic agents. In some embodiments, the compositions disclosed herein are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents.

[0202] The compositions described herein can be used or combined with one or more of chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), genetic modifying agents or gene editors (CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs, etc.), cell therapies such as CAR-T (chimeric antigen receptor T cells), and TCR-T (genetically engineered T cell receptor) agents, or any combination thereof.

[0203] In some embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, the additional therapeutic agent may be an HBV combination drug, another agent for treating HBV, 3-dioxygenase (IDO) inhibitor, antisense oligonucleotide targeting viral mRNA, apolipoprotein A1 modulator, arginase inhibitor, B and T lymphocyte attenuation inhibitor, Bruton's tyrosine kinase (BTK) inhibitor, CCR2 chemokine antagonist, CD137 inhibitor, CD160 inhibitor, CD305 inhibitor, CD4 agonist and modulator, compound targeting HBcAg, compound targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitor. agents, cyclophilin inhibitors, cytokines, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesoid X receptor agonists, gene modifying agents or gene editors, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV vaccines, 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 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, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunoglobulin agonists, immunoglobulin G modulators, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon alpha 1 ligands, interferon alpha 2 ligands, interferon alpha 5 ligand modulators, interferon alpha ligands, interferon alpha ligand modulators, interferon alpha receptor ligands, interferon interferon β ligand, interferon ligand, interferon receptor modulator, interleukin-2 ligand, ipi4 inhibitor, lysine demethylase inhibitor, histone demethylase inhibitor, KDM5 inhibitor, KDM1 inhibitor, killer cell lectin-like receptor subfamily G member 1 inhibitor, lymphocyte activation gene 3 inhibitor, lymphotoxin β receptor activator, microRNA (miRNA) gene therapy agent, Axl modulator, B7-H3 modulator, B7-H4 modulator, CD160 modulator, CD161 modulator, CD27 modulator, CD47 modulator, CD70 modulator, GITR modulator, HEVEM modulator modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPalpha modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2 B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, recombinant scavenger receptor A (SRA) protein, recombinant thymosin alpha-1, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, short interfering RNA (siRNA), short synthetic hairpin RNA (sshRNA), SLC10A1 gene inhibitors, SMAC mimetics, Src The inhibitor may be selected from the group consisting of tyrosine kinase inhibitors, stimulators of interferon genes (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 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, zinc finger nucleases or synthetic nucleases (TALENs), and combinations thereof.

[0204] In some embodiments, the compositions provided are selected from the group consisting of HBV combination medications, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, viral mRNA-targeting antisense oligonucleotides, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV and / or one, two, three, four, or more additional therapeutic agents selected from E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

[0205] In some embodiments, the additional therapeutic agent is an HBV combination drug. Examples of HBV combination drugs include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir and PEG-IFN-α; and INO-1800 (INO-9112 and RG7944).

[0206] In some embodiments, the additional therapeutic agent is another HBV agent. Examples of other drugs for the treatment of HBV infection include α-hydroxytropolone, amdoxovir, β-hydroxycytosine nucleoside, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, 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, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, and U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 2016128 335(A1) (Roche), WO 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and U.S. Patent Application Publication No. 2015031687(A) (Roche).

[0207] In some embodiments, the additional therapeutic agent is an HBV vaccine. In some embodiments, the HBV vaccine is an HBV prophylactic vaccine. Examples of HBV prophylactic 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 prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Products), and others. Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV Vaccine, DTP-HBV Vaccine, 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 These include B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine.

[0208] In some embodiments, the HBV vaccine is a therapeutic HBV vaccine. Examples of therapeutic HBV vaccines include HBsAG-HBIG conjugate, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, and CV. These include I-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 vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, and Lm HBV.

[0209] In some embodiments, the additional therapeutic agent is an HBV DNA polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, bicifovir, and entevir. These include bacil (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fosolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orotate, and HS-10234.

[0210] In some embodiments, the additional therapeutic agent is an immunomodulatory agent. Examples of immunomodulatory agents include lintatolimod, imidole hydrochloride, ingaron, dermaVir, Plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, the polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, AIC-649, and IR-103.

[0211] In some embodiments, the additional therapeutic agent is a Toll-like receptor (TLR) modulator, including modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

[0212] In some embodiments, the TLR modulator is a TLR3 modulator. Examples of TLR3 modulators include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, GS-9688, and ND-1.1.

[0213] In some embodiments, the TLR modulator is a TLR7 modulator. 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, TMX-30X, TMX-202, RG-7863, RG-7795, RG-7854, and compounds disclosed in U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and 20090047249 (Gilead Sciences).

[0214] In some embodiments, the TLR modulator is a TLR8 modulator. Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compounds disclosed in U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira and compounds disclosed in U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics).

[0215] In some embodiments, the TLR modulator is a TLR9 modulator. 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), ritenimod, and CYT-003-QbG10.

[0216] In some embodiments, the additional therapeutic agent is an interferon alpha receptor ligand. Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1 101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), YPEG-rhIFNalpha-2b, MOR-22, pegylated interferon alpha-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MU LTIFERON (registered trademark), interferon α-n1 (HUMOFERON (registered trademark), interferon β-1a (AVONEX (registered trademark), Shaferon, interferon α-2b (Axxo), Alfaferone, interferon α-2b (BioGeneric Pharma), interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, PDferon-B, interferon α-2b (IFN , Laboratorios Bioprofarma, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg A, Realfa 2B (Realfa 2B), Reliferon, interferon alpha-2b (Amega), interferon α-2b (Virchow), ropeg interferon α-2b, rHSA-IFN α-2a (recombinant human serum albumin interferon α-2a fusion protein), rHSA-IFN α 2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α -2b (Changchun Institute of Biological Products), Anterferon, Shanferon, La Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegsta These include Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa).

[0217] In some embodiments, the additional therapeutic agent is a hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include astodrimer.

[0218] In some embodiments, the additional therapeutic agent is a hepatitis B surface antigen (HBsAg) inhibitor. 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-2165, REP-2163, REP-2053, REP-2031, and REP-006, and REP-9AC'. Examples of HBsAg secretion inhibitors include BM601.

[0219] In some embodiments, the additional therapeutic agent is a cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitor. Examples of cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

[0220] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor. Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosed in U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344030 (Gilead Sciences), and U.S. Patent Application Publication No. 2013 / 0344029 (Gilead Sciences).

[0221] In some embodiments, the additional therapeutic agent is an HBV viral entry inhibitor. Examples of HBV viral entry inhibitors include Myrcludex B.

[0222] In some embodiments, the additional therapeutic agent is a viral mRNA-targeting antisense oligonucleotide. Examples of viral mRNA-targeting antisense oligonucleotides include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004.

[0223] In some embodiments, the additional therapeutic agent is a short interfering RNA (SMRNA). , siRNA). Examples of siRNA include TKM-HBV (TKM-HepB) , ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

[0224] In some embodiments, the additional therapeutic agent is DNA-directed RNA interference (ddRNAi). Examples of ddRNAi include BB-HB-3 31 is listed.

[0225] In some embodiments, the additional therapeutic agent is an endonuclease modulator. An example of an endonuclease modulator is PGN-514.

[0226] In some embodiments, the additional therapeutic agent is a ribonucleotide reductase inhibitor. An example of a ribonucleotide reductase inhibitor is Trimidox.

[0227] In some embodiments, the additional therapeutic agent is an HBV E antigen inhibitor. Examples of HBV E antigen inhibitors include wogonin.

[0228] In some embodiments, the additional therapeutic agent is a covalently closed circular DNA (cccDNA) inhibitor. Examples of cccDNA inhibitors include: Examples include BSBI-25 and CHR-101.

[0229] In some embodiments, the additional therapeutic agent is a farnesoid x receptor agonist. An example of a farnesoid X receptor agonist is EYP-001.

[0230] In some embodiments, the additional therapeutic agent is an HBV antibody. Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed). Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, Hepatitis B Immune Globulin (Intravenous, pH4, HBV Infection, Shanghai RAAS Blood Products), and Fovepta (BT-088). Fully human monoclonal antibodies such as HBC-34.

[0231] In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist. An example of a CCR2 chemokine antagonist is propagermanium.

[0232] In some embodiments, the additional therapeutic agent is a thymosin agonist. Examples of thymosin agonists include Thymalfasin, recombinant thymosin alpha 1 (GeneScience).

[0233] In some embodiments, the additional therapeutic agent is a cytokine, examples of which 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.

