Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use

Abstract

Compounds, compositions, and method useful for treating a viral infection, such as human immunodeficiency virus (HIV) and / or hepatitis B virus (HBV) infection, are disclosed. In particular, prodrugs of phosphonamide nucleotide analogues and methods for their preparation and use as therapeutic or prophylactic agents are disclosed.

Description

(19) *EP004667477A2* (11) EP 4 667 477 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 24.12.2025 Bulletin 2025 / 52 (21) Application number: 25200536.8 (22) Date of filing: 05.08.2021 (51) International Patent Classification (IPC): C07F 9 / 6561 (2006.01) (52) Cooperative Patent Classification (CPC): A61P 31 / 12; A61K 45 / 06; A61P 31 / 18; C07F 9 / 65616 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 07.08.2020 US 202063062899 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 21762257.0 / 4 192 474 (71) Applicant: Gilead Sciences, Inc. Foster City, CA 94404 (US) (72) Inventors: • BYUN, Daniel H. Foster City, 94404 (US) • CHUN, Byoung-Kwon Foster City, 94404 (US) • CLARKE, Michael O. Foster City, 94404 (US) • JANSA, Petr Foster City (US) • NADUTHAMBI, Devan Foster City, 94404 (US) • SQUIRES, Neil H. Foster City, 94404 (US) (74) Representative: Carpmaels & Ransford LLP One Southampton Row London WC1B 5HA (GB) Remarks: •This application was filed on 05‑09‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of filing of the divisional application (Rule 68(4) EPC). (54) PRODRUGS OF PHOSPHONAMIDE NUCLEOTIDE ANALOGUES AND THEIR PHARMACEUTICAL USE (57) Compounds, compositions, and method useful for treating a viral infection, such as human immunode- ficiency virus (HIV) and / or hepatitis B virus (HBV) infec- tion, are disclosed. In particular, prodrugs of phospho- namide nucleotide analogues and methods for their pre- paration and use as therapeutic or prophylactic agents are disclosed. EP 4 66 7 47 7 A 2 Processed by Luminess, 75001 PARIS (FR) Description CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application no. 63 / 062,899, filed on August 7, 2020, which is hereby incorporated herein by reference in its entirety for all purposes. FIELD

[0002] Compounds, compositions, and methods useful for treating a viral infection, such as human immunodeficiency virus (HIV) infection, are disclosed. BACKGROUND

[0003] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes that are required for viral replication: reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase are inwide use and have showneffectiveness, particularly when employed in combination with, for example, protease inhibitors and integrase inhibitors. No HIV cure is known, and accordingly, those affected by HIV can require life-long treatments. Improved treatments for HIVand other viral infections are desirable. SUMMARY

[0004] The present disclosure is directed to novel prodrugs of the nucleotide analogue reverse transcriptase inhibitor tenofovir and pharmaceutically acceptable salts thereof. In some embodiments, the compoundsmay be used to treat HIV infections, to inhibit the activity of HIV reverse transcriptase, and / or to reduce HIV replication. In some embodiments, compounds disclosed herein may be effective against a range of known drug-resistant HIV mutants. In some embodi- ments, compounds disclosed herein have properties thatmake it possible for them to be administeredwith less than daily frequency, for example, at weekly, monthly, or longer intervals.

[0005] Inoneembodiment, compoundshaving the following formula (I) or apharmaceuticallyacceptable salt thereof are provided: or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently chosen from C1‑12alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene, C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, bridged C5‑10bicycloalkyl, bridged C5‑10bicycloalkyl-C1‑4alkylene, fused C5‑10bicycloalkyl, C10‑16dispirocycloalkyl, C10‑16dispirocycloalkyl-C1‑4alky- lene, bridged C9‑12tricycloalkyl, bridged C9‑12tricycloalkyl-C1‑4alkylene, C3‑7cycloalkyl-C3‑7cycloalkylene, and 5‑ to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1‑12alkyl, aryl-C1‑4alkylene,C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene,C7‑12spirocycloalk- yl, and C7‑12spirocycloalkyl-C1‑4alkylene is optionally substituted with from one to three Ra; R3, R4, R5, and R6 are independently chosen from C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb; or optionally: R3 and R4 together with the carbon atom to which they are attached form a 3‑ to 6-membered saturated or partially unsaturated carbocyclic ringoptionally substitutedwith fromone to threeRb; andR5andR6are independently chosen fromC1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is 2 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 optionally substituted with from one to three Rb; or R3 and R4 are independently chosen from C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3‑ to 6‑membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; or R3 and R4 together with the carbon atom to which they are attached form a 3‑ to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom towhich theyareattached forma3‑ to 6‑memberedsaturatedor partially unsaturatedcarbocyclic ringoptionally substituted with from one to three Rb; B is R7 is hydrogen or R8; R8 is ‑L1‑(L2)m‑(L3)n‑R8a; L1 is chosen from a bond, ‑C(O)‑, and ‑C(O)O‑; L2 is C1‑6alkylene; L3 is ‑C(O)O‑ or R8a is chosen from C1‑12alkyl, aryl, ‑C(O)‑aryl, ‑C(O)‑C1‑4alkyl, ‑S-C(O)‑C1‑4alkyl, wherein aryl and ‑C(O)‑aryl are optionally substituted with one or two Rc; each Ra is independently chosen from C1‑4alkyl, halo, C1‑4haloalkyl, and ‑O-C1‑4alkyl; each Rb is independently C1‑4alkyl; each Rc is independently C1‑4alkyl or ‑OC(O)‑C1‑4alkyl; m and n are independently 0 or 1; and p is 0, 1, or 2.

[0006] In another embodiment, a pharmaceutical composition is provided comprisinga therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In another embodiment, a pharmaceutical composition is provided comprising a means for maintaining the therapeutically effective concentration of TFV-DP in PBMCs for an extended period of time, and a pharmaceutically acceptable excipient, wherein themeans for maintaining the therapeutically effective concentration of TFV-DP in PBMCs for an extended period of time is a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, a pharmaceutical composition is provided comprising a means for maintaining the therapeutically effective concentration of TFV-DP in PHHs for an extended period of time, and a pharmaceutically acceptable excipient,wherein themeans formaintaining the therapeutically effective concentrationofTFV-DP inPHHs for an extended period of time is a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, a kit or an article of manufacture is provided comprising a compound of formula I, or a 3 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 pharmaceutically acceptable salt thereof, and instructions for use.

[0010] In another embodiment, a kit or an article of manufacture is provided comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and instructions for use.

[0011] In another embodiment, a method of treating an HIV infection by administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided.

[0012] In another embodiment, a method of treating an HIV infection, by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided.

[0013] In another embodiment, a method of preventing an HIV infection, by administering to a subject at risk thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided.

[0014] In another embodiment, a method of preventing an HIV infection, by administering to a subject at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided.

[0015] In another embodiment, a method of treating an HBV infection, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided.

[0016] In another embodiment, a method of treating an HBV infection, by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided.

[0017] In another embodiment, a method of preventing an HBV infection, by administering to a subject at risk thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided.

[0018] In another embodiment, a method of preventing an HBV infection, by administering to a subject at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided.

[0019] In another embodiment, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating an HIV infection is provided.

[0020] In another embodiment, use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for treating an HIV infection is provided.

[0021] In another embodiment, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an HIV infection is provided.

[0022] Inanotherembodiment, acompoundof formula I, or apharmaceutically acceptablesalt thereof, for use in treating an HIV infection is provided.

[0023] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a compoundof formula Ior apharmaceutically acceptable salt thereof, andapharmaceutically acceptable excipient, for use in treating an HIV infection is provided.

[0024] In another embodiment, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating an HBV infection is provided.

[0025] In another embodiment, use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for treating an HBV infection is provided.

[0026] In another embodiment, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an HBV infection is provided.

[0027] Inanotherembodiment, acompoundof formula I, or apharmaceutically acceptablesalt thereof, for use in treating an HBV infection is provided.

[0028] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a compoundof formula I, or apharmaceutically acceptablesalt thereof, andapharmaceuticallyacceptableexcipient, for use in treating an HBV infection is provided.

[0029] In another embodiment, a compoundof formula Ior apharmaceutically acceptable salt thereof, for use inmedical therapy is provided.

[0030] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a compoundof formula I, or apharmaceutically acceptablesalt thereof, andapharmaceuticallyacceptableexcipient, for use in medical therapy is provided.

[0031] In another embodiment, the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as a research tool is provided.

[0032] In another embodiment, amethod of using a compound of formula I in therapy is provided. In particular, amethod of treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of formula I or a pharmaceutically acceptable salt 4 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 thereof, and a pharmaceutically acceptable excipient, is provided.

[0033] In another embodiment, a composition comprisingacompoundof formula Ior apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in a method of treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) is provided.

[0034] In another embodiment, a kit or anarticle ofmanufacture comprisingacomposition effective to treat or prevent an HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat or prevent infection byHIV, is provided. Exemplary compositions comprise a compound of formula I as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0035] In another embodiment, amethodof inhibiting the replicationofHIV is provided.Themethodcomprisesexposing the virus to an effective amount of a compound of formula I or a salt thereof, under conditions where replication of HIV is inhibited.

[0036] In another embodiment, the use of a compound of formula I, or a pharmaceutically acceptable salt thereof to inhibit the activity of HIV reverse transcriptase is provided.

[0037] In another embodiment, the use of a compound of formula I, or a salt thereof, to inhibit the replication of HIV is provided.Other embodiments,maybe set forth in thedetailed descriptionof the embodiments that follows, and in partmay be apparent from the description, ormay be learned by practice, of the claimed embodiments. Thesemay be realized and attained by the processes and compositions particularly pointed out in the description and claims thereof. The foregoing Summary has beenmadewith the understanding that it is to be considered as a brief and general synopsis of some of the embodiments disclosed herein, and is not intended to limit in anymanner the scope, or range of equivalents, to which the appended claims are lawfully entitled. DETAILED DESCRIPTION

[0038] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The description below of several embodiments is made with the under- standing that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Definitions

[0039] Unless the context requires otherwise, throughout the present disclosure and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to."

[0040] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] The term "about" or "approximately," used in connectionwithaquantity is inclusiveof thestatedvalueandhas the meaningdictatedby thecontext (e.g., includes thedegreeof error associatedwithmeasurement of theparticular quantity).

[0042] Asusedherein, the term "administering" or "administration" typically refers to theadministration of a composition to a subject to achieve delivery of an agent that is, or is included, in a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be used for administration to a subject, for example a human. For example, in some embodiments, administrationmay be parenteral. In someembodiments, administrationmaybeby injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve applicationofa fixednumberof doses. In someembodiments, administrationmay involvedosing that is intermittent (e.g., a plurality of dosesseparated in time)and / or periodic (e.g., individual dosesseparatedbyacommonperiodof time). In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0043] "Alkyl" refers to a straight or branched chain hydrocarbon radical, which is saturated, having from one to twelve carbon atoms (C1‑12alkyl), in certain embodiments one to eight carbon atoms (C1‑8alkyl) or one to six carbon atoms (C1‑6alkyl), one to four carbon atoms (C1‑4alkyl), or five to eight carbon atoms (C5‑8alkyl), andwhich is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0044] "Alkylene" refers to a straight or branched chain hydrocarbon radical, which is saturated, having from one to 5 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 twelve carbon atoms (C1‑12alkylene), in certain embodiments one to eight carbon atoms (C1‑8alkylene) or one to six carbon atoms (C1‑6alkylene), or one to four carbon atoms (C1‑4alkylene), and which is divalent. Examples include methylene (-CH2‑), ethylene (-CH2CH2‑), propylene (-CH2CH2CH2‑), 1-methylethylene (-CH(CH3)CH2‑), butylene (-CH2CH2CH2CH2‑), 1-methylpropylene (-CH(CH3)CH2CH2‑), 1,1-dimethylethylene (-C(CH3)2CH2‑), and 1,2-dimethy- lethylene (-CH(CH3)CH(CH3)‑). Unless stated otherwise, the definitions propylene and butylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propylene also includes 1- methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0045] "Amino" refers to the ‑NH2 radical.

[0046] The term "antiviral agent" asusedherein is intended tomeananagent (compoundorbiological) that is effective to inhibit the formation and / or replication of a virus in a subject, for example, a human, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and / or replication of a virus in a subject, for example, a human.

[0047] "Aryl" refers to a single aromatic ring or a bicyclic or multicyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical or an ortho, spirocyclo, or bridged bicyclic ormulticyclic radical having about 9 to 14 atoms inwhich at least one ring is aromatic (e.g., an aryl fused to one ormore aryl or carbocycle). Such bicyclic ormulticyclic ringsmay be optionally substitutedwith one ormore (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the bicyclic or multicyclic ring. It is to be understood that the point of attachment of a bicyclic or multicyclic radical, as defined above, can be at any position of the ring including an aryl or a carbocycle portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4- tetrahydronaphthyl, anthracenyl, and the like.

[0048] "Arylalkylene" refers to an alkylene radical as defined hereinwhich is bonded to an aryl radical as defined herein. Accordingly, the point of attachment of an arylalkylene radical is the alkylene group. The alkylene group of the "arylalkylene" is typically 1 to 6 carbon atoms (i.e., arylC1‑6alkylene). Arylalkylene groups include, but are not limited to, benzyl, 2-phenylethan‑1-yl, 2-phenylethen‑1-yl, naphthylmethyl, 2-naphthylethan‑1-yl, 2-naphthylethen‑1-yl, naphthobenzyl, 2-naphthophenylethan‑1-yl, and the like. The arylalkylene group typically comprises 6 to 20 carbon atoms, e.g., the alkylenemoiety of the arylalkylene group is one to six carbon atoms and the aryl moiety is five to fourteen carbon atoms.

[0049] "Arylcycloalkylene" refers to a cycloalkylene radical as defined herein which is bonded to an aryl radical as defined herein. Accordingly, the point of attachment of an arylcycloalkylene radical is the cycloalkylene group. The cycloalkylene group of the "arylcycloalkylene" is typically 3 to 7 carbon atoms (i.e., arylC3‑7cycloalkylene).

[0050] Asused herein, "bicycloalkyl" refers to a hydrocarbon radical having the specified number carbon atomsand two rings,which ringsmaybebridged, fused, or spirocyclic relative to oneanother. In certain embodiments thebicycloalkyl has from seven to twelve carbon atoms, six to twelve carbon atoms, from six to ten carbon atoms, or from five to ten carbon atoms, and is saturated and attached to the rest of themolecule by a single bond. A bridged bicycloalkyl will have two rings connected via two shared atoms that are non-adjacent. A fused bicycloalkyl will have two rings connected via a shared bond. A spirocyclic bicycloalkyl (denoted "spirocyclo alkyl") will have two rings connected via a single, shared atom. For example, bicycloheptyl may be bridged bicycloheptyl, fused bicycloheptyl, or spirocyclo heptyl, respectively, as exem- plified below:

[0051] "Bridged" refers to a carbocyclic or heterocyclic ring structure described herein containing two non-adjacent atoms in a ring that are connected via a single atomor a divalent group.Exemplary bridgedbicyclic compoundsare bicyclo [2.2.1]heptane and 1,4-diazabicyclo[2.2.2]octane, depicted below: A bridged ring structure may be polycyclic (i.e., bicyclic, tricyclic, etc.).

[0052] As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to 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 6 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered prior to administration of any doses of a second regimen); in someembodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) ormodality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0053] A prefix such as "Cu-v" or "(Cu‑Cv)" indicates that the following group has from u to v carbon atoms. For example, "C1‑6alkyl" indicates that the alkyl group has from one to six carbon atoms.

[0054] "Carbocyclic ring" refers to anon-aromatic hydrocarbon ring, having from three to fifteen carbonatoms, in certain embodiments having from three to ten carbon atoms or from three to seven carbon atoms, or from three to six carbon atoms, and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclo- hexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0055] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon radical, which is saturated, having from three to fifteen carbon atoms (C3‑15cycloalkyl), in certain embodiments having from three to ten carbon atoms (C3‑10cycloalkyl), from three to seven carbon atoms (C3‑7cycloalkyl), from three to six carbon atoms (C3‑6cycloalkyl), or from five to seven carbon atoms (C5‑7cycloalkyl), andwhich is attached to the rest of themoleculebyasingle bond.Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0056] "Cycloalkylene" as used herein refers to a non-aromatic cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkane (i.e., it is divalent). Accordingly, a cyclobutylene radical includes: A cycloalkylene group can have from three to fifteen carbon atoms, from three to ten carbon atoms, from three to seven carbon atoms, or from three to six carbon atoms. As used herein, cycloalkylenemay be saturated or partially unsaturated. Cycloalkylene groups include, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohex- ylene, cyclohexenylene, 1,3-cyclohexadienylene, 1,4-cyclohexadienylene, cycloheptylene, cycloheptenylene, and cy- clooctylene.

[0057] As used herein, the term "dosage form" refers to a physically discrete unit of an active agent (e.g., a therapeutic, prophylactic, or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordancewith a dosing regimen that has beendetermined to correlatewith a desired or beneficial outcome when administered to a relevant population (i.e., with a prophylactic or therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0058] "Fused" refers to a ring structure described herein containing carbocyclic, heterocyclic, aromatic, and / or heteroaromatic rings that are connected via two adjacent atoms. For example, the bicyclic compounds depicted below incorporate a cyclopropane fused to a cyclohexane, a pyrrolidine fused to a benzene, and a thiene fused to a furan, respectively: A fused ring structure may be polycyclic (i.e., bicyclic, tricyclic, etc.).

[0059] "Halo" or "halogen" refers to bromo, chloro, fluoro, and iodo.

[0060] "Haloalkyl" refers to an alkyl as definedherein, wherein one ormore hydrogenatomsare each replaced bya halo substituent. For example, aC1‑6haloalkyl is aC1‑6alkyl wherein one ormore of the hydrogenatomshave been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl group to complete halogenation of the alkyl group. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2- 7 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 trifluoroethyl, 1,2-difluoroethyl, 3-bromo‑2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0061] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having from three to fifteen atoms wherein from one to six atoms are heteroatoms chosen from nitrogen, oxygen and sulfur and attached to the rest of the molecule by a single bond. In certain embodiments, "heterocyclyl" has from three to ten atoms, wherein from one to four atoms are heteroatoms chosen from nitrogen, oxygen and sulfur, or from three to seven atoms, wherein from one to two atoms are heteroatoms chosen from nitrogen, oxygen and sulfur. The nitrogen, carbon or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. As used herein, "heterocyclyl" or "hetero- cyclic ring" refers to rings that are saturated unless otherwise indicated, e.g., in some embodiments "heterocyclyl" or "heterocyclic ring" refers to rings that are saturated or partially saturated where specified. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazoli- dinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1- dioxo-thiomorpholinyl.

[0062] "Hydroxy" or "hydroxyl" refers to the ‑OH radical.

[0063] The term "inhibitor of HIV replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo, or in vivo.

[0064] The term "inhibitor of HBV replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of HBV to replicate in a host cell, whether in vitro, ex vivo, or in vivo.

[0065] "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0066] "Optional" or "optionally" means that the subsequently described event or circumstancesmay or may not occur, and that thedescription includes instanceswheresaidevent or circumstanceoccursand instances inwhich it doesnot. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted and that the description includes both substituted heterocyclyl radicals and heterocyclyl radicals having no substitution.

[0067] "Oxo" refers to the =O substituent.

[0068] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable excipients.

[0069] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition and is compatible with the other ingredients of the formulation and suitable for use in humans or domestic animals without undue toxicity, irritation, allergic response, and the like.

[0070] The term "pharmaceutically acceptable salt," as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of soundmedical judgment, suitable for use in contactwith the tissuesof humans and / or animalswithout undue toxicity, irritation, allergic responseand the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe several pharmaceutically acceptable salts in detail in the Journal of Pharma- ceutical Sciences. S. M. Berge et al., J. Pharma. Sci., 66:119 (1977).

[0071] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX4+ (wherein X is C1‑4alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts of organic carboxylic acids such as acetic, trifluoroacetic, adipic, ascorbic, aspartic, butyric, camphoric, cinnamic, citric, digluconic, glutamic, glycolic, glycerophosphoric, formic, hexanoic, benzoic, lactic, fumaric, tartaric, maleic, hydroxymaleic, malonic, malic, mandelic, isethionic, lactobionic, nicotinic, oxalic, pamoic, pectinic, phenylacetic, 3-phenylpropionic, pivalic, propionic, pyruvic, salicylic, stearic, sulfanilic, tartaric, undecanoic, and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, camphorsulfonic, mesitylenesulfonic, benzene- sulfonic, p-toluenesulfonic acids, naphthalenesulfonic, and 2-naphthalenesulfonic; and inorganic acids, such as hydro- chloric, hydrobromic, sulfuric, phosphoric, nitric, andsulfamicacids.Pharmaceuticallyacceptablesaltsof acompoundofa hydroxy group include the anion of said compound in combinationwith a suitable cation such asNa+ andNX4+ (wherein X is independently selected from H or a C1‑4alkyl group).

