Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same

Abstract

The present disclosure provides prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenosine nucleosides and compositions, methods, and kits thereof. Such compounds are useful for treating viral infections, including human immunodeficiency virus. These compounds have the following formula (I).

Description

[0001] Cross-reference to related applications

[0002] This application claims 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”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to compounds, compositions, and methods for treating viral infections. Background Technology

[0004] Human immunodeficiency virus (HIV) infection is a life-threatening and serious disease with significant public health implications, affecting tens of millions of people worldwide. Currently, there is no cure, so patients affected by HIV may require lifelong treatment, which may include one or more daily treatments and can cause various side effects. Improvements in the treatment of HIV and other viral infections are needed. Summary of the Invention

[0005] This article discloses compounds of formula (I), for example:

[0006]

[0007] in

[0008] The dashed line (----) and the solid line parallel to it together indicate an optional double bond;

[0009] X represents halogen;

[0010] R 1 Indicates (C1-C6) ynyl group;

[0011] R 2 Represents 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 );

[0012] R 3a Indicates H or R e ;

[0013] R 3b This indicates that H may not exist;

[0014] R 4 R represents d Or it may not exist;

[0015] R 5 Represents 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 );

[0016] Each R a Indicates (C1-C 25 )alkyl groups, which may be the same or different;

[0017] Each R a Optionally by an R b replace;

[0018] Each R b Indicates phenyl or cyclohexyl.

[0019] Each R b Optionally selected from one to three independent selections from R f -CH2-OC(=O)(R f ) and -OC(=O)(R f Substitution of groups;

[0020] Each R c1 and R c2 It represents -NH-LC(=O)(OR) f ) and -NH-LC(=O)(OR g (They can be the same or different);

[0021] Each R d Independently represent

[0022] R eRepresents 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 );

[0023] Each R f Independently represent (C1-C) 18 )alkyl;

[0024] Each L independently represents (C1-C 18 )alkylene;

[0025] R g Indicates cyclohexyl; and

[0026] Each R h Independently representing steroidal compound derivatives or bridged, spirocyclic, or fused polycyclic (C7-C6) compounds. 18 Carbon ring,

[0027] The steroidal compound derivative is optionally composed of one to four independently selected compounds from -OH and (C1-C2) groups. 12 Alkyl groups are substituted;

[0028] When R 5 When it is H, then R 2 Not -P(=O)(OR) b (R) c1 ) or -P(=O)(R c1 (R) c2 When R 3a For H, R 3b For H and R 5 When it is H, then R 2 Not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'),

[0029] Where Z represents the bond, (C1-C) 10 )alkyl, C(R) x (R)z ),

[0030] R x and R z Independently selected from H, (C1-C6)alkyl and (C6-C 10 )cycloalkyl,

[0031] R x and R z Each of them is independently and optionally substituted with a (C1-C6)alkyl, oxo, or (C1-C6)alkoxy group; and

[0032] Z' represents H, (C1-C) 10 )alkyl or (C1-C 10 )alkoxy, and wherein Z' is optional

[0033] The ground is substituted with (C1-C6) alkyl, oxo, or (C1-C6) alkoxy groups;

[0034] when

[0035] R 3a For R e And R 3b For H,

[0036] R e It is H or -C (=O)(O-(C1-C6)alkyl) or -C (=O)(C1-C) 25 )alkyl, and

[0037] R 5 For H or -C(=O)(O-(C1-C) 25 When alkyl),

[0038] Then R 2 Not -C(=O)(O-(C1-C) 25 )alkyl); and

[0039] when

[0040] R 2 For H or -C (=O)(O–(C1-C) 10 )alkyl), and

[0041] R 5 -C (=O) (optionally substituted with an oxo group or (C1-C6) alkyl group) 18 )alkyl), -C(=O)-(optionally separated by (C1-C 18 When alkyl-substituted cyclohexyl or -C (=O) (optionally substituted with (C1-C6)alkyl or -OC (=O) ((C1-C6)alkyl)-substituted phenyl),

[0042] Then R e Not (a)H, (b)-C(=O)(O–(C1-C 10 )alkyl) or (c)-C(=O)((C1-C 15 )alkyl);

[0043] Or a pharmaceutically acceptable salt thereof. Subformulas Ia and Ib are also disclosed herein. Methods for their preparation and use are also disclosed herein. Detailed Implementation

[0044] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. Several embodiments are described below with the understanding that this disclosure is intended to be illustrative of the claimed subject matter and not to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0045] I. definition

[0046] The term “about” or “approximately” used in conjunction with a quantity includes the value and has the meaning prescribed by the context (e.g., including the degree of error associated with the measurement of a particular quantity).

[0047] As used herein, the term "administration" generally refers to administering a composition to a subject to achieve delivery of a pharmaceutical agent in or contained in the composition to a target site or site of treatment. Those skilled in the art will recognize a variety of routes of administration that may be used to administer the composition to a subject (e.g., a human) where appropriate. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous). In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administering a fixed number of doses. In some embodiments, administration may involve intermittent (e.g., multiple doses separated by time) and / or periodic (e.g., single doses separated by a common time period) dosing. In some embodiments, administration may involve continuous administration (e.g., infusion) for at least a selected period of time.

[0048] "Alkyl" is a hydrocarbon containing primary, secondary, or tertiary atoms. For example, alkyl groups can have 1 to 25 carbon atoms (i.e., (C1-C2)). 25 Alkyl groups), 1 to 10 carbon atoms (i.e., (C1-C1) 10Alkyl groups, having 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, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl ( i -Pr, isopropyl, -CH(CH3)2), 1-butyl ( n -Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu, isobutyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, tert-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(C (H3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3). "Alkyl" also refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent groups at its center derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., (C1-C1)). 10Alkyl groups are alkyl groups with 1 to 6 carbon atoms (i.e., (C1-C6)alkyl) or 1 to 3 carbon atoms (i.e., (C1-C3)alkyl). Typical alkyl groups 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 (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc.

[0049] As used in this article, the term "(C)" 1-n alkyl (also described as "(C1-C") n Alkyl group”, where n is an integer, alone or in combination with another group, refers to a non-cyclic, straight-chain or branched alkyl group containing 1 to n carbon atoms. 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviations Me represent methyl groups; Et represent ethyl groups; Pr represent propyl groups; iPr represents 1-methylethyl groups; Bu represents butyl groups; and tBu represents 1,1-dimethylethyl groups.

[0050] "alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene groups can have 1 to 25 carbon atoms (i.e., C64 ... 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 1 to 4 carbon atoms (i.e., C46) 1-4 Alkylene. Examples include: methylene, ethylene, propylene, 1-methylethylene, butene, 1-methylpropene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise stated, propylene and butene are defined to include all possible isomers of the group in question having the same number of carbon atoms. Thus, for example, propylene also includes 1-methylethylene, and butene includes 1-methylpropene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0051] "Alkenyl" is a group containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., carbon-carbon sp). 2 Alkenes are straight-chain or branched hydrocarbons with double bonds. For example, alkenes can have 2 to 20 carbon atoms (i.e., C2-C2). 20Alkenyl (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).

[0052] As used in this article, the term "(C)" 2-n "(C)alkenyl", where n is an integer, alone or in combination with another group, refers to an unsaturated, acyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by double bonds. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise specified, the term "(C)alkenyl" is used to refer to an unsaturated, acyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by double bonds. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and 1-butenyl. 2-n "Alkenyl" should be understood to include, where possible, individual stereoisomers, including but not limited to (E) and (Z) isomers and mixtures thereof. Unless otherwise stated, when (C) 2-n When an alkenyl group is substituted, it should be understood that it is substituted on any carbon atom that will have a hydrogen atom, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0053] "Alynyl" is a straight-chain or branched hydrocarbon containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., a carbon-carbon sp triple bond). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C). 20 Alkynes can be 2 to 8 carbon atoms (i.e., C2-C8 alkynes) or 2 to 6 carbon atoms (i.e., C2-C6 alkynes). Examples of suitable alkynes include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0054] As used in this article, the term "(C)" 2-n "(C)ynyl", where n is an integer, alone or in combination with another group, refers to an unsaturated, acyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by a triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. Unless otherwise stated, when (C) 2-n When an alkynyl group is substituted, it should be understood that it is substituted on any carbon atom that will have a hydrogen atom, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0055] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological agent) that effectively inhibits the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of a virus in humans.

[0056] As used herein, the term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl groups include phenyl groups or ortho-, spirocyclic, or bridged bicyclic or polycyclic groups having about 9 to 14 atoms, wherein at least one ring is aromatic (e.g., an aryl group fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic groups may optionally be substituted by one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the bicyclic or polycyclic ring. It should be understood that the connection point of the bicyclic or polycyclic group as defined above can be at any position on the ring, including the aryl or carbocyclic portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracene, etc.

[0057] "Arylalkyl" means an alkyl group as defined herein, wherein one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as described herein (i.e., aryl-alkyl-part). The alkyl group of an "arylalkyl" typically has 1 to 6 carbon atoms (i.e., aryl(C1-C6)alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, 1-phenylprop-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, etc.

[0058] As used in this article, the term "aryl-(C 1-n )alkyl-", where n is an integer, alone or in combination with another group, refers to an alkyl group as defined above having 1 to n carbon atoms, which itself is substituted with an aryl group as defined above. aryl-(C 1-n Examples of alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, and phenylpropyl. Unless otherwise stated, when aryl-(C 1-n When an alkyl group is substituted, it should be understood that the substituent may be attached to an aryl group or its alkyl moiety or both, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0059] The term "carbocyclic" or "carbocyclic group" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cyclodienyl, etc.) ring having 3 to 7 carbon atoms as a monocyclic or polycyclic ring system. In one embodiment, the carbocyclic ring is a monocyclic ring containing 3 to 6 cyclic carbon atoms (i.e., (C3-C6) carbocyclic ring). Carbocyclic rings include bicyclic rings having 7 to 12 carbon atoms and polycyclic carbocyclic rings having up to about 20 carbon atoms, provided that the largest monocyclic ring of the polycyclic carbocyclic ring has 7 carbon atoms. The term "spirocyclic carbocyclic" refers to a carbocyclic ring system in which the rings of the ring system are attached to a single carbon atom (e.g., spiropentane, spiro[4,5]decane, spiro[4,5]decane, etc.). The term "fused carbocyclic ring" refers to a carbocyclic ring system in which the rings of the ring system are connected to two adjacent carbon atoms, such as bicyclic [4,5], [5,5], [5,6], or [6,6] systems, or bicyclic [5,6] or [6,6] systems with 9 or 10 ring atoms arranged (e.g., decahydronaphthalene, norsabenzane, normethane). The term "bridged carbocyclic ring" refers to a carbocyclic ring system in which the rings of the ring system are connected to two non-adjacent carbon atoms (e.g., norbornane, bicyclic [2.2.2]octane, etc.). The "carbocyclic ring" or "carbocyclic group" may optionally be substituted with one or more (e.g., 1, 2, or 3) oxo groups. Non-limiting examples of monocyclic carbocyclic rings 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.

[0060] "Carbocycloalkyl" means an alkyl group as defined herein, wherein one of the hydrogen atoms bonded to a carbon atom is replaced by a carbocyclo group as described herein (i.e., the carbocyclo-alkyl- moiety). The alkyl group of a "carbocycloalkyl" typically has 1 to 6 carbon atoms (i.e., a carbocyclo(C1-C6)alkyl). Typical carbocycloalkyl groups include, but are not limited to, carbocyclo-CH2-, carbocyclo-CH(CH3)-, carbocyclo-CH2CH2-, 2-(carbocyclo)ethyl-1-yl, etc., wherein the "carbocyclo group" moiety includes any of the aforementioned carbocyclo groups.

[0061] The term "chirality" refers to a molecule that has a non-overlapping property with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0062] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having three to fifteen carbon atoms, in some embodiments three to ten carbon atoms or three to seven carbon atoms, and is saturated or partially unsaturated and connected to the rest of the molecule by single bonds. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, cycloheptenyl, and cyclooctyl.

[0063] As used in this article, the term "(C)"3-m "Cycloalkyl", where m is an integer, alone or in combination with another group, refers to a cycloalkyl substituent containing 3 to m carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0064] The term "(C)" used in this article 3-m )cycloalkyl-(C 1-n "alkyl-", where n and m are integers, alone or in combination with another group, refers to an alkyl group as defined above having 1 to n carbon atoms, which itself is substituted by a cycloalkyl group as defined above having 3 to m carbon atoms. (C 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. Unless otherwise stated, when (C 3-m )cycloalkyl-(C 1-n When an alkyl group is substituted, it should be understood that the substituent may be attached to a cycloalkyl group or its alkyl moiety or both, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0065] As used herein, the term "combination therapy" refers to those situations in which a subject simultaneously receives two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). 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 the first regimen are administered before any dose of the second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administering" combination therapy may involve administering one or more agents or modalities to a subject receiving other agents or modalities in the combination. For clarity, combination therapy does not require the individual agents to be administered together in a single composition (or even simultaneously); however, in some embodiments, two or more agents or their active portions may be administered together in the combined composition, or even in the combined compound (e.g., as part of a single chemical complex or covalent entity).

[0066] As used herein, the term "comparable" refers to two or more agents, entities, situations, condition groups, etc., that may not be identical to each other but are similar enough to allow comparisons between them, such that those skilled in the art will understand that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, comparable conditions, environments, individuals, or groups are characterized by a plurality of substantially identical features and one or more features that vary slightly. Those skilled in the art will understand, in any given context, what degree of similarity is required for two or more such agents, entities, situations, condition groups, etc., to be considered comparable. For example, those skilled in the art will understand that environments, individuals, or groups are comparable to each other when characterized by a sufficient number and type of substantially identical features to ensure reasonable conclusions that differences in results or observed phenomena obtained under different environments, individuals, or groups, or between different environments, individuals, or groups, are caused by or indicated by changes in those varying features.

[0067] Unless the context otherwise requires, throughout this disclosure and the claims, the word “comprising” and its variations such as “including” and “containing” shall be interpreted in an open, inclusive sense, that is, as “including but not limited to”.

[0068] A diastereomer is a stereoisomer that has two or more chiral centers or axes and whose molecules are not mirror images of each other. Diastereomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

[0069] As used herein, the term "dosage form" refers to a physically discrete unit of an active agent (e.g., a therapeutic, preventative, or diagnostic agent) intended for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, this amount is a unit dose (or a whole portion thereof) appropriate for administration according to a dosing regimen already determined to be relevant to the desired or beneficial outcome when administered to the relevant population (i.e., with a preventative or therapeutic dosing regimen). Those skilled in the art will understand that the total amount of composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0070] Throughout this specification, the phrase "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in an embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0071] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0072] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine.

[0073] As used in this article, the term "HIV replication inhibitor" is intended to refer to agents that can reduce or eliminate HIV replication in host cells, whether in vitro, ex vivo, or in vivo.

[0074] As used in this article, the term "HBV replication inhibitor" is intended to refer to an agent that can reduce or eliminate HBV replication in host cells, whether in vitro, ex vivo, or in vivo.

[0075] “Mammals” include humans as well as livestock (such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)) and non-livestock (such as wild animals).

[0076] The terms "optional" or "optionally" mean that the event or situation subsequently described may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. For example, "optionally substituted heterocyclic group" means that the heterocyclic group may or may not be substituted, and the description includes substituted heterocyclic groups and unsubstituted heterocyclic groups. It should be understood that when a variable is substituted, for example, as described by the phrase "(C1-C6)alkyl, alone or as part of a group, optionally substituted," the phrase means that the variable (C1-C6)alkyl can be substituted alone, and the variable "(C1-C6)alkyl" can also be substituted when it is part of a larger group such as aryl(C1-C6)alkyl or -(C1-C6)alkyl-SO2-(C1-C6)alkyl-(C3-C7) carbocyclic group. Similarly, when stated, other variables (e.g., (C1-C6) alkenyl, (C1-C6) ynyl, aryl, heteroaryl, heterocyclic, etc.) may also be substituted "alone or as part of a group".

[0077] As used in this article, the term "oxo-substituent" refers to an oxygen atom that is connected to a carbon atom via a double bond (=O) as a substituent.