[0234] In some embodiments, the additional therapeutic agent is a nucleoprotein modulator. In some embodiments, the nucleoprotein modulator is an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include AB- 423, AT-130, GLS4, NVR-1221, NVR-3778, Bay 41-4109, morphotiazine mesylate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158, and DVR-23. Examples of capsid inhibitors are disclosed in U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics), ... Therapeutics), U.S. Patent Application Publication No. 2014 / 0343032 (Roche), WO 2014 / 037480 (Roche), U.S. Patent Application Publication No. 2013 / 0267517 (Roche), WO 2014 / 131847 (Janssen), WO 2014 / 033176 (Janssen), WO 2014 / 033170 (Jans sen), WO 2014 / 033167 (Janssen), WO 2015 / 059212 (Janssen), WO 2015 / 118057 (Janssen), WO 2015 / 011281 (Janssen), WO 2014 / 184365 (Janssen), WO 2014 / 184350 (Janssen), WO 2014 / 161888 (Janssen), WO 2013 / 096744 (Novira), U.S. Patent Application Publication No. 2015 / 0225355 (Novira), U.S. Patent Application Publication No. 2014 / 0178337 (Novira), U.S. Patent Application Publication No. 2015 / 0315159 (Novira), U.S. Patent Application Publication No. 2015 / 0197533 (Novira), U.S. Patent Application Publication No. 2015 / 0274652 (Novira), U.S. Patent Application Publication No. 2015 / 0259324 (Novira), U.S. Patent Application Publication No. 2015 / 0132258 (Novira), U.S. Patent No. 9,181,288 (Novira), WO 2014 / 184350 (Janssen), and WO 2013 / 144129 (Roche).

[0235] In some embodiments, the additional therapeutic agent is a stimulator of retinoic acid-inducible gene 1. Examples of stimulators of retinoic acid-inducible gene 1 include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, and ORI-7170, RGT-100.

[0236] In some embodiments, the additional therapeutic agent is a stimulator of NOD2. An example of a stimulator of NOD2 is SB-9200.

[0237] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, bupalisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, jedatolicib, ME-401, VS-5584, copanlisib, CAI otrose salt, perifosine, RG-7666, GSK-2636771, DS-1202, and the like. -7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, pukitinib 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.

[0238] In some embodiments, the additional therapeutic agent is an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor. Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, G BV-1012, NKTR-218, and the compounds disclosed in U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), and International Publication No. 2014073738 (Flexus and compounds disclosed in WO 2015188085 (Flexus Biosciences, Inc.).

[0239] In some embodiments, the additional therapeutic agent is a PD-1 inhibitor. Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400.

[0240] In some embodiments, the additional therapeutic agent is a PD-L1 inhibitor. 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, CX-072, and BMS-936559.

[0241] In some embodiments, provided compositions are disclosed in any of the following publications: WO 2018 / 026971, U.S. Patent Application Publication No. 2018 / 0044329, U.S. Patent Application Publication No. 2018 / 0044305, U.S. Patent Application Publication No. 2018 / 0044304, U.S. Patent Application Publication No. 2018 / 0044303, U.S. Patent Application Publication No. 2018 / 0044350, U.S. Patent Application Publication No. 2018 / 0057455, U.S. Patent Application Publication No. 2018 / 0057486, U.S. Patent Application Publication No. 2018 / 0057487, U.S. Patent Application Publication No. 2018 / 0057489, U.S. Patent Application Publication No. 2018 / 0057490, U.S. Patent Application Publication No. 2018 / 0057491, U.S. Patent Application Publication No. 2018 / 0057492, U.S. Patent Application Publication No. 2018 / 0057493, U.S. Patent Application Publication No. 2018 / 0057494, U.S. Patent Application Publication No. 2018 / 0057495, U.S. Patent Application Publication No. 2018 / 0057496, U.S. Patent Application Publication No. 2018 / 0057497, U.S. Patent Application Publication No. 2018 / 0057498, U.S. Patent Application Publication No. 2018 / 0057499, U.S. Patent Application Publication No. 2018 / 0057499, U.S. Patent Application Publication No. 2018 / 00574 18 / 0045142, WO 2018 / 0044963, WO 2018 / 044783, WO 2018 / 009505, WO 2018 / 0044329, WO 2017 / 066227, WO 2017 / 087777, U.S. Patent Application Publication No. 2017 / 0145025, WO 2017 / 079669, WO 2017 / 070089, U.S. Patent Application Publication No. 2017 / 107216, WO 2017 / 222976, U.S. Patent Application Publication No. 2017 / 0262253, WO 2017 / 205464, U.S. Patent Application Publication No. 2017 / 0320875, WO 2017 / 192961, WO 2017 / 112730, U.S. Patent Application Publication No. 2017 / 0174679, WO 2017 / 106634, WO 2017 / 202744, WO 2017 / 202275, WO 2017 / 202273, WO 201 and in combination with compounds such as those disclosed in WO 2016 / 142835, WO 2016 / 142852, WO 2016 / 142886, WO 2016 / 142894, and WO 2016 / 142833.

[0242] In some embodiments, the additional therapeutic agent is recombinant thymosin alpha 1. Examples of recombinant thymosin alpha 1 include NL-004 and PEGylated thymosin alpha 1.

[0243] In some embodiments, the additional therapeutic agent is a Bruton's tyrosine kinase (BTK) inhibitor. 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, and AC-0 025, and compounds disclosed in U.S. Patent Application Publication Nos. 20140 / 330015 (Ono Pharmaceutical), 2013 / 0079327 (Ono Pharmaceutical), and 2013 / 0217880 (Ono Pharmaceutical).

[0244] In some embodiments, the additional therapeutic agent is a KDM inhibitor. In some embodiments, the KDM inhibitor is a KDM5 inhibitor. Examples of KDM5 inhibitors include those disclosed in WO 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 2014 / 0275092 ... Pharmaceuticals), U.S. Patent Application Publication No. 2014 / 0371195 (Epitherapeutics), and U.S. Patent Application Publication No. 2014 / 0371214 (Epitherapeutics), U.S. Patent Application Publication No. 2016 / 0102096 (Epitherapeutics), U.S. Patent Application Publication No. 2014 / 0194469 (Quanticel), U.S. Patent Application Publication No. 2014 / 0171432, U.S. Patent Application Publication No. 2014 / 0213591 (Quanticel), U.S. Patent Application Publication No. 2016 / 0039808 (Quanticel), U.S. Patent Application Publication No. 2014 / 0275084 (Quanticel), and WO 2014164708 (Quanticel). In some embodiments, the KDM inhibitor is a KDM1 inhibitor. Examples of KDM1 inhibitors include compounds disclosed in US Pat. No. 9,186,337(B2) (Oryzon Genomics), as well as GSK-2879552, RG-6016, and ORY-2001.

[0245] In some embodiments, the additional therapeutic agent is a hepatitis B virus replication inhibitor. Examples of hepatitis B virus replication inhibitors include isothiafluridine, IQP-HBV, RM-5038, and Xingantie.

[0246] In some embodiments, the additional therapeutic agent is an arginase inhibitor. Examples of arginase inhibitors include CB-1158, C-201, and resminostat.

[0247] In some embodiments, the combination therapy described herein includes gene therapy and / or cell therapy. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of a subject's own immune system to enhance the immune response against infected cells or to kill infected cells or activate the patient's own immune system to find and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

[0248] In some embodiments, the combination therapy described herein includes a gene editor. The genome editing system may be selected from the group consisting of a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system, and a meganuclease system. Examples include cccDNA elimination by targeted cleavage and modifying one or more of the hepatitis B virus (HBV) viral genes. Modifying (e.g., knocking out and / or knocking down) the PreC, C, X, PreSI, PreS2, S, P, or SP genes can: (1) reduce or eliminate PreC, C, X, PreSI, PreS2, S, P, or SP gene expression; (2) alter precore, core, X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or hepatitis B splice protein function (HBe, HBc, HBx, PreS1, PreS2, S). (3) interfering with HBe, HBc, HBx, LHBs, MHBs, SHB, Pol, and / or HBSP proteins; or (3) reducing or eliminating intracellular, serum, and / or parenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHB, Pol, and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P, and / or SP genes may be used to treat HBV. This is done by targeting genes within the cccDNA and / or genes into which HBV DNA has integrated.

[0249] In some embodiments, the combination therapy described herein comprises CAR-T cell therapy. CAR-T cell therapy utilizes a chimeric antigen receptor (CAR). The CAR may comprise a population of immune effector cells genetically engineered to express 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 can be autologous or allogeneic.

[0250] In some embodiments, the combination therapy described herein includes TCR-T cell therapy. The TCR-T cell therapy may include T cells expressing an HBV-specific T cell receptor. The TCR-T cells are genetically engineered to target HBV-derived peptides displayed on the surface of virus-infected cells. T cells expressing an HBV surface antigen (HBsAg)-specific TCR. TCR-T therapy for the treatment of HBV, such as LTCR-H2-1.