[0072] For therapeutic use, salts of active ingredients of the compounds disclosed herein will typically be pharmaceu- tically acceptable, i.e., they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the embodiments disclosed herein. All salts, whether or not derived froma physiologically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0073] Metal salts typically are prepared by reacting the metal hydroxide with a compound according to the embodi- 8 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 mentsdisclosedherein.Examplesofmetal saltswhichareprepared in thiswayaresalts containingLi+,Na+, andK+.A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0074] In addition, saltsmay be formed fromacid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines. Finally, it is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form.

[0075] "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compositionsmay, in someembodiments, be administered to a subject (including a human) who is at risk of having the disease or condition. As used herein, the terms "preventing" and "prevention" encompass the administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein pre‑ or post-exposure of the individual to HIV, or HBV, but before the appearance of symptoms of HIV infection, or HBV infection, and / or prior to the detection of the virus in the blood. The terms also refer to prevention of the appearance of symptoms of the disease and / or to prevent the virus from reaching detectible levels in the blood. The terms include both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event drivenor "ondemand"prophylaxis. The termsalso refer topreventionof perinatal transmissionofHIV frommother tobaby, by administration to the mother before giving birth and to the child within the first days of life. The terms also refer to prevention of transmission of HIV through blood transfusion.

[0076] "Spiro" or "spirocyclo" refers to a ring structuredescribedhereinwhich has two ring structures, eachofwhichmay be carbocyclic or heterocyclic, that are connected via a single, shared atom (which atom is denoted a spiro atom). Accordingly, "spirocyclo" refers to a spiro cycloalkyl radical, or a spiro heterocycloalkyl radical. "Dispiro" or dispirocyclo" refers to a ring structure described herein which has three ring structures, each of which may be carbocyclic or heterocyclic, that are connected via two spiro atoms.

[0077] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers andmixtures thereof and includes "enantiomers", which refers to two stereoisomers whosemolecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, compounds disclosed herein may be in the form of a stereoisomer thereof.

[0078] As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human). In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering from a relevant disease or condition. In some embodiments, a subject is susceptible to a disease or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease or condition. In some embodi- ments, a subject doesnot displayanysymptomor characteristic of adiseaseor condition. In someembodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy and / or prophylaxis is and / or has been administered.

[0079] As used herein, "therapeutically effective amount" is an amount that produces the desired effect for which it is administered. In someembodiments, the term "therapeutically effectiveamount" or "therapeutically effectivedose"means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease or condition in accordance with a therapeutic dosing regimen, to treat the disease or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, stabilizes one or more characteristics of, and / or delays onset of, one ormore symptoms of the disease or condition. Those of ordinary skill in the art will appreciate that the term "therapeutically effective amount" does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amountmaybe formulatedand / or administered inasingle dose. In someembodiments, a therapeutically effectiveamount may be formulated and / or administered in a plurality of doses, for example, as part of a dosing regimen.

[0080] "Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one ormore symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. As used herein, the terms "treatment" and "treating" encompass the administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments 9 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 disclosed herein to alleviate or eliminate symptoms of HIV infection, or HBV infection, and / or to reduce viral load in a subject in need thereof. In some embodiments, a subject is a patient.

[0081] As used herein, "tricycloalkyl" refers to a hydrocarbon radical having the specified number carbon atoms and three rings, which rings may be bridged, fused, spirocyclo, or a combination thereof relative to one another. In certain embodiments, the tricycloalkyl has from ten to sixteen carbonatoms, or fromnine to twelve carbonatoms, and is saturated and attached to the rest of the molecule by a single bond. For example, tricyclodecyl may be bridged tricyclodecyl, fused tricyclodecyl, dispirocyclo decyl, or mixed (e.g., bridged-fused) tricyclodecyl, respectively, as depicted below:

[0082] Theembodimentsdisclosedhereinarealsomeant toencompassall pharmaceutically acceptable compoundsof formula I being isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into thedisclosed compounds include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. In certain embodiments, these radiolabeled compounds are useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action.Certain isotopically labeled compoundsof formula I, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon‑14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0083] In certain embodiments, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.

[0084] Substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula I can be prepared by techniques known to those skilled in the art or by processes analogous to those described in theExamples as set out below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0085] Themethods, compositions, kits and articles of manufacture provided herein use or include compounds (e.g., a compound of formula I) or pharmaceutically acceptable salts thereof, in which from 1 to n hydrogen atoms attached to a carbon atommay be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds increase resistance to metabolism, and thus are useful for increasing the half-life of compounds or pharmaceutically acceptable salts thereof, when administered to a mammal. See, e.g., Allen B. Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, 5 Trends Pharmacol. Sci. 524, 524‑27 (1984). Such compounds can be synthesized by means known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0086] The embodiments disclosed herein are alsomeant to encompass the in vivometabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0087] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)‑ or (S)‑ or, as (D)‑ or (L)‑ for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (‑), (R)‑and (S)‑, or (D)‑and (L)‑ isomersmaybe preparedusing chiral synthons or chiral reagents, or resolvedusingmethodssuchaschromatographyand fractional crystallization. Techniques for thepreparation / isolation of individual enantiomers include chiral synthesis froma suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compoundsdescribedherein contain olefinic doublebondsor other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are 10 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 also intended to be included. Compounds

[0088] Provided herein are compounds that function as anti-HIVagents, or anti-HBVagents, pharmaceutical composi- tions 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 salt, stereoisomer, or mixture of stereoisomers thereof.

[0089] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided: wherein R1 and R2 are independently chosen from C1‑12alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene, C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, bridged C5‑10bicycloalkyl, bridged C5‑10bicycloalkyl-C1‑4alkylene, fused C5‑10bicycloalkyl, C10‑16dispirocycloalkyl, C10‑16dispirocycloalkyl-C1‑4alky- lene, bridged C9‑12tricycloalkyl, bridged C9‑12tricycloalkyl-C1‑4alkylene, C3‑7cycloalkyl-C3‑7cycloalkylene, and 5‑ to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1‑12alkyl, aryl-C1‑4alkylene,C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene,C7‑12spirocycloalk- yl, and C7‑12spirocycloalkyl-C1‑4alkylene is optionally substituted with from one to three Ra; R3, R4, R5, and R6 are independently chosen from C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb; or optionally: R3andR4 togetherwith thecarbonatom towhich theyareattached forma3‑ to 6‑memberedsaturatedorpartially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 are independently chosen from C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl- C1‑4alkylene is optionally substituted with from one to three Rb; or R3 and R4 are independently chosen from C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3- to 6- membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; or R3andR4 togetherwith thecarbonatom towhich theyareattached forma3‑ to 6‑memberedsaturatedorpartially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3‑ to 6‑membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; B is R7 is hydrogen or R8; R8 is ‑L1‑(L2)m‑(L3)n‑R8a; 11 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 L1 is chosen from a bond, ‑C(O)‑, and ‑C(O)O‑; L2 is C1‑6alkylene; L3 is ‑C(O)O‑ or R8a is chosen from C1‑12alkyl, aryl, ‑C(O)‑aryl, ‑C(O)‑C1‑4alkyl, ‑S-C(O)‑C1‑4alkyl, wherein aryl and ‑C(O)‑aryl are optionally substituted with one or two Rc; each Ra is independently chosen from C1‑4alkyl, halo, C1‑4haloalkyl, and ‑O-C1‑4alkyl; each Rb is independently C1‑4alkyl; each Rc is independently C1‑4alkyl or ‑OC(O)‑C1‑4alkyl; m and n are independently 0 or 1; and p is 0, 1, or 2.

[0090] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, B is In some embodiments, B is

[0091] In some embodiments, the compound of formula I is a compound of formula (II): 12 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in formula I.

[0092] In some embodiments, the compound of formula I is a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in formula I.

[0093] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R1and R2 are independently chosen from C1‑8alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cy- cloalkylene,C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, bridgedC5‑10bicycloalkyl, bridgedC5‑10bicycloalkyl- C1‑4alkylene, fused C5‑10bicycloalkyl, C10‑16dispirocycloalkyl, C10‑16dispirocycloalkyl-C1‑4alkylene, bridged C9‑12tricy- cloalkyl, bridged C9‑12tricycloalkyl-C1‑4alkylene, C3‑7cycloalkyl-C3‑7cycloalkylene, and 5‑ to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1‑8alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene, C7‑12spirocycloalkyl, and C7‑12spirocycloalkyl- C1‑4alkylene is optionally substituted with from one to three Ra, wherein Ra is as defined above. In some embodiments, R1 and R2 are independently chosen from C1‑8alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl- C3‑7cycloalkylene,C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, bridgedC5‑10bicycloalkyl-C1‑4alkylene, fused C5‑10bicycloalkyl, C10‑16dispirocycloalkyl-C1‑4alkylene, bridged C9‑12tricycloalkyl-C1‑4alkylene, C3‑7cycloalkyl-C3‑7cy- cloalkylene, and 5‑ to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1‑8alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene, C7‑12spir- ocycloalkyl, and C7‑12spirocycloalkyl-C1‑4alkylene is optionally substituted with from one to three Ra, wherein Ra is as definedabove. In someembodiments, R1 andR2are independently chosen fromC1‑8alkyl, C3‑7cycloalkyl, C3‑7cycloalkyl- C1‑4alkylene, C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, and bridged C5‑10bicycloalkyl-C1‑4alkylene, wherein each C1‑8alkyl, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, and C7‑12spirocycloalkyl- C1‑4alkylene is optionally substituted with from one to three Ra, wherein Ra is as defined above. In some embodiments, R1 and R2 are independently chosen from C5‑8alkyl, C5‑7cycloalkyl, C5‑7cycloalkyl-C1‑4alkylene, C7‑9spirocycloalkyl, C7‑9spirocycloalkyl-C1‑4alkylene, and bridged C5‑7bicycloalkyl-C1‑4alkylene, wherein each C5‑8alkyl, C5‑7cycloalkyl, C5‑7cycloalkyl-C1‑4alkylene, C7‑9spirocycloalkyl, C7‑9spirocycloalkyl-C1‑4alkylene, and bridged C5‑7bicycloalkyl-C1‑4al- kylene is optionally substituted with from one to three Ra, wherein Ra is as defined above.

[0094] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R1and R2 are different. In some embodiments, R1 and R2 are the same. In some embodiments, R1 and R2 are the same and chosen from C1‑8alkyl, aryl-C1‑4alkylene, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, aryl-C3‑7cycloalkylene, C7‑12spir- ocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, bridged C5‑10bicycloalkyl-C1‑4alkylene, fused C5‑10bicycloalkyl, C10‑16dispirocycloalkyl-C1‑4alkylene, bridged C9‑12tricycloalkyl-C1‑4alkylene, C3‑7cycloalkyl-C3‑7cycloalkylene, and 5‑ to 7-memberedmonocyclic heterocyclyl having from1 to 3 heteroatoms chosen fromN,O, andS,wherein eachC1‑8alkyl, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, and C7‑12spirocycloalkyl-C1‑4alkylene is optionally 13 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 substitutedwith fromone to threeRa, wherein Ra is as defined above. In some embodiments, R1 andR2 are the sameand chosen from C1‑8alkyl, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alky- lene, and bridged C5‑10bicycloalkyl-C1‑4alkylene, wherein each C1‑8alkyl, C3‑7cycloalkyl, C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, andC7‑12spirocycloalkyl-C1‑4alkylene is optionally substitutedwith fromone to threeRa, wherein Ra is as defined above. In some embodiments, R1 and R2 are the same and chosen from C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, C7‑12spirocycloalkyl-C1‑4alkylene, and bridged C5‑10bicycloalkyl-C1‑4alkylene, wherein each C3‑7cycloalkyl-C1‑4alkylene, C7‑12spirocycloalkyl, and C7‑12spirocycloalkyl-C1‑4alkylene is optionally substituted with from one to three Ra, wherein Ra is as defined above. In some embodiments, R1 and R2 are the same and chosen from C1‑8alkyl andC3‑7cycloalkyl, wherein eachC1‑8alkyl and C3‑7cycloalkyl is optionally substituted with from one to three Ra, wherein Ra is as defined above.

[0095] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R1and R2 are independently chosen from 14 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0096] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R1 is chosen from 15 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0097] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R2 is chosen from 16 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0098] In some embodiments, R1 and R2 are the same and chosen from 17 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 In some embodiments, R1 and R2 are the same and chosen from In some embodiments, R1 and R2 are the same and chosen from In some embodiments, R1 and R2 are the same and chosen from In someembodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R3, R4, R5, and R6are independently chosen fromC1‑3alkyl,C3‑5cycloalkyl, andaryl-C1‑4alkylene,whereineachC1‑3alkyl,C3‑5cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb, wherein Rb is as defined above. In some embodiments, R3, R4, R5, and R6 are independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb, wherein Rb is as defined above.

[0099] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R3and R5 are the same. In some embodiments, R3 and R5 are both methyl. In some embodiments, R3 and R5 are both ethyl. In some embodiments, R3 and R5 are both cyclopropyl. In some embodiments, R3 and R5 are both benzyl. 18 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0100] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R4and R6are thesame. Insomeembodiments,R4andR6arebothethyl or bothbenzyl. In someembodiments,R4andR6areboth methyl. In some embodiments, R4 and R6 are both ethyl. In some embodiments, R4 and R6 are both cyclopropyl. In some embodiments, R4 and R6 are both benzyl.

[0101] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R3and R4 are the same. In some embodiments, R3 and R4 are both methyl. In some embodiments, R3 and R4 are both ethyl. In some embodiments, R3 and R4 are both cyclopropyl. In some embodiments, R3 and R4 are both benzyl.

[0102] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R5and R6 are the same. In some embodiments, R5 and R6 are both methyl. In some embodiments, R5 and R6 are both ethyl. In some embodiments, R5 and R6 are both cyclopropyl. In some embodiments, R5 and R6 are both benzyl.

[0103] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R3and R4 together with the carbon atom to which they are attached form a 3‑ to 5‑membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 are independently chosen fromC1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally sub- stitutedwith fromone to threeRb,wherein eachRb is as definedabove. In someembodiments,R3 andR4 togetherwith the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb, wherein Rb is as defined above. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with the carbon atom to which they are attached formacyclobutane ringoptionally substitutedwith fromone to threeRb. In someembodiments, the cyclopropane ring or the cyclobutane ring is unsubstituted. In some embodiments, the cyclopropane ring or the cyclobutane ring is substitutedwith oneRb. In someembodiments, the cyclopropane ring or the cyclobutane ring is substitutedwith twoRb. In some embodiments, the cyclopropane ring or the cyclobutane ring is substituted with three Rb. In some embodiments, R5 and R6 are independently chosen from C1‑3alkyl, C3‑5cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cy- cloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb. In some embodiments, R5 and R6 are independently chosen frommethyl, ethyl, cyclopropyl, and benzyl, wherein eachmethyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb, and R5 andR6 are independently chosen frommethyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb.

[0104] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R3and R4are independently chosen fromC1‑4alkyl,C3‑6cycloalkyl, andaryl-C1‑4alkylene,whereineachC1‑4alkyl,C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached forma3‑ to 5‑membered saturated or partially unsaturated carbocyclic ring optionally substituted with fromone to threeRb,whereinRb is as definedabove. In someembodiments, R5 andR6 togetherwith the carbonatom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substitutedwith fromone to threeRb,whereinRb is asdefinedabove. In someembodiments, R5 and R6 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with from one to three Rb. In some embodiments, R5 and R6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with from one to three Rb. In some embodiments, the cyclopropane ring or the cyclobutane ring is unsubstituted. In someembodiments, the cyclopropane ring or the cyclobutane ring is substitutedwith one Rb. In some embodiments, the cyclopropane ring or the cyclobutane ring is substituted with two Rb. In some embodiments, the cyclopropane ring or the cyclobutane ring is substitutedwith threeRb. In someembodiments,R3andR4 are independently chosen from C1‑3alkyl, C3‑5cycloalkyl, and aryl-C1‑4alkylene, wherein each C1‑4alkyl, C3‑6cycloalkyl, and aryl-C1‑4alkylene is optionally substituted with from one to three Rb. In some embodiments, R3 and R4 are independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb. In some embodiments, R3 and R4 are independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with fromone to threeRb; andR5andR6 togetherwith the carbonatom towhich theyare attached formacyclopropane ringor a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substitutedwith fromone to threeRb.

[0105] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceuticallyacceptable salt thereof,R3and R4 together with the carbon atom to which they are attached form a 3‑ to 5‑membered saturated or partially unsaturated carbocyclic ringoptionally substitutedwith fromone to threeRb; andR5andR6 togetherwith the carbonatom towhich they are attached form a 3‑ to 5‑membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with fromone to threeRb; andR5andR6 togetherwith the carbonatom towhich theyareattached formacyclopropane ring or a cyclobutane ring,wherein the cyclopropane ring or the cyclobutane ring is optionally substitutedwith fromone to three 19 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Rb, wherein Rb is as defined above. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with from one to three Rb. In some embodiments, R5 and R6 together with the carbon atom to which they are attached form a cyclopropane ring. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with from one to three Rb. In some embodiments, R5 and R6 together with the carbon atom to which they are attached form a cyclobutane ring. In some embodiments, R3 andR4 together with the carbon atom towhich they are attached form a cyclopropane ring optionally substituted with from one to three Rb and R5 and R6 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with thecarbonatomtowhich theyareattached formacyclopropane ringoptionally substitutedwith fromone to threeRbandR5 and R6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclobutane ringoptionally substitutedwith fromone to threeRbandR5andR6 togetherwith thecarbonatom towhich they are attached form a cyclopropane ring optionally substituted with from one to three Rb. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with from one to three Rb and R5 and R6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with from one to three Rb.

[0106] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, each Rb is independentlymethyl, ethyl, propyl, or butyl. In someembodiments, eachRb is independentlymethyl, ethyl, or propyl. In some embodiments, each Rb is independently methyl or ethyl. In some embodiments, each Rb is methyl. In some embodiments, each Rb is ethyl.

[0107] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R3, R4, R5, and R6 are the same. In some embodiments, R3, R4, R5, and R6 are each C1‑3alkyl, C3‑5cycloalkyl, or aryl- C1‑4alkylene, wherein each C1‑3alkyl, C3‑5cycloalkyl, or aryl-C1‑4alkylene is optionally substituted with from one to three Rb, wherein Rb is as defined above. In some embodiments, R3, R4, R5, and R6 are each methyl, ethyl, cyclopropyl, or benzyl, wherein eachmethyl, ethyl, cyclopropyl, or benzyl is optionally substitutedwith fromone to threeRb, whereinRb is as defined above. In some embodiments, R3, R4, R5, and R6 are each methyl or cyclopropyl. In some embodiments, R3, R4, R5, and R6 are eachmethyl. In some embodiments, R3, R4, R5, and R6 are each ethyl. In some embodiments, R3, R4, R5, and R6 are each cyclopropyl. In some embodiments, R3, R4, R5, and R6 are each benzyl.

[0108] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R7 is hydrogen. In some embodiments, R7 is R8.

[0109] In some embodiments of the compound of formula I, II, or III, R8 is ‑L1‑L2‑L3‑R8a. In some embodiments, R8 is ‑L1‑(L3)n‑R8a. In someembodiments, R8 is ‑L1‑(L2)m‑R8a. In someembodiments, R8 is ‑L 1‑L3‑R8a. In someembodiments, R8 is ‑L1‑L2‑R8a. In some embodiments, R8 is ‑L1‑R8a. In some embodiments, R8 is R8a. In some embodiments, R8 is chosen from 20 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 In some embodiments, R8 is chosen from 21 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 22 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 and In some embodiments, R8 is chosen from

[0110] In someembodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, L1 is a bond. In some embodiments, L1 is ‑C(O)‑. In some embodiments, L1 is ‑C(O)O‑.

[0111] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, L2 is chosen from ‑CH2‑, ‑CH2‑CH2‑, ‑CH2‑CH2‑CH2‑, ‑CH2‑CH2‑CH2‑CH2‑, ‑CH2‑C(CH3)2‑, ‑CH2‑CH2‑CH2‑CH2‑CH2‑, 23 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 ‑CH2‑C(CH3)2‑CH2‑, ‑CH2‑CH2‑C(CH3)2‑, ‑CH2‑C(CH3)2‑CH2‑CH2‑, and ‑CH2‑CH2‑CH2‑C(CH3)2‑. In some embodi- ments, L2 is chosen from ‑CH2‑, ‑CH2‑CH2‑, ‑CH2‑CH2‑CH2‑, ‑CH2‑C(CH3)2‑, ‑CH2‑C(CH3)2‑CH2‑, ‑CH2‑CH2‑C(CH3)2‑, and ‑CH2‑C(CH3)2‑CH2‑CH2‑. In some embodiments, L2 is-CH2‑. In some embodiments, L2 is ‑CH2‑CH2‑. In some embodiments, L2 is ‑CH2‑CH2‑CH2‑. In some embodiments, L2 is ‑CH2‑C(CH3)2‑. In some embodiments, L2 is ‑CH2‑C(CH3)2‑CH2‑. In some embodiments, L2 is ‑CH2‑CH2‑C(CH3)2‑. In some embodiments, L2 is ‑CH2‑C(CH3)2‑CH2‑CH2‑.