[0078] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance formulated in combination with the pharmacologically active ingredient of the pharmaceutical composition and compatible with other components of the formulation and suitable for human or animal use without undue toxicity, irritation, allergic reactions, etc.

[0079] Examples of pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + (where X is C) 1-4 Salts of alkyl groups. Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts of the following: organic carboxylic acids, 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, glycerophosphate, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, ethanesulfonic acid, lactobionic acid, nicotinic acid, oxalic acid, dihydroxynaphthyl acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, pentanoic 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 aminosulfonic acid. Pharmaceutically acceptable salts of compounds with hydroxyl groups include the anion of the compound with a suitable cation such as Na+. + and NX4 + (where X is independently selected from H or C) 1-4 Combinations of alkyl groups.

[0080] For therapeutic use, salts of the active ingredients of the compounds disclosed herein will generally be pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify compounds of the embodiments disclosed herein. All salts (whether or not derived from physiologically acceptable acids or bases) are within the scope of the embodiments disclosed herein.

[0081] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to the embodiments disclosed herein. An example of a metal salt prepared in this manner is one containing Li. + Na + and K + Salts with low solubility can be precipitated from solutions of salts with high solubility by adding a suitable metal compound.

[0082] Additionally, salts can be formed by the addition of certain organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids) to an acid with a basic center (typically an amine). Finally, it should be understood that the compositions herein comprise both unionized and zwitterionic forms of the compounds disclosed herein.

[0083] "Pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). Such a medium includes all pharmaceutically acceptable excipients.

[0084] As used herein, the term "prevention" refers to the administration of a compound, composition, or pharmaceutically acceptable salt according to this disclosure before or after human exposure to a virus, but before the onset of disease symptoms and / or before the virus is detected in the blood. In some embodiments, the term also refers to prevention of the onset of disease symptoms and / or prevention of the virus reaching detectable levels in the blood. The term also covers the administration of a compound or composition according to embodiments of the invention disclosed herein (also known as pre-exposure prophylaxis or PrEP) before an individual's exposure to a virus to prevent HIV infection from taking hold and / or to prevent the establishment of permanent infection and / or to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood upon the individual's exposure to the virus. The term includes pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. The term also refers to prevention of perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the child in the first few days of life. The term also refers to prevention of HIV transmission via blood transfusion.

[0085] “Spiral” or “spirocyclic” refers to the aryl, carbocyclic, or heterocyclic structure described herein, which is attached to an existing ring structure in the disclosed compounds via a single atom shared by the spirocyclic structure and existing ring structures. For example, the following bicyclic compounds combine spirocyclopropane (i.e., a cyclopropane ring forming a spirocyclic ring with cyclohexane), spirocyclo1,3-dithiocyclopentane (i.e., a 1,3-dithiocyclopentane forming a spirocyclic ring with cycloheptane), and spirocyclopentene (i.e., a cyclopentene ring forming a spirocyclic ring with cyclohexene), respectively:

[0086]

[0087] The term "stereoisomer" refers to a compound having the same chemical composition but with different spatial arrangements of atoms or groups. For example, a stereoisomer is a compound consisting 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. This disclosure contemplates a variety of stereoisomers and mixtures thereof, and includes diastereomers, enantiomers, etc. In any embodiment disclosed herein, the compound may be in the form of its stereoisomer.

[0088] As used herein, the term "steroidal compound," alone or in combination with another group, means optionally composed of one to six independently selected from -OH and (C1-C6) groups. 12"A tetracyclic hydrocarbon ring substituted with an alkyl group (hexadecylhydro-1H-cyclopentadienyl[a]phenanthrene); "steroidal compounds" include, but are not limited to, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, β-sitosterol, campesterol, cholesterol, stigmasterol, stigmasterol, campesterol, brassosterol, ergosterol, lupeol, and cycloartenol.

[0089] As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human). In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the human subject is an adult, adolescent, or pediatric subject. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject is a person with one or more characteristics of susceptibility or risk to a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who has been given and / or has been given a diagnosis and / or treatment and / or prevention.

[0090] As used herein, a “therapeutic effective amount” is an amount that produces the desired effect when administered. In some embodiments, the term “therapeutic effective amount” or “therapeutic effective dose” means an amount sufficient to treat a disease, disorder, and / or condition when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to such a disease, disorder, and / or condition. In some embodiments, a therapeutic effective amount is an amount that reduces the incidence and / or severity of one or more symptoms of a disease, disorder, and / or condition, stabilizes one or more characteristics of a disease, disorder, and / or condition, and / or delays the onset of one or more symptoms of a disease, disorder, and / or condition. Those skilled in the art will understand that the term “therapeutic effective amount” does not actually require successful treatment in a particular individual. Rather, a therapeutic effective amount can be an amount that provides a specific desired pharmacological response in a large number of subjects when administered to a patient who requires such treatment. In some embodiments, reference to a therapeutic effective amount can refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or symptom) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will understand that in some embodiments, the therapeutically effective amount may be formulated and / or administered as a single dose. In some embodiments, the therapeutically effective amount may be formulated and / or administered in multiple doses, for example, as part of a dosing regimen.

[0091] The term “treatment” includes, to the extent that it relates to a disease or condition, preventing the occurrence of a disease or condition, suppressing a disease or condition, eliminating a disease or condition, and / or alleviating one or more symptoms of a disease or condition.

[0092] The term "treatment" in relation to treating a patient's disease state includes (i) suppressing or improving the patient's disease state, such as stopping or slowing its progression; or (ii) alleviating the patient's disease state, i.e., causing the remission or cure of the disease state. In the case of HIV, treatment includes reducing the patient's HIV viral load.

[0093] As used herein, the term "treatment" is intended to mean the administration of a compound or composition according to the invention to alleviate or eliminate symptoms of HIV infection and / or reduce the viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the invention after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the invention to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the infant in the first few days of life.

[0094] As used herein, the term "treatment" is intended to mean the administration of a compound or composition according to embodiments disclosed herein to alleviate or eliminate one or more symptoms of HIV or HBV infection and / or reduce the viral load in a patient. In some embodiments, the term "treatment" also encompasses the administration of a compound or composition according to embodiments disclosed herein after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to embodiments of the invention disclosed herein to prevent, for example, perinatal transmission of HIV from mother to infant, by administration to the mother before delivery and to the infant in the first few days of life. The term "treatment" also encompasses the administration of a compound or composition according to embodiments of the invention disclosed herein both before and after an individual's exposure to the virus.

[0095] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds that are isotopically labeled by having one or more atoms replaced by atoms with different atomic masses or mass numbers. 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... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. In some embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of the formulas disclosed herein, such as those incorporating a radioisotope, can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) They are particularly useful for this purpose because they are easy to incorporate and readily available detection methods.

[0096] In some implementations, heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages due to its greater metabolic stability. For example, it may increase the half-life in vivo or reduce the dosage requirement. Therefore, in some cases, heavier isotopes may be preferred.

[0097] Using positron emission isotopes such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the formulas disclosed herein can generally be prepared using techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0098] The methods, compositions, kits, and articles provided herein use or include compounds disclosed herein or pharmaceutically acceptable salts thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds increase resistance to metabolism and are therefore useful for increasing the half-life of the compounds or pharmaceutically acceptable salts thereof when administered to mammals. See, for example, 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.

[0099] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds. EFdA is not intended to be included in the embodiments disclosed herein. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein to an animal (such as a rat, mouse, guinea pig, monkey, or human) at a detectable dose, allowing sufficient time for metabolism and separation of its metabolites from urine, blood, or other biological samples.

[0100] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. Unless specifically disclosed, this disclosure is intended to include all such possible isomers as well as their racemic, non-racemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0101] II. compound

[0102] This document provides compounds used as antiviral agents (in some embodiments, anti-HIV agents), pharmaceutical compositions comprising 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 salts, stereoisomers, or mixtures of stereoisomers thereof.

[0103] In one embodiment, a compound of formula (I) is provided:

[0104]

[0105] in

[0106] The dashed line (----) and the solid line parallel to it together indicate an optional double bond;

[0107] X represents halogen;

[0108] R 1 Indicates (C1-C6) ynyl group;

[0109] R 2 Represents 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 );

[0110] R 3a Indicates H or R e ;

[0111] R 3b This indicates that H may not exist;

[0112] R 4 R represents d Or it may not exist;

[0113] R 5 Represents 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 );

[0114] Each R a Indicates (C1-C 25 )alkyl groups, which may be the same or different;

[0115] Each R a Optionally by an R b replace;

[0116] Each R b Indicates phenyl or cyclohexyl.

[0117] Each R b Optionally selected from one to three independent selections from R f -CH2-OC(=O)(R f ) and -OC(=O)(R f Substitution of groups;

[0118] Each R c1 and R c2 It represents -NH-LC(=O)(OR) f ) and -NH-LC(=O)(OR g (They can be the same or different);

[0119] Each R d Independently represent

[0120] R e Represents 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 );

[0121] Each R f Independently represent (C1-C) 18 )alkyl;

[0122] Each L independently represents (C1-C 18 )alkylene;

[0123] R g Indicates cyclohexyl; and

[0124] Each R h Independently representing steroidal compound derivatives or bridged, spirocyclic, or fused polycyclic (C7-C6) compounds. 18 Carbon ring,

[0125] The steroidal compound derivative is optionally composed of one to four independently selected compounds from -OH and (C1-C2) groups. 12 Alkyl groups are substituted;

[0126] When R 5 When it is H, then R 2 Not -P(=O)(OR) b (R) c1 ) or -P(=O)(R c1 (R) c2 ),

[0127] When R 3a For H, R 3b For H and R 5 When it is H, then R 2 Not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'),

[0128] Where Z represents the bond, (C1-C) 10 )alkyl, C(R) x (R) z ),

[0129] R x and R z Independently selected from H, (C1-C6)alkyl and (C6-C 10 )cycloalkyl,

[0130] R x and R z Each of them is independently and optionally substituted with a (C1-C6)alkyl, oxo, or (C1-C6)alkoxy group; and

[0131] Z' represents H, (C1-C) 10)alkyl or (C1-C 10 )alkoxy, and

[0132] Z' is optionally substituted with (C1-C6)alkyl, oxo, or (C1-C6)alkoxy groups;

[0133] when

[0134] R 3a For R e And R 3b For H,

[0135] R e It is H or -C (=O)(O-(C1-C6)alkyl) or -C (=O)(C1-C) 25 )alkyl, and

[0136] R 5 For H or -C(=O)(O-(C1-C) 25 When alkyl),

[0137] Then R 2 Not -C(=O)(O-(C1-C) 25 )alkyl); and

[0138] when

[0139] R 2 For H or -C (=O)(O–(C1-C) 10 )alkyl), and

[0140] R 5 -C (=O) (optionally substituted with an oxo group or (C1-C6) alkyl group) 18 )alkyl), -C(=O)-(optionally separated by (C1-C 18 When alkyl-substituted cyclohexyl or -C (=O) (optionally substituted with (C1-C6)alkyl or -OC (=O) ((C1-C6)alkyl)-substituted phenyl),

[0141] Then R e Not (a)H, (b)-C(=O)(O–(C1-C 10 )alkyl) or (c)-C(=O)((C1-C 15 )alkyl);

[0142] Or its pharmaceutically acceptable salt.

[0143] A compound of formula (Ia):

[0144]

[0145] in

[0146] X represents F or Cl;

[0147] R 2 Represents H, -C (=O)(R) a -C(=O)(R) b ) or -P(=O)(OR b (R) c1 ),

[0148] R 3 Represents H, -C (=O)(R) a ) or -C(=O)(OR a );

[0149] R 5 Represents H, -C (=O)(R) a ) or -P(=O)(OR b (R) c1 );

[0150] Each R a Independently represent (C1-C) 25 )alkyl;

[0151] Each R a Independently and arbitrarily by an R b replace;

[0152] Each R b Independently indicates that it is optionally selected from one to three independently chosen from R. f and -OC(=O)(R f ) substituted phenyl groups;

[0153] R c1 It represents -NH-LC(=O)(OR) g );

[0154] Each R f Independently represent (C1-C) 18 )alkyl;

[0155] L represents (C1-C) 18 )alkylene; and

[0156] R g Indicates cyclohexyl;

[0157] The prerequisite is

[0158] When R 5 When it is H, then R 2 Not -P(=O)(OR) b (R) c1 ),

[0159] When R3 and R 5 When it is H, then R 2 Not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'),

[0160] Where Z represents the bond, (C1-C) 10 )alkyl, C(R) x (R) z ),

[0161] R x and R z Independently selected from H, (C1-C6)alkyl and (C6-C 10 )cycloalkyl,

[0162] Where R x and R z Each of them is independently and optionally substituted with a (C1-C6)alkyl, oxo, or (C1-C6)alkoxy group; and

[0163] Where Z' represents H, (C1-C 10 )alkyl or (C1-C 10 Z' is substituted with (C1-C6) alkoxy, and Z' is optionally substituted with (C1-C6) alkyl, oxo or (C1-C6) alkoxy.

[0164] when

[0165] R 3 It is H or -C (=O)(O-(C1-C6)alkyl) or -C (=O)(C1-C) 25 )alkyl, and

[0166] R 5 When it is H,

[0167] Then R 2 Not -C(=O)(O-(C1-C) 25 )alkyl); and

[0168] when

[0169] R 2 For H, and

[0170] R 5 -C(=O)((C1-C) 18 When alkyl),

[0171] R 3 Not H, -C (=O)(O–(C1-C) 10 )alkyl)) or -C(=O)((C1-C 15 )alkyl);

[0172] Or its pharmaceutically acceptable salt.

[0173] A compound of the following formula (Ib):

[0174]

[0175] in

[0176] X represents F or Cl;

[0177] R 2 Represents -C(=O)(R) a ),

[0178] R 5 Represents H or -C (=O)(R) a ),

[0179] Each R a Independently represented by an optional R b Replacement (C1-C) 25 )alkyl;

[0180] Each R b Independently represents a phenyl group optionally substituted with one to three groups independently selected from -CH3 and -OC(=O)-CH3;

[0181] and

[0182] The prerequisite is

[0183] When R 5 When it is H, then R 2 Not -C(=O)(C1-C5 alkyl) or -C(=O)(Z-butyl-Z'),

[0184] Where Z represents the bond, (C1-C) 10 )alkyl, C(R) x (R) z ),

[0185] R x and R z Independently selected from H and (C1-C6) alkyl groups, and

[0186] R x and R z Each of them is independently and optionally substituted with a (C1-C6)alkyl, oxo, or (C1-C6)alkoxy group; and

[0187] Where Z' represents H, (C1-C 10 )alkyl or (C1-C 10 Z' is substituted with (C1-C6) alkoxy, and Z' is optionally substituted with (C1-C6) alkyl, oxo or (C1-C6) alkoxy.

[0188] Or its pharmaceutically acceptable salt.

[0189] The following description applies to one or more formulas (Formulas I, Ia, and Ib) disclosed herein. X may be selected from halogens. In some embodiments, X is Cl. In some embodiments, X is F. In some embodiments, X is Br. In some embodiments, X is I.

[0190] R 1 It can be selected from (C1-C6) ynyl groups. In some embodiments, R 1 It is acetylene-based. In some embodiments, R 1 It is propynyl. In some embodiments, R 1 It is butynyl. In some embodiments, R 1 It is a pentyrynyl group. In some embodiments, R 1 It is hexyne group.