[0251] In some embodiments, methods of treating and / or preventing HBV infection comprise administering a combination therapy comprising a provided composition and one, two, three, or four additional therapeutic agents selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).

[0252] In some embodiments, methods of treating and / or preventing HBV infection comprise administering a combination therapy comprising a provided composition and a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).

[0253] In some embodiments, methods for treating and / or preventing HBV infection comprise administering a combination therapy comprising a provided composition and an HBV DNA polymerase inhibitor. In some embodiments, methods for treating and / or preventing HBV infection include the use of provided compositions and HBV DNA polymerase inhibitors, immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors, viral mRNA-targeting antisense oligonucleotides, siRNA, miRNA gene therapy drugs, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus E antigen inhibitors, recombinant SRA proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies, including HBV antibodies targeting the surface antigen of the hepatitis B virus, and bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAb ... bs®, TandAbs®, Fab derivatives, or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, stimulators of NOD2, stimulators of NOD1, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B and T lymphocyte attenuation inhibitors, CD 305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, recombinant thymosin alpha-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPalpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, epigenetic modifiers, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, e.g., CRISPR (CRISPR and at least one additional therapeutic agent selected from the group consisting of a gene modifier or editor such as a nuclease (including Cas9), zinc finger nuclease, or synthetic nuclease (TALEN), an IAP inhibitor, a SMAC mimetic, a KDM5 inhibitor, an IDO inhibitor, and a hepatitis B virus replication inhibitor.

[0254] In some embodiments, a method for treating and / or preventing HBV infection comprises combining (i) a provided composition; (ii) an HBV DNA polymerase inhibitor; and (iii) an immunomodulatory agent, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody, including an HBV antibody targeting a surface antigen of the hepatitis B virus, and a bispecific antibody, and an "antibody-like" therapeutic protein (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, a stimulator of RIG-I-like receptors, a P The method includes administering a combination therapy comprising one or two additional therapeutic agents selected from the group consisting of D-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators, and one or two additional therapeutic agents selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigens, siRNAs, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0255] In some embodiments, methods of treating and / or preventing HBV infection comprise administering a combination therapy comprising a provided composition, an HBV DNA polymerase inhibitor, and at least a second additional therapeutic agent selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody, including an HBV antibody targeting a hepatitis B virus surface antigen, and a bispecific antibody, and an "antibody-like" therapeutic protein (e.g., DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, a stimulator of RIG-I-like receptors, a PD-1 inhibitor, a PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO inhibitor, and a stimulator of NOD2.

[0256] In some embodiments, methods for treating and / or preventing HBV infection comprise administering a combination therapy comprising a provided composition and an HBV DNA polymerase inhibitor and at least a 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, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein inhibitor).

[0257] In some embodiments, the method of treating and / or preventing HBV infection comprises (i) a provided composition and (ii) a combination of a medicament selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®). and a first additional therapeutic agent selected from an immunomodulator, a TLR modulator, an interferon alpha receptor ligand, a hyaluronidase inhibitor, a recombinant IL-7, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBcAg targeting compound, a cyclophilin inhibitor, an HBV vaccine, an HBV viral entry inhibitor, an NTCP inhibitor, a viral mRNA-targeting antisense oligonucleotide, an siRNA, an miRNA gene therapy agent, an endonuclease modulator, a ribonucleotide reductase inhibitor, a hepatitis B virus E antigen inhibitor, or a recombinant SRA tag. proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies including HBV antibodies targeting the surface antigen of the Hepatitis B virus, and bispecific antibodies, and "antibody-like" therapeutic proteins (DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, TCR-like antibodies, etc.), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or core antigens), phosphoprotein modulators), stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, stimulators of NOD2, stimulators of NOD1, IDO inhibitors, recombinant thymosin α1, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B and T lymphocyte attenuation factor inhibitors,Epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPalpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, e.g., CRISPR (CRISPR and at least a second additional therapeutic agent selected from the group consisting of a gene modifier or editor, such as a nuclease (including Cas9), zinc finger nuclease, or synthetic nuclease (TALEN), an IAP inhibitor, a SMAC mimetic, a KDM5 inhibitor, and a hepatitis B virus replication inhibitor.

[0258] In some embodiments, the method of treating and / or preventing HBV infection comprises (i) a provided composition and (ii) a combination of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir (iii) a first additional therapeutic agent selected from the group consisting of alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iv) a first additional therapeutic agent selected from the group consisting of pegylated interferon alfa-2b (PEG-INTRON®), MULTIFERON®, interferon alfa 1b (HAPGEN®), interferon alfa 2b (INTRON®), or pegylated interferon alfa 2b (INTRON®). A (registered trademark), pegylated interferon alpha 2a (PEGASYS (registered trademark), interferon alpha-n1 (HUMOFERON (registered trademark), ribavirin interferon beta-1a (AVONEX (registered trademark), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutektra, Chaferon, interferon alpha-2b (AXXO), Alphaferon, interferon alpha-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, Blaufenon-B (BLAUFERON-B), Blaufenon-A (BLAUFERON-A), Intermax alpha, Realdilon, Lansion, Pegaferon, PDferon-B, interferon alpha-2b (IFN, Laboratorios Bioprofarma), alpha interferon 2b, Calferon, PegNano, FeronSure, PeziHep, interferon alpha-2b (Zydus-Cadila), Optipeg A, Rea Alpha 2B, Reliferon, interferon alpha 2b (Amega), interferon alpha 2b (Virchow), peginterferon alpha 2b (Amega), Reaferon-EC, Prokiferon, Uniferon, Uriflon, interferon alpha-2b (Changchun Institute of Biological Products), Interferon, Shanferon, MOR-22, interleukin 2 (IL-2, Immunex), recombinant human interleukin 2 (Shenzhen Neptunus), Liferon, Ka Shu Ning, Shan Sheng Lei Ta and at least a second additional therapeutic agent selected from the group consisting of I, Intefen, Sinogen, Fucantai, Alloferon, and Cermoleukin.

[0259] In some embodiments, a method of treating and / or preventing an HBV infection comprises (i) a provided composition; (ii) a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) an immunomodulatory agent, a TLR modulator, an HBsAg inhibitor, an HBsAg inhibitor, or an HBsAg inhibitor. and at least a second additional therapeutic agent selected from the group consisting of Ag secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies targeting hepatitis B virus surface antigens and HBX antibodies including bispecific antibodies, and "antibody-like" therapeutic proteins (DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, IDO inhibitors, stimulators of NOD2.

[0260] In some embodiments, methods of treating and / or preventing HBV infection include (i) a provided composition and (ii) a combination of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®). and (iii) at least a 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, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein modulator).

[0261] In some embodiments, a method of treating and / or preventing HBV infection comprises (i) a provided composition; (ii) a first therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) an immunomodulatory agent, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody and bispecific antibody, including an HBV antibody targeting the surface antigen of hepatitis B virus, and an "antibody-like" therapeutic protein (e.g., DARTs®). and (iv) one, two, or three additional therapeutic agents selected from the group consisting of an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting the surface antigen of hepatitis B virus, an siRNA, a miRNA gene therapy agent, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein modulator).

[0262] In some embodiments, a method of treating and / or preventing an HBV infection comprises (i) a provided composition; (ii) a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) an immunomodulatory agent, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody, including an HBV antibody targeting the surface antigen of the hepatitis B virus, and a bispecific antibody, and an "antibody-like" therapeutic protein (e.g., DAR and (iv) administering a combination therapy comprising one or two additional therapeutic agents selected from the group consisting of an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting the surface antigen of hepatitis B virus, an siRNA, an miRNA gene therapy agent, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein modulator).

[0263] In some embodiments, the method of treating and / or preventing an HBV infection comprises: (i) providing (ii) a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) an immunomodulatory agent, a TLR7 modulator, a TLR8 modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody, including an HBV antibody targeting the surface antigen of hepatitis B virus, and a bispecific antibody, and an "antibody-like" therapeutic agent. and one, two, three, or four additional therapeutic agents selected from the group consisting of: a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, a stimulator of RIG-I-like receptor, a PD-1 inhibitor, a PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO inhibitor, a stimulator of NOD2, an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an siRNA, a miRNA gene therapy agent, an sshRNAs, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein modulator).