[0112] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, L3 is ‑C(O)O‑. In some embodiments, L3 is

[0113] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R8a is chosen from C1‑12alkyl, aryl, ‑C(O)‑C1‑4alkyl, ‑S-C(O)‑C1‑4alkyl, wherein aryl is optionally substituted with one or two Rc. In some embodiments, R8a is chosen from C1‑8alkyl, aryl, ‑C(O)‑C1‑4alkyl, ‑S-C(O)‑C1‑4alkyl, wherein aryl is optionally substituted with one or two Rc

[0114] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, each Ra is independently chosen from C1‑4alkyl, halo, and C1‑4haloalkyl. In some embodiments, each Ra is independently C1‑4alkyl. In some embodiments, eachRa is independently halo. In some embodiments, eachRa is independentlyC1‑4ha- loalkyl. In some embodiments, each Ra is independently ‑O-C1‑4alkyl. In some embodiments, each Ra is independently chosen from methyl, ethyl, n-propyl, isopropyl, fluoro, methoxy, and trifluoromethyl.

[0115] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, each Rb is independently methyl or ethyl.

[0116] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, each Rc is independently C1‑4alkyl. In some embodiments, each Rc is independently ‑OC(O)‑C1‑4alkyl. In some embodiments, each Rc is independently methyl or-OC(O)‑methyl.

[0117] In someembodiments of the compoundof formula I, II, or III, or a pharmaceutically acceptable salt thereof,mand nareboth0. In someembodiments,m is 0andn is 1. In someembodiments,m is1andn is0. In someembodiments,mand n are both 1.

[0118] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, p is 0 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0119] In someembodimentsof thecompoundof formula I, II, or III, or apharmaceutically acceptable salt thereof,R1and R2 are the same andR3, R4, R5, andR6 are the same. In some embodiments, R1 andR2 are the same andR3, R4, R5, and R6 are each methyl or cyclopropyl. In some embodiments, R1 and R2 are the same and R3, R4, R5, and R6 are each cyclopropyl. In some embodiments, R1 and R2 are the same and R3, R4, R5, and R6 are each methyl.

[0120] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R7 is hydrogen and R1 and R2 are the same.

[0121] In some embodiments, R7 is hydrogen and R3, R4, R5, and R6 are the same. In some embodiments, R7 is hydrogen and R3, R4, R5, and R6 are each methyl or cyclopropyl. In some embodiments, R7 is hydrogen and R3, R4, R5, 24 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 and R6 are each cyclopropyl. In some embodiments, R7 is hydrogen and R3, R4, R5, and R6 are each methyl.

[0122] In some embodiments of the compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R7 is hydrogen,R1andR2are the same, andR3,R4,R5, andR6are the same. In someembodiments,R7 is hydrogen,R1 andR2 are the same, andR3,R4,R5, andR6are eachmethyl or cyclopropyl. In someembodiments,R7 is hydrogen,R1 andR2are the same, and R3, R4, R5, and R6 are each cyclopropyl. In some embodiments, R7 is hydrogen, R1 and R2 are the same, and R3, R4, R5, and R6 are each methyl.

[0123] In some embodiments, the compound of formula I or II is a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined in formula I.

[0124] In some embodiments of the compound of formula IV, R1 andR2 are different. In some embodiments, R1 and R2 are the same.

[0125] In some embodiments, the compound of formula I or III is a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R7, and R8 are as defined above.

[0126] In some embodiments of the compound of formulaV, R1 and R2 are different. In some embodiments, R1 and R2 are the same. In some embodiments R7 is H. In some embodiments, R7 is R8.

[0127] In some embodiments, the compounds have the formula: 25 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 26 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 27 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 28 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 29 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 30 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compounds have the formula: 31 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 or

[0129] When any variable is a non-symmetrical, divalent group, both orientations of the group are intended to be covered, unless specified otherwise. For example, when L3 is ‑C(O)O‑, both orientations of ‑C(O)O‑ are included (i.e., when R8 is ‑L1‑L3‑R8a, both ‑L1‑C(O)O-R8a and ‑L1‑OC(O)‑R8a are included), or when L2 is ‑CH2‑CH2‑C(CH3)2‑, both orientations of-CH2‑CH2‑C(CH3)2‑ are included (i.e., when R8 is ‑L1‑L2‑R8a, both R8 is ‑L1‑CH2‑CH2‑C(CH3)2‑R8a and ‑L1‑C(CH3)2‑CH2‑CH2‑R8a are included).

[0130] It is understood that any embodiment of the compounds of any one of formulas I, II, III, IV, and V, as set forth above, and any specific group or substituent set forth herein (e.g., R1, R2, R3, R4, R5, R6, R7, R8, and substituents thereof) in the compounds of formulas I, II, III, IV, and V as set forth above, may be independently combined with other embodiments and / or substituents of compounds of any one of formulas I, II, III, IV, and V, to form embodiments not specifically set forth above. In addition, in the event that a list of substituents are not listed for any particular R1, R2, R3, R4, R5, R6, R7, and R8 group in a particular embodiment and / or claim, it is understood that each individual substituent may be deleted from the particular embodiment and / or claim and that the remaining list of substituents will be considered to be within the scope of the embodiments disclosed herein.

[0131] Thecompoundsof formulas I, II, III, IV, andV, or pharmaceutically acceptable salts thereof, areprodrugs,with the promoiety being cleaved rapidly in intracellular environments to yield tenofovir (TFV). In some embodiments, the compounds of formulas I, II, III, IV, and V, or the pharmaceutically acceptable salts thereof, are suitable for use in long-acting formulations. For certain patients, for example, those with difficult or limited access to health care, adherence to daily oral treatment or prophylactic regimens to treat or prevent viral infections (e.g., HIV infection) can be challenging. Drugs that offer favorable pharmaceutical or physicochemical properties for slow release (for example, improved potency, long acting pharmacokinetics, reduced solubility, enhanced plasma stability, and / or other properties) can be amenable to less frequent administration and can provide for better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the emergence of drug resistance.

[0132] Without intending to be bound by theory, it is believed that the low solubility of the compounds of formulas I, II, III, IV, andV, or pharmaceutically acceptable salts thereof, can result in slow release of the compounds after intramuscular or subcutaneous administration and sustained intracellular levels of the pharmacologically active agent, tenofovir dipho- sphate (TFV-DP), making them capable of maintaining the therapeutically effective concentration of TFV-DP in relevant cell types for an extended period of time and useful as durable or long acting agents to treat or prevent viral infection. The development of poorly soluble prodrugs for safe andeffective long acting injectable formulations is discussed inRemenar, Mol. Pharmaceutics 2014, 11, 1739‑1749. Pharmaceutical Compositions

[0133] In someembodiments, thepresentdisclosureprovidesapharmaceutical compositioncomprisingacompoundof the present disclosure, and a pharmaceutically acceptable excipient.

[0134] In someembodiments, the pharmaceutical composition comprises one, two, three, or four additional therapeutic agents, as more fully set forth below.

[0135] In some embodiments, a composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound of the present disclosure in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure. It is alsounderstood that anyof themethods, kits, articles ofmanufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the presentdisclosureoranyotheractive ingredient administeredseparately, sequentially or simultaneouslywithacompound of the present disclosure.

[0136] In some embodiments, the pharmaceutical compositions described above are for use in a human or an animal.

[0137] The disclosure further includes a compound of the present disclosure for administration as a single active 32 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 ingredient of a pharmaceutically acceptable composition that can be prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing therewith.

[0138] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient havingasynergistic effectwithother active ingredients in knowndrugs, or administrationof thecompoundof the present disclosure together with such drugs. Methods of Treatment HIV Infection

[0139] The present disclosure provides methods of treating and / or preventing human immunodeficiency virus (HIV) infection in a subject. In some embodiments, a method of treating and / or preventing HIV infection in a subject comprises administering to the subject a composition provided herein. In some embodiments, the method is for treating and / or preventing HIV‑1 infection. In some embodiments, the method is for treating and / or preventing HIV‑2 infection.

[0140] In some embodiments, amethod of treatingHIV infection in a subject in need thereof comprises administering to the subject a composition provided herein. In some such embodiments, the subject is HIV positive. In some such embodiments, the subject is of unknown HIV status. In some such embodiments, the subject is not HIV negative.

[0141] In some embodiments, amethod of preventing HIV infection in a subject at risk thereof comprises administering to the subject a composition provided herein. In some such embodiments, the subject is HIV negative. In some embodiments, the subject is at risk of acquiring HIV infection.

[0142] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, Tcell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0143] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, Tcell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0144] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof. HBV Infection

[0145] The present disclosure provides methods of treating and / or preventing hepatitis B virus (HBV) infection in a subject. In someembodiments, amethodof treating and / or preventingHBV infection in a subject comprises administering to the subject a composition provided herein.

[0146] In someembodiments, amethodof treatingHBV infection in a subject in need thereof comprisesadministering to the subject a composition provided herein.

[0147] In some embodiments, amethod of preventingHBV infection in a subject at risk thereof comprises administering to the subject a composition provided herein. In some such embodiments, the subject is at risk of acquiring HBV infection.

[0148] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV polymerase inhibitors, HBV capsid modulators, agonists of TLR7, TLR8, and TLR9, cytokines, immune checkpoint inhibitors, FLT3 ligands, interferon alpha receptor ligands, interferon alpha, interferon lambda, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, HBV X protein (HBx) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides, short interfering RNAs (siRNA) and DNA directed RNA interference (ddRNAi), endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen (HBeAg) inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, T cell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HBV antigensor peptides,CAR-Tcell therapy, thymosinagonists, retinoicacid-inducible gene1stimulators,NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine‑2, 3-dioxygenase (IDO1) pathway inhibitors, anti-OX40, anti- 33 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 CD40, anti-CD160, HBV gene editors, PAPD5 / PAPD7 inhibitors, ZCCHC14 inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, epigenetic regulators, inducers of tertiary lymphoid aggregates, antagonists of IAP / XIAP, nucleic acid polymers (e.g., NAPs and STOPS), modulators of lipid metabolism or trafficking, arginase inhibitors, and other drugs for treating HBV, and combinations thereof.

[0149] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir, and combinations thereof.

[0150] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir. HIV Combination Therapy

[0151] In certain embodiments, a method for treating an HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method for treating an HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0152] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceu- tically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.

[0153] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents which are suitable for treating an HIV infection.

[0154] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents. Administration of HIV Combination Therapy

[0155] In certain embodiments, a compound disclosed herein is administered with one, two, three, or four additional therapeutic agents. Co-administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one, two, three, or four additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one, two, three, or four additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.

[0156] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one, two, three, or four additional therapeutic agents. For example, the compound disclosedhereinmaybeadministeredwithin seconds,minutes, or hours of theadministration of theone, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followedwithin secondsorminutesbyadministrationof aunit doseof one, two, three, or four additional therapeutic agents. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by administrationof aunit doseof a compounddisclosedhereinwithin secondsorminutes. Inother embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1‑12 hours), by administration of a unit dose of one, two, three, or four additional therapeutic agents. In yet other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1‑12 hours), by administration of a unit dose of a compound disclosed herein.

[0157] In certain embodiments, a kit comprising a compounddisclosedherein (e.g.,a compoundof formula I, II, III, IV, or V), or a pharmaceutically acceptable salt thereof, in combinationwith one ormore (e.g., one, two, three, or four) additional therapeutic agents is provided.

[0158] In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor or an HIV capsid 34 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 polymerization inhibitor. HIV Combination Therapy

[0159] In the above embodiments, the additional therapeutic agent or agents may be an anti-HIV agent. In some instances, the additional therapeutic agent can be HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, 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, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T-cell receptors, TCR-T, autologousT-cell therapies, engineeredBcells), latency reversingagents, 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 inhibitor, Fatty acid synthase inhibitor, HIV vif genemodulators, Vif dimerization antagonists, HIV‑1 viral infectivity factor inhibitors, HIV‑1Nefmodulators, TNFalpha ligand inhibitors, HIV Nef inhibitors, 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, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK‑4 inhibitors,CDK‑6 inhibitors,CDK‑9 inhibitors,CXCR4modulators, dendritic ICAM‑3grabbingnonintegrin 1 inhibitors,HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP depen- dent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-Glycoprotein modulators, TAT protein inhibitors, Prolylendopeptidase inhibitors, Phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vac- cines, and combinations thereof.

[0160] In some embodiments, the additional therapeutic agent or agents are selected from combination drugs for HIV, otherdrugs for treatingHIV,HIVprotease inhibitors,HIVreverse transcriptase inhibitors,HIV integrase inhibitors,HIVnon- catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0161] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIVentry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0162] In some embodiments, the additional therapeutic agent or agents are chosen from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, Tcell and NK cell recruiting bispecific antibodies, chimeric Tcell receptors targetingHIVantigens, pharmacokinetic enhancers, and other drugs for treatingHIV, and combinations thereof.

[0163] In some embodiments, the additional therapeutic agent or agents are chosen from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0164] In some embodiments, the additional therapeutic agent or agents are chosen from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir. HIV Combination Drugs

[0165] Examples of combination drugs include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegra- vir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamidehemifumarateandemtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analog; COMBI- 35 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 VIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY (bicte- gravir + emtricitabine + tenofovir alafenamide), DOVATO, TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir +abacavir + lamivudine, lopinavir + ritonavir + zidovudine+ lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, and lamivudine; cabotegravir + rilpivirine; 3-BNC 117 + albuvirtide, elpida (elsulfavirine; VM‑1500; VM‑1500A. Other HIV Drugs

[0166] Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB‑728-T, 1,5- dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABX‑464, AG‑1105, APH‑0812, bryostatin analogs, BIT‑225, CYT‑107, CS-TATI‑1, fluoro-beta-D-arabinose nucleic acid (FANA)‑modified antisense oligonucleotides, FX‑101, griffithsin, HGTV‑43, HPH‑116, HS‑10234, hydroxy- chloroquine, IMB‑10035, IMO‑3100, IND‑02, JL‑18008, LADAVRU, MK‑1376, MK‑2048, MK‑4250, MK‑8507, MK‑8558, MK‑8591 (islatravir), NOV‑205, OB‑002H, ODE-Bn-TFV, PA‑1050040 (PA‑040), PC‑707, PGN‑007, QF‑036, S‑648414, SCY‑635, SB‑9200, SCB‑719, TR‑452, TEV‑90110, TEV‑90112, TEV‑90111, TEV‑90113, RN‑18, DIACC‑1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF‑4467, thrombospondin analogs, TBL‑1004HI, VG‑1177, xl‑081, AVI-CO‑004, rfhSP-D, [18F]‑MC‑225, URMC‑099-C, RES‑529, Verdinexor, IMC-M113V, IML‑106, antiviral fc conjugate (AVC), and VIR‑576. HIV Protease Inhibitors

[0167] ExamplesofHIVprotease inhibitors include, but arenot limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC‑09 + ritonavir, AEBL‑2, DG‑17, GS‑1156, TMB‑657 (PPL‑100), T‑169, BL‑008, MK‑8122, TMB‑607, GRL‑02031, and TMC‑310911. HIV Ribonuclease H Inhibitors

[0168] Examples of HIV ribonuclease H inhibitors include NSC‑727447. HIV Nef Inhibitors

[0169] Examples of HIV Nef inhibitors include FP‑1. HIV Reverse Transcriptase Inhibitors

[0170] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC‑007, ACC‑008, AIC‑292, F‑18, KM‑023, PC‑1005, M1-TFV, M2-TFV, VM‑1500A-LAI, PF‑3450074, elsulfavirine (sustained release oral, HIV infection), doravirine + islatravir (fixed dose combination / oral tablet formulation, HIV‑1 infection), elsulfavirine (long acting injectable nanosuspension, HIV infection), and elsulfavirine (VM‑1500).

[0171] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX‑1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX‑157, dapivirine, doravirine, etravirine, OCR‑5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS‑9131), GS‑9148, MK‑8504, islatravir, MK‑8583, VM‑2500, and KP‑1461. 36 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 HIV Integrase Inhibitors

[0172] Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivativesof 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivativesof aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK‑351, bictegravir, AVX‑15567, cabotegravir (long acting injectable), diketo quinolin‑4‑1 derivatives, integrase-LEDGF inhibitor, ledgins, M‑522, M‑532, MK‑0536, NSC‑310217, NSC‑371056, NSC‑48240, NSC‑642710, NSC‑699171, NSC‑699172, NSC‑699173, NSC‑699174, stilbenedisulfonic acid, T‑169, STP‑0404, VM‑3500 and cabotegravir.

[0173] Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include, but are not limited to, CX‑05045, CX‑05168, and CX‑14442. HIV Viral Infectivity Factor Inhibitors

[0174] Examples of HIV viral infectivity factor inhibitors include 2-amino-N‑(2-methoxyphenyl)‑6‑((4-nitrophenyl)thio) benzamide derivatives. HIV Entry Inhibitors

[0175] Examples of HIVentry (fusion) inhibitors include, but are not limited to, AAR‑501, LBT‑5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0176] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO‑140), adaptavir (RAP‑101), nifeviroc (TD‑0232), anti- GP120 / CD4 or CCR5 bispecific antibodies, B‑07, MB‑66, polypeptide C25P, TD‑0680, thioraviroc and vMIP (Haimipu).

[0177] Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, griffithsin (gp41 / gp120 / gp160 inhibitor), BMS‑986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV‑1 fusion inhibitors (P26-Bapc), ITV‑1, ITV‑2, ITV‑3, ITV‑4, CPT‑31, Cl3hmAb, lipuvirtide, PIE‑12 trimer and sifuvirtide.

[0178] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs

[0179] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicide, Radha‑108 (receptol) 3B3- PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP‑0831, VVX‑004, and BMS‑663068.

[0180] Examples of gp160 inhibitors include fangchinoline.

[0181] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT‑1188, N15 peptide, and vMIP (Haimipu). HIV Maturation Inhibitors

[0182] Examples of HIV maturation inhibitors include, but are not limited to, BMS‑955176, GSK‑3640254 and GSK‑2838232. Latency Reversing Agents

[0183] Examples of latency reversing agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS‑9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL‑0580, apabetalone), ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG‑1387, LBW‑242), SMAC mimetics (including TL32711, LCL161, GDC‑0917, HGS1029, AT‑406, Debio‑1143), PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), NIZ‑985, IL‑15 modulating antibodies (including IL‑15, IL‑15 fusion proteins, and IL‑15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH‑0812, and GSK‑343. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones. Histone Deacetylase (HDAC) Inhibitors

[0184] In some embodiments, the agents as described herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP,MITR;Gene ID: 9734). Examples of HDAC inhibitors includewithout limitation, abexinostat, ACY‑241, 37 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 AR‑42, BEBT‑908, belinostat, CKD‑581, CS‑055 (HBI‑8000), CT‑101, CUDC‑907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ‑26481585), resminostat, ricolinostat, romidepsin, SHP‑141, TMB-ADC, valproic acid (VAL‑001), vorinostat, tinostamustine, remetinostat, and entinostat. Capsid Inhibitors

[0185] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacapavir (GS‑6207), GS-CA1, AVI‑621, AVI‑101, AVI‑201, AVI‑301, and AVI-CAN1‑15 series, PF‑3450074, HIV‑1 capsid inhibitors (HIV‑1 infection, Shandong University), and compounds described in (GSK WO2019 / 087016). Immune Checkpoint Modulators

[0186] In various embodiments, the agents as described herein, are combinedwith one ormore blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In variousembodiments, the immunecheckpoint proteinsor receptors regulateTcell responses (e.g., reviewed inXu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the 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).

[0187] Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing Tcell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamilymember 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HIHLA2, B7H7); inducible Tcell costimulator (ICOS, CD278); inducible Tcell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD‑1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7‑1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM‑1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen9 (LY9,CD229,SLAMF3);SLAM familymember 6 (SLAMF6,CD352); SLAM familymember 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor, three Ig domainsand longcytoplasmic tail 1 (KIR,CD158E1); killer cell lectin like receptorC1 (KLRC1,NKG2A,CD159A); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domainsand longcytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0188] In various embodiments, the agents described herein, are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation 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 Tcell activation inhibitor 1 (VTCN1, B7H4); V-set immunor- egulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamilymember 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); Tcell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, 38 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In variousembodiments, theagents, asdescribedherein, are combinedwith oneormoreagonist or activators of oneormore T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors includewithout limitationCD27,CD70;CD40,CD40LG; inducibleTcell costimulator (ICOS,CD278); inducibleT cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7‑1), CD28; nectin cell adhesionmolecule 2 (NECTIN2, CD112); CD226 (DNAM‑1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0189] In various embodiments, the agents as described herein, are combinedwith one ormore blockers or inhibitors of one ormore NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94). In various embodiments, the agents as described herein, are combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM‑1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64‑75; Fang, et al., Semin Immunol. (2017) 31:37‑54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671‑688.