[0191] R 2 Can be selected from 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 Those skilled in the art will recognize the structures represented herein by this nomenclature. For example, those skilled in the art will recognize the structure named -P(=O)(R). c1 (R) c2 Groups such as ) can also be represented as follows:

[0192]

[0193] Similarly, those skilled in the art will recognize that the designation is -P(=O)(OR) b (R) c1 Groups such as ) can also be represented as follows:

[0194]

[0195] Similarly, those skilled in the art will recognize that the designation is -C(=O)(R) a Groups such as ) can also be represented as follows:

[0196]

[0197] Similarly, those skilled in the art will recognize that the designation is -C(=O)(OR) a Groups such as ) can also be represented as follows:

[0198]

[0199] In some implementation schemes, R 2 For H. In some implementations, R 2 -C(=O)(R) a In some implementations, R 2 -C(=O)((C1-C) 25 )alkyl). In some embodiments, R 2 -C(=O)((C1-C) 18 )alkyl). In some embodiments, R 2 -C(=O)((C1-C) 12 )alkyl). In some embodiments, R 2 It is a -C (=O) ((C1-C6) alkyl group). In some embodiments, R 2 It is a -C (=O) ((C1-C4) alkyl group). In some embodiments, R 2 It is -C(=O)(methyl). In some embodiments, R 2 It is -C(=O)(isopropyl). In some embodiments, R 2 It is -C (=O) (a (C1-C4) alkyl group substituted with a phenyl group). In some embodiments, R 2 It is -C (=O) (a (C1-C4) alkyl group substituted with a phenyl group), wherein the phenyl group is substituted with -CH3. In some embodiments, R 2 It is -C (=O) (a (C1-C4) alkyl group substituted with a phenyl group), wherein the phenyl group is substituted with an acetoxy group. In some embodiments, R 2 It is -C(=O) ((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with -CH3 and acetoxy.

[0200] In some implementation schemes, R 2 -C(=O)(OR) a In some implementations, R 2 -C(=O)((C1-C) 16 )alkoxy). In some implementations, R 2 -C(=O)((C1-C) 12 )alkoxy).

[0201] In some implementation schemes, R 2 -C(=O)(R) b In some implementations, R 2 For -C(=O)(aryl). In some implementations, R 2 It is -C (=O) (cycloalkyl). In some embodiments, R 2 For -C (=O) (phenyl substituted with (C1-C4) alkyl). In some embodiments, R 2 It is -C(=O)(phenyl). In some embodiments, R 2 For -C (=O) (cyclohexyl). In some implementations, R 2 For -C (=O) (phenyl substituted with ester). In some embodiments, R 2 For -C (=O) (cyclohexyl group substituted with (C1-C4) alkyl groups). In some embodiments, R 2 For -C(=O) (phenyl substituted with -CH2-C(=O)-(C1-C6)alkyl). In some embodiments, R 2 For -C(=O) (phenyl substituted with -CH2-C(=O)-(C1-C4)alkyl). In some embodiments, R 2 For -C (=O) (phenyl substituted with ester). In some embodiments, R 2 It is -C(=O) (phenyl substituted with ester), wherein the ester moiety is (C1-C) 16 )alkyl esters, (C1-C 12 alkyl esters, (C1-C6)alkyl esters, (C6-C6)alkyl esters 12 )alkyl esters or (C 12 -C 16 Alkyl esters.

[0202] In some implementation schemes, R 2 -C(=O)(OR) d In some implementations, R 5 -C(=O)(OR) d ), where R d for In some implementation schemes, R 2 -C(=O)(OR) d ), where R d for

[0203] In some implementation schemes, R 2 -P(=O)(OR) b (R) c1 In some implementations, R 2-P(=O)(O-phenyl)(R c1 In some implementations, R 2 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 2 -P(=O)(OR) b (-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 2 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 2 -P(=O)(OR) b (-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl). In some embodiments, R 2 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl). In some embodiments, R 2 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C4-C8)cycloalkyl). In some embodiments, R 2 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-cyclohexyl). In some embodiments, R 2 -P(=O)(R) c1 (R) c2 In some implementations, R 2 -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl) 2 In some implementations, R 2 It is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl) 2 .

[0204] In some implementation schemes, R 2 It contains phosphate residues. In some embodiments, R 2 It contains phosphate ester derivative residues. In some embodiments, R 2 It contains monophosphate residues. In some embodiments, R 2 It contains diphosphate residues. In some embodiments, R 2 It contains triphosphate residues. In some embodiments, R 2 Contains phosphonates. In some embodiments, R 2 It contains phosphate ester polyester. In some embodiments, R2 It contains a phosphate diester. In some embodiments, R 2 It contains triphosphates. In some embodiments, R 2 It contains a phosphate amide ester. In some embodiments, R 2 It contains monophosphate esters. In some embodiments, R 2 It contains a diphosphate diamide ester. In some embodiments, R 2 It contains thiophosphate esters. In some embodiments, R 2 It contains selenophosphate. In some embodiments, R 2 It contains boron phosphate esters.

[0205] In some implementation schemes, R 2 -C(=O)(R) h In some implementations, R 2 -C(=O)(OR) h In some implementations, R 2 -C(=O)((C7-C) 10 (Carbon ring). In some implementations, R 2 -C(=O)(bridge connecting double rings (C7-C) 10 (Carbon ring). In some implementations, R 2 For -C (=O) (bicyclo[2.2.2]octane). In some embodiments, R 2 For -C(=O)(spirobicyclic (C7-C) 10 (Carbon ring). In some implementations, R 2 For -C(=O)(spiro[5.3]nonane). In some embodiments, R 2 For -C(=O)(spiro[5.3]nonane). In some embodiments, R 2 For -C(=O)(spiro[3.3]heptane). In some embodiments, R 2 -C(=O)(O-bridge connecting double rings (C7-C) 10 (Carbon ring). In some implementations, R 2 For -C(=O)(O-bicyclo[2.2.2]octane). In some embodiments, R 2 -C(=O)(O-spirobicyclic (C7-C) 10 (Carbon ring). In some implementations, R 2 For -C(=O)(O-spiro[5.3]nonane). In some embodiments, R 2 For -C(=O)(O-spiro[5.3]nonane). In some embodiments, R 2 It is -C(=O)(O-spiro[3.3]heptane).

[0206] In some implementation schemes, R 2 -C(=O)(LR) h In some implementations, R 2 for

[0207]

[0208] In equation I, R 3a Can be selected from H and R e And R 3b This indicates that H is either absent or not present. In some implementations, R... 3a For H. In some implementations, R 3a For R e In some implementations, R 3b For H. In some implementations, R 3b It does not exist. In some implementations, R 3a R 3b With R 2 Same. In some implementations, R 3a R 3b With R 2 Different. In some implementations, R 3a R 3b It can be for R 2 List any possible substituents.

[0209] In some implementation schemes, R 4 It does not exist. In some implementations, R 4 For R d In some implementations, R 4 With R 3a Same. In some implementations, R 4 With R 3a Different. In some implementations, R 4 With R 3a R 3b Same. In some implementations, R 4 With R 3a R 3b Different. In some implementations, R 4 It can be for R 3a R 3b List any possible substituents.

[0210] R 5 It can be 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 implementations, R 5 With R 3a R 3b Same. In some implementations, R 5 With R 3a Same. In some implementations, R 5 With R 2 Same. In some implementations, R 5 With R 3a R 3b Different. In some implementations, R 5 With R 3a Different. In some implementations, R 5 With R 2 Different. In some implementations, R 5 It can be for R 2 List any possible substituents. In some implementations, R 5 It can be for R 3a R 3b List any possible substituents. In some implementations, R 5 It can be for R 3a List any possible substituents. In some implementations, R 2 R 5 and R 3a R 3b Same. In some implementations, R 2 R 5 and R 3a Same. In some implementations, R 2 R 5 and R 3a R 3b Not all are the same. In some implementations, R 2 R 5 and R 3a They are not all the same.

[0211] In some implementation schemes, R 5 For H. In some implementations, R 5 -C(=O)(R) a In some implementations, R 5 It is -C(=O)(isopropyl). In some embodiments, R5 -C(=O)(OR) a In some implementations, R 5 -C(=O)(OR) a In some implementations, R 5 -C(=O)((C1-C) 16 )alkoxy). In some implementations, R 5 -C(=O)((C1-C) 12 )alkoxy). In some implementations, R 5 For -C (=O)((C1-C4)alkoxy). In some embodiments, R 5 It is -C (=O) (a (C1-C4) alkyl group substituted with a phenyl group), wherein the phenyl group is substituted with -CH3. In some embodiments, R 5 It is -C (=O) (a (C1-C4) alkyl group substituted with a phenyl group), wherein the phenyl group is substituted with an acetoxy group. In some embodiments, R 5 It is -C(=O) ((C1-C4)alkyl substituted with phenyl), wherein the phenyl is substituted with -CH3 and acetoxy.

[0212] In some implementations, R5 is -C(=O)(R b In some implementations, R 5 For -C (=O) (phenyl substituted with (C1-C4) alkyl). In some embodiments, R 5 For -C (=O) (cyclohexyl group substituted with (C1-C4) alkyl groups). In some embodiments, R 5 For -C(=O) (phenyl substituted with -CH2-C(=O)-(C1-C6)alkyl). In some embodiments, R 5 It is a -C(=O) (phenyl substituted with -CH2-C(=O)-(C1-C4)alkyl).

[0213] In some implementation schemes, R 5 -C(=O)(OR) d In some implementations, R 5 -C(=O)(OR) d ), where R d for In some implementation schemes, R 5 -C(=O)(OR) d ), where R d for

[0214] In some implementation schemes, R 5 -P(=O)(OR)b (R) c1 In some implementations, R 5 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 5 -P(=O)(OR) b (-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 5 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R 5 -P(=O)(OR) b (-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl). In some embodiments, R 5 It is -P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl). In some embodiments, R 5 -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl) 2 In some implementations, R 5 It is -P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl) 2 .

[0215] In some implementation schemes, R 5 It contains phosphate residues. In some embodiments, R 5 It contains phosphate ester derivative residues. In some embodiments, R 5 It contains monophosphate residues. In some embodiments, R 5 It contains diphosphate residues. In some embodiments, R 5 It contains triphosphate residues. In some embodiments, R 5 Contains phosphonates. In some embodiments, R 5 It contains phosphate ester polyester. In some embodiments, R 5 It contains a phosphate diester. In some embodiments, R 5 It contains triphosphates. In some embodiments, R 5 It contains a phosphate amide ester. In some embodiments, R 5 It contains monophosphate esters. In some embodiments, R 5 It contains a diphosphate diamide ester. In some embodiments, R 5 It contains thiophosphate esters. In some embodiments, R 5It contains selenophosphate. In some embodiments, R 5 It contains boron phosphate esters.

[0216] In some implementation schemes, R 5 -C(=O)(R) h In some implementations, R 5 -C(=O)(OR) h In some implementations, R 5 -C(=O)(LR) h In some implementations, R 5 -C(=O)(O-spirobicyclic (C7-C) 10 (Carbon ring). In some implementations, R 5 For -C(=O)(O-spiro[5.3]nonane). In some embodiments, R 5 For -C(=O)(O-spiro[5.3]nonane). In some embodiments, R 5 For -C(=O)(O-spiro[3.3]heptane). In some embodiments, R 5 For -C(=O)(O-spiro[5.3]nonane). In some embodiments, R 5 -C(=O)(bridge connecting double rings (C7-C) 10 (Carbon ring). In some implementations, R 5 For -C (=O) (bicyclo[2.2.2]octane). In some embodiments, R 5 for

[0217] In some implementations, at least one R a For (C1-C 25 )alkyl. In some embodiments, at least one R a For (C1-C 18 )alkyl. In some embodiments, at least one R a It is (C1-C6) alkyl. In some embodiments, at least one R a It is (C1-C4) alkyl. In some embodiments, at least one R a By an R b replace.

[0218] In some implementations, at least one R b It is phenyl. In some embodiments, at least one R b It is cyclohexyl. In some embodiments, at least one R b R fReplacement. In some implementations, at least one R b -CH2-OC(=O)(R) f ) replace. In some implementations, at least one R b By -OC(=O)(R f ) replace. In some implementations, at least one R b For R, which is chosen independently f A group and a -OC(=O)(R) f ) substituted phenyl. In some embodiments, at least one R b It is a phenyl group substituted with -CH3, -CH3 and -OC(=O)(CH3).

[0219] In some implementation schemes, R c1 and R c2 At least one of them is -NH-LC(=O)(OR) f In some implementations, R c1 and R c2 At least one of them is -NH-LC(=O)(OR) b In some implementations, R c1 and R c2 Same. In some implementations, R c1 and R c2 different.

[0220] In some implementations, at least one R d It contains dioxane. In some embodiments, R d It contains dioxane. In some embodiments, R d It contains 1,3-dioxacyclopentane. In some embodiments, R d It comprises dioxanes substituted with one to three additional groups selected from (C1-C6) alkyl and oxo groups. In some embodiments, R d It contains 1,3-dioxacyclopentanes substituted with oxo groups. In some embodiments, R d It comprises 1,3-dioxacyclopentanes substituted with oxo and methyl groups. In some embodiments, R d It is a (C1-C6) alkyl-dioxane. In some embodiments, R d It is -CH2-dioxacyclopentane. In some embodiments, R d It is -CH2-dioxacyclopentane, wherein the dioxacyclopentane is substituted with an oxo group and a methyl group. In some embodiments, at least one R d yes In some implementations, at least one R d yes

[0221] In some implementation schemes, R e For H. In some implementations, R e -C(=O)(R) a In some implementations, R e -C(=O)(OR) a In some implementations, R e -C(=O)-LOR f In some implementations, R e -C(=O)-LOC(=O)(R) f ).

[0222] In some implementation schemes, R e is -C(=O)-OLC(=O)(OR f In some implementations, R e -C(=O)-LSC(=O)(R f In some implementations, R e -C(=O)(R) b In some implementations, R e -C(=O)(OR) b ).

[0223] In some implementation schemes, R e is -C(=O)-OLC(=O)(OR d In some implementations, R e -C(=O)(R) d In some implementations, R e -C(=O)(R) h In some implementations, R e -C(=O)(OR) h In some implementations, R e for

[0224] In some implementation schemes, R f It is a (C1-C6) alkyl group. In some embodiments, R f It is a (C1-C3) alkyl group.

[0225] In some embodiments, at least one L is a (C1-C6) alkylene group. In some embodiments, at least one L is a (C1-C4) alkylene group. In some embodiments, at least one R... h For spiral bicyclic (C7-C) 10) carbon ring. In some embodiments, at least one R h To connect the two ring roads (C7-C) 10 ) carbon ring. In some embodiments, at least one R h It is a fused polycyclic carbon ring.

[0226] In some implementations, at least one R h To be optionally selected by one to four independently chosen from -OH and (C1-C) 12 ) alkyl-substituted steroidal compound derivatives. In some embodiments, R h It contains bile acid conjugates. In some embodiments, R h It contains sterols.

[0227] In some implementations, each -C(=O)(R h Independently selected

[0228]

[0229] In some implementations, -C(=O)(OR) h )for

[0230]

[0231] Where R y Independently selected from H, (C1-C8)alkyl, and (C1-C8)alkenyl, and each R y It can be independently and optionally substituted with (C1-C6) alkyl groups.

[0232] In some implementations, each -C(=O)(LR) h Independently selected

[0233]

[0234] In some embodiments, the compounds disclosed herein have the following formula:

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] Or a pharmaceutically acceptable salt thereof. For compounds described above using the language “X = F, Cl”, this is intended to be identical to the separate explicit disclosure of each compound (the compound wherein X = F and the separate compound wherein X = Cl).

[0250] In some implementations, the compound is

[0251]

[0252] Or its pharmaceutically acceptable salt.

[0253] In some implementations, the compound is

[0254]

[0255] Or its pharmaceutically acceptable salt.

[0256] In some implementations, the compound is

[0257]

[0258] Or its pharmaceutically acceptable salt.

[0259] III. Pharmaceutical Composition

[0260] In some embodiments, this disclosure provides pharmaceutical compositions comprising the compounds of this disclosure and pharmaceutically acceptable excipients.

[0261] In some embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as described in more detail below.

[0262] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts may be prepared using one or more pharmaceutically acceptable excipients, which may be selected according to conventional practice. Tablets may contain excipients, including gliding agents, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when intended for delivery by means other than oral administration. In some embodiments, the composition may contain excipients such as those described in Rowe et al., “Handbook of Pharmaceutical Excipients,” 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid dosage form, including solid oral dosage forms.

[0263] The compositions comprise those suitable for various routes of administration, including oral administration. The compositions may be present in unit dosage forms and may be prepared by any of the methods well known in the pharmaceutical field. Such methods include the step of associating an active ingredient (e.g., a compound of this disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by homogeneously and tightly associating the active ingredient with a liquid excipient or a finely divided solid excipient, or both, and then, if desired, shaping the product. Techniques and formulations are generally available in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0264] The compositions described herein suitable for oral administration may exist 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.