[0264] In some embodiments, methods for treating and / or preventing HBV infection include combining provided compositions with the compounds described in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 (Gilead Sciences), and / or U.S. Patent No. 8,722,054 (Gilead Sciences). Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344029 (GileadSciences), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent Application Publication No. 2014 / 0343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 2013 / 0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen) ), WO 2014033167 (Janssen), WO 2015 / 059212 (Janssen), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO 2013096744 (Novira), U.S. Patent Application Publication No. 2015 / 0225355 (Novira), U.S. Patent Application Publication No. 2014 / 0178337 (Novira), U.S. Patent Application Publication No. No. 2015 / 0315159 (Novira), U.S. Patent Application Publication No. 2015 / 0197533 (Novira), U.S. Patent Application Publication No. 2015 / 0274652 (Novira), U.S. Patent Application Publication No. 2015 / 0259324 (Novira), U.S. Patent Application Publication No. 2015 / 0132258 (Novira), U.S. Patent No. 9,181,288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), U.S. Patent Application Publication No. 2010 / 0015178 (Incyte), U.S. Patent Application Publication No. 2016 / 137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), WO 2015188085 (Flexus Biosciences, Inc.), U.S. Patent Application Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0217880 (Ono Pharmaceutical), International Publication No. 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 2014 / 0275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 2014 / 0371195 (Epitherapeutics), and U.S. Patent Application Publication No. 2014 / 0371214 (Epitherapeutics), U.S. Patent Application Publication No. 2016 / 0102096 (Epitherapeutics), U.S. Patent Application Publication No. 2014 / 0194469 (Quanticel), U.S. Patent Application Publication No. 2014 / 0171432, U.S. Patent Application Publication No. 2014 / 0213591 (Quanticel), U.S. Patent Application Publication No. 2016 / 0039808 (Quanticel), U.S. Patent Application Publication No. 2014 / 0275084 (Quanticel), WO 2014164708 (Quanticel), U.S. Patent No. 9,186,337 (B2) (Oryzon and administering a combination therapy comprising one or two compounds disclosed in the literature (Genomics).

[0265] In certain embodiments, the provided compositions can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents in any dosage relative to the provided compositions.

[0266] In some embodiments, provided compositions are used in combination with tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, provided compositions are used in combination with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, provided compositions are used in combination with 5-10 g, 5-15 g, 5-20 g, 5-25 g, 25-30 g, 20-30 g, 15-30 g, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, provided compositions are used in combination with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, provided compositions are used in combination with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The compositions can be used in combination with the agents provided herein in any dosage amount relative to the composition (as if each combination of dosage amounts were specifically and individually listed).

[0267] In some embodiments, provided compositions are used in combination with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, provided compositions are used in combination with 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 250-350 mg, 250-400 mg, 350-400 mg, or 300-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, provided compositions are used in combination with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, provided compositions are used in combination with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, provided compositions are used in combination with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Provided compositions can be used in combination with agents provided herein in any dosage amount relative to the provided compositions (as if each combination of dosage amounts were specifically and individually listed).

[0268] In some embodiments, kits are provided that include a composition disclosed herein in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1-3, or 1-4) additional therapeutic agents. The provided compositions can be used in kits just as if each individual composition were specifically and individually listed for use in the kit. HIV combination therapy

[0269] In certain embodiments, there is provided a method for treating an HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents. In one embodiment, there is provided a method for treating an HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents.

[0270] In certain embodiments, a method is provided for treating HIV infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents.

[0271] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0272] In certain embodiments, the present disclosure 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, two, three, or four agonists suitable for treating HIV infection. Methods are provided that include administering the compound in combination with an additional therapeutic agent.

[0273] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0274] In some embodiments, a compound disclosed herein is administered with one, two, three, or four additional therapeutic agents. Co-administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents such that therapeutically effective amounts of both the compound disclosed herein and the one, two, three, or four additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more administrations.

[0275] Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of unit doses of one, two, three, or four additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours of administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by unit doses of one, two, three, or four additional therapeutic agents. Alternatively, in other embodiments, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by unit doses of one, two, three, or four additional therapeutic agents. In still other embodiments, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein.

[0276] In some embodiments, the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents in a combination formulation for simultaneous administration to a subject, e.g., as a solid dosage form for oral administration.

[0277] In some embodiments, kits are provided that include a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four) additional therapeutic agents.

[0278] In certain embodiments, a compound of any formula disclosed herein is formulated as a tablet that may optionally include one or more other compounds useful in the treatment of HIV. In certain embodiments, the tablet may include another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleoside inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0279] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or capsid polymerization inhibitor.

[0280] In one embodiment, such tablets are suitable for once-daily administration. HIV combination therapy

[0281] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV combination therapy. In such embodiments, the additional therapeutic agent(s) can be an anti-HIV agent. In the above embodiments, the additional therapeutic agent(s) can be an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immunomodulatory agent, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editor (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), a cell therapy (such as chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, etc.), a latency reactivator, a compound targeting the HIV capsid, a capsid polymerization inhibitor, an HIV bNAb, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a broadly neutralizing HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe anti-HIV agent may be selected from POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof. In some embodiments, the additional therapeutic agent can be selected from an HIV capsid inhibitor, an HIV TAT or Rev inhibitor, a genetically engineered B cell, a fatty acid synthase inhibitor, an HIV-1 Nef modulator, a TNFα ligand inhibitor, an HIV Nef inhibitor, an IFN antagonist, a CD3 antagonist, a CDK-4 inhibitor, a CDK-6 inhibitor, a cytochrome P450 3 inhibitor, a CXCR4 modulator, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, an RNA polymerase modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, and combinations thereof.

[0282] In some embodiments, the additional therapeutic agent is an HIV combination medication, another HIV therapeutic agent, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry (fusion) inhibitor, an HIV maturation inhibitor, a latency reactivator, a capsid inhibitor, an immune system therapeutic agent, or a PI3K inhibitor. The therapeutic agent is selected from the group consisting of an HIV antibody, a bispecific antibody, and an "antibody-like" therapeutic protein, and combinations thereof.

[0283] In some embodiments, the additional therapeutic agent or agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, HIV antigen-targeting chimeric T cell receptors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0284] In some embodiments, the additional therapeutic agent or additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0285] In some embodiments, the additional therapeutic agent or agents are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination drugs

[0286] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV combination medication. Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); DF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide, emtricitabine, and cobicistat); BIKTARVY® (bictegravir, tenofovir alafenamide) and emtricitabine); bictegravir, tenofovir disoproxil, and emtricitabine; bictegravir, tenofovir alafenamide, and lamivudine; bictegravir, tenofovir disoproxil, and lamivudine; bictegravir, abacavir and lamivudine, efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRI MEQ® (dolutegravir, abacavir, and lamivudine); JULUCA® (dolutegravir, ripirvirin), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); dolutegravir and lamivudine; dolutegravir and abacavir; cabotegravir and lamivudine; cabotegravir and abacavir; cabotegravir and rilpivirine; 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; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disoproxil fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine; and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride. In some embodiments, the additional agent is a tenofovir analog, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + albuvirtide, Elpida (elsulfavirine, VM-1500), and VM-1500A, or a combination thereof. Other HIV drugs

[0287] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one other HIV drug. Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy drug, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-10 7, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, 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.Further examples of other drugs for treating HIV include AAV-eCD4-Ig gene therapy, Bevirimat derivatives, ABBV-382, APH0202, bryostatin-1, bryostatin analogs, BG-HIV, BRII-732, CS-TATI-1, fluorobeta-D-arabinose nucleic acid (FANA)-modified antisense oligonucleotides, FX-101, Griffithsin, GSK-3739937, GSK-3739937 (long-acting), hydroxychloroquine, IMB-10035, JL-18008, LADAVRU, MK-8558, OB-002H, ODE-Bn-TFV, PC-707, QF-036, S-648414, DIAC These include, but are not limited to, C-1010, Fasnall, 2-CLIPS peptide, HRF-4467, thrombospondin analogs, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugates (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, and combinations thereof. HIV protease inhibitors

[0288] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV protease inhibitor. 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, MK-8122, TMB-607, and TMC-310911. Additional examples of HIV protease inhibitors include, but are not limited to, ASC-09 + ritonavir, AEBL-2, GS-1156, GRL-02031, and combinations thereof.

[0289] Additional examples of HIV protease inhibitors are described, for example, in U.S. Pat. No. 10,294,234, and U.S. Patent Application Publication No. 2020 / 030327, and U.S. Patent Application Publication No. 2019 / 210978. HIV reverse transcriptase inhibitors

[0290] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV reverse transcriptase inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500). Additional examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (extended-release oral, HIV infection), doravirine + islatravir (fixed-dose combination / oral tablet formulation, HIV-1 infection), elsulfavirine (long-acting injectable nanosuspension, HIV infection), or combinations thereof.

[0291] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (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, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, tenofovir octadecyloxyethyl ester (AGX-1009), MK-8583, and combinations thereof.