[0190] In some embodiments, the one ormore immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibodymimetic) inhibitor ofPD-L1 (CD274),PD‑1 (PDCD1)orCTLA4. Insomeembodiments, the oneormore immunecheckpoint inhibitors comprisesa small organicmolecule inhibitor ofPD-L1 (CD274), PD‑1 (PDCD1) orCTLA4. In someembodiments, the smallmolecule inhibitor ofCD274orPDCD1 is selected from thegroup consisting of GS‑4224, GS‑4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI‑002.

[0191] Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimu- mab, BMS‑986218, AGEN1181, AGEN1884, BMS‑986249, MK‑1308, REGN‑4659, ADU‑1604, CS‑1002, BCD‑145, APL‑509, JS‑007,BA‑3071,ONC‑392,AGEN‑2041, JHL‑1155,KN‑044,CG‑0161, ATOR‑1144,PBI‑5D3H5,BPI‑002, as well asmulti-specific 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).

[0192] Examplesof inhibitors ofPD-L1 (CD274) orPD‑1 (PDCD1) that canbeco-administered includewithout limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP‑224, MEDI0680 (AMP‑514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS‑936559, CK‑301, PF‑06801591, BGB-A317 (tislelizumab), GLS‑010 (WBP‑3055), AK‑103 (HX‑008), AK‑105, CS‑1003, HLX‑10, MGA‑012, BI‑754091, AGEN‑2034, JS‑001 (toripalimab), JNJ‑63723283, geno- limzumab (CBT‑501), LZM‑009, BCD‑100, LY‑3300054, SHR‑1201, SHR‑1210 (camrelizumab), Sym‑021, ABBV‑181(budigalimab), PD1-PIK, BAT‑1306, (MSB0010718C), CX‑072, CBT‑502, TSR‑042 (dostarlimab), 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, as well as multi-specific inhibitors FPT‑155 (CTLA4 / PD-L1 / CD28), PF‑06936308 (PD‑1 / CTLA4), MGD‑013 (PD‑1 / LAG‑3), FS‑118 (LAG‑3 / PD-L1) MGD‑019 (PD‑1 / CTLA4), KN‑046 (PD‑1 / CTLA4), MEDI‑5752 (CTLA4 / PD‑1), RO‑7121661 (PD‑1 / TIM‑3), XmAb‑20717 (PD‑1 / CTLA4), AK‑104 (CTLA4 / PD‑1), M7824 (PD-L1 / TGFβ-EC domain), CA‑170 (PD-L1 / VISTA), CDX‑527 (CD27 / PD-L1), LY‑3415244 (TIM3 / PDL1), and INBRX‑105 (4‑1BB / PDL1).

[0193] In various embodiments, the agents as described herein are combined with anti-TIGIT antibodies, such as BMS‑986207, RG‑6058, AGEN‑1307 TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

[0194] In various embodiments, the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of 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, NCBIGene ID: 355), TNFRSF7 (CD27, NCBIGene ID: 939), TNFRSF8 (CD30, NCBIGene ID: 943), TNFRSF9 (4‑1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), 39 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264,TRAILR4,NCBIGene ID: 8793), TNFRSF11A (CD265,RANK,NCBIGene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), 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).

[0195] Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF‑04518600, RG‑7888, GSK‑3174998, INCAGN1949, BMS‑986178, GBR‑8383, ABBV‑368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0196] Exampleanti-TNFRSF5 (CD40)antibodies that canbeco-administered includewithout limitationRG7876,SEA- CD40, APX‑005M and ABBV‑428.

[0197] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX‑1127) is co-administered.

[0198] Example anti-TNFRSF9 (4‑1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF‑05082566), AGEN2373 and ADG‑106.

[0199] Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, 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, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, e.g., in WO2017096179 and WO2018089628. Bi-and Tri-Specific Natural Killer (NK)‑Cell Engagers

[0200] In various embodiments, the agents as described herein, are combinedwith a bi-specificNK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H and NKG2F), natural cytotoxicity receptors (NKp30,NKp44andNKp46), killer cellC-type lectin-like receptor (NKp65,NKp80), Fc receptorFcγR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR‑2DS and KIR‑3DS), DNAM‑1 and CD137 (41BB). As appropriate, the anti- CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co- administered targetCD16andoneormoreHIV-associatedantigensasdescribedherein.BiKEsandTriKEsaredescribed, e.g., in Felices, et al.,MethodsMolBiol. (2016) 1441:333‑346; Fang, et al., Semin Immunol. (2017) 31:37‑54.Examples of a trispecific NK cell engager (TRiKE) include OXS‑3550, HIV-TriKE, and CD16-IL‑15-B7H3 TriKe. Indoleamine-pyrrole‑2,3-dioxygenase (IDOI) inhibitors

[0201] In various embodiments, the agents as described herein, are combined with an inhibitor of indoleamine 2,3- dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV‑0801, epacadostat, F‑001287, GBV‑1012, GBV‑1028, GDC‑0919, indoximod, NKTR‑218, NLG‑919-based vaccine, PF‑06840003, pyranonaphthoquinone derivatives (SN‑35837), resminostat, SBLK‑200802, BMS‑986205, and shIDO- ST, EOS‑200271, KHK‑2455, LY‑3381916. Toll-Like Receptor (TLR) Agonists

[0202] In various embodiments, the agents as described herein, are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation AL‑034, DSP‑0509, GS‑9620 (vesatolimod), vesatolimod analog, LHC‑165, TMX‑101 (imiquimod), GSK‑2245035, resiquimod, DSR‑6434, DSP‑3025, IMO‑4200, MCT‑465, MEDI‑9197, 3M‑051,SB‑9922, 3M‑052, Limtop, TMX‑30X, TMX‑202,RG‑7863,RG‑7854,RG‑7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen),WO2014 / 023813 (Janssen), US20080234251 (ArrayBiophar- ma), 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). TLR7 / TLR8 agonists include NKTR‑262, telratolimod and BDB‑001. TLR8 40 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 agonists include without limitation E‑6887, IMO‑4200, IMO‑8400, IMO‑9200, MCT‑465, MEDI‑9197, motolimod, resi- quimod, GS‑9688, VTX‑1463, VTX‑763, 3M‑051, 3M‑052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), 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 Therapeu- tics). TLR9 agonists include without limitation 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 agonist include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH‑33,MCT‑465,MCT‑475, andND‑1.1. TLR4 agonists include G‑100 and GSK‑1795091. CDK inhibitors or antagonists

[0203] In someembodiments, the agents described herein are combinedwith an inhibitor or antagonist ofCDK. In some embodiments, the CDK inhibitor or antagonist is selected from the group consisting of VS2‑370. STING agonists, RIG-I and NOD2 modulators

[0204] In some embodiments, the agents described herein are combinedwith a stimulator of interferon genes (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-dimethylxanthenone‑4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP. In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT‑100, or NOD2modulator, such as SB‑9200, and IR‑103. LAG‑3 and TIM‑3 inhibitors

[0205] In certain embodiments, the agents as described herein are combined with an anti-TIM‑3 antibody, such as TSR‑022, LY‑3321367, MBG‑453, INCAGN‑2390.

[0206] In certain embodiments, the antibodies or antigen-binding fragments described herein are combinedwith an anti LAG‑3 (Lymphocyte-activation) antibody, such as relatlimab (ONO‑4482), LAG‑525, MK‑4280, REGN‑3767, IN- CAGN2385. Interleukin agonists

[0207] In certainembodiments, theagents describedherein are combinedwith an interleukin agonist, suchas IL‑2, IL‑7, IL‑15, IL‑10, IL‑12 agonists; examples of IL‑2 agonists such as proleukin (aldesleukin, IL‑2); BC-IL (Cel-Sci), pegylated IL‑2 (eg NKTR‑214); modified variants of IL‑2 (eg THOR‑707), bempegaldesleukin, AIC‑284, ALKS‑4230, CUI‑101, Neo‑2 / 15 ; examples of IL‑15 agonists, such as 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 a IL‑15 ‑PD‑1 fusion protein N‑809; examples of IL‑7 include CYT‑107.

[0208] Examples of additional immune-based therapies that can be combined with an agent of this disclosure include interferon alfa; interferon alfa‑2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; FLT3 agonists such as CDX‑301 and GS‑3583; gepon; normferon, peginterferon alfa‑2a, peginterferon alfa‑2b, RPI-MN Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0209] Examples of PI3K inhibitors include, but are not limited to, idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG‑319, AZD‑8186, BAY‑1082439, CLR‑1401, CLR‑457, CUDC‑907, DS‑7423, EN‑3342, GSK‑2126458, GSK‑2269577, GSK‑2636771, INCB‑040093, LY‑3023414, MLN‑1117, PQR‑309, RG‑7666, RP‑6530, RV‑1729, SAR‑245409, SAR‑260301, SF‑1126, TGR‑1202, UCB‑5857, VS‑5584, XL‑765, and ZSTK‑474. alpha‑4 / beta‑7 Antagonists

[0210] Examples of Integrin alpha‑4 / beta‑7 antagonists include, but are not limited to, PTG‑100, TRK‑170, abrilumab, 41 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 etrolizumab, carotegrast methyl, and vedolizumab. HIV Targeting Antibodies

[0211] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV‑1 antibodies), TMB‑360, and those targeting HIV gp120 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibody, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibody, camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM‑1 antibodies, DCVax‑001, gp140 targeted antibodies, gp41-based HIV therapeutic antibo- dies, human recombinant mAbs (PGT‑121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB‑66, clone 3 humanmonoclonal antibody targeting KLIC (HIV infection), GS‑9721, BG-HIV, VRC-HIVMAB091‑00-AB.

[0212] Various bNAbs may be used. Examples include, but are not limited to, those described in U.S. Patent No. 8673307, 9,493,549, 9,783,594, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, and 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.Additional examples include those described in Klein et al., Nature, 492(7427): 118‑22 (2012), Horwitz et al., ProcNatl AcadSciUSA,110(41): 16538‑43 (2013),Scheid, et al., Science, 333 : 1633‑1637 (2011),Scheid, et al.,Nature, 458:636‑640 (2009), Eroshkin et al, Nucleic Acids Res., 42 (Database issue):Dl 133‑9 (2014), Mascola et al., Immunol Rev., 254(l):225‑44 (2013), such as 2F5, 4E10,M66.6, CAP206-CH12, 10E81 (all of which bind theMPERof gp41); PG9, PG16, CH01‑04 (all of which bind V1V2-glycan), 2G12 (which binds to outer domain glycan); b12, HJ16, CH103‑106, VRC01‑03,VRC-PG04,04b,VRC-CH30‑34, 3BNC62,3BNC89, 3BNC91,3BNC95,3BNC104, 3BNC176, and8ANC131 (all of which bind to the CD4 binding site).

[0213] Additional broadly neutralizing antibodies which can be used as a second therapeutic agent in a combination therapy are described, e.g., in 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 2017 / 133639; WO 2017 / 133640, which are hereby incorporated herein by reference in their entireties for all purposes. Additional examples include those described in 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 U S A, 110(41): 16538‑43 (2013), Scheid, et al., Science, 333 : 1633‑1637 (2011), Scheid, et al., Nature, 458:636‑640 (2009), Eroshkin et al, Nucleic Acids Res., 42 (Database issue):Dl 133‑9 (2014), Mascola et al., Immunol Rev., 254(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 bind the MPER of gp41).

[0214] Examples of additional antibodies include, but arenot limited to, bavituximab,UB‑421,BF520.1,BiIA-SG,CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10‑1074-LS, Cl3hmAb, GS‑9722 (elipovimab), DH411‑2, 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‑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-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.

[0215] Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR‑441236, VRC‑01 / PGDM‑1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01.

[0216] Examples of in vivo delivered bNAbs include AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01; and engineered B-cells encoding 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301). Pharmacokinetic Enhancers

[0217] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir. 42 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Additional Therapeutic Agents

[0218] Examples of additional therapeutic agents include, but are not limited to, the compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boeh- ringer Ingelheim). HIV Vaccines

[0219] ExamplesofHIVvaccines include, butarenot limited to, peptidevaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccine, CD4-derived peptide vaccines, vaccine combinations, adenoviral vector vaccines (an adenoviral vector such as Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus i.e. rhAd), adeno-associated virus vector vaccines, Chimpanzee adenoviral vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackieviruses based vaccines, enteric virus based vaccines, Gorilla adenovirus vaccines, lentiviral vector based vaccine, arenavirus vaccines (such as LCMV, Pichinde), bi-segmented or tri-segmented arenavirus based vaccine, trimer-based HIV‑1 vaccine, measles virus based vaccine, flavivirus vector based vaccines, tobacco mosaic virus vector based vaccine, Varicella-zoster virus based vaccine, Human parainfluenza virus 3 (PIV3) based vaccines, poxvirus based vaccine (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus based vaccine, rhabdovirus-based vaccines, such as VSVandmarabavirus; recombinant humanCMV (rhCMV) based vaccine, alphavirus-based vaccines, such as semliki forest virus, venezuelan equine encephalitis virus and sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298‑16); LNP formulated mRNA based therapeutic vaccines; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0220] Examples of vaccines include: AAVLP-HIV vaccine, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triplexvaccine,ChAdOx1.HTI,ChimigenHIVvaccine,ConMSOSIP.v7gp140, rgp120 (AIDSVAX),ALVACHIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV‑1 subtype C vaccine, MPER‑656 liposome subunit vaccine, Remune, ITV‑1, Contre Vir, Ad5-ENVA‑48, DCVax‑001 (CDX‑2401), Vacc‑4x, Vacc-C5, VAC‑3S, multiclade DNA recombinant adenovirus‑5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA- CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA‑51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT‑06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF‑59, rVSVIN HIV‑1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT‑20, DNK‑4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX‑2, N123-VRC‑34.01 inducing epitope-basedHIV vaccine, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV‑1, Ad‑4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB- HV‑11, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / - nef / nev (HVTN505), MVATG‑17401, ETV‑01, CDX‑1401, DNA and Sev vectors vaccine expressing SCaVII, 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, VIR‑1111, IHV‑001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / ne- f / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines (such as DermaVir), gag-based DNA vaccine, GI‑2010, gp41 HIV‑1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccines, ITV‑2, ITV‑3, ITV‑4, LIPO‑5,multicladeEnv vaccine,MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160HIV vaccine, RNActiveHIV vaccine, SCB‑703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc‑4x+ romidepsin, variant gp120polypeptide vaccine, rAd5gag-pol envA / B / Cvaccine,DNA.HTI andMVA.HTI, VRC- HIVDNA016‑00-VP + VRC-HIVADV014‑00-VP, INO‑6145, JNJ‑9220, gp145 C.6980; eOD-GT8 60mer based vaccine, PD‑201401,env (A,B,C,A / E) / gag (C)DNAVaccine, gp120 (A,B,C,A / E)protein vaccine,PDPHV‑201401,Ad4-EnvCN54, EnvSeq‑1 Envs HIV‑1 vaccine (GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine, HIV‑1 iglb12 neutralizingVRC‑01antibody-stimulating anti-CD4vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT),MVA- BN HIV‑1 vaccine regimen, UBI HIV gp120, mRNA based prophylactic vaccines, VPI‑211, and TBL‑1203HI. Birth Control (Contraceptive) Combination Therapy

[0221] In certain embodiments, the agents described herein are combinedwith a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraceptive) that can be combined with an agent of this disclosure include 43 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nome- gestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, uli- pristal acetate, and any combinations thereof.

[0222] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (teno- fovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEF- SEY® (tenofovir alafenamide, emtricitabine, and rilpivirine);GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide and elvitegravir; tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection); tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemi- fumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; PEGylated raltegravir; raltegravir and lamivudine; maraviroc; tenofovir + emtricitabine +maraviroc, enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didano- sine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha‑108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0223] In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combinedwith an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcrip- tase. In another specific embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmaco- kinetic enhancer. In another embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0224] In another embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combinedwith a first additional therapeutic agent chosen from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir and a second additional therapeutic agent chosen from emtricitabine and lamivudine.

[0225] In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent (a contraceptive) selected from thegroup consisting of cyproteroneacetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersoneacetate, ulipristal acetate, and any combinations thereof. Gene Therapy and Cell Therapy

[0226] In certain embodiments, the agents described herein are combined with a gene or cell therapy regimen. Gene therapyandcell therapy includewithout limitation thegeneticmodification tosilenceagene;genetic approaches todirectly kill the infectedcells; the infusionof immunecells designed to replacemostof thepatient’sown immunesystem toenhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Examples of cell therapy include LB‑1903, ENOB-HV‑01, GOVX-B01, HSPCs overexpressing ALDH1 (LV‑800, HIV infection), AGT103-T, and SupT1 cell based therapy. Examples of dendritic cell therapy include AGS‑004. CCR5 gene editing agents include SB‑728T. CCR5 gene inhibitors include Cal‑1, and lentivirus vector CCR5 shRNA / - TRIM5alpha / TAR decoy-transduced autologousCD34-positive hematopoietic progenitor cells (HIV infection / HIV-related lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4 expressing CD4-positive T-cells are co-administered with one or more multi-specific 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. 44 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Gene Editors

[0227] In certain embodiments, the agents describedherein are combinedwith ageneeditor,e.g.,anHIV targetedgene editor. In various embodiments, the genomeediting systemcan be selected from the group consisting of: aCRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonucleases complex, and a meganuclease complex. An illustrative HIV targeting CRISPR / Cas9 system includes without limitation EBT‑101. CAR-T Cell Therapy

[0228] In someembodiments, the agents described herein can be co-administeredwith a population of immuneeffector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. The HIVantigen include an HIVenvelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site ongp120, theCD4-inducedbinding site ongp120,Nglycanongp120, theV2of gp120, themembraneproximal region ongp41. The immuneeffector cell is aT-cell or anNKcell. In someembodiments, theT-cell is aCD4+T-cell, aCD8+T-cell, or a combination thereof. Cells can be autologous or allogeneic. Examples of HIV CAR-T include convertible CAR-T, VC- CAR-T, CMV-N6-CART, anti-CD4 CART-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T-cells, anti-CD4 MicAbody antibody + anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP‑120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide. TCR T-cell Therapy

[0229] In certain embodiments, the agents described herein are combined with a population of TCR-T-cells. TCR-T- cells are engineered to target HIV derived peptides present on the surface of virus-infected cells, for example, ImmTAV. B-cell Therapy

[0230] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells geneticallymodified to express broadly neutralizing antibodies, suchas3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019.

[0231] Acompound as disclosed herein (e.g., any compound of formula I, II, III, IV,orV)maybe combinedwith one, two, three, or four additional therapeutic agents in any dosage amount of the compound of formula I, II, III, IV, orV (e.g., from 1 mg to 500 mg of compound).

[0232] In oneembodiment, kits comprising a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.

[0233] In one embodiment, the additional therapeutic agent or agents of the kit is an anti-HIVagent, selected from HIV protease inhibitors,HIVnon-nucleosideornon-nucleotide inhibitorsof reverse transcriptase,HIVnucleosideornucleotide inhibitors of 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, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous Tcell therapies), compounds that target theHIV capsid, latency reversing agents, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIVantibodies, broadly neutralizing HIVantibodies, bispecific antibodiesand "antibody-like" therapeuticproteins,HIVp17matrix protein inhibitors, IL‑13antagonists, peptidyl-prolyl cis- trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase‑3 (MLK‑3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK‑9 inhibitors, dendritic ICAM‑3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0234] In some embodiments, the additional therapeutic agent or agents of 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 reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, 45 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 and "antibody-like" therapeutic proteins, and combinations thereof.