[0265] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable excipients and optional other therapeutic agents. Pharmaceutical compositions containing an active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, they may be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0266] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form can vary depending on the intended treatment subjects and the mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 mg to 1000 mg of the active material, formulated together with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises about 5% to about 95% (by weight) of the total composition.

[0267] In some embodiments, in one variation, compositions comprising compounds of the present disclosure or pharmaceutically acceptable salts thereof do not contain agents that affect the metabolic rate of the active ingredient. Therefore, it should be understood that, in one aspect, compositions comprising compounds of the present disclosure do not contain agents that would affect (e.g., slow down, inhibit, or delay) the metabolism of the compounds of the present disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of the present disclosure. It should also be understood that any of the methods, kits, articles, etc., detailed herein in one aspect do not contain agents that would affect (e.g., slow down, inhibit, or block) the metabolism of the compounds of the present disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of the present disclosure.

[0268] In some embodiments, the above-described pharmaceutical composition is used in humans or animals.

[0269] This disclosure also includes compounds of the disclosure applied as a single active ingredient in a pharmaceutically acceptable composition, the active ingredient being prepared by conventional methods known in the art, for example by conjugating the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing the active ingredient with them.

[0270] In one aspect, this document provides for the use of the compounds of this disclosure as a second or other active ingredient that has a synergistic effect with other active ingredients in known pharmaceutical products, or for the administration of the compounds of this disclosure together with such pharmaceutical products.

[0271] The compounds disclosed herein can also be used as prodrugs or other suitable modified forms that release the active ingredient in vivo.

[0272] IV. Treatment

[0273] HIV infection

[0274] This disclosure provides methods for treating and / or preventing human immunodeficiency virus (HIV) infection in subjects in need. In some embodiments, the method for treating and / or preventing HIV infection in a subject in need includes administering the composition provided herein to the subject. In some embodiments, the method is used for treating and / or preventing HIV-1 infection. In some embodiments, the method is used for treating and / or preventing HIV-2 infection.

[0275] In some embodiments, a method of treating an HIV-infected subject in need includes administering the composition provided herein to the subject. In some such 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.

[0276] In some embodiments, methods for preventing HIV infection in subjects in need include administering the composition provided herein to the subject. In some such embodiments, the subject is HIV-negative. In some embodiments, the subject is at risk of acquiring HIV infection.

[0277] In some embodiments, this disclosure provides compositions for treating and / or preventing HIV infection in a subject.

[0278] In some embodiments, this disclosure provides compositions for manufacturing medicaments for treating and / or preventing HIV infection in a subject.

[0279] In some embodiments, this disclosure provides methods for treating and / or preventing HIV infection in subjects in need, including administering to the subject a combination therapy comprising the composition provided herein and one or more (e.g., one, two, three, one or two, or one to three) adjunctive therapeutic agents. In some embodiments, a method is provided for treating HIV infection in human subjects who are infected with HIV or at risk of such infection, including administering to the human subject a therapeutically effective amount of the composition disclosed herein combined with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) adjunctive therapeutic agents. In some embodiments, the subject is receiving or has received one or more adjunctive therapeutic agents. In some embodiments, the adjunctive therapeutic agents are selected from the same class of therapeutic agents. In some embodiments, the adjunctive therapeutic agents are selected from different classes of therapeutic agents. In some embodiments, the adjunctive therapeutic agent is suitable for treating and / or preventing HIV infection. In some embodiments, the adjunctive therapeutic agent is not used for treating and / or preventing HIV infection.

[0280] In some embodiments, the combination therapy includes administration of the composition provided herein and one, two, three, four, or more additional therapeutic agents. In some embodiments, the combination therapy includes administration of the composition provided herein and two additional therapeutic agents. In some embodiments, the combination therapy includes administration of the composition provided herein and three additional therapeutic agents. In some embodiments, the combination therapy includes administration of the composition provided herein and four additional therapeutic agents.

[0281] The adjunctive therapy can be any adjunctive therapy disclosed herein. In some embodiments, the adjunctive therapy is disclosed in the HIV combination therapy section of this document. In some embodiments, the adjunctive therapy is disclosed in the HBV combination therapy section of this document.

[0282] In some implementations, the adjunctive therapeutic agent is an anti-HIV agent. For example, in some implementations, the adjunctive therapeutic agent is selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptor TCR-T, autologous T-cell therapy, engineered B cells), latency reversal agents, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, 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-1 viral infection 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, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0283] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for the treatment and / or prevention of HIV infection, other drugs for the treatment of HIV, 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 reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0284] In some implementations, the adjunctive treatment is a combination drug for treating and / or preventing HIV infection. Examples of combination drugs for treating and / or preventing HIV infection include... (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (elvitegravir, cobistat, tenofovir disoproxil fumarate and emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat, and ertiravir); direravir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertiravir; (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( Lopinavir and ritonavir); (Durutexvir, Abacavir, and Lamivudine); BIKTARVY (Bicagvir + Emtricitabine + Tenofovir Alambutamide), DOVATO, (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Durutvir and rilpivirine; Durutvir and rilpivirine hydrochloride; Durutvir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Durutvir + 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; cabotevir + rilpivirine; elsulfavirine (VM-1500; VM-1500A) binds to and activates signal transduction via this kinase.

[0285] In some implementations, the adjunctive therapy is a drug used to treat and / or prevent HIV infection. Examples of other drugs used to treat and / or prevent HIV infection include acetaminophen, arapovir, BanLec, deferiphenone, Gamimune, mitfalin, naltrexone, alpha-1 protease inhibitor (Prolastin), REP 9, RPI-MN, VSSP, H1 virus, 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, IN D-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-63 5. SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0286] In some implementations, the adjunctive treatment is an HIV protease inhibitor. Examples of HIV protease inhibitors include ampravir, atazanavir, becanavir, deruravir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

[0287] In some implementations, 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.

[0288] In some implementations, the adjunctive treatment is a non-nucleoside or non-nucleotide reverse transcriptase inhibitor. Examples of non-nucleoside or non-nucleotide reverse transcriptase inhibitors include dapirine, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and isavirin (VM-1500).

[0289] In some implementations, the adjunctive therapeutic agent is a nucleoside or nucleotide reverse transcriptase inhibitor. Examples of nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate hemifumarate. and VIDEX (Didanoxin, DDL), Abacavir, Abacavir sulfate, Alovudine, Alitabin, Cinovine, Didanoxin, Avtabin, Fertinavir, Fivudinetimate, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil fumarate, Fivudinetimate, Lamivudine, Phosphatidylcholine, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-8583, VM-2500 and KP-1461.

[0290] In some implementations, the adjunctive treatment is an HIV integrase inhibitor. Examples of HIV integrase inhibitors include erteiravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine kinase inhibitors, tyrosine kinase inhibitor derivatives, quercetin, quercetin derivatives, retegvir, dulutegravir, JTK-351, bicretiravir, and AVX-1. 5567, 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 cabotevir.

[0291] In some implementations, HIV integrase inhibitors are non-catalytic site (i.e., allosteric) integrase inhibitors (NCINIs). Examples of NCINIs include CX-05045, CX-05168, and CX-1442.

[0292] In some implementations, the adjunctive treatment is an HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include cineviroline, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[0293] In some implementations, the adjunctive treatment is a CCR5 inhibitor. Examples of CCR5 inhibitors include apravirone, vevicvirone, maravirone, cinevirovirone, leronlimab (PRO-140), adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0294] In some implementations, the adjunctive therapeutic agent is a gp41 inhibitor. Examples of gp41 inhibitors include epovitamide, epovitamide, BMS-986197, epovitamide biomodifier, epovitamide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifviride.

[0295] In some implementations, the adjunctive therapeutic agent is a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0296] In some implementations, the additional therapeutic agent is a gp120 inhibitor. Examples of gp120 inhibitors include Radha-108 (receptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, Fostersavir tromethamine, IQP-0831, and BMS-663068.

[0297] In some implementations, the additional therapeutic agent is a CXCR4 inhibitor. Examples of CXCR4 inhibitors include praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0298] In some implementations, the adjunctive treatment is an HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232.

[0299] In some implementations, the adjunctive therapeutic agent is a latency reversal agent. Examples of latency reversal agents include toll-like receptor (TLR) agonists (including TLR7 agonists, such as GS-9620), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, iomycin, IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW-242), and SMAC mimics. Drugs (including TL32711, LCL161, GDC-0917, HGS1029, AT-406), PMA, SAHA (aminosuccinate or succinyl, aniline and isohydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion protein and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as lagozola analogs, APH-0812, GSK-343).

[0300] In some implementations, the additional therapeutic agent is an HDAC inhibitor, such as 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, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidesin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0301] In some implementations, the additional therapeutic agent is a PKC activator. Examples of PKC activators include indolinamide, prostratin, phorbol B, and DAG-lactone.

[0302] In some embodiments, the additional therapeutic agent is a capsid inhibitor. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-destroying 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 the AVI-CAN1-15 series, as well as the compounds described in this patent (GSK WO2019 / 087016).

[0303] In some embodiments, the additional therapeutic agent is selected from one or more inhibitory immune checkpoint proteins or receptors as blockers or inhibitors and / or one or more stimulators, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape of infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0304] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); transmembrane and immunoglobulin domain-containing receptors 2 (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitors 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory factors (ICOS, CD278); inducible T cell costimulatory factor ligands (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 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC MHC class I polypeptide-associated sequence A (MICA); MHC class I polypeptide-associated 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); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); containing T cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9);Lymphocyte activation 3 (LAG3, CD223); Signal transduction 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); Retinic acid early transcript 1E (RAET1E; ULBP4); Retinic acid early transcript 1G (RAET1G; ULBP5); Retinic acid early transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); Cytokine lectin-like receptor C 1 (KLRC1, NKG2A, CD159A); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); cytotoxic lectin-like receptor C2 (KLRC2, CD159c, NKG2C); cytotoxic lectin-like receptor C3 (KLRC3, NKG2E); cytotoxic lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic immunoglobulin-like receptor, two Ig domains and long... Cytoplasmic tail 1 (KIR2DL1); cytotoxic immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 2 (KIR2DL2); cytotoxic immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 3 (KIR2DL3); cytotoxic immunoglobulin-like receptor with three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0305] In some implementations, the adjunctive therapeutic agent is a blocker or inhibitor of one or more T-cell suppressor immune checkpoint proteins or receptors. Examples of T-cell suppressor 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 immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated... Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In various implementation schemes, the reagents described herein are combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors.Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (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); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0306] In some implementations, 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, cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agent as described herein is 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); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, 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.

[0307] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors 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 includes BPI-002.

[0308] In some implementations, the adjunctive treatment is a CLTA4 inhibitor. Examples of CLTA4 inhibitors include ipilimumab, trimemumab, 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, and ATOR-1144. PBI-5D3H5, BPI-002, and 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).

[0309] In some implementations, the adjunctive treatment is an inhibitor of PD-L1 (CD274) or PD-1 (PDCD1). Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, 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, and AAGEN-2. 034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarone (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 (Dotalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-0 35. 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), FS-118 (LAG-3 / PD-L1)M GD-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(CTL A4 / 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).

[0310] In some implementations, the additional therapeutic agent is an anti-TIGIT antibody. Examples of anti-TIGIT antibodies include BMS-986207, RG-6058, and AAGEN-1307.

[0311] In some implementations, the adjunctive therapeutic agent is an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such as agonists of one or more of the following: 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: 355), TN FRSF7 (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 ...9 (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 939), TNFRSF9 (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 939), TNFRSF9 (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 939), TNFRSF 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: 8794), ...CD268, NCBI gene ID: 8792), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11 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).

[0312] In some implementations, the adjunctive therapeutic agent is an anti-TNFRSF4 (OX40) antibody. Examples of anti-TNFRSF4 (OX40) antibodies include MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0313] In some implementations, 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.

[0314] In some implementations, the additional therapeutic agent is an anti-TNFRSF7 (CD27) antibody. An example of an anti-TNFRSF7 (CD27) antibody is varigramab (CDX-1127).

[0315] In some implementations, the adjunctive therapeutic agent is an anti-TNFRSF9 (4-1BB, CD137) antibody. Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies include urogenumab, urogenumab (PF-05082566), AGEN2373, and ADG-106.

[0316] In some implementations, 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 those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0317] In some implementations, the additional therapeutic agent is an antibody or fragment thereof that co-targets TNFRSF4 (OX40) and TNFRSF18 (GITR). Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0318] In some implementations, the adjunctive therapeutic agent is a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against: NK cell activation receptors such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell adjuvants include those that target CD16 and one or more HIV-associated antigens. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods MolBiol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adjuvants (TRiKE) include OXS-3550 and CD16-IL-15-B7H3 TriKe.

[0319] In some implementations, 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, an NLG-919-based vaccine, PF-06840003, a pyranoquinone derivative (SN-35837), remixstat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0320] In some implementations, the adjunctive therapeutic agent is 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 include AL-034, DSP-0509, GS-9620 (Vesamox), LHC-165, TMX-101 (Imiquimod), GSK-2245035, Remiquimod, 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (VentirxPharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Examples of TLR7 / TLR8 agonists are NKTR-262, teiramod, and BDB-001.Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, requimide, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), and US20080234251 (Array). The compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Exemplary TLR9 agonists include AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, 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 rapamod and polyICLC. Apoxxim、 IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

[0321] In some implementations, the additional therapeutic agent is an interferon gene stimulator (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-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

[0322] In some implementations, the additional therapeutic agent is a RIG-I modulator (such as RGT-100) or a NOD2 modulator (such as SB-9200 and IR-103).

[0323] In some implementations, the additional therapeutic agent is an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0324] In some implementations, the adjunctive therapeutic agent is an anti-LAG-3 (lymphocyte activation) antibody, such as renalalimab (ONO-4482), LAG-525, MK-4280, REGN-3767, and INCAGN2385.

[0325] In some implementations, the additional therapeutic agent is an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include proleukin (aldeleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, ALKS-4230, and 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-15Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; Examples of IL-7 include CYT-107.

[0326] In some implementations, the adjunctive therapeutic agent is selected from immunotherapy including the following: interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; Flt3 agonist; gepon; nomofuron, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0327] In some implementations, the adjunctive therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, orotic acid (CAI), copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifoxine, pictilisib, pilaralisib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, and 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.

[0328] In some implementations, the adjunctive therapeutic agent is an integrin α-4 / β-7 antagonist. Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, alirubumab, itralizumab, carotegrast methyl, and vedolizumab.

[0329] In some implementations, the adjunctive 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... Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360 and antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, 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, recombinant human mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0330] In some implementations, the additional therapeutic agent is a bNAb. Examples include U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, which include antibodies 12A12, 12A21, NIH45-46, etc. 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. Other examples include those described in the following literature: 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 Special): DL 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to the outer domain glycan); 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).

[0331] In some implementations, the adjunctive therapeutic agent is a broadly neutralizing antibody, such as those described in, for example, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO The references described in WO 2017 / 133639 and WO 2017 / 133640 are incorporated herein by reference in their entirety for all purposes. Other examples include those described in the following literature: 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 Special): Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2 and LN01 (all of these combined with gp41 MPER).

[0332] Additive antibodies that can be used as adjunctive therapies 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, MDX010 (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-VRC2 6.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.

[0333] Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0334] Examples of in vivo delivered bnab include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

[0335] In some implementations, the additional therapeutic agent is a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobistat and ritonavir.