[0292] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include those described in U.S. Patent Application Publication Nos. 2007 / 049754, 2016 / 250215, 2016 / 237062, 2016 / 251 347, U.S. Patent Application Publication No. 2002 / 119443, U.S. Patent Application Publication No. 2013 / 065856, U.S. Patent Application Publication No. 2013 / 090473, U.S. Patent Application Publication No. 2014 / 221356, and WO 04096286. HIV integrase inhibitors

[0293] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV integrase inhibitor, examples of which include elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, 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, VM-3500, and cabotegravir.

[0294] Examples of HIV non-catalytic or allosteric integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442. Additional examples of HIV integrase inhibitors include, but are not limited to, elvotegravir (sustained-release microcapsules), pegylated raltegravir, cabotegravir (long-acting injectable), STP-0404, or combinations thereof.

[0295] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication No. 2014 / 221356 and U.S. Patent Application Publication No. 2016 / 016973. HIV viral infectivity factor inhibitors

[0296] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV viral infectivity inhibitor, including, but not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives. HIV entry inhibitors

[0297] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors, and CXCR4 inhibitors. Additional examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, gp160 inhibitors, and combinations thereof.

[0298] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (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). Additional examples of CCR5 inhibitors include, but are not limited to, maraviroc (long-acting injectable nanoemulsion), thiolaviroc, and combinations thereof.

[0299] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide. Examples of gp41 inhibitors include, but are not limited to, gliptisin (gp41 / gp120 / gp160 inhibitor), CPT-31, Cl3hmAb, lipvirtide, HIV-1 fusion inhibitor (P26-Bapc), and combinations thereof.

[0300] Examples of CD4 binding inhibitors include ibalizumab and CDA analogs.

[0301] Examples of gp120 inhibitors include Radha-108 (receptor) 3B3-PE38, BanLec, bentonite-based nanodrugs, fostemsavir tromethamine, IQP-0831, and BMS-663068. Additional examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicides, BMS818251, VVX-004, and combinations thereof.

[0302] Examples of gp160 inhibitors include, but are not limited to, fangchinoline.

[0303] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0304] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232. Latent infection reactivator

[0305] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one latent infection reactivator. Examples of latent infection reactivators 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 (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (e.g., largazole analogs), APH-0812, GSK-343, and Toll-like receptor modulators. Additional examples of latent infection reactivating agents include, but are not limited to, Toll-like receptor (TLR) agonists (including TLR7 agonists (e.g., GS-9620), TLR8 agonists, and TLR9 agonists), (e.g., ZL-0580, apabetalone), IAP antagonists (e.g., inhibitors of apoptosis proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), NIZ-985, IL-15 modified antibodies (including L-15, IL-15 fusion proteins, and IL-15 receptor agonists), and combinations thereof.

[0306] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0307] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone is an example.

[0308] Additional examples of TLR7 agonists include, but are not limited to, those described in US Patent Application Publication No. 2010 / 143301.

[0309] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. 2017 / 071944. Histone deacetylase (HDAC) inhibitors

[0310] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with an inhibitor of histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat. Capsid inhibitors

[0311] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one capsid inhibitor. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. In some embodiments, at least one compound of the present disclosure is combined with GS-6207. Additional examples of capsid inhibitors include, but are not limited to, lenacapavir, GS-CA1, PF-3450074, HIV-1 capsid inhibitor (HIV-1 infection, Shandong University), compounds described in GSK's International Patent Application Publication No. WO 2019 / 087016, and combinations thereof.

[0312] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication No. 2018 / 051005 and U.S. Patent Application Publication No. 2016 / 108030. Cytochrome P450 3 inhibitors

[0313] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one inhibitor of cytochrome P450 3. Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553. RNA polymerase modulators

[0314] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one RNA polymerase modulator, including, but not limited to, those described in U.S. Patent No. 10,065,958 and U.S. Patent No. 8,008,264. Immune Checkpoint Modulators

[0315] In various embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activating or stimulating stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in infection treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (reviewed, e.g., in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0316] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (B TLA); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R);T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoin; Retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0317] In various embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PV RIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, agents as described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0318] In various embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0319] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0320] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0321] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JN J-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budidalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallimab) ), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB08655 0, MAX10181, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 ( Examples of antibodies that may be used include, but are not limited to, PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0322] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307. Agonists or activators of members of the TNF receptor superfamily (TNFRSF)

[0323] In various embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 3 55), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 8796), :8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID:8793), TNFRSF11A (CD265, RANK, NCBI gene ID:8792), TNFRSF11B (NCBI gene ID:4982), TNFRSF12A (CD266, NCBI gene ID:51330), TNFRSF13B (CD267, NCBI gene ID:23495), TNFRSF13C (CD268, NCBI gene ID:115650), TNFRSF TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0324] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF- 04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0325] Examples of anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0326] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0327] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0328] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017 / 096179 and WO 2018 / 089628. Bi- and tri-specific natural killer (NK) cell-inducing factors

[0329] In various embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a bispecific NK cell inducer (BiKE) or trispecific NK-cell engager (TriKE) (e.g., without an Fc domain), or a bispecific antibody (e.g., with an Fc domain) against an NK cell activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific NK cell inducers that can be co-administered target CD16 and one or more HIV-associated antigens, as described herein. For BiKE and TriKE, see, for example, Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3TriKE. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors;

[0330] In various embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, Epacad These include, but are not limited to, stat, 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, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. immune system therapy

[0331] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one immune system therapy. Examples of immune system therapies include toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (PDL-1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycobacterial agents. These include phenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0332] Examples of TLR agonists include vesatolimod (GS-9620), lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and tellulatorimod. Toll-like receptor (TLR) agonists

[0333] In various embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Exemplary TLR7 agonists that may be co-administered include AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication Nos. 2010 / 0143301 (Gilead Sciences), 2011 / 0098248 (Gilead Sciences), and ... Sciences), and Gilead Sciences No. 2009 / 0047249, Janssen No. 2014 / 0045849, Janssen No. 2014 / 0073642, Janssen No. WO 2014 / 056953, Janssen No. 2014 / 076221 (Janssen), US Patent Application Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), US Patent Application Publication No. 2008 / 0234251 (Array Biopharma), WO 2008 / 0306050 (Array Biopharma), US Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), US Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), US Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), US Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), US Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), 2014 / 0066432 (Ventirx Pharma), 2014 / 0088085 (Ventirx Pharma), 2014 / 0275167 (Novira Therapeutics), and 2013 / 0251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, telluritolimod, and BDB-001.Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in U.S. Patent Application Publication No. 2014 / 0045849 (Janssen) and U.S. Patent Application Publication No. 2014 / 0073642 (J Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Examples of compounds include, but are not limited to, compounds disclosed in U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics).TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include, but are not limited to, G-100 and GSK-1795091. CDK inhibitors or antagonists

[0334] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor or antagonist of a CDK, hi some embodiments, the inhibitor or antagonist of a CDK is selected from the group consisting of VS2-370. STING agonists, RIG-I and NOD2 modulators

[0335] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a stimulator of interferon genes (STING) receptor agonist or activator. In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP. In some embodiments, an agent described herein is combined with a RIG-I modulator, such as RGT-100, or a NOD2 modulator, such as SB-9200 and IR-103. LAG-3 and TIM-3 inhibitors

[0336] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0337] In some embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385. Interleukin agonists

[0338] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one interleukin agonist. In some embodiments, the agent described herein is an interleukin agonist, such as an IL-2, IL-7, IL-15, IL-10, or IL-12 agonist; an example of an IL-2 agonist is Proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), benpardesleukin, AIC-284, ALKS-4230, CU Examples of IL-15 agonists include I-101, Neo-2 / 15; ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Scintrin (pegylated Il-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0339] Examples of additional immune system therapies that can be combined with the agents of the present disclosure include, but are not limited to, interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma; FLT3 agonists such as CDX-301, GS-3583, Gapion, Nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and RPI-MN. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0340] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one PI3K inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, bupalisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, puquinitib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, and GSK-212645. 8, GSK-2269577, 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. Alpha-4 / beta-7 antagonists

[0341] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one alpha-4 / beta-7 antagonist. Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0342] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV antibody, bispecific antibody, and "antibody-like" therapeutic protein. Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, multispecific antibodies, bNAbs (broadly neutralizing HIV antibodies), BMS-936559, TMB-360, and HIV These include those targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, and MB-66. Additional examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, gp120 bispecific monoclonal antibody, PCT121.414.LS, ibalizumab (second generation), KLIC (HIV infection) targeting clone 3 human monoclonal antibody, GS-9721, BG-HIV, VRC-HIVMAB091-00-AB, and combinations thereof.