[0235] In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and anHIV nucleoside or nucleotide inhibitor of reverse transcriptase. In a specific embodiment, the kit includes a compounddisclosedherein, or apharmaceutically acceptable salt thereof, andanHIVnucleosideornucleotide inhibitor of reverse transcriptaseandanHIVnon-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, thekit includesacompounddisclosedherein, or apharmaceutically acceptable salt thereof, andanHIVnucleosideor nucleotide inhibitor of reverse transcriptase, andanHIVprotease inhibitingcompound. Inanadditional embodiment, thekit includesa compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the kit includesa compounddisclosedherein, or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, anHIV nucleoside inhibitor of reverse transcriptase and anHIV capsid inhibitor. In a specificembodiment, thekit includesacompounddisclosedherein, or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three or four HIV bNAbs. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase. HIV Long acting Therapy

[0236] Examples of drugs that are being developed as long acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA,VM‑1500LAI,maraviroc (LAI), tenofovir implant, islatravir implant, doravirine, raltegravir, and long acting dolutegravir. HBV Combination Therapy

[0237] In certain embodiments, a method for treating or preventing an HBV infection is provided, comprising admin- istering to the human a therapeutically effective amount of a composition described herein, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an HBV infection is provided, comprising administering to the human a therapeutically effective amount of a composition described herein, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0238] In certain embodiments, the present description provides a method for treating an HBV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a composition described herein, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents which are suitable for treating an HBV infection.

[0239] The compounds described herein may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and "antibody-like" therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), an antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases,TALENs), cell therapiessuchasCAR-T (chimeric antigen receptorT-cell), andTCR- T (an engineered T cell receptor) agent or any combination thereof.

[0240] In some embodiments, the additional therapeutic agent or agents are selected from HBV combination drugs, HBV vaccines, HBV polymerase inhibitors, HBV capsid modulators, agonists of TLR7, TLR8, and TLR9, cytokines, immune checkpoint inhibitors, FLT3 ligands, interferon alpha receptor ligands, interferon alpha, interferon lambda, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, HBV X protein (HBx) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides, short interfering RNAs (siRNA) and DNA directed RNA interference (ddRNAi), endonucleasemodulators, ribonucleotide reductase inhibitors, HBVEantigen (HBeAg) inhibitors, covalently closed circular DNA (cccDNA) inhibitors, famesoid X receptor agonists, HBV antibodies, T cell and NK cell recruiting bispecific antibodies, chimeric Tcell receptors targetingHBVantigens or peptides,CAR-Tcell therapy, thymosin agonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, 46 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 indoleamine‑2, 3-dioxygenase (IDO1)pathway inhibitors, anti-OX40, anti-CD40,anti-CD160,HBVgeneeditors,PAPD5 / - PAPD7 inhibitors, ZCCHC14 inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, epigenetic regulators, inducers of tertiary lymphoidaggregates, antagonists of IAP / XIAP, nucleic acid polymers (e.g.,NAPsandSTOPS),modulators of lipid metabolism or trafficking, arginase inhibitors, and other drugs for treating HBV, and combinations thereof.

[0241] In some embodiments, the additional therapeutic agent or agents are chosen from adefovir, entecavir, telbi- vudine, lamivudine, and lenacapavir, and combinations thereof.

[0242] In some embodiments, the additional therapeutic agent or agents are chosen from adefovir, entecavir, telbi- vudine, lamivudine, and lenacapavir. HBV Combination Drugs

[0243] Examples of combination drugs for the treatment of HBV include, but are not limited to, TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX‑203, lamivudine, and PEG-IFN-alpha; ABX‑203 adefovir, and PEG-IFNal- pha; and INO‑1800 (INO‑9112 and RG7944). Other HBV Drugs

[0244] Examples of other drugs for the treatment of HBV include, but are not limited to, alpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides, AL‑034, CCC‑0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), JNJ‑56136379, nitazoxanide, birinapant, NJK14047, NOV‑205 (molixan, BAM‑205), oligotide, mivo- tilate, feron, GST-HG‑131, levamisole, KaShuNing, alloferon,WS‑007, Y‑101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm,KW‑3, BP-Inter‑014, oleanolic acid, HepB-nRNA, cTP‑5 (rTP‑5), HSK-II‑2, HEISCO‑106‑1, HEISCO‑106, Hepbarna, IBP- B‑006IA, Hepuyinfen, DasKloster 0014‑01, ISA‑204, Jiangantai (Ganxikang), MIV‑210, OB-AI‑004, PF‑06, picroside, DasKloster‑0039, hepulantai, IMB‑2613, TCM‑800B, reduced glutathione, RO‑6864018, RG‑7834, UB‑551, and ZH‑2N, and the compounds described in US20150210682, (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). HBV Vaccines

[0245] HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include, but are not limited to, Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP‑0101; LBYW‑0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V‑419, CVI-HBV‑001, Tetra- bhay, hepatitisBprophylactic vaccine (AdvaxSuperD),Hepatrol‑07,GSK‑223192A,ENGERIXB®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI‑20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, TrivacHB,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.

[0246] Examples of HBV therapeutic vaccines include, but are not limited to, 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 / antigenvaccine,Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO‑1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG‑17909, AdTG‑17910 AdTG‑18202, ChronVac-B, TG‑1050, and Lm HBV. HBV DNA Polymerase Inhibitors

[0247] Examples ofHBVDNApolymerase inhibitors include, but arenot limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX‑157, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC‑019754, FMCA, AGX‑1009, AR-II‑04‑26, HIP‑1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS‑10234. 47 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Immunomodulators

[0248] Examples of immunomodulators include, but are not limited to, rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ‑440,WF‑10,AB‑452, ribavirin, IL‑12, INO‑9112, polymer polyethyleneimine (PEI), Gepon, VGV‑1, MOR‑22, CRV‑431, JNJ‑0535, TG‑1050, ABI-H2158, BMS‑936559,GS‑9688, RO‑7011785, RG‑7854, AB‑506, RO‑6871765, AIC‑649, and IR‑103. Toll-like Receptor (TLR) Modulators

[0249] In various embodiments, the agents as described herein, are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation AL‑034, DSP‑0509, GS‑9620 (vesatolimod), vesatolimod analog, LHC‑165, TMX‑101 (imiquimod), GSK‑2245035, resiquimod, DSR‑6434, DSP‑3025, IMO‑4200, MCT‑465, MEDI‑9197, 3M‑051,SB‑9922, 3M‑052, Limtop, TMX‑30X, TMX‑202,RG‑7863,RG‑7854,RG‑7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen),WO2014 / 023813 (Janssen), US20080234251 (ArrayBiophar- ma), 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). An TLR7 / TLR8 agonist that can be co-administered is NKTR‑262, telratolimod and BDB‑001. Example TLR8 agonists that can be co-administered include without limitation E‑6887, IMO‑4200, IMO‑8400, IMO‑9200, MCT‑465, MEDI‑9197, motolimod, resiquimod, GS‑9688, VTX‑1463, VTX‑763, 3M‑051, 3M‑052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Phar- ma), 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). Example TLR9 agonists that can be co-administered include without limitation 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 agonist include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH‑33,MCT‑465,MCT‑475, andND‑1.1. Examples of TLR4 agonist include G‑100, and GSK‑1795091Interferon Alpha Receptor Ligands

[0250] Examples of interferon alpha receptor ligands include, but are not limited to, interferon alpha‑2b (INTRON A®), pegylated interferon alpha‑2a (PEGASYS®), PEGylated interferon alpha‑1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEGinterferon alfa‑2a (YPEG-rhIFNalpha‑2a), P‑1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeginterferon alfa‑2b (YPEG-rhIFNalpha‑2b), MOR‑22, peginterferon alfa‑2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1(HU- MOFERON®), interferon beta‑1a (AVONEX®), Shaferon, interferon alfa‑2b (Axxo), Alfaferone, interferon alfa‑2b (Bio- Generic Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa‑2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa‑2b (Amega), interferon alfa‑2b (Virchow), ropeginterferon alfa‑2b, rHSA-IFN alpha‑2a (recom- binant human serum albumin interferon alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha‑(1b, 2a, 2b), peginterferon alfa‑2b (Amega), peginterferon alfa‑2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa‑2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha‑2b, SFR‑9216, and Interapo (Interapa). Hyaluronidase Inhibitors

[0251] Examples of hyaluronidase inhibitors include, but are not limited to, astodrimer. 48 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Hepatitis B Surface Antigen (HBsAg) Inhibitors

[0252] ExamplesofHBsAg inhibitors include, but arenot limited to,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’.

[0253] Examples of HBsAg secretion inhibitors include, but are not limited to, BM601. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors

[0254] Examples of Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors include, but are not limited to, AGEN‑2041, AGEN‑1884, ipilumimab, belatacept, PSI‑001, PRS‑010, Probody mAbs, tremelimumab, and JHL‑1155. Cyclophilin Inhibitors

[0255] Examples of cyclophilin inhibitors include, but are not limited to, CPI‑431‑32, EDP‑494, OCB‑030, SCY‑635, NVP‑015, NVP‑018, NVP‑019, STG‑175, and the compounds described in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences). HBV Viral Entry Inhibitors

[0256] Examples of HBV viral entry inhibitors include, but are not limited to, Myrcludex B. Antisense Oligonucleotides

[0257] Examplesof antisenseoligonucleotides targetingviralmRNA include, but arenot limited to, ISIS-HBVRx, IONIS- HBVRx, IONIS-GSK6-LRx, GSK‑3389404, and RG‑6004. Antisense oligonucleotides targeting host factors such as PD- L1 are also known. Short Interfering RNAs (siRNA)and ddRNAi

[0258] Examples of siRNA include, but are not limited to, TKM-HBV (TKM-HepB), ALN-HBV,SR‑008,HepB-nRNA, and ARC‑520, ARC‑521, ARB‑1740, ARB‑1467.

[0259] Examples of DNA-directed RNA interference (ddRNAi) include, but are not limited to, BB-HB‑331. Endonuclease Modulators

[0260] Examples of endonuclease modulators include, but are not limited to, PGN‑514. Ribonucelotide Reductase Inhibitors

[0261] Examples of inhibitors of ribonucleotide reductase include, but are not limited to, Trimidox. HBV E Antigen Inhibitors

[0262] Examples of HBV E antigen (HBeAg) inhibitors include, but are not limited to, wogonin. Covalently Closed Circular DNA (cccDNA) Inhibitors

[0263] Examples of cccDNA inhibitors include, but are not limited to, BSBI‑25, and CHR‑101. Farnesoid X receptor agonist

[0264] Examplesof farnesoidx receptoragonists include,but arenot limited to,EYP‑001, cilofexor,EDP‑305,MET‑409, Tropifexor, AKN‑083, RDX‑023, BWD‑100, LMB‑763, INV‑3, NTX‑023‑1, EP‑024297 and GS‑8670. HBV Antibodies

[0265] Examples of HBVantibodies targeting the surface antigens of the hepatitis B virus include, but are not limited to, 49 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 GC‑1102, XTL‑17, XTL‑19, KN‑003, IV Hepabulin SN, fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed), and anti-HBsAg (small, medium, large).

[0266] Examples of HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include, but are not limited to, 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).

[0267] Fully human monoclonal antibodies include, but are not limited to, HBC‑34. CCR2 Chemokine Antagonists

[0268] Examples of CCR2 chemokine antagonists include, but are not limited to, propagermanium. Thymosin Agonists

[0269] Examples of thymosin agonists include, but are not limited to, Thymalfasin, recombinant thymosin alpha 1 (GeneScience). Cytokines

[0270] Examples of cytokines include, but are not limited to, interferon alpha, interferon lambda, recombinant IL‑7, CYT‑107, interleukin‑2 (IL‑2, Immunex), recombinant human interleukin‑2 (Shenzhen Neptunus), IL‑15, IL‑21, IL‑24, celmoleukin and CD4, CD8, or B cell-targeted cytokines including, but not limited to, IL‑2, IL‑7, IL‑12, IL‑15, and IL‑21. Nucleoprotein modulators

[0271] Nucleoprotein modulators may be either HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include, but are not limited to, GS‑4882, AB‑423, AT‑130, GLS4, NVR‑1221, NVR‑3778, AL‑3778, BAY 41‑4109, morphothiadine mesilate, ARB‑168786, ARB‑880, JNJ‑379, RG‑7907, HEC‑72702, AB‑506, ABI-H0731, JNJ‑440, ABI-H2158 and DVR‑23.

[0272] Examples of capsid inhibitors include, but are not limited to, the compounds described in US20140275167 (Novira Therapeutics), 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 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882 (Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395 (Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881 (Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (The Penn State Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

[0273] Examples of transcript inhibitors include, but are not limited to, the compounds described in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta). WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma). Retinoic Acid-inducible Gene 1 Stimulators

[0274] Examples of stimulators of retinoic acid-inducible gene 1 include, but are not limited to, SB‑9200, SB‑40, SB‑44, ORI‑7246, ORI‑9350, ORI‑7537, ORI‑9020, ORI‑9198, ORI‑7170, and RGT‑100. NOD2 Stimulators

[0275] Examples of stimulators of NOD2 include, but are not limited to, SB‑9200. 50 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0276] Examples of PI3K inhibitors include, but are not limited to, idelalisib, ACP‑319, AZD‑8186,AZD‑8835, buparlisib, CDZ‑173, CLR‑457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN‑3342, TGR‑1202, alpelisib, duvelisib, IPI‑549, UCB‑5857, taselisib, XL‑765, gedatolisib, ME‑401, VS‑5584, copanlisib, CAI orotate, perifosine, RG‑7666, GSK‑2636771, DS‑7423, panulisib, GSK‑2269557, GSK‑2126458, CUDC‑907, PQR‑309, INCB‑40093, pilaralisib, BAY‑1082439, puquitinib mesylate, SAR‑245409, AMG‑319, RP‑6530, ZSTK‑474, MLN‑1117, SF‑1126, RV‑1729, sonolisib, LY‑3023414, SAR‑260301, TAK‑117, HMPL‑689, tenalisib, voxtalisib, and CLR‑1401. Indoleamine‑2, 3-dioxygenase (IDOI) Pathway Inhibitors

[0277] In various embodiments, the agents as described herein, are combined with an inhibitor of indoleamine 2,3- dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV‑0801, epacadostat, F‑001287, GBV‑1012, GBV‑1028, GDC‑0919, indoximod, NKTR‑218, NLG‑919-based vaccine, PF‑06840003, pyranonaphthoquinone derivatives (SN‑35837), resminostat, SBLK‑200802, BMS‑986205, and shIDO- ST, EOS‑200271, KHK‑2455, LY‑3381916 Recombinant Thymosin Alpha‑1

[0278] Examples of recombinant thymosin alpha‑1 include, but are not limited to, NL‑004 and PEGylated thymosin alpha‑1. Bruton’s Tyrosine Kinase (BTK) Inhibitors

[0279] Examples of BTK inhibitors include, but are not limited to, ABBV‑105, acalabrutinib (ACP‑196), ARQ‑531, BMS‑986142, dasatinib, ibrutinib, GDC‑0853, PRN‑1008, SNS‑062, ONO‑4059, BGB‑3111, ML‑319, MSC‑2364447, RDX‑022, X‑022, AC‑058, RG‑7845, spebrutinib, TAS‑5315, TP‑0158, TP‑4207, HM‑71224, KBP‑7536, M‑2951, TAK‑020, AC‑0025, and the compounds described in US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical). KDM Inhibitors

[0280] Examples of KDM5 inhibitors include, but are not limited to, the compounds described in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).

[0281] Examples of KDM1 inhibitors include, but are not limited to, the compounds described inUS9186337B2 (Oryzon Genomics), GSK‑2879552, and RG‑6016. STING agonists

[0282] Examples of STING agonists include, but are not limited to, SB‑11285, AdVCA0848, STINGVAX, and the compounds described in WO 2018065360 ("Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH,Germany),WO2018009466 (Aduro Biotech),WO2017186711 (InvivoGen),WO2017161349 (ImmuneSensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck),WO2014179760 (University of California),WO2018098203 (Janssen),WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), and WO2018060323 (Boehringer). Non-nucleoside reverse transcriptase inhibitors (NNRTI)

[0283] Examples of NNRTI include, but are not limited to, the compounds described in WO2018118826 (Merck), WO2018080903(Merck),WO2018119013 (Merck),WO2017100108 (Idenix),WO2017027434 (Merck),WO2017007701 (Merck), and WO2008005555 (Gilead). HBV Replication Inhibitors

[0284] Examples of hepatitis B virus replication inhibitors include, but are not limited to, isothiafludine, IQP-HBV, 51 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 RM‑5038, and Xingantie. Arginase Inhibitors

[0285] Examples of arginase inhibitors include, but are not limited to, CB‑1158, C‑201, and resminostat. Gene Therapy and Cell Therapy

[0286] Gene therapy and cell therapy includes the geneticmodification to silence agene; genetic approaches to directly kill the infectedcells; the infusionof immunecells designed to replacemostof thepatient’sown immunesystem toenhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Gene Editors

[0287] Examples of genome editing systems include, but are not limited to, a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system; e.g., cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes. Altering (e.g., knocking out and / or knocking down) the PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interfering with Precore, Core, X protein, Long surface protein, middle surface protein, S protein (also known asHBs antigen andHBsAg), polymerase protein, and / or Hepatitis B spliced protein function (HBe,HBc,HBx, PreS1, PreS2, S, Pol, and / or HBSPor (3) reducing or eliminating the intracellular, serum and / or intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P and / or SP gene(s) is performed by targeting the gene(s) within HBV cccDNA and / or integrated HBV DNA. CAR-T cell therapy

[0288] CAR T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein theCARcomprises anHBVantigen-binding domain. The immune effector cell is a Tcell or anNK cell. In some embodiments, the Tcell is a CD4+ Tcell, a CD8+ Tcell, or a combination thereof. Cells can be autologous or allogeneic. TCR-T cell therapy

[0289] TCRTcell therapy includesTcells expressingHBV-specificTcell receptors. TCR-Tcells are engineered to target HBV derived peptides presented on the surface of virus-infected cells (e.g., peptides presented in HLA / pMHC). In some embodiments, the T-cells express HBV surface antigen (HBsAg)‑specific TCR. Examples of TCR-T therapy directed to treatment of HBV include, but are not limited to, LTCR-H2‑1.

[0290] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents chosen from immunomo- dulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus, including anti-HBsAg (small, medium, large), and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid- inducible gene 1, stimulators of RIG-I like receptors, PD‑1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2, and one or two additional therapeutic agents chosen from HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0291] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent chosen from: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, including anti-HBsAg (small, medium, large), bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene1, stimulators ofRIG- I like receptors, PD‑1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO1 inhibitors, and stimulators of 52 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 NOD2.

[0292] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent chosen from: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus, including anti-HBsAg (small, medium, large), siRNA,miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

[0293] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with compounds such as those described in U.S. Publication No. 2010 / 0143301 (Gilead Sciences), U.S. PublicationNo. 2011 / 0098248 (GileadSciences), U.S. PublicationNo. 2009 / 0047249 (GileadSciences), U.S. Patent No. 8722054 (Gilead Sciences), U.S. Publication No. 2014 / 0045849 (Janssen), U.S. Publication No. 2014 / 0073642 (Jans- sen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), U.S. Publication No. 2014 / 0350031 (Janssen), WO2014 / 023813 (Janssen), U.S. Publication No. 2008 / 0234251 (Array Biopharma), U.S. PublicationNo. 2008 / 0306050 (ArrayBiopharma),U.S.PublicationNo. 2010 / 0029585 (VentirxPharma),U.S.Publication No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), U.S. Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057(Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085(Flexus Biosciences, Inc.), U.S. Publication No. 2014 / 0330015 (Ono Phar- maceutical), U.S. Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0217880 (Ono pharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constel- lation Pharmaceuticals), US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Oryzon Genomics), and other drugs for treating HBV, and combinations thereof. Administration Routes of Administration

[0294] Thecompoundof formula I, II, III, IV,orV,orapharmaceutically acceptable salt thereof, (also referred tohereinas the active ingredient) can be administered by any route appropriate to the condition to be treated. Suitable routes include, but are not limited to, oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that a suitable route may vary with, for example, the condition of the recipient. In certain embodiments, the compounds disclosed can be dosed parenterally. In certain embodiments, the compounds disclosed can be dosed intravenous, subcutaneous, or intramuscular. In certain embodiments, the compounds disclosed are orally bioavailable and can be dosed orally.

[0295] In some embodiments, the compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof, is administeredwith a syringe suitable for administration of the compound. In someembodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof, is administered with an auto-injector comprising a syringe. In some embodiments, the syringe is disposable. In some embodiments, thesyringe is reusable. In someembodiments, thesyringe ispre-filledwith thecompound formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof. Dosing Regimen

[0297] In some embodiments, the compound, such as a compound of formula I, II, III, IV, or V, or a pharmaceutically 53 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 acceptable salt thereof, is administered to a subject in accordancewith an effective dosing regimen for a desired period of time or duration, such as at least about once a day, at least about once aweek, at least about once amonth, at least about once every 2months, at least about once every 3months, at least about once every 4months, at least about once every 6 months, or at least about once every 12months or longer. In someembodiments, the compound is administered on a daily or intermittent schedule. In some embodiments, the compound is administered on a weekly schedule. In some embodi- ments, the compound is administeredonamonthly schedule. In someembodiments, the compound is administeredevery two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every fourmonths. In someembodiments, the compound is administered every fivemonths. In some embodiments, the compound is administered every 6 months.