[0336] Examples of additional therapeutic agents include WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (GileadSciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728(Gilead Sciences), WO2013 / 006738(Gilead Sciences), WO 2013 / 159064(Gilead Sciences), WO 2014 / 100323(Gilead Sciences), US 2013 / 0165489(University of Pennsylvania), US 2014 / 0221378(Japan) Tobacco)、US 2014 / 0221380(Japan Tobacco)、WO Compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (PharmaResources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0337] In some implementations, the adjunctive treatment 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 monkey, 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, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pitend), and others. Vaccines based on two- or three-segmented arenaviruses; vaccines based on measlesviruses; vaccines based on flavivirus vectors; vaccines based on tobacco mosaic virus vectors; vaccines based on varicella-zoster virus; vaccines based on human parainfluenza virus 3 (PIV3); vaccines based on poxviruses (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); vaccines based on fowlpox virus; vaccines based on rhabdoviruses, such as VSV and Malabar virus; vaccines based on recombinant human CMV (rhCMV); vaccines based on alphaviruses, such as Simelik Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI:10.1128 / CVI.00298-16); mRNA-based therapeutic vaccines formulated by LNP; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0338] Examples of vaccines include: rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1C subtype vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-level DNA recombinant adenovirus-5 (rAd5), rAd5 gag-polenv A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvant vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env) CladeC+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 vaccines + 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 pseudovirus vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC Class II epitope heterozygous peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage 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+romidesin, variant gp120 peptide vaccine, rAd5gag-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; based on eOD-GT8 60-mer vaccines, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccines, gp120(A, B, C, A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccines (GLA-SE adjuvant), HIV p24gag original-boost plasmid DNA vaccines, arenavirus-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimens, UBI HIV gp120, mRNA-based prophylactic vaccines, and TBL-1203HI.

[0339] In some implementations, the additional treatment is a contraceptive (i.e., a birth control pill). Examples of contraceptives include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenediamine acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0340] In some embodiments, the provided composition is combined with one, two, three, four or more additional therapeutic agents selected from the following: (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistatin, and ertiravir); BIKTARVY (bicagvir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobistatin; emtricitabine; tenofovir; tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (Durutexvir, Abacavir and Lamivudine); Durutvir, Abacavir Sulfate and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvirtide; ( Lopinavir and ritonavir); (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0341] In some embodiments, the provided composition is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the agent or pharmaceutical composition disclosed herein is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In further embodiments, the agent or pharmaceutical composition disclosed herein is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the agent or pharmaceutical composition disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the agent or pharmaceutical composition disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0342] In some embodiments, the provided composition is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide fumarate.

[0343] In some embodiments, the provided composition is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0344] In some embodiments, the provided composition is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and the second adjunctive therapeutic agent being selected from the group consisting of emtricitabine and lamivudine.

[0345] In some embodiments, the provided composition is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, wherein the second adjunctive therapeutic agent is emtricitabine.

[0346] In some embodiments, the provided composition is combined with a first adjunctive therapeutic agent (contraceptive), the first adjunctive therapeutic agent being selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenediamine acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0347] In some implementations, the adjunctive therapeutic agent is gene therapy or cell therapy. Gene therapy or cell therapy includes genetic modification of a silencing gene; gene-based methods that 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 locate and kill infected cells; and gene-based methods that modify cell activity to further alter the endogenous immune response 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 implementations, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some implementations, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0348] In some implementations, the adjunctive therapeutic agent is a gene editor (e.g., an HIV-targeted gene editor). In some implementations, the genome editing system is selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and broad-spectrum nuclease complexes. Exemplary HIV-targeted CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0349] In some implementations, the adjunctive therapeutic agent is CAR-T cell therapy. CAR-T cell therapy comprises an immune effector cell population engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains 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-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some implementations, 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 CART cell therapy, CD4CAR+C34-CXCR4+CCR5 ZFN T cells, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0350] In some implementations, the adjunctive therapeutic agent is TCR-T cell therapy. TCR-T cell therapy involves TCR-T cells engineered to target HIV-derived proteins (such as ImmTAV) present on the surface of virus-infected cells.

[0351] In some embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells that has been genetically modified 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), May 17, 2019).

[0352] HBV infection

[0353] This disclosure provides methods for treating and / or preventing hepatitis B virus (HBV) infection in subjects in need. In some embodiments, the method of treating and / or preventing HBV infection in a subject in need includes administering the composition provided herein to the subject.

[0354] In some implementations, methods of treating HBV infection in subjects in need include administering the composition provided herein to the subject.

[0355] In some embodiments, methods for preventing HBV infection in subjects in need include administering the composition provided herein to the subject. In some such embodiments, the subject is at risk of acquiring HBV infection.

[0356] In some embodiments, this disclosure provides compositions for treating and / or preventing HBV infection in a subject.

[0357] In some embodiments, this disclosure provides compositions for manufacturing medicaments for treating and / or preventing HBV infection in a subject.

[0358] In some embodiments, this disclosure provides methods for treating and / or preventing HBV infection in subjects in need, including administering a combination therapy comprising the composition provided herein and one or more additional therapeutic agents to the subject. In some embodiments, the subject is receiving or has 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 different classes of therapeutic agents. In some embodiments, the additional therapeutic agents are used for treating and / or preventing HBV infection. In some embodiments, the additional therapeutic agents are not used for treating and / or preventing HBV infection.

[0359] In some embodiments, this disclosure provides a method for treating HBV infection, comprising administering to a subject in need a therapeutically effective amount of the composition disclosed herein combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents suitable for treating HBV infection.

[0360] In some embodiments, the compositions disclosed herein are combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compositions disclosed herein are combined with two 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 they may be selected from different classes of therapeutic agents.

[0361] The compositions described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (such as...). Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALEN), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents, or any combination thereof.

[0362] In some implementations, the additional treatment may be an anti-HBV agent. For example, adjunctive therapies can be selected from the following groups: HBV combination drugs, other drugs used to treat HBV, 3-dioxygenase (IDO) inhibitors, antisense oligonucleotides targeting viral mRNA, apolipoprotein A1 modulators, arginase inhibitors, B and T attenuating factor inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, cyclic protein inhibitors, cytokines, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesol X receptor agonists, gene modifiers or gene editors, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, and HBV...RNase inhibitors, HBV vaccines, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus e antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunoglobulins Protein agonists, immunoglobulin G modulators, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon α1 ligands, interferon α2 ligands, interferon α5 ligand modulators, interferon α ligands, interferon α ligand modulators, interferon α receptor ligands, interferon β ligands, interferon ligands, interferon receptor modulators, interleukin-2 ligands, IPI4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, lymphocytes Cell activation gene 3 inhibitors, lymphotoxin β receptor activators, microRNA (miRNA) gene therapy agents, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, Hevem modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators Synergists, Tim-4 regulators, Tyro regulators, Na+-taurocholate cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein regulators, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, recombinant scavenger receptor A (SRA) protein, recombinant thymosin α-1, retinoic acid-induced gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNADNA polymerase inhibitors, short interfering RNA (siRNA), short synthetic hairpin RNAs (sshRNAs), SLC10A1 gene inhibitors, SMAC mimics, Src tyrosine kinase inhibitors, stimulators of interferon gene (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) regulators, viral ribonucleotide reductase inhibitors, zinc finger nucleases or synthetic nucleases (TALENs), and combinations thereof.

[0363] In some embodiments, the provided composition is combined with one, two, three, four or more adjunctive therapeutic agents selected from the group consisting of: HBV combination drugs, 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, cyclophilic protein inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, and HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-induced 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 α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

[0364] In some implementations, the additional treatment is an HBV combination therapy. Examples of HBV combination therapies include... (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-α; ABX-203, adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0365] In some implementations, the adjunctive treatment is another HBV drug. Examples of other drugs used to treat HBV infection include alpha-hydroxytophenone, amadoxovir, beta-hydroxycytosine nucleoside, AL-034, CCC-0975, evitabine, ezetimibe, cyclosporine A, gentiopicroside, JNJ-56136379, nitrozonide, birenapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mirtovalidone, feron, GST-HG-131, levamisole, casserotonin, alloferon, WS-007, and Y-101 (Ti Fen). Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, and US20150210682 (Roche), US Compounds disclosed in 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche).

[0366] In some implementations, the adjunctive treatment is an HBV vaccine. In some implementations, the HBV vaccine is a prophylactic HBV vaccine. Examples of prophylactic HBV 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 (AdvaxSuper D), Hepatrol-07, GSK-223192A, and ENGERIX. Recombinant Hepatitis B Vaccine (Intramuscular Injection, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Hansenula polymorpha yeast, Intramuscular Injection, Hualan Biological Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Eufravac, Eutravac, Anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix HepB, Comvax, DTP-Hib-HBV Vaccine, DTP-HBV Vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine.

[0367] In some implementations, the HBV vaccine is a therapeutic HBV vaccine. Examples of therapeutic HBV vaccines include HBsAG-HBIG complex, 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), and therapeutic vaccines based on recombinant VLPs (HBV infection, VLP). Biotech), AdTG-17909, AdTG-17910AdTG-18202, ChronVac-B, TG-1050 and Lm HBV.

[0368] In some implementations, the adjunctive treatment is an HBV DNA polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include adefovir. Enqutabin Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, bexifovir, entecavir Entecavir maleate, telbivudine Pradefovir, Clavudine, Ribavirin, Lamivudine Phosphatidylcholine, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234.

[0369] In some implementations, the adjunctive therapeutic agent is an immunomodulator. Examples of immunomodulators include rapamod, amidoline hydrochloride, ingaron, demavir, hydroxychloroquine, prazolam, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, AIC-649, and IR-103.

[0370] In some implementations, the additional therapeutic agent is a Toll-like receptor (TLR) modulator. TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

[0371] In some implementations, the TLR modifier is a TLR3 modifier. Examples of TLR3 modifiers include rasamotome, polyICLC, and... Apoxxim、 IPH-33, MCT-465, MCT-475, GS-9688, and ND-1.1.

[0372] In some embodiments, the TLR modifier is a TLR7 modifier. Examples of TLR7 modifiers include GS-9620, GSK-2245035, imiquimod, resimod, 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).

[0373] In some implementations, the TLR regulator is a TLR8 regulator. Examples of TLR8 modulators include motomoxicillin, remiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), and US20100029585 (Ventirx). The compounds disclosed in US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics).

[0374] In some implementations, the TLR modifier is a TLR9 modifier. Examples of TLR9 modifiers include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, and CYT-003-QbG10.

[0375] In some implementations, the additional therapeutic agent is an interferon alpha receptor ligand. Examples of interferon alpha receptor ligands include interferon alpha-2b. Pegylated interferon α-2a Pegylated interferon α-1b, interferon Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant supercompound interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 Interferon β-1a Shaferon, Interferon α-2b (Axxo), Alfaferone, Interferon α-2b (BioGeneric Pharma), Interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermaxα, Realdiron, Lanstion, Pegaferon, PDferon-B, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), α-interferon α-2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α2b (Zydus-Cadila), Interferon α2a, Optipeg A, Realfa2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon α2a fusion protein), rHSA-IFNα2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa).

[0376] In some implementations, the additional therapeutic agent is a hyaluronidase inhibitor. An example of a hyaluronidase inhibitor is Stormomer.

[0377] In some implementations, the adjunctive 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-2163, REP-2165, REP-2053, REP-2031, and REP-006 and REP-9AC′. An example of an HBsAg secretion inhibitor is BM601.

[0378] In some implementations, the adjunctive 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, ipilimumab, beraccept, PSI-001, PRS-010, Probody monoclonal antibody, tremelimumab, and JHL-1155.

[0379] In some embodiments, the additional therapeutic agent is a cyclic protein inhibitor. Examples of cyclic protein inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

[0380] In some implementations, the additional treatment is an HBV entry inhibitor. An example of an HBV entry inhibitor is Myrcludex B.

[0381] In some implementations, the additional therapeutic agent is an antisense oligonucleotide that targets viral mRNA. Examples of antisense oligonucleotides that target viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004.

[0382] In some implementations, the additional therapeutic agent is a short interfering RNA (siRNA). Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

[0383] In some implementations, the additional therapeutic agent is DNA-directed RNA interference (ddRNAi). An example of ddRNAi is BB-HB-331.

[0384] In some implementations, the additional therapeutic agent is an endonuclease modulator. An example of an endonuclease modulator is PGN-514.

[0385] In some implementations, the additional therapeutic agent is a ribonucleotide reductase inhibitor. An example of a ribonucleotide reductase inhibitor is Trimidox.

[0386] In some implementations, the additional therapeutic agent is an HBV E antigen inhibitor. An example of an HBV E antigen inhibitor is baicalin.

[0387] In some implementations, the additional therapeutic agent is a covalently closed circular DNA (cccDNA) inhibitor. Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0388] In some implementations, the additional therapeutic agent is a farnesoid X receptor agonist. An example of a farnesoid X receptor agonist is EYP-001.

[0389] In some implementations, the adjunctive therapeutic agent is an HBV antibody. Examples of HBV antibodies targeting the surface antigen of the 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 immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088). Fully human monoclonal antibodies include HBC-34.

[0390] In some implementations, the additional therapeutic agent is a CCR2 chemokine antagonist. An example of a CCR2 chemokine antagonist is propaguinale.

[0391] In some implementations, the adjunctive therapeutic agent is a thymosin agonist. Examples of thymosin agonists are thymosin alpha 1 and recombinant thymosin alpha 1 (GeneScience).

[0392] In some implementations, the additional therapeutic agent is a cytokine. Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simmoleukin.

[0393] In some embodiments, the additional therapeutic agent is a nucleoprotein modulator. In some embodiments, the nucleoprotein modulator is an inhibitor of the HBV core protein or capsid protein. Examples of nucleoprotein modulators include AB-423, AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, mofexidine mesylate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158, and DVR-23. Examples of capsid inhibitors include compounds disclosed in the following literature: US20140275167 (NoviraTherapeutics), US20130251673 (Novira...). Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 ( Janssen), WO2014033167(Janssen), WO2015 / 059212(Janssen), WO2015118057(Janssen), WO2015011281(Janssen), WO2014184365(Janssen), WO2014184350( Janssen), WO2014161888(Janssen), WO2013096744(Novira), US20150225355(Novira), US20140178337(Novira), US20150315159(Novira), US20150197533(N ovira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche).

[0394] In some implementations, the additional therapeutic agent is a retinoic acid-inducible gene 1 stimulator. Examples of retinoic acid-inducible gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

[0395] In some implementations, the additional therapeutic agent is a NOD2 stimulant. An example of a NOD2 stimulant is SB-9200.

[0396] In some implementations, the adjunctive therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Examples of PI3K inhibitors include edalixib, ACP-319, AZD-8186, AZD-8835, bupalixib, CDZ-173, CLR-457, idalixib, neratinib, regoratinib, regoratinib sodium, EN-3342, TGR-1202, avocadolixib, duvelixib, IPI-549, UCB-5857, tacelilixib, XL-765, glazolixib, ME-401, VS-5584, copanlixib, orotic acid CAI, perifoxine, RG-7666, GSK-2636771, DS-7423, panulilixib, and GSK... -2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, Pilarisib, BAY-1082439, Praquitinib Mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, Sonolisibu, LY-3023414, SAR-260301, TAK-117, HMPL-689, Tenalisib, Voxtalisib, and CLR-1401.

[0397] In some embodiments, the additional therapeutic agent is an inhibitor of the indoleamine-2,3-dioxygenase (IDO) pathway. Examples of IDO inhibitors include icardolstat (INCB24360), remixstat (4SC-201), indomod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

[0398] In some implementations, the adjunctive treatment is a PD-1 inhibitor. Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pildizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400.

[0399] In some implementations, the adjunctive treatment 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.

[0400] In some embodiments, the provided composition is combined with compounds such as those disclosed in the following documents: WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, U S20180045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO201 7066227, WO2017087777, US20170145025, WO2017079669, WO2017070089, US2017107216 , WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO20 17112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO201720227 3. WO2017202274, WO2017202276, WO2017180769, WO2017118762, WO2016041511, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894 and WO2016142833.

[0401] In some implementations, the additional therapeutic agent is recombinant thymosin α-1. Examples of recombinant thymosin α-1 include NL-004 and pegylated thymosin α-1.

[0402] In some implementations, the adjunctive therapeutic agent is a Bruton's tyrosine kinase (BTK) inhibitor. Examples of BTK inhibitors include ABBV-105, acalatinib (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, spetinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and US20140330015 (Ono Compounds disclosed in US20130079327 (OnoPharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0403] 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 compounds disclosed in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), and WO2014164708 (Quanticel). In some implementations, the KDM inhibitor is a KDM1 inhibitor. Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, RG-6016, and ORY-2001.

[0404] In some implementations, the adjunctive treatment is a hepatitis B virus replication inhibitor. Examples of hepatitis B virus replication inhibitors include isothifluzidine, IQP-HBV, RM-5038, and Xingantie.