[0343] Various bNAbs can be used, including, for example, those described in U.S. Patent No. 8,673,307, U.S. Patent No. 9,493,549, U.S. Patent No. 9,783,594, U.S. Patent No. 10,239,935, U.S. Patent Application Publication No. 2018 / 371086, U.S. Patent Application Publication No. 2020 / 223907, WO 2014 / 063059, WO 2012 / 158948, WO 2015 / 117008, and International Application Nos. PCT / US2015 / 41272 and WO 2015 / 117008. No. 17 / 096221, including, but not limited to, antibodies 12A12, 12A21, NIH45-46, BANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. et al., Nature, 492(7427):118-22(2012), Horwitz et al., Proc Natl Acad Sci USA, 110(41):16538-43(2013), Scheid, et al., Science, 333:1633-1637(2011), Scheid, et al., Nature, 458:636-640(2009), Eroshkin et al., Nucleic Acids Res., 42(Database Issue):Dl 133-9(2014), Mascola et al., Immunol Rev., 254(1):225-44(2013), for example, 2F5, 4E10, M66.6 , CAP206-CH12, 10E81, etc. (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which bind to the outer domain glycans); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0344] Additional broadly neutralizing antibodies that can be used as second therapeutic agents in combination therapy are described, for example, in U.S. Pat. No. 8,673,307, U.S. Pat. No. 9,493,549, U.S. Pat. No. 9,783,594, and WO 2012 / 154312, WO 2012 / 158948; WO 2013 / 086533, WO 2013 / 142324, WO 2014 / 063059; WO 2014 / 089152, WO 2015 / 048 462; WO 2015 / 103549, WO 2015 / 117008, WO 2016 / 014484; WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO 2017 / 096221; WO 2017 / 133639, WO 2017 / 133640, the entire contents of which are incorporated herein by reference for all purposes. Additional examples include Sajadi, et al., Cell. (2018) 173(7):1783-1795; Sajadi, et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427):118-22(2012); Horwitz et al., Proc Natl Acad Sci USA,110(41):16538-43(2013),Scheid,et al.,Science,333:1633-1637(2011),Scheid,et al.,Nature,458:636-640(2009),Eroshkin et al,Nucleic Acids Res.,42(Database issue): D1133-9 (2014), Mascola et al., Immunol Rev., 254(1):225-44 (2013) (e.g., 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind to the MPER of gp41)).

[0345] Examples of additional antibodies include BF520.1, BiIA-SG, CH01, CH59, CAP256V2LS, DH270.1, DH270.6, D1D2, Cl3hmAb, GS-9722 (elipovimab), BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, and PGT -123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-134, PGT-135, PGT-128, PGT-136, PGT -137, PGT-138, PGT-139, DH511-2, N49P7.1, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, IMC-HIV, iMabm36, eCD4-Ig, IOMA, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354B G426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, These include, but are not limited to, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01. Examples of such HIV-targeting agents include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, 10-1074, 10-1074-LS, GS-9722, DH411-2, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, N6LS, N49P6, N49P7, N49P9, N49P11, and VRC01. Examples of HIV bispecific antibodies include VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014, and TMB-bispecific. Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01, and combinations thereof.

[0346] Examples of in vivo delivered bNAbs include AAV8-VRC07 and mRNA encoding the anti-HIV antibody VRC01. Further examples of in vivo delivered bNAbs include engineered B cells encoding 3BNC117 (Hartweger et al., Exp Med. 2019, 1301). Pharmacokinetic enhancers

[0347] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional medications

[0348] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one additional therapeutic agent. Examples of additional HIV therapeutic agents include those described 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), U.S. Patent Application Publication No. 2013 / 0165489 (University of Pennsylvania), U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), WO 2013 / 091096 (Boehringer Ingelheim), WO 2018 / 145021 (Gilead Sciences), and WO 2017 / 106 346 (Gilead Sciences), the entire contents of which are incorporated herein by reference. HIV vaccine

[0349] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV vaccine. 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 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclad DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV 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, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, 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 vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, 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, conjugate polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclad Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160. HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer vaccine, PD-201401, env(A,B,C,A / E) / gag(C) DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector-based immunotherapy (Vaxwave, TheraT), MVA-BN HIV vaccine regimen, UBI HIV gp120, mRNA-based protease inhibitor Additional examples of HIV vaccines include, but are not limited to, HIV MAG DNA vaccines, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus macaque, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enteric virus-based vaccines, gorilla adenovirus vaccines, lentivirus-vector-based vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), bipartite or tripartite arenavirus-based vaccines, and trimer-based HI. V-1 vaccines, measles virus-based vaccines, flavivirus vector-based vaccines, tobacco mosaic virus vector-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (such as mutant vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines, such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298-16); LNP-based mRNA-based therapeutic vaccines; LNP-based self-replicating RNA / self-replicating RNA vaccines, and combinations thereof.Examples of other additional agents that are vaccines include AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChadOx1.tHIVconsv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen. HIV vaccines, ConM SOSIP.v7 gp140, MPER-656 liposomal subunit vaccine, Pennvax-G / MVA-CMDR, ChAdV63.HIVconsv, SeV-EnvF, N123-VRC-34.01 derived epitope-based HIV vaccine, GOVX-C55, TVI-HIV-1, ENOB-HV-11, ENOB-HV-12, MagaVax, SCaVII-expressing DNA and SeV vector vaccines, VIR-1111, DermaVir, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector-based vaccine, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer center), and combinations thereof. Combined birth control (contraceptive) therapy

[0350] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one birth control or contraceptive regimen. Therapeutic agents used for birth control (contraception) that can be combined with the agents of the present disclosure include, but are not limited to, cyproterone acetate, desostril, ethinyl estradiol, ethynodiol, etonogestrill, levomycin, levonorgestrel, linepolistin, misoprostrol, nomedistrol acetate, norelgestromin, norethindrone, noregestrol, norelgestromin, norethoxyfene, sedisterone acetate, and any combination thereof. HIV combination therapy

[0351] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents selected from the following: ATRIPLA® (efavirenz, tenofovir disoproxil fumarole), elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, tenofovir alafenamide, and emtricitabine), COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCO VY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ (registered trademark) ABV (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; Ralteglar; Raltegravir and lamivudine; Maraviroc; Enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (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; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir;Indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazides; lamivudine, nevirapine, and zidovudine; abacavir and abacavir sulfate. The additional therapeutic agent may be selected from, for example, tenofovir alafenamide and elvitegravir; tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection); pegylated raltegravir; lamivudine + lopinavir + ritonavir + abacavir; tenofovir + emtricitabine + maraviroc, and combinations thereof.

[0352] It will be understood by those skilled in the art that the additional therapeutic agents listed above may fall into more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

[0353] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another particular embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, 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 inhibitor of reverse transcriptase, 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 inhibitors of reverse transcriptase. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor or capsid polymerization inhibitor. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV capsid inhibitor or capsid polymerization inhibitor. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four HIV bNAbs. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four HIV bNAbs. A bNAb is combined with an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, or an HIV capsid polymerization inhibitor, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In another embodiment, a compound disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. Gene Therapy and Cell Therapy

[0354] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with gene therapy and cell therapy regimens. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cell activity to further alter endogenous immune responsiveness to infection. Examples of cell therapy include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-31, GOVX-B01, HSPC-overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapy include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells are co-administered with one or more multispecific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy. Gene Editor

[0355] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with a gene editor, such as an HIV-targeting gene editor. In various embodiments, the genome editing system can be selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV targets for the CRISPR / Cas9 system include, but are not limited to, EBT-101. CAR-T cell therapy

[0356] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are The antibody can be co-administered with a population of immune effector cells engineered to express a CAR (Carrier Antigen Receptor), where the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. 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 can be autologous or allogeneic. HIV Examples of CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duo CAR-T, anti-CD4 CAR-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, anti-CD4 MicAbody antibody+anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide. TCR-T cell therapy

[0357] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a population of TCR-T cells that are genetically engineered to target an HIV-derived peptide, e.g., ImmTAV, present on the surface of virally infected cells. B cell therapy

[0358] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one B cell therapy. In some embodiments, an antibody or antigen-binding fragment described herein is combined with a population of B cells genetically engineered to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019).

[0359] A compound disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three, or four additional therapeutic agents in any dosage relative to the compound of Formula I (e.g., 1-500 mg of compound).