[0298] In some embodiments, the compound, such as a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is subcutaneously or intramuscularly administered to a subject at least about once a month. In some embodiments, the compound (e.g., a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof), is subcutaneously or intramuscularly administered to a subject at least about once every 2 months or at least about once every 3 months, or at least about once every 4 months, or at least about once every 6 months. In some embodiments, the compound (e.g., a compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof), is subcutaneously administered to a subject at least about once a month. In some embodiments, the compound (e.g., a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof), is subcutaneously administered to a subject at least about once every 2months. In someembodiments, the compound (e.g., a compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof), is subcutaneously administered to a subject at least about once every 3 months.

[0299] In some embodiments, the dosage or dosing frequency of a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is adjusted over the course of the treatment, based on the judgment of the administering physician.

[0300] In some embodiments, a compound as disclosed herein (e.g., a compound of formula I, II, III, IV, or V) or a pharmaceutically acceptable salt thereof, may be administered in a dosage amount that is effective. For example, the dosage amount can be from 1 mg to 1000 mg of compound.

[0301] In some embodiments, the methods disclosed herein comprise event-driven administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, to the subject.

[0302] As used herein, the terms "event-driven" and "event-driven administration" refer to administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event) that would expose the individual to HIV (or that would otherwise increase the individual’s risk of acquiring HIV); and / or (2) during an event (or more than one recurring event) that would expose the individual to HIV (or that would otherwise increase the individual’s risk of acquiring HIV); and / or (3) after an event (or after thefinal event ina seriesof recurringevents) thatwouldexpose the individual toHIV (or thatwouldotherwise increase the individual’s risk of acquiring HIV). In some embodiments, the event driven administration is performed pre- exposure of the subject to the HIV. In some embodiments, the event driven administration is performed post-exposure of the subject to the HIV. In some embodiments, the event driven administration is performed pre-exposure of the subject to the HIV and post-exposure of the subject to the HIV.

[0303] In some embodiments, the compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof, is administered before exposure of the subject to the HIV.

[0304] Anexample of event driven dosing regimen includes administration of the compoundof formula I, II, III, IV,orV,or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to HIV exposure (e.g., first sexual activity with sex partner known tobeHIVpositive, including sexual intercourse), followedbyadministration of the compoundof formula I, II, III, IV, or V, or a pharmaceutically acceptable salt, every 24 hours during the period of exposure (e.g., sexual activity with sex partner known to beHIV positive), followed by a further administration of the compound of formula I, II, III, IV, orV, or a pharmaceutically acceptable salt thereof, after the last exposure (e.g., sexual activity with sex partner known to be HIV positive), and one last administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0305] A further example of an event driven dosing regimen includes administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, within 24 hours before HIVexposure (e.g., sexual activity with sex partner known to be HIV positive), then daily administration during the period of exposure (e.g., sexual activity with sex partner known to beHIVpositive, including the last sexual intercourse), followed by a last administration approximately 24 hours later after the last exposure (which may be an increased dose, such as a double dose).

[0306] In certain embodiments, e.g., when administered as PrEP, the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily. In certain embodiments, e.g., when administered as event-drivenPrEP, the compoundof formula I, II, III, IV, orV,or a pharmaceutically acceptable salt thereof, is administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, or 12 to 12 hours prior to an event thatwould increase the individual’s risk of acquiringHIV (e.g., prior to sexorother exposure to theHIVvirus). In some 54 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 embodiments, the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered within 10days, 7days, 5days, 72hours, 60hours, 48hours, 24hours, 12hours, 9hours, 6hours, 4hours, 3hours, 2hours, or 1hourprior toanevent thatwould increase the individual’s riskof acquiringHIV (e.g., prior to sexorotherexposure to the HIV virus). In certain embodiments, when the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered prior to an event (e.g., administered prior to the event) that would increase the individual’s risk of acquiringHIV, it is administered daily prior to the event (e.g., sexual activity). In certain embodiments, when the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered prior to an event that would increase the individual’s risk of acquiring HIV, it is administered one to three times prior to the event.

[0307] In some embodiments, e.g., when administered as part of an event-driven PrEP regimen, the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered during the time of HIV-exposure. In certain embodimentswherein the compound of formula I, II, III, IV, orV, is administered before exposure, the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., as a single dose) during the time of HIV-exposure (e.g., during the time period of sexual activity with sex partner known to beHIV positive). In some embodiments, thecompoundof formula I, II, III, IV,orV,or apharmaceutically acceptable salt thereof, is administereddaily (e.g., for 1 to 7 days) after final exposure to the HIV (e.g., after a period of sexual activity with sex partner known to be HIV positive). In some embodiments, the administration is continued for 1 or 2 days after final exposure to HIV.

[0308] Additional examples of PrEP and / or PEP can be found, for example, at the clinical trial summary titled "On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men" (Clinical Trial # NCT01473472); the clinical trial summary titled "Prevention of HIV in Île-de-France" (Clinical Trials #NCT03113123), and atMolina, et al. N. Engl. J. Med. 2015, 353:2237‑2246, the disclosure of each of which is incorporated herein by reference in its entirety.

[0309] In some embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV‑1 and / or HIV‑2) comprise administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments,methods for reducing the risk of acquiringHIV (e.g., HIV‑1 and / orHIV‑2) comprise administration to an individual at risk of acquiring HIV. Examples of individuals at high risk for acquiring HIV include, without limitation, an individual who is at risk of sexual transmission of HIV.

[0310] In some embodiments, the reduction in risk of acquiring HIV is at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In some embodiments, the reduction in risk of acquiringHIV is at least about 75%. In someembodiments, the reduction in risk of acquiringHIV is about 80%, about 85%, or about 90%. Formulation

[0311] Formulations suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous sterile injection solutionswhichmay contain anti-oxidants, buffers, bacteriostats and soluteswhich render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. In certain embodiments the suspension is a microsuspension. In certain embodiments the suspension is a nanosuspension.

[0312] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and sub- cutaneous (SC) administration) will include one or more excipients. Excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. Examples of suitable excipients are well known to the person skilled in theart of parenteral formulationandmaybe found,e.g., inHandbookofPharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0313] In certain embodiments, the active ingredient (e.g., a compound of formula I, II, III, IV, or V) is present as a free acid.

[0314] In certain embodiments the pharmaceutical composition disclosed herein is a parenteral formulation. In certain embodiments, the formulation is administered subcutaneously to a subject. In certain embodiments, the formulation is administered intramuscularly to a subject.

[0315] The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particularmode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 mg to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5% to about 95% of the total compositions (weight: weight or wt:wt).

[0316] It should beunderstood that in addition to the ingredients particularlymentionedabove the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents. 55 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Kits and Articles of Manufacture

[0317] Kits that comprise a compound of the present disclosure, or an enantiomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above, are also included in the present disclosure. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, anda label and / or instructions for useof thecompounds in the treatment of the indications, suchas thediseasesor conditions, described herein. In one embodiment, kits comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combinationwith oneormore (e.g., one, two, three, four, oneor two, or one to three, or one to four) additional therapeutic agents are provided.

[0318] Provided herein are also articles of manufacture that include a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, implant, or intravenous bag.

[0319] In someembodiments, the present disclosure relates to a kit comprising a compound of formula I, II, III, IV,orVor a pharmaceutically acceptable salt thereof. In one embodiment, the kit may comprise one, two, three, or four additional therapeutic agents as described hereinbefore. The kit may further comprise instructions for use, e.g., for use in inhibiting an HIV integrase, such as for use in treating an HIV infection or AIDS, or as a research tool. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.

[0320] In some embodiments, the present disclosure also relates to a pharmaceutical kit comprising one or more containers comprising a compound formula I, II, III, IV, or V or a pharmaceutically acceptable salt thereof. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, useor saleof pharmaceuticals,whichnotice reflectsapproval by theagency for themanufacture, useor sale for humanadministration. Eachcomponent (if there ismore thanone component) canbepackaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kitsmay be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0321] In some embodiments, disclosed herein are articles of manufacture comprising a unit dosage of a compound of formula I, II, III, IV, or V or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed. Abbreviations

[0322] ACN acetonitrile Aldrithiol‑2 or Aldrithiol™‑2 2,2’-dipyridyldisulfide aq aqueous BLQ below the limit of quantitation Bn benzyl Boc tert-butoxycarbonyl CC50 50% cytotoxic concentration d doublet DCM dichloromethane dd doublet of doublets DMAP dimethylaminopyridine 56 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 DMF dimethylformamide DMSO dimethyl sulfoxide DP diphosphate dt doublet of triplets EC50 half maximal effective concentration EDCI 1-ethyl‑3‑(3-dimethylaminopropyl)carbodiimide or N-(3-dimethylaminopropyl)‑N’-ethyl- carbodiimide hydrochloride ELSD evaporative light scattering detector EtOAc ethyl acetate FBS fetal bovine serum GTD genotype D h hour(s) HBV hepatitis B virus Hex hexane(s) HIV human immunodeficiency virus HPLC high performance liquid chromatography Hz hertz J coupling constant LCMS liquid chromatography-mass spectrometry M molar m multiplet MeOH methanol mg milligram(s) MHz megahertz min minute(s) mL or ml milliliter(s) mm millimeter(s) mmol millimole(s) MT‑4 or MT4 metallothionein 4 human T cell line N normal 57 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 NAP nucleic acid polymer NMP N-methyl‑2-pyrrolidone NMR nuclear magnetic resonance p pentet PBMC peripheral blood mononuclear cell PBS phosphate buffered saline PEG polyethylene glycol PHH primary human hepatocytes PMPA (R)‑(((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphonic acid or (R)‑9‑(2- phosphonomethoxypropyl)adenine or tenofovir prep preparative pyr pyridine q quartet RPMI Roswell Park Memorial Institute (culture medium) RT room temperature s singlet STOPS™ S-antigen Transport-inhibiting Oligonucleotide Polymers t triplet td triplet of doublets TEA triethylamine TFV tenofovir TFV-DP tenofovir disphosphate µ micron TP triphosphate µM micromolar ZCCHC CCHC-type zinc finger protein

[0323] The following examples are provided for purposes of illustration, not limitation. EXAMPLES

[0324] 58 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0325] Compounds of formula A can be prepared in two‑ or three-step sequences from geminally disubstituted amino acidsaccording toGeneralSchemeA.Aminoacidscanbeconverted toaminoester intermediatesof formulaavia reaction with alcohols in the presenceof thionyl chloride or 4NHCl in dioxane.Alternatively, protectedaminoacids canbeesterified with alcohols in the presence of EDCI, DMAP and ACN. The resulting N-protected amino esters can be deprotected by treatment with 4NHCl in dioxane andDCM to yield amino ester intermediates of formula a. Intermediates of formula a can be coupled with (R)‑(((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphonic acid (PMPA) using triphenylpho- sphine, 2,2’-dipyridyldisulfide, triethylamine and pyridine to yield compounds of formula A.

[0326] Compounds of formula Awherein R1 andR2 are different can be prepared in one step fromPMPA, intermediates of formula b, andalcohols different from that used tomake formula b (R1≠R2) according toGeneral SchemeB.This canbe done by combining PMPA, intermediates of formula b and an alcohol with triphenylphosphine, 2,2’-dipyridyldisulfide, triethylamine and pyridine to yield compounds of formula A wherein R1and R2 are different. 59 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0327] Compounds of formula C can be prepared in one step from compounds of formula A according to General Scheme C. Compounds of formula A can be mixed with anhydrides and pyridine to yield compounds of formula C. Alternatively, compounds of formula A can be mixed with acid chlorides and pyridine to yield compounds of formula C. Alternatively, compounds of formulaA can be mixed with carboxylic acids, EDCI, DMAP and ACN to yield compounds of formula C. RA is defined by R8 when L1 is ‑C(O)‑.

[0328] Compounds of formula D can be prepared in three steps from compounds of formula A according to General Scheme D (this is in addition to preparation in one step according to General Scheme C with the appropriate RA). Compounds of formula A can be mixed with the monobenzyl ester of a dicarboxylic acid, EDCI, DMAP and ACN. The benzyl protectinggroupof the resultingproduct canbe removedbymixingwith10%Pd / CandEtOAcunderanatmosphere ofH2. The carboxylic acid of the resulting product can be alkylated bymixingwith an alkyl halide as definedbyR8a, sodium iodide, potassium carbonate and DMF to yield compounds of formula D. 60 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0329] Compounds of formula E can be prepared in one step from compounds of formula A according to General Scheme E. Compounds of formula A can be mixed with chloroformates and pyridine to yield compounds of formula E. Alternatively, compounds of formula A can be mixed with alcohols, triphosgene, DMAP and DCM to yield compounds of formula E. RB is defined by R8 when L1 is ‑C(O)O‑.

[0330] Compoundsof formulasF‑1, F‑2,andF‑3 canbeprepared inone step fromcompoundsof formulaAaccording to General Scheme F. Compounds of formula A can be mixed with alkyl halides as defined by R8a, cesium carbonate and DMF to yield compounds of formulas F‑1, F‑2, and F‑3. Alternatively, compounds of formula A can be mixed with alkyl halides as defined by R8a, potassium bicarbonate and NMP to yield compounds of formulas F‑1, F‑2, and F‑3. Example 1: Dihexyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (1)

[0331] 61 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of hexyl 2-amino‑2-methylpropanoate hydrochloride (1a)

[0332] Toasuspensionof2-amino‑2-methyl-propanoicacid (5g,48.5mmol) in1-hexanol (49.5g,485mmol)wasadded thionyl chloride (7.07mL, 97mmol) over 10min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30min. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature and the reaction was quenchedwith water (100mL). The aqueous layer was washed with 1: 1 EtOAc:Hex (50 mL x 2) and concentrated. The residue was taken up in water (20 mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 1a. 1H NMR (400 MHz, Methanol‑d4) δ 4.27 (t, J= 6.6 Hz, 2H), 1.77 - 1.67 (m, 2H), 1.59 (s, 6H), 1.46 - 1.33 (m, 6H), 0.99 - 0.89 (m, 3H).

[0333] (R)‑(((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphonic acid (PMPA) (100 mg, 0.35 mmol), inter- mediate 1a (234 mg, 1.04 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2’-dipyridyldisulfide (307 mg, 1.39 mmol) and triethylamine (0.38 mL, 2.79mmol) were combined in pyridine (2mL) under argon. The reaction was heated to 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and, and dried over sodium sulfate. After removal of the drying agent, the resulting solutionwas concentrated andwas loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50mL). The product containing solution was concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (1). 1H NMR (400MHz, DMSO‑d6) δ 8.17 (s, 1H), 8.13 (s, 1H), 7.19 (s, 2H), 4.33 - 4.14 (m, 4H), 4.11 - 3.91 (m, 5H), 3.63 - 3.48 (m, 2H), 1.61 - 1.51 (m,4H), 1.401.46 - 1.35 (m, 12H), 1.33 - 1.19 (m, 12H), 1.06 (d,J=6.2Hz, 3H), 0.84 (td, J=6.9, 2.1Hz, 6H). 31P NMR (162 MHz, DMSO‑d6) δ 18.41 (t, J = 10.2 Hz). LCMS: MS m / z = 626.36 [M+1], tR = 1.78 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2%ACN at 2µl / min. HPLC: tR = 3.35min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 2: Bis(2-ethylbutyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azane- diyl))(R)‑bis(2-methylpropanoate) (2)

[0334] 62 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of 2-ethylbutyl 2-amino‑2-methylpropanoate hydrochloride (2a)

[0335] To a suspension of 2-amino‑2-methyl-propanoic acid (20 g, 194 mmol) in 2-ethylbutan‑1-ol (85.3 g, 835 mmol) was added thionyl chloride (28.3 mL, 388mmol) over 10min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to90 °C for 16h.The reactionwascooled to room temperatureand the reactionwasquenchedwithwater (100mL). The aqueous layer waswashedwith 1: 1 EtOAc:Hex (50mL x 2) and concentrated. The residuewas taken up in water (20 mL) and concentrated (x 2). The residuewas takenup in toluene and concentrated to afford intermediate2a. 1HNMR (400 MHz, DMSO-d6) δ 8.77 (s, 3H), 4.08 (d, J = 5.5 Hz, 2H), 1.49 (s, 7H), 1.33 (p, J = 7.3 Hz, 4H), 0.86 (t, J = 7.5 Hz, 6H).

[0336] PMPA (100mg, 0.35mmol), intermediate 2a (195mg, 0.87mmol) and triethylamine (0.38mL, 2.79mmol) were combined in pyridine (1mL) and heated to 70 °C for 5min under an atmosphere of argon. A solution of triphenylphosphine (344mg, 1.39mmol), 2,2’-dipyridyldisulfide (307mg, 1.39mmol) in pyridine (1mL)was added. The reactionwas stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodiumbicarbonate (5mL x 2), water (5mL), and, and dried over sodiumsulfate. The productwas loaded onto silica gel (12 g). EtOAc (100mL)waseluted anddiscarded. Theproductwas recoveredwith 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å100x30mmcolumn,25%‑100%acetonitrile inwater gradientover30min run) to afford the title compound (2). 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.17 (s, 2H), 4.31 - 4.12 (m, 4H), 4.05 - 3.89 (m, 5H), 3.66 - 3.47 (m, 2H)), 1.54 - 1.22 (m, 22H), 1.06 (d, J = 6.2 Hz, 3H), 0.83 (td, J = 7.4, 3.3 Hz, 12H). 31P NMR (162 MHz, DMSO-d6) δ 18.43 (t, J = 10.2 Hz). LCMS: MS m / z = 626.38 [M+1], tR = 1.74 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2%ACN at 2µl / min. HPLC: tR = 3.31min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 3: Dibenzyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (3)

[0337] Synthesis of benzyl 2-amino‑2-methylpropanoate hydrochloride (3a)

[0338] To a suspension of 2-amino‑2-methyl-propanoic acid (2 g, 19.4mmol) in benzyl alcohol (10.4 g, 97.0mmol) was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to90 °C for 16h.The reactionwascooled to room temperatureand the reactionwasquenchedwithwater (100mL). The aqueous layer waswashedwith 1: 1 EtOAc:Hex (50mL x 2) and concentrated. The residuewas taken up in water (20 mL) and concentrated (x 2). The residuewas takenup in toluene and concentrated to afford intermediate3a. 1HNMR (400 MHz, DMSO-d6) δ 8.46 (s, 3H), 7.46 - 7.33 (m, 5H), 5.26 (s, 2H), 1.49 (s, 6H). 63 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0339] PMPA (100mg, 0.35mmol), intermediate 3a (239mg, 1.04mmol) and triethylamine (0.38mL, 2.79mmol) were combined in pyridine (1mL) and heated to 70 °C for 5min under an atmosphere of argon. A solution of triphenylphosphine (344mg, 1.39mmol), 2,2’-dipyridyldisulfide (307mg, 1.39mmol) in pyridine (1mL)was added. The reactionwas stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodiumbicarbonate (5mL x 2), water (5mL), and, and dried over sodiumsulfate. The productwas loaded onto silica gel (12 g). EtOAc (100mL)waseluted anddiscarded. Theproductwas recoveredwith 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å100x30mmcolumn,25%‑100%acetonitrile inwater gradientover30min run) to afford the title compound (3). 1HNMR (400MHz, DMSO-d6) δ 8.13 (s, 1H), 8.12 (s, 1H), 7.39 - 7.28 (m, 10H), 7.22 (s, 2H), 5.17 - 5.03 (m,4H), 4.28 -4.06 (m,4H), 3.91 - 3.83 (m,1H), 3.63 -3.45 (m,2H), 1.391.44 - 1.34 (m,12H), 1.00 (d,J=6.2Hz, 3H). 31P NMR (162 MHz, DMSO-d6) δ 18.71 (t, J = 9.2 Hz). LCMS: MS m / z = 638.13 [M+1], tR = 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2%ACN at 2µl / min. HPLC: tR = 2.91min;HPLCsystem:Agilent 1100 series.; Column:Gemini 5µC18110A, 50 x 4.6mm;Solvents: Acetonitrilewith 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 4: Dipentyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (4)

[0340] Synthesis of pentyl 2-amino‑2-methylpropanoate hydrochloride (4a)