[0405] In some implementations, the additional therapeutic agent is an arginase inhibitor. Examples of arginase inhibitors include CB-1158, C-201, and remixstat.

[0406] In some implementations, the combination therapies described herein include gene therapy and / or cell therapy. Gene therapy and cell therapy include: genetic modification of silencing genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace a large portion of the subject'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 locate and kill infected cells; and genetic methods that alter cell activity to further modify the endogenous immune response to infection.

[0407] In some implementations, the combination therapies described herein include gene editors. Genome editing systems may be selected from the group consisting of: CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and large-scale nuclease systems; for example, cccDNA elimination via targeted cleavage and alteration of one or more of the hepatitis B virus (HBV) viral genes. Altering (e.g., knocking out and / or knocking down) PreC, C, X, PreSI, PreS2, S, P, or SP genes means (1) reducing or eliminating expression of PreC, C, X, PreSI, PreS2, S, P, or SP genes; (2) interfering with the function of precore, core, X protein, long surface protein, intermediate surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or hepatitis B splicing protein (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP); or (3) reducing or eliminating intracellular, serum, and / or parenchymal levels of HBe, HBc, HBx, LHB, MHB, SHB, Pol, and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P, and / or SP genes is performed by targeting HBV cccDNA and / or integrating these genes into HBV DNA.

[0408] In some embodiments, the combination therapies described herein include CAR-T cell therapy. CAR-T cell therapy may include a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HBV antigen-binding domain. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic.

[0409] In some implementations, the combination therapies described herein include TCR-T cell therapy. TCR-T cell therapy may include: T cells expressing an HBV-specific T cell receptor; TCR-T cells engineered to target HBV-derived peptides present on the surface of virus-infected cells; T cells expressing an HBV surface antigen (HBsAg)-specific TCR; and TCR-T therapies targeting HBV, such as LTCR-H2-1.

[0410] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and one, two, three, or four additional therapeutic agents selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine

[0411] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and a first additional therapeutic agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine

[0412] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and an HBV DNA polymerase inhibitor. In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclic protein inhibitors, HBV vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (such as... Fab derivatives or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators (HBV core protein or capsid protein regulators), retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β-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, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B and T lymphocyte attenuating factor inhibitors, CD3 05 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, recombinant thymosin α-1, BTK inhibitors, TIGIT modifiers, CD47 modifiers, SIRPα modifiers, ICOS modifiers, CD27 modifiers, CD70 modifiers, OX40 modifiers, epigenetic modifiers, NKG2D modifiers, Tim-4 modifiers, B7-H4 modifiers, B7-H3 modifiers, NKG2A modifiers, GITR modifiers, CD160 modifiers, HEVEM modifiers, CD161 modifiers, Axl modifiers, Mer modifiers, Tyro modifiers, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), IAP inhibitors, SMAC mimics, KDM5 inhibitors, IDO inhibitors, and hepatitis B virus replication inhibitors.

[0413] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition, (ii) an HBV DNA polymerase inhibitor, and (iii) one or more additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus), and bispecific antibodies and “antibody-like” therapeutic proteins (such as… Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators, and one or more additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0414] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of the hepatitis B virus), and bispecific antibodies and "antibody-like" therapeutic proteins (such as...). Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators.

[0415] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0416] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine And at least a second adjunctive therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclic protein inhibitors, HBV vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (such as... Fab derivatives and TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators (HBV core protein or capsid protein regulators), retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, IDO inhibitors, recombinant thymosin α-1, 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, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B and T lymphocyte attenuating factor inhibitors. Epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα 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, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), IAP inhibitors, SMAC mimics, KDM5 inhibitors, and hepatitis B virus replication inhibitors.

[0417] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine and (iii) at least a second adjunctive therapy selected from the group consisting of: pegylated interferon alpha-2b Interferon α1b Interferon α-2b Pegylated interferon α-2a Interferon α-n1 Ribavirin, Interferon β-1a Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, Interferon α-2b (AXXO), Alfaferone, Interferon α-2b (BioGeneric Pharma), Feron, Interferon-α2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), α-interferon α-2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α-2b (Zydus-Cadila), Optipeg A, Realfa2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Pegylated Interferon α-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, Interleukin-2 (IL-2, Immunex), Recombinant Human Interleukin-2 (Shenzhen Neptunus), Layfferon, Kashuning, Shangsheng Leitai, INTEFEN, SINOGEN, Fukangtai, Alloferon, and Ximo Interleukin.

[0418] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine and (iii) at least a second adjunctive therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and “antibody-like” therapeutic proteins (such as… Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, IDO inhibitors, and NOD2 stimulators.

[0419] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine And (iii) at least a second adjunctive therapy selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0420] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine (iii) Select one, two, or three supplemental therapeutic agents from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of the hepatitis B virus), and bispecific antibodies and "antibody-like" therapeutic proteins (such as...). (Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators; and (iv) one or two additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0421] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine (iii) One or two additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (such as... (Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators; and (iv) one or two additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0422] In some implementations, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; and (ii) a first additional treatment agent selected from the group consisting of adefovir. Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir Telbivudine or lamivudine and (iii) one, two, three, or four additional therapeutic agents selected from the group consisting of: immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (such as... Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, NOD2 stimulators, HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0423] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and one or more compounds such as those described in U.S. Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Publication No. 2009 / 0047249 (Gilead Sciences), and U.S. Patent No. 8722054 (Gilead Sciences). Sciences), US Publication No. 2014 / 0045849 (Janssen), US Publication No. 2014 / 0073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US Publication No. 2014 / 0350031 (Janssen), WO2014 / 023813 (Janssen), US Publication No. 2008 / 0234251 (Array Biopharma), US Publication No. 2008 / 0306050 (Array Biopharma), US Publication No. 2010 / 0029585 (Ventirx Pharma), US Publication No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), US Publication No. 2012 / 0082658 (Ventirx Pharma), US Publication No. 2012 / 0219615 (Ventirx Pharma), US Publication No. 2014 / 0066432 (Ventirx Pharma), US Publication No. 2014 / 0088085 (Ventirx Pharma), US Publication No. 2014 / 0275167 (Novira Therapeutics), US Publication No. 2013 / 0251673 (Novira Therapeutics), US Patent No. 8513184 (Gilead Sciences), US Publication No. 2014 / 0030221 (Gilead Sciences), US Publication No. 2013 / 0344030 (Gilead Sciences), US Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), US Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO20141 61888(Janssen)、WO2013096744(Novira)、US20150225355(Novira)、US20140178337( Novira), US20150315159(Novira), US20150197533(Novira), US20150274652(Novira) , US20150259324(Novira), US20150132258(Novira), US9181288(Novira), WO20141843 50 (Janssen), WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), US Publication No. 2014 / 0330015 (Ono Pharmaceutical), US Publication No. 2013 / 0079327 (Ono Pharmaceutical), US Publication No. 2013 / 0217880 (Ono Pharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation)Those disclosed in US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), and US9186337B2 (Oryzon Genomics), as well as other medicines for the treatment of HBV and combinations thereof.

[0424] In some embodiments, the provided composition may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dosage of the provided composition.

[0425] In some embodiments, the provided composition is combined with tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 5 mg-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 5 mg-10 mg, 5 mg-15 mg, 5 mg-20 mg, 5 mg-25 mg, 25 mg-30 mg, 20 mg-30 mg, 15 mg-30 mg, or 10 mg-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The provided composition may be combined with the pharmaceutical agents provided herein at any dosage of the composition, as each combination of dosages is specifically and individually listed.

[0426] In some embodiments, the provided composition is combined with 100 mg-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 100 mg to 150 mg, 100 mg to 200 mg, 100 mg to 250 mg, 100 mg to 300 mg, 100 mg to 350 mg, 150 mg to 200 mg, 150 mg to 250 mg, 150 mg to 300 mg, 150 mg to 350 mg, 150 mg to 400 mg, 200 mg to 250 mg, 200 mg to 300 mg, 200 mg to 350 mg, 200 mg to 400 mg, 250 mg to 350 mg, 250 mg to 400 mg, 350 mg to 400 mg or 300 mg to 400 mg tenofovir disoproxil fumarate, tenofovir disoproxil fumarate or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate. The provided composition may be combined with the pharmaceutical agents provided herein at any dose of the provided composition, as with each combination of doses specifically and individually listed.

[0427] In some embodiments, a kit is provided that contains a combination of the compositions disclosed herein with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. The provided compositions may be used in the kit as if each composition were specifically and individually listed for use in the kit.

[0428] HIV combination therapy

[0429] In some embodiments, a method is provided for treating HIV infection in a human who is infected with HIV or at risk of such infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method is provided for treating HIV infection in a human who is infected with HIV or at risk of such infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0430] In some embodiments, a method for treating HIV infection is provided, the method comprising administering to a human a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0431] In one embodiment, a pharmaceutical composition is provided comprising a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0432] In some embodiments, this disclosure provides a method for treating HIV infection, the method comprising administering to a patient in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0433] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents. In other embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In still other embodiments, the 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 they may be selected from different classes of therapeutic agents.

[0434] Administration of HIV combination therapy

[0435] In some embodiments, the compounds disclosed herein are administered together with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally means administering the compounds disclosed herein and one, two, three, or four additional therapeutic agents simultaneously or sequentially, such that therapeutically effective amounts of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in two or more doses.

[0436] Co-administration includes administering a unit dose of the compound disclosed herein before or after administering a unit dose of one, two, three, or four additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours after administering one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1-12 hours).

[0437] In some embodiments, the compounds disclosed herein are combined with one, two, three or four additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

[0438] In some embodiments, a kit is provided that contains a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three or four) additional therapeutic agents.

[0439] In some embodiments, compounds of any kind disclosed herein are formulated into tablets, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablets may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0440] In one specific embodiment, the kit contains the compounds disclosed herein or pharmaceutically acceptable salts thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor.

[0441] In some implementations, such tablets are suitable for once-daily administration.

[0442] HIV combination therapy

[0443] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV combination therapy. In the above embodiments, one or more additional therapeutic agents may be anti-HIV agents. In the above embodiments, one or more adjunctive therapeutic agents may be anti-HIV agents selected from the group consisting of: HIV combination drugs, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptors, TCR-T, autologous T-cell therapy), latency reversal agents, compounds targeting the HIV capsid, capsid polymerization inhibitors, HIV bNAb, immunotherapy, 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 infection 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, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.In some implementations, the adjunctive therapeutic agent may be selected from HIV capsid inhibitors, HIV Tat or Rev inhibitors, engineered B cells, fatty acid synthase inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, IFN antagonists, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, and combinations thereof.

[0444] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, 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 reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0445] In some embodiments, one or more adjunctive therapeutic agents are selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, agonists of HIV bNAb, TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for the treatment of HIV, as well as combinations thereof.

[0446] In some implementations, one or more adjunctive therapeutic agents are selected from durutexvir, cabotevir, islatravir, direravir, bicagvir, issavirline, rilpivirline, and lenacapavir, as well as combinations thereof.

[0447] In some implementations, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, 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 reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0448] HIV combination therapy

[0449] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV combination drug. Examples of combination drugs include... (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat and erteiravir); (Direravir, tenofovir alafenamide, emtricitabine and cobistat); (Bicagvir, tenofovir alafenamide, and emtricitabine); Bicagvir, tenofovir disoproxil fumarate, and emtricitabine; Bicagvir, tenofovir alafenamide, and lamivudine; Bicagvir, tenofovir disoproxil fumarate, and lamivudine; Bicagvir, abacavir, and lamivudine; Efaviraxyl, lamivudine, and tenofovir disoproxil fumarate; Lamivudine and tenofovir disoproxil fumarate; Tenofovir and lamivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertitravir; (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( Lopinavir and ritonavir); (Durutvir, Abacavir and Lamivudine); (Durutexvir, Rilpivirine); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); dulutegravir and lamivudine; dulutegravir and abacavir; cabotevir and lamivudine; cabotevir and abacavir; cabotevir and rilpivirine; atazanavir and cobistat; atazanavir sulfate and cobistat; atazanavir sulfate and ritonavir; duravir and cobistat; dulutegravir and rilpivirine hydrochloride; dulutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; retigvir and lamivudine; doravir Virilin, lamivudine, and tenofovir disoproxil fumarate; doravirin, lamivudine, and tenofovir disoproxil fumarate; dulutegravir + 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 implementations, the adjuvant is a tenofovir analogue, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotevir + rilpivirine, 3-BNC117 + ibovite, elpida (isavirin, VM-1500) and VM-1500A or a combination thereof.

[0450] Other HIV medications

[0451] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one other HIV medication. Examples of other medications used to treat HIV include acetaminophen, arapovir, BanLec, deferiphenone, Gamimune, mitfalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, M K-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, S B-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576. Additional examples of other drugs used to treat HIV include, but are not limited to, AAV-eCD4-Ig gene therapy, bevirimat derivatives, ABBV-382, APH0202, lichenstatin-1, lichenstatin analogs, BG-HIV, BRII-732, CS-TATI-1, antisense oligonucleotides modified with fluoro-β-D-arabinose (FANA), 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, and S-64. 8414, DIACC-1010, Fasnall, 2-CLIPS peptide, HRF-4467, thromboretin analogue, 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 conjugate (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.

[0452] HIV protease inhibitors

[0453] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV protease inhibitor. Examples of HIV protease inhibitors include ampravir, atazanavir, becanavir, drenellavir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, 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.

[0454] Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent Nos. 10,294,234 and U.S. Patent Application Publications Nos. US2020030327 and US2019210978.

[0455] HIV reverse transcriptase inhibitors

[0456] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV reverse transcriptase inhibitor. Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapirine, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and isavirin (VM-1500). Additional examples of non-nucleoside or non-nucleotide inhibitors of HIV 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, isavirin (extended-release oral, for HIV infection), doravirine + isavirin (fixed-dose combination / oral tablet formulation, for HIV-1 infection), isavirin (long-acting injectable nanosuspension, for HIV infection), or combinations thereof.

[0457] Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate. and VIDEX (Didanoxin, DDL), Abacavir, Abacavir Sulfate, Alovudine, Alitabin, Cinovine, Didanoxin, Avtabin, Fetinavivir, Fosalvudinetidoxil, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753, Tenofovir Disoproxil Orotate, Fosalvudinetidoxil, Lamivudine, Phosphazid, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, tenofovir alafenamide (AGX-1009), MK-8583, and combinations thereof.

[0458] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0459] HIV integrase inhibitors

[0460] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV integrase inhibitor. Examples of HIV integrase inhibitors include erteiravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, ginsenoside tricarboxylic acid, derivatives of ginsenoside tricarboxylic acid, phenethyl caffeate, derivatives of phenethyl caffeate, tyrosine kinase inhibitors, derivatives of tyrosine kinase inhibitors, quercetin, derivatives of quercetin, retegvir, dulutegravir, JTK-351, bicretiravir, and AVX-1. 5567, 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 cabotevir.

[0461] Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442. Additional examples of HIV integrase inhibitors include, but are not limited to, erteiravir (extended-release microcapsules), pegylated retegvir, cabotevir (long-acting injectable), STP-0404, or combinations thereof.

[0462] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2014221356 and US2016016973.

[0463] HIV infection factor inhibitors

[0464] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV infectious agent inhibitor. Examples of HIV infectious agent inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives.

[0465] HIV entry inhibitors

[0466] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include xenicovirol, CCR5 inhibitors, gp41 inhibitors, CD4 attachment 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.

[0467] Examples of CCR5 inhibitors include apravirone, vevicvirone, maravirone, cinnickvirone, leronlimab (PRO-140), adatavir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu). Additional examples of CCR5 inhibitors include, but are not limited to, maravirone (a long-acting injectable nanoemulsion), thioravirone, and combinations thereof.

[0468] Examples of gp41 inhibitors include epovitamide, epovitide, BMS-986197, epovitide biomodifications, epovitide biosimilars, HIV fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifviride. Examples of gp41 inhibitors include, but are not limited to, griffithsin (a gp41 / gp120 / gp160 inhibitor), CPT-31, Cl3hmAb, lipuvirtide, HIV-1 fusion inhibitors (P26-Bapc), and combinations thereof.