[0360] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0361] In one embodiment, the additional therapeutic agent or agents of the kit are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulatory agents, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (such as chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, etc.), compounds targeting the HIV capsid, latency reactivators, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, T The anti-HIV agent is selected from an AT protein inhibitor, an HIV Nef modulator, an Hck tyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, an HIV splicing inhibitor, a Rev protein inhibitor, an integrin antagonist, a nucleoprotein inhibitor, a splicing factor modulator, a COMM domain-containing protein 1 modulator, an HIV ribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendritic ICAM-3-grabbing nonintegrin 1 inhibitor, an HIV GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and combinations thereof.

[0362] In some embodiments, the additional therapeutic agent or agents of the kit are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0363] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and one, two, three, or four HIV bNAbs. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor.In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor or an HIV capsid polymerization inhibitor, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase, and an HIV capsid inhibitor. Combined birth control (contraceptive) therapy

[0364] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one birth control combination therapy. Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norregestromin, norethindrone, nortinodrel, norgestimate, ormeloxifene, segestrel acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0365] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one gene and / or cell therapy. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to kill infected cells or activate the patient's own immune system to detect and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

[0366] An example of a dendritic cell therapy is AGS-004.

[0367] An example of a CCR5 gene editing drug is SB-728T.

[0368] An example of a CCR5 gene inhibitor is Cal-1. Gene Editor

[0369] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one gene editor, wherein the genome editing system is selected from the group consisting of a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system, and a meganuclease system.

[0370] An example of an HIV-targeting CRISPR / Cas9 system includes EBT-101. CAR-T cell therapy

[0371] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one CAR-T cell therapy. A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. 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 can be autologous or allogeneic.

[0372] Examples of HIV CAR-T include VC-CAR-T, an anti-CD4 CAR cell therapy, and autologous hematopoietic stem cells genetically engineered to express the CD4 CAR and C46 peptide. TCR-T cell therapy

[0373] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one TCR-T cell therapy, wherein the TCR-T cells are genetically engineered to target an HIV-derived peptide displayed on the surface of virally infected cells. HIV long-acting therapy

[0374] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one long-acting HIV therapy. Examples of drugs being developed as long-acting regimens include cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, MK-8591 implant, doravirine, raltegravir, and long-acting dolutegravir. HBV combination therapy

[0375] In certain embodiments, a method is provided for treating or preventing HBV infection in a human having or at risk of infection, the method comprising administering to the human a therapeutically effective amount of a composition described herein in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In one embodiment, a method is provided for treating HBV infection in a human having or at risk of infection, the method comprising administering to the human a therapeutically effective amount of a composition described herein in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0376] In some embodiments, a pharmaceutical composition is provided that includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, and a pharmaceutically acceptable excipient.

[0377] In some embodiments, kits are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0378] In some embodiments, an agent of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, an agent of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, an agent of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, an agent of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents.

[0379] In certain embodiments, when the agents of the present disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0380] Co-administration of an agent disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of an agent disclosed herein with one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0381] Co-administration includes administration of a unit dose of an agent disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. The therapeutic agents may be administered within seconds, minutes, or hours of the administration of the therapeutic agent(s). For example, in some embodiments, a unit dose of an agent disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of an agent disclosed herein. In some embodiments, a unit dose of an agent disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of an agent disclosed herein.

[0382] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents in a combination preparation for simultaneous administration to a subject, e.g., as a solid dosage form for oral administration.

[0383] In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in combination with HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B core antigen (HBcAg) inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, viral mRNA-targeting antisense oligonucleotides, short interfering RNA (siRNA) and ddRNAi endonuclease modifiers, ribonuclease reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, caspase 9 stimulators, CD3 modulators, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, ZCC and / or combinations thereof. The compositions described herein may be combined with one, two, three, four, or more additional therapeutic agents selected from HC14 inhibitors, derivatives of tertiary lymphoid aggregates, nucleic acid polymers (e.g., NAP and STOPS), PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, gene and cell therapies, gene editors, CAR-T cell therapies, TCR-T cell therapies, other HBV drugs, and combinations thereof. In certain embodiments, the present disclosure provides a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a composition described herein in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents suitable for treating an HBV infection.

[0384] The compounds described herein can be used or combined with one or more of chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), genetic modifying agents or gene editors (CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs, etc.), cell therapies such as CAR-T (chimeric antigen receptor T cells), and TCR-T (genetically engineered T cell receptor) agents, or any combination thereof. Additional examples include, but are not limited to, DARPins®, anti-pMHC TCR-like antibodies, homing meganucleases (e.g., ARCUS), and combinations thereof.

[0385] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents, examples of which include, but are not limited to, 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B and T lymphocyte attenuation inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, and hepatitis B core antibodies. Compounds targeting HBV 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, free fatty acid (Ffa) receptor 2 (Ffar2; PR43) agonists, free fatty acid (Ffa) receptor 3 (Ffar3; GPR441) agonists, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBVRNAse inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein inhibitors, 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, apoptosis protein family proteins (I AP) inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine 2 inhibitors, ribonucleotide reductase inhibitors, interleukin 2 ligand, 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, CD16 0 modulators, CD161 modulators, CD27 modulators, CD47 modulators, non-canonical RNA polymerase PAPD5 inhibitors, non-canonical RNA polymerase PAPD7 inhibitors, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPalpha modulators, TIGIT modulators, T Im-4 modulators, Tyro modulators, Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nuclear protein modulators, OX-40 receptor agonists, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNAThese include DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulators of interferon genes (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-7 modulators, TLR-8 modulators, TLR-9 agonists, TLR9 agonists or gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof. HBV combination drugs

[0386] In some embodiments, a compound described herein is combined with at least one other drug combination for the treatment of HBV. Examples of other drug combinations for the treatment of HBV include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir, and PEG-IFN-α; and INO-1800 (INO-9112 and RG7944). do. Other HBV medications

[0387] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one other HBV drug. Examples of other drugs for the treatment of HBV infection include α-hydroxytropolone, amdoxovir, β-hydroxycytosine nucleoside, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, 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, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, as well as U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 201612 8335(A1) (Roche), WO 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and U.S. Patent Application Publication No. 2015031687(A) (Roche). Additional examples of other drugs for the treatment of HBV include, but are not limited to, antroquinonol, ARB-199, ccc-R08, HH-003, heparatide, NCO-48 fumarate, XTYW-001, SFA-001, ENOB-HB-01, QL-007 sofosbuvir, lizipasvir, PA-1010, HPN-BV1, STSG-0002, and combinations thereof. HBV vaccine

[0388] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HBV vaccine, which includes both prophylactic and therapeutic vaccines. Examples of HBV prophylactic 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 prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Huanan Biological Products), and others. Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pen These include tabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, 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. Additional vaccines include, but are not limited to, CARG-101, YS-HBV-001, IR-101H, TVAX-008, and combinations thereof.

[0389] Examples of HBV therapeutic vaccines include HBsAG-HBIG conjugate, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-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 vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, and Lm HBV. Additional examples of HBV therapeutic vaccines include, but are not limited to, HepT cells, hepatitis B therapeutic DNA vaccine, VVX-001, GSK-3528869A (ChAd155-hli-HBV+MVA-HBV+Hbc-HBs / AS01B-4), VBI-2601, VTP-300 (ChAdOx1-SIi-HBV-CPmut-TPA-Ssh prime and MVA-SIi-HBV-CPmut-TPA-Ssh boost), MVA-BN, AVA-2100, HBV-ADV311, YS-HBV-002, HBV arenavirus vaccines disclosed, for example, in WO2017076988 and WO2017198726, and combinations thereof. HBV DNA polymerase inhibitors

[0390] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is combined with at least one HBV DNA polymerase inhibitor, examples of which include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, bicifovir, and entecavir. (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocillovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusorin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orotate, and HS-10234. Additional examples of HBV DNA polymerase inhibitors include, but are not limited to, tenofovir exalidex, ATI-2173, AiB-001, and combinations thereof. immunomodulators

[0391] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one immunomodulatory agent. Examples of immunomodulatory agents include lintatolimod, imidole hydrochloride, ingaron, dermaVir, Plaquenil (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. Toll-like receptor (TLR) modulators

[0392] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793), TLR11, TLR12, and TLR13. TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

[0393] Examples of TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0394] Examples of TLR modulators include, but are not limited to, AK-0701.

[0395] Examples of TLR4 modulators include, but are not limited to, G-100 and GSK-1795091.

[0396] Examples of TLR7 modulators include GS-9620 (vesatolimod), GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, D, telluritolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds described in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences). Additional examples of TLR7 modulators include, but are not limited to, AL-034, DSP-0509, LHC-165, and TMX-101 (imiquimod), and combinations thereof.