[0341] To a suspension of 2-amino‑2-methyl-propanoic acid (2 g, 19.4 mmol) in 1-pentanol (8.55 g, 97.0 mmol) was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to90 °C for 16h.The reactionwascooled to room temperatureand the reactionwasquenchedwithwater (100mL). The aqueous layer waswashedwith 1: 1 EtOAc:Hex (50mL x 2) and concentrated. The residuewas taken up in water (20 mL) and concentrated (x 2). The residuewas takenup in toluene and concentrated to afford intermediate4a. 1HNMR (400 MHz,DMSO‑d6) δ 8.56 (s, 3H), 4.17 (t, J = 6.5Hz, 2H), 1.68 - 1.57 (m, 2H), 1.48 (s, 6H), 1.36 - 1.28 (m, 4H), 0.92 - 0.86 (m, 3H). 64 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0342] PMPA (100mg, 0.35mmol), intermediate 4a (219mg, 1.04mmol) and triethylamine (0.38mL, 2.79mmol) were combined in pyridine (1mL) and heated to 70 °C for 5min under an atmosphere of argon. A solution of triphenylphosphine (344mg, 1.39mmol), 2,2’-dipyridyldisulfide (307mg, 1.39mmol) in pyridine (1mL)was added. The reactionwas stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodiumbicarbonate (5mL x 2), water (5mL), and, and dried over sodiumsulfate. The productwas loaded onto silica gel (12 g). EtOAc (100mL)waseluted anddiscarded. Theproductwas recoveredwith 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å100x30mmcolumn,25%‑100%acetonitrile inwater gradientover30min run) to afford the title compound (4). 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.19 (s, 2H), 4.32 - 4.11 (m, 4H), 4.09 - 3.90 (m, 5H), 3.63 - 3.47 (m, 2H), 1.56 (q, J=6.7Hz, 4H), 1.45 - 1.35 (m, 12H), 1.27 (p, J=3.6Hz, 8H), 1.06 (d, J=6.2 Hz, 3H), 0.90 - 0.79 (m, 6H). 31P NMR (162 MHz, DMSO‑d6) δ 18.43 (t, J = 10.1 Hz). LCMS: MSm / z = 598.25 [M+1], tR = 1.61min; LC system: ThermoAccela 1250UHPLC;MSsystem: ThermoLCQFleet; Column: Kinetex 2.6µXB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2% ACN at 2µl / min. HPLC: tR = 3.11 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µC18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 5: Dipentyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (5)

[0343] Synthesis of neopentyl 2-amino‑2-methylpropanoate hydrochloride (5a)

[0344] To a suspension of 2-amino‑2-methyl-propanoic acid (2 g, 19.4 mmol) in 2,2-dimethylpropan‑1-ol (8.55 g, 97.0 mmol)wasadded thionyl chloride (2.83mL, 38.8mmol) over 10minat 5 °Cunder anatmosphereof argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction washeated to90 °C for 16h. The reactionwascooled to room temperature and the reactionwasquenchedwithwater (100 mL). Theaqueous layerwaswashedwith 1: 1EtOAc:Hex (50mLx2) and concentrated. The residuewas takenup inwater (20mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 5a. 1H NMR (400 MHz, DMSO‑d6) δ 8.67 (s, 3H), 3.88 (s, 2H), 1.51 (s, 6H), 0.94 (s, 9H). 65 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0345] PMPA (100mg, 0.35mmol), intermediate 5a (219mg, 1.04mmol) and triethylamine (0.38mL, 2.79mmol) were combined in pyridine (1mL) and heated to 70 °C for 5min under an atmosphere of argon. A solution of triphenylphosphine (344mg, 1.39mmol), 2,2’-dipyridyldisulfide (307mg, 1.39mmol) in pyridine (1mL)was added. The reactionwas stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodiumbicarbonate (5mL x 2), water (5mL), and, and dried over sodiumsulfate. The productwas loaded onto silica gel (12 g). EtOAc (100mL)waseluted anddiscarded. Theproductwas recoveredwith 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å100x30mmcolumn,25%‑100%acetonitrile inwater gradientover30min run) to afford the title compound (5).1H NMR (400 MHz, DMSO‑d6) δ 8.15 (s, 1H), 8.12 (s, 1H), 7.17 (s, 2H), 4.30 - 3.67 (m, 9H), 3.63 - 3.50 (m,2H), 1.48 - 1.39 (m,12H), 1.05 (d, J=6.2Hz, 3H), 0.89 (d, J=5.1Hz, 18H). 31PNMR(162MHz,DMSO‑d6) δ 18.52 - 18.37 (m). LCMS: MSm / z = 589.12 [M+1], tR = 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2% ACN at 2µl / min. HPLC: tR = 3.06 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 6: Diisopentyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (6)

[0346] Synthesis of isopentyl 2-amino‑2-methylpropanoate hydrochloride (6a)

[0347] To a suspension of 2-amino‑2-methyl-propanoic acid (2 g, 19.4mmol) in 3-methylbutan‑1-ol (8.55 g, 97.0mmol) was added thionyl chloride (2.83mL, 38.8mmol) over 10min at 5 °C under an atmosphere of argon in a sealed tube. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was heated to90 °C for 16h.The reactionwascooled to room temperatureand the reactionwasquenchedwithwater (100mL). The aqueous layer waswashedwith 1: 1 EtOAc:Hex (50mL x 2) and concentrated. The residuewas taken up in water (20 mL) and concentrated (x 2). The residuewas takenup in toluene and concentrated to afford intermediate6a. 1HNMR (400 MHz,DMSO‑d6) δ8.71 - 8.54 (m, 3H), 4.20 (t, J=6.7Hz, 2H), 1.75 - 1.62 (m, 1H), 1.52 (q, J=6.7Hz, 2H), 1.48 (s, 6H), 0.90 (d, J = 6.6 Hz, 6H). 66 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0348] PMPA (100 mg, 0.35 mmol) and intermediate 6a (219 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and, and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromato- graphy (Gemini 5µmC18‑110Å 100 x 30mm column, 25%‑100% acetonitrile in water gradient over 30min run) to the title compound (6). 1H NMR (400MHz, DMSO‑d6) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.17 (s, 2H), 4.32 - 3.91 (m, 9H), 3.63 - 3.50 (m, 2H), 1.70 -1.58 (m,2H), 1.51 -1.34 (m,16H), 1.07 (d,J=6.3Hz,3H), 0.89 -0.84 (m,12H). 31PNMR(162MHz,DMSO‑d6)δ 18.60 - 18.39 (m). LCMS: MSm / z = 598.10 [M+1], tR = 1.60 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2% ACN at 2µl / min. HPLC: tR = 3.14 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 7: Bis(3-ethylpentyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azane- diyl))(R)‑bis(2-methylpropanoate) (7)

[0349] Synthesis of 3-ethylpentyl 2-amino‑2-methylpropanoate hydrochloride (7b)

[0350] To a solution of 2-amino‑2-methyl-propanoic acid (2 g, 9.84 mmol), 3-ethylpentan‑1-ol (1.37 g, 11.8 mmol) and HATU (2.34 g, 9.84 mmol) in DCM (50mL) was added TEA (5.37 mL, 39.4mmol) followed by DMAP (60mg, 0.49mmol). After 3 h, the reaction was diluted with DCM (50 mL) and washed with a saturated sodium bicarbonate solution (50 mL), water (50mL), and brine (50mL). The organicswere dried over sodiumsulfate, filtered and concentrated. Intermediate 7a waspurifiedby silicagel chromatography (0‑50%EtOAc inHex). Intermediate7awasdissolved in 4NHCl in dioxane (48.5 mL, 194mmol). After 2 h, the reactionwasconcentrated. The residuewas takenup inwater (20mL) andconcentrated (this process was repeated twice). The residue was taken up in toluene and concentrated to afford intermediate 7b. 1H NMR (400MHz,DMSO‑d6) δ8.57 (s, 3H), 4.20 (t, J=6.8Hz, 2H), 1.61 - 1.54 (m, 2H), 1.48 (s, 5H), 1.35 - 1.26 (m, 6H), 0.87 - 0.81 (m, 6H). 67 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0351] PMPA (100 mg, 0.35 mmol) and intermediate 7b (335 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (7). 1H NMR (400MHz, DMSO‑d6) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.17 (s, 2H), 4.32 - 3.90 (m, 9H), 3.63 - 3.48 (m, 2H), 1.55 - 1.48 (m, 4H), 1.46 - 1.35 (m, 12H), 1.29 - 1.22 (m, 10H), 1.06 (d, J = 6.2 Hz, 3H), 0.83 - 0.77 (m, 12H). 31PNMR (162MHz,DMSO‑d6)δ18.44 (t,J=9.6Hz). LCMS:MSm / z=654.17 [M+1], tR=1.92min; LCsystem:ThermoAccela1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2 min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2% ACN at 2µl / min. HPLC: tR = 3.50 min; HPLC system:Agilent 1100 series.; Column:Gemini 5µC18110A, 50x 4.6mm;Solvents: Acetonitrilewith 0.1%TFA,Waterwith 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 8: Bis(3,3-dimethylbutyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(a- zanediyl))(R)‑bis(2-methylpropanoate) (8)

[0352] Synthesis of 3,3-dimethylbutyl 2-amino‑2-methyl-propanoate hydrochloride (8a)

[0353] 2-amino‑2-methyl-propanoicacid (2g,19.4mmol)and3,3-dimethylbutan‑1-ol (9.91g,97.0mmol)were takenup in 4NHCl in dioxane (19.4mL, 77.6mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for16h.The reactionwascooled to roomtemperatureandconcentrated.The residuewas takenup inwater (20mL)and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 8a. 1H NMR (400 MHz, DMSO‑d6) δ 8.47 (s, 3H), 4.23 (t, J = 7.1 Hz, 2H), 1.56 (t, J = 7.1 Hz, 2H), 1.46 (s, 6H), 0.93 (s, 9H). 68 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0354] PMPA (100 mg, 0.35 mmol) and intermediate 8a (315 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (8). 1H NMR (400MHz, DMSO‑d6) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.17 (s, 2H), 4.32 - 3.90 (m, 9H), 3.65 - 3.48 (m, 2H), 1.49 (q, J = 7.2 Hz, 4H), 1.45 - 1.34 (m, 12H), 1.06 (d, J = 6.2 Hz, 3H), 0.89 (d, J = 3.7 Hz, 18H). 31P NMR (162 MHz, DMSO‑d6) δ 18.47 (t, J = 9.6 Hz). LCMS:MSm / z = 626.21 [M+1], tR = 1.73min; LC system: ThermoAccela 1250UHPLC; MS system: Thermo LCQFleet; Column: Kinetex 2.6µXB-C18 100A, 50 x 4.6mm; Solvents: acetonitrile with 0.1%acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0 min 2‑100% acetonitrile, 2.0 min‑3.05 min 100% acetonitrile, 3.05 min‑3.2min 100%‑2% acetonitrile, 3.2 min‑3.5min 2%ACN at 2µl / min. HPLC: tR = 3.25min; HPLC system: Agilent 1100 series.; Column:Gemini 5µC18110A, 50 x 4.6mm;Solvents: Acetonitrilewith 0.1%TFA,Waterwith 0.1%TFA;Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 9: Di-tert-butyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (9)

[0355]

[0356] PMPA(100mg,0.35mmol)and tert-butyl 2-amino‑2-methylpropanoatehydrochloride ( 204mg,1.04mmol)were suspended in2mLof tolueneandconcentratedunder reducedpressure twice.Pyridine (1mL)and triethylamine (0.38mL, 2.79 mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodiumsulfate. The productwas loaded onto silica gel (12 g). EtOAc (100mL)was eluted anddiscarded. The productwas recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified byHPLCchromatography (Gemini 5µmC18‑110Å100 x 30mmcolumn, 25%‑100%acetonitrile inwater gradient over 30min run) to afford the title compound (9). 1H NMR (400 MHz, DMSO‑d6) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.17 (s, 2H), 4.29 (dd, J=14.3, 3.8Hz, 1H), 4.18 (dd, J=14.4, 6.0Hz, 1H), 4.12 (d, J=10.6Hz, 1H), 4.02 (d, J=10.6Hz, 1H), 3.98 - 3.92 (m, 1H), 1.45 - 1.30 (m, 30H), 1.07 (d, J=6.3Hz, 3H). 31PNMR (162MHz,DMSO‑d6) δ18.60 - 18.39 (m). LCMS:MSm / z= 570.27 [M+1], tR = 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6µ XB-C18 100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min‑2.0min 2‑100%acetonitrile, 2.0min‑3.05min 100%acetonitrile, 3.05min‑3.2min 100%‑2%acetonitrile, 3.2min‑3.5 min 2%ACNat 2µl / min. HPLC: tR = 2.86min; HPLC system: Agilent 1100 series.; Column: Gemini 5µC18 110A, 50 x 4.6 mm;Solvents:Acetonitrilewith0.1%TFA,Waterwith0.1%TFA;Gradient: 0min‑5.0min2‑98%ACN,5.0min‑6.0min98% ACN at 2 mL / min. Example 10: Dihexyl 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (2S,2’S)‑bis(2-methylbutanoate) (10)

[0357] 69 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of hexyl (2S)‑2-amino‑2-methyl-butanoate hydrochloride (10a)

[0358] (2S)‑2-amino‑2-methyl-butanoic acid (1 g, 8.6mmol) and 1-hexanol (4.36g, 42.7mmol)were takenup in 4NHCl in dioxane (5.58mL, 22.3mmol) under anatmosphere of argon in a sealed tube. The reactionwasheated to 90 °C for 16 h. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20 mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 10a. 1H NMR (400MHz, DMSO‑d6) δ 4.02 (t, J =6.5Hz, 2H), 1.64 - 1.43 (m, 4H), 1.35 - 1.24 (m, 6H), 1.17 (s, 3H), 0.90 - 0.84 (m, 3H), 0.78 (t, J =7.5 Hz, 3H).

[0359] PMPA (100 mg, 0.35 mmol) and intermediate 10a (248 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (10). 1HNMR (400MHz,Acetonitrile‑d3) δ8.24 (s, 1H), 8.04 (s, 1H), 6.14 (s, 2H), 4.33 (dd, J=14.5, 3.3Hz, 1H), 4.23 - 4.06 (m, 5H), 3.98 - 3.92 (m, 1H), 3.73 - 3.43 (m, 4H), 1.90 - 1.60 (m, 8H), 1.57 (s, 3H), 1.42 (s, 3H), 1.39 - 1.28 (m, 12H), 1.19 (d, J = 6.3 Hz, 3H), 0.95 - 0.87 (m, 6H), 0.83 (t, J = 7.4 Hz,30H), 0.78 (t, J = 7.4 Hz, 3H). 31P NMR (162 MHz, Acetonitrile‑d3)δ17.48 (t,J=9.8Hz). LCMS:MSm / z=654.4 [M+1], tR=1.17min; LCsystem:Agilent 1260 Infinity IIHPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0‑1.00 min 10%‑100% acetonitrile, 1.00‑1.35 min 100% acetonitrile, 1.35‑1.36min 100‑10%acetonitrile at 2µL / min.HPLC: tR= 3.55min;HPLCsystem:Agilent 1100 series.; Column:Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 11: Dihexyl 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (2S,2’S)‑bis(2-methyl‑3-phenylpropanoate) (11)

[0360] 70 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of hexyl (2S)‑2-amino‑2-methyl‑3-phenyl-propanoate hydrochloride (11a)

[0361] (2S)‑2-amino‑2-methyl‑3-phenyl-propanoic acid (1 g, 5.6 mmol) and 1-hexanol (2.85 g, 27.9 mmol) were taken up in 4NHCl in dioxane (5.58mL, 22.3mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reactionwas cooled to room temperature and concentrated. The residuewas takenup inwater (20mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 11a. 1H NMR (400 MHz,DMSO‑d6) δ7.29 - 7.19 (m,3H), 7.16 - 7.10 (m, 2H), 4.04 - 3.93 (m, 2H), 2.89 (d, J=12.9Hz, 1H), 2.76 (d, J=12.9Hz, 1H), 1.59 - 1.50 (m, 2H), 1.31 - 1.24 (m, 6H), 1.22 (s, 3H), 0.90 - 0.83 (m, 3H).

[0362] PMPA (100 mg, 0.35 mmol) and intermediate 11a (275 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (11). 1HNMR(400MHz,DMSO‑d6) δ8.12 (s, 1H), 8.04 (s, 1H), 7.30 -7.08 (m,12H), 4.27 - 3.82 (m,9H), 3.61 (d, J= 8.7 Hz, 2H), 3.11 - 2.87 (m, 4H), 1.55 - 1.39 (m, 10H), 1.27 - 1.14 (m, 12H), 0.97 (d, J = 6.3 Hz, 3H), 0.86 - 0.78 (m, 6H). 31PNMR (162MHz, DMSO‑d6) δ 18.45 - 18.23 (m). LCMS:MSm / z = 778.4 [M+1], tR = 1.27min; LC system: Agilent 1260 Infinity IIHPLC;MSsystem:G6124BSingleQuad;Column:Kinetix 2.6uC18100A,50mmx2.1mm;Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0‑1.00 min 10%‑100% acetonitrile, 1.00‑1.35 min 100% acetonitrile, 1.35‑1.36 min 100‑10% acetonitrile at 2 µL / min.HPLC: tR = 3.86 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 12: Bis(trans‑4‑(tert-butyl)cyclohexyl) 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl) phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (12)

[0363] Synthesis of trans‑4‑(tert-butyl)cyclohexyl 2-amino‑2-methylpropanoate hydrochloride (12b)

[0364] To a solution of 2-amino‑2-methyl-propanoic acid (2 g, 9.84 mmol), trans-4‑(tert-butyl)cyclohexan‑1-ol (1.69 g, 10.8 mmol) and HATU (2.34 g, 9.84 mmol) in DCM (50 mL) was added TEA (5.37 mL, 39.4 mmol) followed by DMAP (60 mg, 0.49 mmol). After 3 h, the reaction was diluted with DCM (50 mL) and washed with a saturated sodium bicarbonate solution (50mL),water (50mL), andbrine (50mL).Theorganicsweredriedover sodiumsulfate, filteredandconcentrated. Intermediate 12awas purified by silica gel chromatography (0‑50%EtOAc in Hex). Intermediate 12awas dissolved in 4N HCl in dioxane (48.5mL, 194mmol). After 2 h, the reaction was concentrated. The residue was taken up in water (20mL) 71 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 12b. 1H NMR (400 MHz, DMSO‑d6) δ 8.50 (s, 3H), 4.71 - 4.59 (m, 1H), 2.02 - 1.93 (m, 2H), 1.81 - 1.75 (m, 2H), 1.41 - 1.27 (m, 2H), 1.19 - 0.95 (m, 3H), 0.85 (s, 9H).