[0469] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0470] Examples of gp120 inhibitors include Radha-108 (receptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, Fostersavir tromethamine, IQP-0831, and BMS-663068. Additional examples of gp120 inhibitors include, but are not limited to, anti-HIV antimicrobial agents, BMS818251, VVX-004, and combinations thereof.

[0471] Examples of gp160 inhibitors include, but are not limited to, tetrandrine.

[0472] Examples of CXCR4 inhibitors include plexafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0473] HIV maturation inhibitors

[0474] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232.

[0475] Latency reversal agent

[0476] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one latency reversal agent. Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-Bromo domain 4 (BRD4) inhibitors, iomycin, PMA, SAHA (salinomycin B, aniline, and salinomycin B), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as lagozolar analogs), as well as APH-0812, GSK-343, and Toll-like receptor modulators. Additional examples of latency reversal agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists such as GS-9620, TLR8 agonists and TLR9 agonists) (such as ZL-0580, apabelon), IAP antagonists (inhibitors of apoptosis proteins such as APG-1387, LBW-242), SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists) and combinations thereof.

[0477] Examples of HDAC inhibitors include romidesin, vorinostat, and pabistat.

[0478] Examples of PKC activators include indolinamide, prostratin, phorbol B, and DAG-lactone.

[0479] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0480] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0481] Histone deacetylase (HDAC) inhibitors

[0482] In some embodiments, the compound as described herein or a pharmaceutically acceptable salt thereof is combined with an inhibitor of histone deacetylases such as 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, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, romidesin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0483] Capsid inhibitors

[0484] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one capsid inhibitor. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-destructive 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 disclosed herein is combined with GS-6207. Additional examples of capsid inhibitors include, but are not limited to, lenakapavir, GS-CA1, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), compounds described in GSK Patent Publication WO2019 / 087016, and combinations thereof.

[0485] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0486] Cytochrome P450 3 inhibitors

[0487] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cytochrome P450 3 inhibitor. Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0488] RNA polymerase regulators

[0489] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one RNA polymerase regulator. Examples of RNA polymerase regulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264.

[0490] Immune checkpoint modulators

[0491] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., 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 (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0492] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); transmembrane and immunoglobulin domain-containing receptors 2 (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitors 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory factors (ICOS, CD278); inducible T cell costimulatory factor ligands (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 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC MHC class I polypeptide-associated sequence A (MICA); MHC class I polypeptide-associated 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); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); containing T cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9);Lymphocyte activation 3 (LAG3, CD223); Signal transduction 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); Retinic acid early transcript 1E (RAET1E; ULBP4); Retinic acid early transcript 1G (RAET1G; ULBP5); Retinic acid early transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); Cytokine lectin-like receptor C 1 (KLRC1, NKG2A, CD159A); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); cytotoxic lectin-like receptor C2 (KLRC2, CD159c, NKG2C); cytotoxic lectin-like receptor C3 (KLRC3, NKG2E); cytotoxic lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic immunoglobulin-like receptor, two Ig domains and long... Cytoplasmic tail 1 (KIR2DL1); cytotoxic immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 2 (KIR2DL2); cytotoxic immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 3 (KIR2DL3); cytotoxic immunoglobulin-like receptor with three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0493] 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 suppressive immune checkpoint proteins or receptors. Exemplary T-cell suppressor 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 immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated proteins. Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In various implementation schemes, the reagents described herein are combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors.Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (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); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0494] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are 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, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptors D1 (KLRD1, CD94). In various embodiments, the agent as described herein is 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); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, 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.

[0495] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors 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 includes BPI-002.

[0496] Examples of CTLA4 inhibitors that can be used co-administered include, but are not limited to: ipilimumab, trimemumab, 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, and ATO. R-1144, PBI-5D3H5, BPI-002, and 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).

[0497] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, 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-754091. AGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181 (Bug's maize), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), 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, INCB086550, MAX10181, and 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), and PD-L1 (PD-L1 / PD-L1). -L1)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(C TLA4 / 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).

[0498] In various implementation schemes, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058 and AGEN-1307.

[0499] TNF receptor superfamily (TNFRSF) agonists or activators

[0500] In various embodiments, the compound as described herein or a pharmaceutically acceptable salt thereof is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being, for example, agonists of one or more of the following: 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, NC... TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TR4, DR5, TRAILR2, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TR4, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, DR4, TRAILR1, 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, DR4, TRAILR2, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, DR4 AILR3 (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, ...CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 115650), 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).

[0501] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0502] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0503] In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

[0504] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered together include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373, and ADG-106.

[0505] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0506] Bispecific and trispecific natural killer (NK) cell adaptors

[0507] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with bispecific NK cell adjuvants (BiKE) or trispecific NK cell adjuvants (TriKE) (e.g., without Fc) or bispecific antibodies against (e.g., with Fc) the following: NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, anti-CD16 binding bispecific molecules may or may not have an Fc. Exemplary bispecific NK cell adjuvants that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adjuvants (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0508] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0509] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0510] Immunotherapy

[0511] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one immunotherapy. Examples of immunotherapy 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; hydroxychloroquine; prazolam (aldeleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolic acid. Mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymeric 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; nifedipine; pegylated interferon α-2a; pegylated interferon α-2b; recombinant interleukin-15; RPI-MN; STING modulator; RIG-I modulator; NOD2 modulator; SB-9200; and IR-103.

[0512] Examples of TLR agonists include vesamote (GS-9620), lefetemod, tilsotolimod, rapamod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motomod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and tetramod.

[0513] Toll-like receptor (TLR) agonists

[0514] In various embodiments, a compound as 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).Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesamote), vesamote analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (VentirxPharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, teiramod, and BDB-001.TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), and US20080234251 (Array). The compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, 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 retamivir, polyICLC, etc. Apoxxim、 IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0515] CDK inhibitors or antagonists

[0516] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370.

[0517] STING agonists, RIG-I and NOD2 modulators

[0518] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with interferon gene stimulators (STING). 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-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-1 modulators (such as RGT-100) or NOD2 modulators (such as SB-9200 and IR-103).

[0519] LAG-3 and TIM-3 inhibitors

[0520] In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0521] In some embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0522] Interleukin agonists

[0523] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one interleukin agonist. In some embodiments, the agents described herein are combined with: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12); examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); BC-IL (Cel-Sci), polyethylene glycol-modified IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, A... Examples of IL-15 agonists include LKS-4230, CUI-101, and 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 Synthorin (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.

[0524] Examples of additional immunotherapies that can be combined with the agents disclosed herein include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, gepon, nomfullon, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0525] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0526] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one PI3K inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, orotic acid (CAI), copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifoxine, pictilisib, pilaralisib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, and 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.

[0527] α-4 / β-7 antagonists

[0528] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one α-4 / β-7 antagonist. Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, aliruzumab, itralizumab, carotegrast methyl, and vedolzumab.

[0529] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0530] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are 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... Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bNAb (broadly neutralizing HIV antibody), BMS-936559, TMB-360 and those antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, 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, recombinant human mAb (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), clone 3 human monoclonal antibody targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB, and combinations thereof.

[0531] Various bNAbs can be used. Examples include, but are not limited to, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including 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. Other examples include, but are not limited to, those described in the following literature: 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 Special): DL 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to the outer domain glycan); 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).

[0532] Further broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO The references 2017 / 133639 and WO 2017 / 133640 are incorporated herein by reference in their entirety for all purposes. Other examples include those described in the following literature: 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 Special): Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all of which combine with gp41 MPER).

[0533] Examples of supplemental antibodies include, but are not limited to, BF520.1, BiIA-SG, CH01, CH59, CAP256V2LS, DH270.1, DH270.6, D1D2, Cl3hmAb, GS-9722 (epavirinab), BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, 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, 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, DH511.11P, 2F5, 7b2 and LN01.Examples of drugs that target HIV in this way include babiramab, 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. 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 antibodies. 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.

[0534] Examples of in vivo delivered bNAbs include AAV8-VRC07 and mRNA encoding the anti-HIV antibody VRC01. Additional examples of in vivo delivered bNAbs include engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

[0535] Pharmacokinetic enhancers

[0536] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobistat and ritonavir.

[0537] Additional treatment

[0538] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one additional therapeutic agent. Examples of adjunctive therapeutic agents include compounds disclosed in the following publications: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US The following publications are incorporated herein by reference in their entirety: WO 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), WO 2013 / 091096 (Boehringer Ingelheim), WO 2018 / 145021 (Gilead Sciences), and WO2017 / 106346 (Gilead Sciences).

[0539] HIV vaccine

[0540] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are 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, multi-level DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol envA / 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 pseudovirus vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective 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+romidesin, variant gp120 peptide vaccine, rAd5gag-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; vaccines based on eOD-GT860 polymers, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccines, gp120(A, B, C, A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1Envs HIV vaccines (GLA-SE adjuvant), HIV p24gag pri, me-boost plasmid DNA vaccines, isanoplasmic virus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV vaccine regimens, UBI HIV gp120, mRNA-based prophylactic vaccines, and TBL-1203HI. Additional examples of HIV vaccines include, but are not limited to, HIV... MAGDNA vaccines, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, 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, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pittend), arenavirus-based vaccines based on bisegmented or trisegmented arenaviruses, and HIV-1 based on trimers. Vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Malabar virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Simelik Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI:10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines and combinations thereof. Examples of other adjuvant agents used in vaccines include, but are not limited to, AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1gp140 adjuvanted vaccine, and ChAdOx1.HIV consv1 vaccine, CMV-MVA trivalent vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConMSOSIP.v7 gp140, MPER-656 liposomal subunit vaccine, Pennvax-G / MVA-CMDR, ChAdV63.HIVconsv, SeV-EnvF, HIV vaccine based on N123-VRC-34.01 inducible epitope, GOVX-C55, TVI-HIV-1, ENOB-HV-11, ENOB-HV-12, MagaVax, DNA and Sev vector vaccines expressing SCaVII, VIR-1111, DermaVir, HIV-1iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, arenavirus-based vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), and combinations thereof.

[0541] Combination therapy with birth control pills

[0542] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one contraceptive or birth control regimen. Therapeutic agents for contraception (birth control) that can be combined with the agents disclosed herein include, but are not limited to, cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, nomeprogesterone acetate, norethindrone, norethindrone, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0543] HIV combination therapy

[0544] In one specific embodiment, the 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: (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); (Bicagvir, tenofovir alafenamide and emtricitabine); Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistatin and ertiravir); Adefovir; Adefovir dipyridamole; Cobistatin; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir alafenamide hemifumarate; (Durutexvir, Abacavir and Lamivudine); Durutvir, Abacavir Sulfate and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvirtide; ( Lopinavir and ritonavir); (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate. Additional treatment agents may be selected from, for example, tenofovir alafenamide and erteiravir; tenofovir alafenamide + erteiravir (rectal preparation, HIV infection); pegylated retegvir; lamivudine + lopinavir + ritonavir + abacavir; tenofovir + emtricitabine + maraviro, and combinations thereof.

[0545] Those skilled in the art will understand that the additional therapeutic agents listed above may include more than one of the categories listed above. Specific categories are not intended to limit the function of the compounds listed in those categories.

[0546] In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In yet another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In still another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some 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 yet 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 one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four HIV bNAbs. In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four HIV bNAbs and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four HIV bNAbs, an HIV capsid inhibitor or HIV capsid polymerization inhibitor, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another embodiment, the compound disclosed herein or a pharmaceutical composition thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0547] Gene therapy and cell therapy

[0548] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with gene or cell therapy regimens. Gene and cell therapies include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace a large portion of a 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 locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies 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, autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 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.

[0549] Gene-edited products

[0550] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with a gene editor (e.g., an HIV-targeted gene editor). In various embodiments, the genome editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and a wide range of nuclease complexes. Exemplary HIV-targeted CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0551] CAR-T cell therapy

[0552] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, may be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains 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-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a proximal membrane 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 may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5ZFN T cells, anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0553] TCR T-cell therapy

[0554] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with a population of TCR-T cells. The TCR-T cells are engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

[0555] B-cell therapy

[0556] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one B-cell therapy. In some embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells genetically modified 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), May 17, 2019).

[0557] The compounds disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three or four additional therapeutic agents at any dose of the compound of Formula I (e.g., 1 mg to 500 mg of the compound).

[0558] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0559] In one embodiment, one or more additional therapeutic agents in the kit are anti-HIV agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptors, TCR-T, autologous T-cell therapy), compounds targeting the HIV capsid, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, 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 infection 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, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0560] In some implementations, one or more additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, 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 reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0561] In one specific embodiment, the kit contains a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another specific embodiment, the kit contains a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In yet another specific embodiment, the kit contains a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In still another embodiment, the kit contains a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the kit contains 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 yet another embodiment, the kit contains a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In one specific embodiment, 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 one specific embodiment, 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 HIV capsid polymerization inhibitor, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In one specific embodiment, the kit contains the compounds disclosed herein or pharmaceutically acceptable salts thereof, a nucleoside inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor.

[0562] Combination therapy with birth control pills

[0563] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one contraceptive drug combination therapy. Therapeutic agents used with contraceptive drugs (birth control pills) include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, nomedroxyprogesterone acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0564] Gene therapy and cell therapy

[0565] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one gene and / or cell therapy. Gene and cell therapies include genetic modification of silencing genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace a large portion of a 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 locate and kill infected cells; and genetic methods that alter cell activity to further modify the endogenous immune response to infection.

[0566] Examples of dendritic cell therapy include AGS-004.

[0567] Examples of CCR5 gene-editing drugs include SB-728T.

[0568] Examples of CCR5 gene inhibitors include Cal-1.

[0569] Gene-edited products

[0570] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one gene editor. The genome editing system is selected from the group consisting of: CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and large-scale nuclease systems.

[0571] Examples of HIV targeting the CRISPR / Cas9 system include EBT-101.

[0572] CAR-T cell therapy

[0573] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one CAR-T cell therapy. An immune effector cell population is engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains 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-induced binding site on gp120, a N-glycan on gp120, V2 of gp120, and a proximal membrane 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.

[0574] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, and autologous hematopoietic stem cells genetically engineered to express CD4CAR and C46 peptides.

[0575] TCR-T cell therapy

[0576] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one TCR-T cell therapy. The TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0577] Long-term treatment for HIV

[0578] In some implementations, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one long-acting HIV therapy. Examples of drugs being developed as long-acting regimens include cabotevir, rilpivirine, any integrase LA, VM-1500LAI, maraviro (LAI), tenofovir implant, MK-8591 implant, doravirine, retegvir, and long-acting durutexvir.

[0579] HBV combination therapy

[0580] In some embodiments, a method for treating or preventing HBV infection in a human being at risk of HBV infection is provided, comprising administering to the human a therapeutically effective amount of the composition described herein combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) adjunctive therapeutic agents. In one embodiment, a method for treating HBV infection in a human being at risk of HBV infection is provided, comprising administering to the human a therapeutically effective amount of the composition described herein combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) adjunctive therapeutic agents.

[0581] In some embodiments, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and pharmaceutically acceptable excipients.

[0582] In some embodiments, a medicament kit is provided that contains a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0583] In some embodiments, the pharmaceutical agent of this disclosure or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the pharmaceutical agent of this disclosure or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, the pharmaceutical agent of this disclosure or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In some embodiments, the pharmaceutical agent of this 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 they may be selected from different classes of therapeutic agents.

[0584] In some embodiments, when the pharmaceutical agent of this disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more doses.

[0585] The co-administration of the drug disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the drug disclosed herein and one or more additional therapeutic agents, such that a therapeutically effective amount of each drug is present in the patient.

[0586] Co-administration includes administering a unit dose of the agent disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. The agent disclosed herein may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the agent disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the agent disclosed herein within seconds or minutes. In some embodiments, a unit dose of the agent disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the agent disclosed herein several hours (e.g., 1-12 hours).