[0397] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, and 3M -052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688, and U.S. Patent Application Publication Nos. 20140045849 (Janssen), 20140073642 (Janssen), WO 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), U.S. Patent Application Publication Nos. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication Nos. 20080234251 (Array Biopharma), 20080306050 (Array Biopharma), No. 20100029585 (Ventirx Pharma), No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx Pharma), No. 20140275167 (Novira Therapeutics), No. 20130251673 (Novira No. 9,670,205, U.S. Patent Application Publication No. 20160289229, U.S. Patent Application No. 15 / 692161, and U.S. Patent Application No. 15 / 692093.

[0398] TLR7 / TLR8 modulators include, but are not limited to, NKTR-262, telluritolimod, and BDB-001.

[0399] Examples of TLR-8 inhibitors include, but are not limited to, ZG-170607.

[0400] Exemplary TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, sergantolimod (GS-9688), HRS-9950, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds described in U.S. Patent Application Publication No. 2016289229 (Gilead). Sciences), U.S. Patent Application Publication Nos. 20140045849 (Janssen), 20140073642 (Janssen), WO 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), U.S. Patent Application Publication Nos. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication Nos. 20080234251 (Array Biopharma), 20080306050 (Array Biopharma), 20100029585 (Ventirx Pharma), 20110092485 (Ventirx Pharma), U.S. Patent No. 20110118235 (Ventirx Pharma), U.S. Patent No. 20120082658 (Ventirx Pharma), U.S. Patent No. 20120219615 (Ventirx Pharma), U.S. Patent No. 20140066432 (Ventirx Pharma), U.S. Patent No. 20140088085 (Ventirx Pharma), U.S. Patent No. 20140275167 (Novira Therapeutics), and U.S. Patent No. 20130251673 (Novira Therapeutics), U.S. Patent No. 9670205 (Gilead Sciences, Inc.), U.S. Patent Application Publication No. 20160289229 (Gilead Sciences, Inc.), International Publication No. 2017 / 048727 (Gilead Sciences, Inc.), U.S. Patent Application Publication No. 20180065938 (Gilead Sciences, Inc.), and the compounds disclosed in US Pat. No. 20180086755 (Gilead Sciences, Inc.).

[0401] 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), ritenimod, and CYT-003-QbG10. Additional examples of TLR9 modulators include AST-008, cobitolimod, CMP-001, S-540956, ritenimod, MGN-1601, BB-001, BB-006, CYT-003, tilsotolimod, PUL-042, and combinations thereof.

[0402] Examples of TLR7, TLR8 and TLR9 modulators include those described in WO 2017047769 (Teika Seiyaku), WO 2015014815 (Janssen), WO 2018045150 (Gilead Sciences Inc), WO 2018045144 (Gilead Sciences Inc), WO 2015162075 (Roche), WO 2017034986 (University of (of Kansas), same as No. 2018095426 (Jiangsu Hengrui Medicine Co Ltd), same as No. 2016091698 (Roche), same as No. 2016075661 (GlaxoSmithKline Biologicals), same as No. 2016180743 (Roche), same as No. 2018089695 (Dynavax Technologies), same as No. 2016055553 (Roche), same as No. 2015168279 (Novartis), same as No. 2016107536 (Medshine Discovery), same as No. 2018086593 (Livo(Shanghai) Pharmaceutical), same as No. 2017106607 (Merck), same as No. 2017061532 (Sumitomo Dainippon) Pharma), same as No. 2016023511 (Chia Tai Tianqing Pharmaceutical), same as No. 2017076346 (Chia Tai Tianqing Pharmaceutical), same as No. 2017046112 (Roche), same as No. 2018078149 (Roche), same as No. 2017040233 (3M Co), same as No. 2016141092 (Gilead Sciences), same as No. 2018049089 (Bristol Myers Squibb), same as No. 2015057655 (Eisai Co Ltd), same as No. 2017001307 (Roche), same as No. 2018005586 (Bristol Myers Squibb), same as No. 201704023 (3M Co), same as No. 2017163264 (Council of Scientific and Industrial Research (India)), No. 2018046460 (GlaxoSmithKline No. 2018047081 (Novartis), No. 2016142250 (Roche), No. 2015168269 (Novartis), No. 201804163 (Roche), No. 2018038877 (3M Co), No. 2015057659 (Eisai Co) Ltd), No. 2017202704 (Roche), No. 2018026620 (Bristol Myers Squibb), No. 2016029077 (Janus Biotherapeutics), Patent No. 201803143 (Merck), Patent No. 2016096778 (Roche), Patent No. 2017190669 (Shanghai De Novo Pharmatech), U.S. Patent No. 09884866 (University of Minnesota), International Publication No. 2017219931 (Sichuan KelunBiotech Biopharmaceutical), No. 2018002319 (Janssen Sciences), No. 2017216054 (Roche), No. 2017202703 (Roche), No. 2017184735 (IFM Therapeutics), No. 2017184746 (IFM Therapeutics), No. 2015088045 (Takeda Pharmaceutical), No. 201 7038909 (Takeda Pharmaceutical), 2015095780 (University of Kansas), and 2015023958 (University of Kansas).

[0403] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a TLR7, TLR8, TLR9 agonist, or a combination thereof. Interferon α receptor ligand

[0404] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one interferon alpha receptor ligand. Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPE G-interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), YPEG interferon alpha-2b (YPEG-rhIFNalpha-2b), MOR-22, pegylated interferon alpha-2b (PEG-INTRON®), Bioferon, Novaferon ), Inmutag (Inferon), MULTIFERON®, interferon alpha-n1 (HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, Blauferon-B, Blauferon-C, Blauferon-D, Blauferon-E, Blauferon-F, Blauferon-H, Blauferon-I ... BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PD-Ferron-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 alpha-2b (Amega), interferon alpha-2b ( Virchow), ropeg interferon α-2b, rHSA-IFN α-2a (recombinant human serum albumin interferon α-2a fusion protein), rHSA-IFN α 2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute Examples of interferon alpha receptor ligands include, but are not limited to, PEG-IFN-alpha. hyaluronidase inhibitors

[0405] In certain embodiments, the compounds described herein or pharmaceutically acceptable salts thereof comprise at least Both are combined with a hyaluronidase inhibitor. An example of a hyaluronidase inhibitor is astodrimer. Hepatitis B surface antigen (HBsAg) inhibitors

[0406] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one hepatitis B surface antigen inhibitor. 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-2165, REP-2163, REP-2053, REP-2031, and REP-006, and REP-9AC'. Additional examples of HBsAg inhibitors include GP-605.

[0407] An example of an HBsAg secretion inhibitor includes BM601. Additional examples of HBsAg secretion inhibitors include, but are not limited to, GST-HG-131, AB-452, ALG-010093, and combinations thereof. Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

[0408] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one inhibitor of cytotoxic T lymphocyte-associated protein 4. Examples of cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, probody mAbs, tremelimumab, and JHL-1155. Cyclophilin inhibitors

[0409] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one cyclophilin inhibitor. Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds described in U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 20140030221 (Gilead Sciences), U.S. Patent Application Publication No. 20130344030 (Gilead Sciences), and the compounds described in U.S. Patent Application Publication No. 20130344030 (Gilead Sciences). and compounds described in US Pat. No. 20130344029 (Gilead Sciences). HBV virus entry inhibitor

[0410] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HBV viral entry inhibitor. An example of an HBV viral entry inhibitor is Myrcludex B. Hepatitis B large envelope protein inhibitor

[0411] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one Hepatitis B large envelope protein inhibitor. Examples of Hepatitis B large envelope protein inhibitors include, but are not limited to, GP-605, GST-HG-121, ALG-010093, and ALG-01013. Viral mRNA-targeting antisense oligonucleotides

[0412] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one viral mRNA-targeting antisense oligonucleotide. Examples of viral mRNA-targeting antisense oligonucleotides include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Additional examples of otides include, but are not limited to, IONIS-HBV-LRx, BNC-1701, and combinations thereof. Short interfering RNA (siRNA) and ddRNAi

[0413] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one siRNA and / or ddRNAi.

[0414] Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467. Additional examples of siRNAs include, but are not ...

Claims

1. Formula: 【Chemistry 1-1】 [Chemistry 1-2] or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 2, further comprising at least one additional therapeutic agent.

4. 4. The pharmaceutical composition of claim 3, wherein the at least one additional therapeutic agent comprises abacavir, tenofovir alafenamide, tenofovir disoproxil, emtricitabine, bictegravir, dolutegravir, cabotegravir, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof, or a combination thereof.

5. The pharmaceutical composition of claim 3, wherein the at least one additional therapeutic agent comprises adefovir, entecavir, telbivudine, lamivudine, or a combination thereof.

6. A composition for treating an HIV infection in a human having said infection, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 2 to 5.

7. A composition for treating HIV infection in a human having said infection or for preventing HIV infection in a human at risk of having said infection, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

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