[0587] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

[0588] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more adjunctive therapeutic agents selected from HBV combination drugs, 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, cyclic protein inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi, endonuclease modulators, ribonucleotide reductase inhibitors, and HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, caspase 9 stimulators, CD3 modulators, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, ZCCHC14 inhibitors, tertiary lymphocyte aggregate inducers, nucleic acid polymers (e.g., NAP and STOPS), PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, gene therapy and cell therapy, gene editing agents, CAR-T cell therapy, TCR-T cell therapy, other HBV drugs, and combinations thereof. In some embodiments, this specification provides a method for treating HBV infection, comprising administering to a patient in need a therapeutically effective amount of the composition described herein combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) adjunctive therapeutic agents suitable for treating HBV infection.

[0589] The compounds described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (such as...). Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALEN), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents, or any combination thereof. Additional examples include, but are not limited to, those containing, Fab derivatives, antibody-drug conjugates (ADCs), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALEN), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents, or any combination thereof. Anti-pMHC TCR-like antibodies, homing wide-range nucleases (e.g., ARCUS), and combinations thereof.

[0590] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more adjunctive therapeutic agents, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B and T lymphocyte attenuating factor inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclic protein inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesol 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, HBV RNase inhibitors, HBV viral 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 (IAP) inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators. Indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, cytotoxic lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin β receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, and non-classical RNA polymerase PAPD5 inhibitors.Non-classical RNA polymerase PAPD7 inhibitors, CD70 regulators, GITR regulators, Hevem regulators, ICOS regulators, Mer regulators, NKG2A regulators, NKG2D regulators, OX40 regulators, SIRPα regulators, TIGIT regulators, Tim-4 regulators, Tyro regulators, Na+-taurocholic acid cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein regulators, OX-40 receptor agonists, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors. Retinoic acid-induced gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA / DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimics, Src tyrosine kinase inhibitors, interferon gene stimulators (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-7 regulators, TLR-8 regulators, TLR-9 agonists, TLR9 agonists or gene stimulators, toll-like receptor (TLR) regulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

[0591] HBV combination therapy

[0592] In some embodiments, the compounds described herein are combined with at least one combination drug for treating HBV. Examples of combination drugs for treating HBV include... (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-α; ABX-203, adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0593] Other HBV medications

[0594] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one other HBV drug. Examples of other drugs used to treat HBV include α-hydroxytophenone, amdoxovir, β-hydroxycytosine nucleoside, AL-034, CCC-0975, evitabine, ezetimibe, cyclosporine A, gentiopicroside, JNJ-56136379, nitrozonide, brenalapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mirtovalidone, feron, GST-HG-131, levamisole, cathunin, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, and US20150210682 (Roche), US The compounds described in 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche). Additional examples of other medications used to treat HBV include, but are not limited to, droquinol, ARB-199, ccc-R08, HH-003, hopratide, NCO-48 Fumarate, XTYW-001, SFA-001, ENOB-HB-01, QL-007 Sofosbuvir, ledipasvir, PA-1010, HPN-BV1, STSG-0002, and combinations thereof.

[0595] HBV vaccine

[0596] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HBV vaccine. HBV vaccines include 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, and ENGERIX. Recombinant Hepatitis B Vaccine (Intramuscular Injection, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Hansenula polymorpha yeast, Intramuscular Injection, Hualan Biological Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Eufravac, 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 B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine. Supplemental vaccines include, but are not limited to, CARG-101, YS-HBV-001, IR-101H, TVAX-008, and combinations thereof.

[0597] Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (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), and recombinant VLP-based therapeutic vaccines (HBV infection, VLP). Biotech), AdTG-17909, AdTG-17910AdTG-18202, ChronVac-B, TG-1050 and Lm HBV. Additional examples of therapeutic HBV vaccines include, but are not limited to, HepTcell, therapeutic DNA vaccines for hepatitis B, 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 isovirus vaccines (disclosed, for example, in WO2017076988 and WO2017198726), and combinations thereof.

[0598] HBV DNA polymerase inhibitors

[0599] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is combined with at least one HBV DNA polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include adefovir. Enqutabin Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, bexifovir, entecavir Entecavir maleate, telbivudine Felosivir, Pradefovir, Clavudine, Ribavirin, Lamivudine Azide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. Additional examples of HBV DNA polymerase inhibitors include, but are not limited to, tenofovir alafenamide, ATI-2173, AiB-001, and combinations thereof.

[0600] Immunomodulators

[0601] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one immunomodulator. Examples of immunomodulators include rapamod, amidoline hydrochloride, ingaron, dermaVir, hydroxychloroquine, prazolam, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, polymeric 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.

[0602] Toll-like receptor (TLR) modulators

[0603] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with agonists of Toll-like receptors (TLRs), such as agonists 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 modifiers include modifiers for TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13.

[0604] Examples of TLR3 modifiers include retinoic acid, polyICLC, Apoxxim、 IPH-33, MCT-465, MCT-475 and ND-1.1.

[0605] Examples of TLR modifiers include, but are not limited to, AK-0701.

[0606] Examples of TLR4 modifiers include, but are not limited to, G-100 and GSK-1795091.

[0607] Examples of TLR7 modulators include GS-9620 (Vesamote), GSK-2245035, Imiquimod, Resimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop D, Tramod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds described in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Additional examples of TLR7 modulators include, but are not limited to, AL-034, DSP-0509, LHC-165, TMX-101 (imiquimod), and combinations thereof.

[0608] Examples of TLR8 modulators include motomodil, rescimodil, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), and US20100029585 (Ventirx). The compounds described in US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Application No. 9670205, US20160289229, US Patent Application No. 15 / 692161, and US Patent Application No. 15 / 692093.

[0609] TLR7 / TLR8 modifiers include, but are not limited to, NKTR-262, Tramod, and BDB-001.

[0610] Examples of TLR-8 inhibitors include, but are not limited to, ZG-170607.

[0611] Examples of TLR8 agonists that can be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, retinomod, selgantolimod (GS-9688), HRS-9950, VTX-1463, VTX-763, 3M-051, 3M-052, and US2016289229 (Gilead). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Patent Nos. 9670205 (Gilead Sciences, Inc.), US20160289229 (Gilead Sciences, Inc.), WO2017 / 048727 (Gilead Sciences, Inc.), US20180065938 (Gilead Sciences, Inc.), and US20180086755 (Gilead Sciences, Inc.).

[0612] Examples of TLR9 modifiers 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), literimod, and CYT-003-QbG10. Additional examples of TLR9 modifiers include AST-008, copitomolimod, CMP-001, S-540956, linimod, MGN-1601, BB-001, BB-006, CYT-003, tisoltolimod, PUL-042, and combinations thereof.

[0613] Examples of TLR7, TLR8, and TLR9 regulators include WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo(Shanghai)Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo Dainippon Pharma), WO2016023511 (ChiaTai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (Bristol Myers Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO201800558X (Bristol Myers Squibb), WO201704023 (3M Co), WO2017163264 (Council of Scientific and Industrial Research(India)), WO2018046460 (GlaxoSmithKlineBiologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co) Ltd), WO2017202704 (Roche), WO2018026620 (Bristol Myers Squibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan KelunBiotech The compounds described in WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), and WO2015023958 (University of Kansas) are listed.

[0614] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are co-administered with TLR7, TLR8, TLR9 agonists or combinations thereof.

[0615] Interferon α receptor ligand

[0616] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one interferon α receptor ligand. Examples of interferon α receptor ligands include interferon α-2b (INTRON). ), pegylated interferon α-2a Pegylated interferon α-1b, interferon α-1b Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant supercompound interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 interferon Shaferon, interferon α-2b (Axxo), Alfaferone, interferon α-2b (BioGenericPharma), interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermaxα, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon α-2b (IFN, Laboratorios Bioprofarma), α-interferon α-2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon α2b (Zydus-Cadila), interferon α2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon α2a fusion protein), rHSA-IFNα2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shanghai Biotech, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa). Additional examples of interferon α receptor ligands include, but are not limited to, PEG-IFN-α.

[0617] Hyaluronidase inhibitor

[0618] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include astodrimer.

[0619] Hepatitis B surface antigen (HBsAg) inhibitors

[0620] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are 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-2163, REP-2165, REP-2053, REP-2031, and REP-006 and REP-9AC′. Another example of an HBsAg inhibitor includes GP-605.

[0621] Examples of HBsAg secretion inhibitors include BM601. Additional examples of HBsAg secretion inhibitors include, but are not limited to, GST-HG-131, AB-452, ALG-010093, and combinations thereof.

[0622] Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

[0623] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor. Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, beracipex, PSI-001, PRS-010, Probody monoclonal antibody, tremelimumab, and JHL-1155.

[0624] Cyclic protein inhibitors

[0625] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cyclic protein inhibitor. Examples of cyclic protein inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds described in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

[0626] HBV virus enters inhibitor

[0627] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HBV entry inhibitor. Examples of HBV entry inhibitors include Myrcludex B.

[0628] Hepatitis B large envelope protein inhibitor

[0629] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are 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.

[0630] Antisense oligonucleotides targeting viral mRNA

[0631] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one antisense oligonucleotide targeting viral mRNA. Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Additional examples of antisense oligonucleotides targeting viral mRNA include, but are not limited to, IONIS-HBV-LRx, BNC-1701, and combinations thereof.

[0632] Short interfering RNA (siRNA) and ddRNAi

[0633] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one siRNA and / or ddRNAi.

[0634] Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467. Additional examples of siRNAs include, but are not limited to, AB-729, DCR-HBVS, RG-6084 (PD-L1), RG-6217, ALN-HBV-02, JNJ-3989 (ARO-HBV), STSG-0002, ALG-010133, ALG-ASO, LUNAR-HBV, DCR-HBVS (DCR-S219), and combinations thereof.

[0635] Examples of DNA-guided RNA interference (ddRNAi) include BB-HB-331.

[0636] Endonuclease regulators

[0637] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one endonuclease modulator. Examples of endonuclease modulators include PGN-514.

[0638] Ribonucleotide reductase inhibitors

[0639] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one ribonucleotide reductase inhibitor. Examples of ribonucleotide reductase inhibitors include Trimidox.

[0640] Non-nucleoside reverse transcriptase inhibitors

[0641] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one nonnucleoside reverse transcriptase inhibitor. Examples of nonnucleoside reverse transcriptase inhibitors (NNRTIs) include, but are not limited to, the compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), and WO2008005555 (Gilead).

[0642] HBV replication inhibitors

[0643] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HBV replication inhibitor. Examples of hepatitis B virus replication inhibitors include, but are not limited to, GP-31502, isothifluzidine, IQP-HBV, RM-5038, and Xingantie.

[0644] HIV-1 reverse transcriptase inhibitors

[0645] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV-1 reverse transcriptase inhibitor. Examples of HIV-1 reverse transcriptase inhibitors include, but are not limited to, 2,5,6-substituted pyrimidinone derivatives (HBV).

[0646] Inhibitors of non-classical RNA polymerases PAPD5 and PAPD7

[0647] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one noncanonical RNA polymerase PAPD5 and / or PAPD7 inhibitor. Examples of noncanonical RNA polymerase PAPD5 and PAPD7 inhibitors include, but are not limited to, PAPD5 and PAPD7 that target and lock onto nucleic acid antisense oligonucleotides (HBV infection).

[0648] HBV E antigen inhibitors

[0649] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HBVE antigen inhibitor. Examples of HBVE antigen inhibitors include baicalin.

[0650] Covalently closed circular DNA (cccDNA) inhibitors

[0651] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cccDNA inhibitor. Examples of cccDNA inhibitors include BSBI-25 and CHR-101. Another example of a cccDNA inhibitor includes, but is not limited to, ccc-R08.

[0652] Farnesol X receptor agonists

[0653] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one farnesoid X receptor (FXR) agonist. Examples of farnesoid X receptor agonists include EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670. Another example of a farnesoid X receptor agonist is cilofexor.

[0654] Caspase-9 stimulator

[0655] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one caspase-9 stimulator. Examples of caspase-9 stimulators include, but are not limited to, ENOB-HB-01.

[0656] CD3 modulators

[0657] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one CD3 modulator. Examples of CD3 modulators include, but are not limited to, IMC-I109V.

[0658] Ffar2 and Ffar3 agonists

[0659] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one Ffar2 and / or Ffar3 agonist. Examples of Ffar2 and Ffar3 agonists include, but are not limited to, SFA-001.

[0660] HBV antibody

[0661] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one 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, HumabsBioMed). Additional examples of HBV antibodies targeting the surface antigen of hepatitis B virus include lenvervimab, VIR-3434, and combinations thereof.

[0662] Examples of HBV antibodies (including monoclonal and polyclonal antibodies) include Zutectra, Shang Sheng Gan Di, UmanBig (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, Hepatitis B Immunoglobulin (intravenous, pH 4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0663] Fully human monoclonal antibodies include HBC-34.

[0664] Antibodies against HBV viral peptide / major histocompatibility complex (MHC) class I (pMHC) complexes are described, for example, in Sastry et al., J Virol. 2011 Mar; 85(5):1935-42 and WO2011062562.

[0665] CCR2 chemokine antagonists

[0666] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one CCR2 chemokine antagonist. Examples of CCR2 chemokine antagonists include propargyl germanium.

[0667] thymosin agonists

[0668] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one thymosin agonist. Examples of thymosin agonists include thymosin alpha 1 and recombinant thymosin alpha 1 (GeneScience).

[0669] Cytokines

[0670] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cytokine. Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simmoleukin.

[0671] Interleukin agonists

[0672] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with interleukin agonists, including but not limited to IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include proleukin (aldeleukin, IL-2); PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, and AIC-284. 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 Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

[0673] Nucleoprotein regulators

[0674] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one nucleoprotein modulator. The nucleoprotein modulator may be an inhibitor of the HBV core protein or capsid protein. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, mofexidine mesylate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23. Additional examples of nucleoprotein modulators include, but are not limited to, AB-836, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, ARB-1820, GST-HG-141, JNJ-632, GST-HG-141, KL-060332, ABI-H3733, AK-0605, HRS-5091, VNRX-9945, CB-HBV-001, AK-0605, SOC-10, SOC-11, and combinations thereof.

[0675] Examples of capsid inhibitors include compounds described in the following patents: US20140275167 (NoviraTherapeutics), US20130251673 (Novira Therapeutic...

Claims

1. A compound having the following formula: or ， Or its pharmaceutically acceptable salt.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the following formula: ， Or its pharmaceutically acceptable salt.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the following formula: 。 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the following formula: ， Or its pharmaceutically acceptable salt.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the following formula: 。 6. A compound having the following formula: ， Or its pharmaceutically acceptable salt.

7. 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 thereof.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

9. The pharmaceutical composition of claim 8, wherein the at least one additional therapeutic agent comprises abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, emtricitabine, bicagvir, dulutegravir, cabotevir, N-(( S )-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1 H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1 H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-1-yl)acetamide, its pharmaceutically acceptable salts, or combinations thereof.

10. The pharmaceutical composition of claim 8, wherein the at least one additional therapeutic agent comprises adefovir, entecavir, telbivudine, lamivudine, or a combination thereof.

11. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating said infection in humans suffering from HIV infection.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

14. The pharmaceutical composition of claim 13, wherein the at least one additional therapeutic agent comprises abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, emtricitabine, bicagvir, dulutegravir, cabotevir, N-(( S )-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1 H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1 H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-1-yl)acetamide, its pharmaceutically acceptable salts, or combinations thereof.

15. The pharmaceutical composition of claim 13, wherein the at least one additional therapeutic agent comprises adefovir, entecavir, telbivudine, lamivudine, or a combination thereof.

16. Use of the compound of claim 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating said infection in humans with HIV infection or for preventing said infection in humans at risk of developing HIV infection.

17. A compound having the following formula: ， Or its pharmaceutically acceptable salt.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

20. The pharmaceutical composition of claim 19, wherein the at least one additional therapeutic agent comprises abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, emtricitabine, bicagvir, dulutegravir, cabotevir, N-(( S )-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1 H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1 H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-1-yl)acetamide, its pharmaceutically acceptable salts, or combinations thereof.

21. The pharmaceutical composition of claim 19, wherein the at least one additional therapeutic agent comprises adefovir, entecavir, telbivudine, lamivudine, or a combination thereof.

22. Use of the compound of claim 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating said infection in humans with HIV infection or for preventing said infection in humans at risk of developing HIV infection.