[0365] PMPA (100 mg, 0.35 mmol) and intermediate 12b (290 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (12). 1H NMR (400 MHz, DMSO‑d6) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.16 (s, 2H), 4.57 - 4.44 (m, 2H), 4.28 (dd, J = 14.3, 3.8Hz, 1H), 4.21 - 4.06 (m, 3H), 3.98 - 3.91 (m, 1H), 3.63 - 3.48 (m, 2H), 1.96 - 1.86 (m, 4H), 1.79 - 1.68 (m, 4H), 1.44 - 1.32 (m, 12H), 1.29 - 1.17 (m, 4H), 1.13 - 0.90 (m, 9H), 0.82 (s, 18H). 31PNMR (162MHz,DMSO‑d6) δ 18.27 (t, J = 9.5Hz). LCMS: MSm / z = 734.14 [M+1], tR = 1.99 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column:Kinetex2.6µXB-C18100A,50x4.6mm;Solvents: acetonitrilewith0.1%acetic acid,waterwith0.1%acetic acid; Gradient: 0min‑2.0min 2‑100%acetonitrile, 2.0min‑3.05min 100%acetonitrile, 3.05min‑3.2min 100%‑2% acetonitrile, 3.2 min‑3.5 min 2% ACN at 2µl / min. HPLC: tR = 4.13 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA,Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 13: Bis((4,4-dimethylcyclohexyl)methyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl) phosphoryl)bis(azanediyl))(R)‑bis(2-methylpropanoate) (13)

[0366] Synthesis of (4,4-dimethylcyclohexyl)methyl 2-amino‑2-methylpropanoate hydrochloride (13a)

[0367] 2-amino‑2-methyl-propanoic acid (1 g, 9.7 mmol) and (4,4-dimethylcyclohexyl)methanol (2.76 g, 19.4 mmol) were taken up in 4NHCl in dioxane (9.7mL, 38.8mmol) under an atmosphere of argon in a sealed tube. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20mL)and concentrated (x 2). The residuewas takenup in tolueneandconcentrated to afford intermediate13a. 1H NMR (400MHz, DMSO‑d6) δ 8.58 (s, 3H), 4.04 (d, J = 6.0Hz, 2H), 1.61 - 1.41 (m, 10H), 1.40 - 1.31 (m, 2H), 1.25 - 1.08 (m, 3H), 0.88 (d, J = 11.2 Hz, 6H). 72 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0368] PMPA (100 mg, 0.35 mmol) and intermediate 13a (276 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (13). 1HNMR (400MHz,DMSO‑d6) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.17 (s, 2H), 4.32 - 4.14 (m, 4H), 3.98 - 3.82 (m, 5H),3.65 -3.49 (m,2H),1.55 -1.27 (m,22H), 1.12 (t,J=7.1Hz,8H),1.06 (d,J=6.2Hz,3H), 0.87 (d,J=2.2Hz,6H), 0.84 (d, J=2.4Hz,6H). 31PNMR(162MHz,DMSO‑d6)δ18.35 (t,J=9.7Hz). LCMS:MSm / z=706.40 [M+1], tR=1.30min;Agilent. HPLC: tR = 3.78 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 14: Bis(2-cyclohexylethyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bi- s(azanediyl))(R)‑bis(2-methylpropanoate) (14)

[0369] Synthesis of 2-cyclohexylethyl 2-amino‑2-methylpropanoate hydrochloride (14a)

[0370] 2-Amino‑2-methyl-propanoic acid (1 g, 9.7mmol) and 2-cyclohexylethanol (3.73 g, 29.1mmol) were taken up in 4NHCl indioxane (9.7mL,38.8mmol) underanatmosphereofargon inasealed tube.The reactionwasheated to90 °C for 16 h. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20 mL) and concentrated (x 2). The residue was taken up in toluene and concentrated to afford intermediate 14a. 1H NMR (400MHz, DMSO‑d6) δ8.64 (s, 3H), 4.20 (t, J=6.7Hz, 2H), 1.72 - 1.58 (m, 5H), 1.56 - 1.42 (m, 7H), 1.40 - 1.27 (m, 2H), 1.27 - 1.09 (m, 3H), 0.99 - 0.81 (m, 2H). 73 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0371] PMPA (100 mg, 0.35 mmol) and intermediate 14a (223 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (14). 1HNMR (400MHz,DMSO‑d6) δ 8.17 (s, 1H), 8.13 (s, 1H), 7.17 (s, 2H), 4.32 - 3.91 (m, 9H), 3.64 - 3.48 (m, 2H), 1.69 - 1.56 (m, 10H), 1.51 - 1.27 (m, 18H), 1.24 - 1.11 (m, 6H), 1.07 (d, J = 6.3 Hz, 3H), 0.96 - 0.82 (m, 4H). 31P NMR (162MHz,DMSO‑d6) δ 18.43 (t, J =9.7Hz). LCMS:MSm / z =678.40 [M+1], tR = 1.32min; LCsystem: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0‑1.00 min 10%‑100% acetonitrile, 1.00‑1.35 min 100% acetonitrile, 1.35‑1.36 min 100‑10% acetonitrile at 2 µL / min. HPLC: tR = 3.34 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑5.0 min 2‑98% ACN, 5.0 min‑6.0 min 98% ACN at 2 mL / min. Example 15: Bis(cyclohexylmethyl) 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl) bis(azanediyl))(2S,2’S)‑bis(2-methyl‑3-phenylpropanoate) (15)

[0372] Synthesis of cyclohexylmethyl (S)‑2-amino‑2-methyl‑3-phenylpropanoate hydrochloride (15a)

[0373] (2S)‑2-Amino‑2-methyl‑3-phenyl-propanoic acid (1 g, 5.6 mmol) and cyclohexylmethanol (1.91 g, 16.7 mmol) were takenup in 4NHCl in dioxane (5.58mL, 22.3mmol) under anatmosphere of argon in a sealed tube. The reactionwas heated to 90 °C for 16 h. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20mL)and concentrated (x 2). The residuewas takenup in tolueneandconcentrated to afford intermediate15a. 1H NMR(400MHz,DMSO‑d6) δ8.65 (s, 3H), 7.39 - 7.28 (m,3H), 7.21 - 7.16 (m,2H), 3.98 (dd, J=10.6, 6.2Hz, 1H), 3.87 (dd, J = 10.6, 6.1 Hz, 1H), 3.15 (s, 2H), 1.72 - 1.46 (m, 9H), 1.27 - 1.09 (m, 3H), 1.03 - 0.85 (m, 2H).

[0374] PMPA (100 mg, 0.35 mmol) and intermediate 15a (326 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1mL) and triethylamine (0.38mL, 2.79mmol) were added and the reaction heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (457 mg, 1.74 mmol), 2,2’-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The 74 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100mL) was eluted and discarded. The product was recovered with 15%MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5µmC18‑110Å 100 x 30 mm column, 25%‑100% acetonitrile in water gradient over 30min run) to afford the title compound (15). 1HNMR (400MHz,Acetonitrile‑d3) δ 8.23 (s, 1H), 7.85 (s, 1H), 7.36 - 7.12 (m, 10H), 5.90 (s, 2H), 4.22 (dd, J = 14.5, 3.4 Hz, 1H), 4.06 - 3.75 (m, 6H), 3.70 - 3.50 (m, 4H), 3.11 - 2.93 (m, 4H), 1.79 - 1.61 (m, 13H), 1.49 (s, 3H), 1.36 - 1.14 (m, 8H), 1.08 (d, J = 6.2 Hz, 3H), 1.04 - 0.87 (m, 4H). 31PNMR (162MHz, Acetonitrile‑d3) δ 17.81 - 17.56 (m). LCMS: MSm / z = 802.30 [M+1], tR = 1.35 min; LC system: LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0‑1.00 min 10%‑100% acetonitrile, 1.00‑1.35 min 100% acetonitrile, 1.35‑1.36 min 100‑10% acetonitrile at 2 µL / min.HPLC: tR = 3.34 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µC18 110A, 50 x 4.6 mm;Solvents:Acetonitrilewith0.1%TFA,Waterwith0.1%TFA;Gradient: 0min‑5.0min2‑98%ACN,5.0min‑6.0min98% ACN at 2 mL / min. Example 16: Hexyl (1R,2R)‑1‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)((1‑(hexyloxy)‑2- methyl‑1-oxopropan‑2-yl)amino)phosphoryl)amino)‑2-ethylcyclopropane‑1-carboxylate (16) Example 17: Dihexyl 1,1’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (1R,1’R,2R,2’R)‑bis(2-ethylcyclopropane‑1-carboxylate) (17)

[0375] Synthesis of hexyl (1R,2R)‑1‑((tert-butoxycarbonyl)amino)‑2-ethylcyclopropane‑1-carboxylate (16a)

[0376] To a mixture of (1R,2R)‑1‑((tert-butoxycarbonyl)amino)‑2-ethylcyclopropane‑1-carboxylic acid (1.0 g, 4.36 mmol), n-hexanol (0.82 mL, 6.542 mmol), and 1-ethyl‑3‑(3-dimethylaminopropyl)carbodiimide hydrochloride (813 mg, 5.234mmol) in acetonitrile (30mL) was added DMAP (1.07 g, 8.723mmol). Themixture was stirred at room temperature for 15h, quenchedwith water, and concentrated in vacuo. The obtained residuewas purified by silica gel chromatography (EtOAc0 to70% inhexanes) toafford intermediate16a. 1HNMR(400MHz,Acetonitrile‑d3)δ5.93 (broadsinglet, 1H), 4.08 (t, J = 6.5 Hz, 2H), 1.68‑1.51 (m, 3H), 1.50 - 1.28 (m, 18H), 1.13 (dd, J = 8.9, 4.8 Hz, 1H), 0.94‑0.82 (m, 6H). Synthesis of hexyl (1R,2R)‑1-amino‑2-ethylcyclopropane‑1-carboxylate hydrochloride (16b)

[0377] To a solution of intermediate 16a (600 mg, 1.914 mmol) in DCM (12 mL) was added 4MHCl in dioxane (1.9 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 2h, concentrated in vacuo, co- evaporated with DCM several times, and dried under high vacuum for 15h to afford intermediate 16b. 1H NMR (400MHz, Acetonitrile-d3) δ 8.59 (bs, 3H), 4.21 (m, 2H), 1.97 (m, 1H), 1.87 (dd, J = 10.1, 5.8 Hz, 1H), 1.75‑1.61(m, 4H), 1.54 (m, 1H), 1.47 - 1.25 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H), 0.95 - 0.88 (m, 3H). 75 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0378] Amixture of PMPA (100mg, 0.348 mmol), intermediate 16b (174mg, 0.696 mmol), and triethylamine (0.73 mL, 2.785 mmol) in pyridine (1 mL) was heated to 50°C for 5 min and a freshly prepared bright yellow solution of 2,2’- dipyridyldisulfide (460mg, 2.089mmol) and triphenylphosphine (548mg, 2.089mmol) in pyridine (1mL)was added to the reactionmixture.The resulting reactionmixturewasstirredat 90 °C for 5hours. Intermediate1a (234mg,1.045mmol)was added. The reaction mixture was stirred at 90 °C for 18h, concentrated in vacuo, and purified by silica gel column chromatography (MeOH 0 to 15% in DCM) to afford amixture of the products, which was separated by preparative HPLC (0.1%TFA-containingACN35%to90% in0.1%TFA-containingwater).Eachcompoundwasdissolved inACN(3mL)and triethylamine (three drops) was added to generate free formand re-purified by neutral HPLC (ACN10 to 100% inwater for 12 min, 100% ACN for 5 min) to afford 16 and 17.

[0379] 16: 1HNMR (400MHz, Acetonitrile-d3) δ 8.24‑8.21 (m, 1H), 8.05‑8.02 (m, 1H), 6.13 (m, 2H), 4.32 (m, 1H), 4.23 - 4.04 (m, 5H), 4.02 - 3.84 (m, 2H), 3.78 - 3.59 (m, 2H), 3.47 (m, 1H), 1.76 (m, 1H), 1.68 - 1.52 (m, 5H), 1.51 - 1.22 (m, 21H), 1.17 (d, J = 6.22Hz, 3H), 0.98 - 0.83 (m, 9H). 31PNMR (162MHz, Acetonitrile-d3) δ 19.44, 18.94. LCMS:MSm / z = 652.27 [M+1]; tR = 1.66 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.64 min (45%) and 6.68 min (55%); HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18100A, 100 x 4.6mm;Solvents: Acetonitrile with 0.1%TFA,Waterwith 0.1%TFA;Gradient: 0min‑8.5min 2‑98%ACN at 1.5 mL / min.

[0380] 17: 1H NMR (400 MHz, Acetonitrile-d3) δ 8.23 (s, 1H), 8.03 (s, 1H), 6.07 (s, 2H), 4.35 (dd, J = 14.5, 3.2 Hz, 1H), 4.21 - 4.07 (m, 4H), 4.08 - 3.84 (m, 4H), 3.73 (dd, J=12.7, 8.4Hz, 1H), 3.51 (dd, J=12.6, 10.1Hz, 1H), 1.72 - 1.09 (m, 26H), 0.98 - 0.84 (m, 12H). 31P NMR (162 MHz, Acetonitrile-d3) δ 20.76. LCMS: MS m / z = 678.30 [M+1]; tR = 1.69 min; LC system:ThermoAccela1250UHPLC;MSsystem:ThermoLCQFleet;Column:PhenomenexKinetex2.6µXB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8min‑1.85min100%‑2%acetonitrile, 1.85min‑2.00min2%ACNat1800µl / min.HPLC: tR=6.81min;HPLC system: 1290 Infinity II.; Column:Phenomenex2.6µC18100A, 100 x4.6mm;Solvents: Acetonitrilewith 0.1%TFA,Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 18: Hexyl 1‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)((1‑(hexyloxy)‑2-methyl‑1-oxo- propan‑2-yl)amino)phosphoryl)amino)cyclobutane‑1-carboxylate (18) Example 19: Dihexyl 1,1’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(cyclobutane‑1-carboxylate) (19)

[0381] 76 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis hexyl 1-aminocyclobutane‑1-carboxylate hydrochloride (18a)

[0382] To amixture of 1-aminocyclobutane‑1-carboxylic acid (1.5 g, 13.03mmol) and n-hexanol (30mL)was added 4M HCl in dioxane (6.5 mL, 26.06 mmol)) slowly at room temperature The resulting mixture was heated at 80°C for 15h, and concentrated at 65 °C under high vacuum. The solid residuewas trituratedwith ether and the filter cakewashedwith ether anddriedunder high vacuum for 15h toafford intermediate18a. 1HNMR(400MHz,Acetonitrile-d3) δ8.74 (bs, 3H), 4.25 (t, J = 6.5Hz, 2H), 2.84 - 2.70 (m, 2H), 2.58 (m, 2H), 2.32 - 2.05 (m, 2H), 1.80 - 1.62 (m, 2H), 1.53 - 1.23 (m, 6H), 0.93 (m, 3H).

[0383] Compounds 18 and 19 were prepared from PMPA by a similar procedure used for 16 and 17.

[0384] 18: 1HNMR (400MHz,Acetonitrile-d3) δ8.22 (s, 1H), 8.06 (s, 1H), 6.31 (m, 2H), 4.34 (m, 1H), 4.23 - 4.02 (m, 5H), 4.01 - 3.85 (m, 2H), 3.82 - 3.60 (m, 2H), 3.47 (m, 1H), 2.68 - 2.23 (m, 4H), 2.03 - 1.82 (m, 2H), 1.73 - 1.56 (m, 4H), 1.53 - 1.25 (m, 18H), 1.17 (d, J=6.2Hz, 3H), 0.96 - 0.84 (m, 6H). 31PNMR(162MHz,Acetonitrile-d3) δ18.31, 18.29. LCMS:MSm / z= 638.38 [M+1]; tR = 1.77 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: PhenomenexKinetex2.6µXB-C18100A,50x3.0mm;Solvents: acetonitrilewith0.1%formicacid,waterwith0.1%formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2%ACN at 1800µl / min. HPLC: tR = 6.50 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min.

[0385] 19: 1H NMR (400 MHz, Acetonitrile-d3) δ 8.22 (s, 1H), 8.04 (s, 1H), 6.23 (s, 2H), 4.34 (dd, J = 14.5, 3.2 Hz, 1H), 4.22 - 4.01 (m, 5H), 4.02 - 3.86 (m, 2H), 3.82 - 3.66 (m, 2H), 3.49 (dd, J = 12.7, 10.2Hz, 1H), 2.65 - 2.30 (m, 8H), 2.01 - 1.80 (m, 4H), 1.65 (m, 4H), 1.49 - 1.24 (m, 12H), 1.17 (d, J =6.2Hz, 3H), 0.98‑0.85 (m, 6H). 31PNMR (162MHz, Acetonitrile-d3) δ18.78. LCMS:MSm / z=650.37 [M+1]; tR =1.79min; LCsystem:ThermoAccela 1250UHPLC;MSsystem:ThermoLCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.56 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µC18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 20: Hexyl 1‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)((1‑(hexyloxy)‑2-methyl‑1-oxo- propan‑2-yl)amino)phosphoryl)amino)cyclopropane‑1-carboxylate (20)

[0386] 77 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of hexyl 1-aminocyclopropane‑1-carboxylate hydrochloride (20a)

[0387] Intermediate 20a was obtained from 1-aminocyclopropane‑1-carboxylic acid in a similar method shown for intermediate18a. 1HNMR(400MHz,Acetonitrile-d3)δ8.52 (bs, 3H), 4.17 (t, J=6.6Hz, 2H), 1.75 - 1.58 (m,4H), 1.52 -1.42 (m, 2H), 1.43 - 1.28 (m, 6H), 1.03 - 0.82 (m, 3H).

[0388] Amixture of PMPA (170 mg, 0.59 mmol), intermediate 1a (199 mg, 0.89 mmol), 2,2’-dipyridyldisulfide (782 mg, 3.55 mmol), triphenylphosphine (931 mg, 3.55 mmol), and triethylamine (0.66 mL, 4.74 mmol) in pyridine (3 mL) was heated to 70 °C for 1h. Intermediate20a (197mg, 0.89mmol) in pyridine (1mL)wasaddedand the reactionmixture stirred at 70 °C for 18h. Upon concentration in vacuo the residue was purified by silica gel column chromatography (MeOH 0 to 15% inDCM) andprep. HPLC (ACN10 to 100% inwater for 12min, 100%ACN for 5min) to afford the title compound (20). 1HNMR (400MHz,Acetonitrile-d3) δ8.25‑8.20 (m, 1H), 8.10‑8.06 (m, 1H), 6.48 (s, 2H), 4.42 - 4.26 (m, 2H), 4.24 - 3.82 (m, 7H), 3.71 (m, 1H), 3.57‑3.42 (m, 1H), 1.73 - 1.21 (m, 26H), 1.16 (d, J = 6.2Hz, 3H), 0.95‑0.81 (m, 6H). 31PNMR (162MHz, Acetonitrile-d3)δ19.92,19.85.LCMS:MSm / z=624.30 [M+1]; tR=1.76min;LCsystem:ThermoAccela1250UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.21 min (43%), 6.28 min (54%); HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 21: Bis(trans‑4‑(trifluoromethyl)cyclohexyl) 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy) methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (21) Example 22: Hexyl 2‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)((2-methyl‑1-oxo‑1‑((trans‑4‑(tri- fluoromethyl)cyclohexyl)oxy)propan‑2-yl)amino)phosphoryl)amino)‑2-methylpropanoate (22)

[0389] 78 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Synthesis of trans‑4‑(trifluoromethyl)cyclohexyl 2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoate (21a)

[0390] To a mixture of 2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoic acid (650 mg, 3.20 mmol), trans‑4‑(trifluor- omethyl)cyclohexan‑1-ol (1076mg, 6.40mmol), and 1-ethyl‑3‑(3-dimethylaminopropyl)carbodiimide, hydrochloride (993 mg, 6.40 mmol) in acetonitrile (30 mL) was added DMAP (781 mg, 6.40 mmol). The mixture was stirred at room temperature for 15h, quenched with water, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (EtOAc 0 to 70% in hexane) to afford intermediate 21a. 1H NMR (400 MHz, Acetonitrile-d3) δ 5.60 (bs, 1H), 4.66 (m, 1H), 2.27‑2.09 (m, 1H), 2.07 - 1.91 (m, 4H), 1.59‑1.30 (m, 19H). Synthesis of trans‑4‑(trifluoromethyl)cyclohexyl 2-amino‑2-methylpropanoate hydrochloride (21b)

[0391] To a solution of intermediate 21a (451 mg, 1.28 mmol) in DCM (10 mL) was added 4M HCl in dioxane (1.6 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 15h, concentrated in vacuo, co- evaporated with DCM several times, and dried under high vacuum for 15h to afford intermediate 21b. 1H NMR (400MHz, Acetonitrile-d3) δ 8.62 (bs, 3H), 4.79 (m, 1H), 2.20 (s, 1H), 2.10 (d, J= 4.9 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.65 (s, 6H), 1.54 - 1.44 (m, 4H).

[0392] AmixtureofPMPA (100mg,0.348mmol), intermediate21b (303mg,1.04mmol), 2,2’-dipyridyldisulfide (460mg, 2.089 mmol), triphenylphosphine (548 mg, 2.089 mmol), and triethylamine (0.4 mL, 2.785 mmol) in pyridine (2 mL) was 79 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 heated at 80 °C for 3h and intermediate 1a (117mg, 0.522mmol) in pyridine (0.5mL) added. Themixturewas heated at 80 °C for 15h, concentrated in vacuo, and purified by silica gel column chromatography (MeOH 0 to 15% in DCM) to afford a mixtureof twoproductswhichwere separatedbyprepHPLC (ACN10 to100% inwater for 12min, 100% for 5min) to afford 21 and 22.

[0393] 21: 1H NMR (400MHz, Acetonitrile-d3) δ 8.24 (s, 1H), 8.07 (s, 1H), 6.35 (s, 2H), 4.66 (m, 2H), 4.34 (dd, J = 14.5, 3.2Hz, 1H), 4.17 (dd,J=14.5, 7.1Hz, 1H), 3.94 (m,1H), 3.77 - 3.62 (m,2H), 3.55 (d,J=10.7Hz, 1H), 3.47 (dd,J=12.6, 9.8 Hz, 1H), 2.18 (m, 2H), 2.10 - 1.89 (m, 8H), 1.57‑1.27 (m, 20H), 1.19 (d, J=6.2Hz, 3H). 31PNMR (162MHz,Acetonitrile-d3) δ17.89. LCMS:MSm / z=758.27 [M+1]; tR =1.70min; LCsystem:ThermoAccela 1250UHPLC;MSsystem:ThermoLCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.12 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µC18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min.

[0394] 22: 1HNMR (400MHz,Acetonitrile-d3) δ8.23 (s, 1H), 8.06 (s, 1H), 6.17 (s, 2H), 4.75 - 4.55 (m, 1H), 4.37‑4.30 (m, 1H), 4.24 - 4.01 (m, 3H), 3.93 (m, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 3.56 (m, 1H), 3.45 (m, 1H), 2.26 - 2.11 (m, 1H), 2.10 - 1.90 (m, 4H), 1.63 (m, 2H), 1.56 - 1.23 (m, 22H), 1.18 (m, 3H), 0.96 - 0.80 (m, 3H). 31PNMR (162MHz, Acetonitrile-d3) δ 17.96, 17.90. LCMS:MSm / z = 692.25 [M+1]; tR = 1.74min; LC system: Thermo Accela 1250 UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.25 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µC18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 23: Hexyl (((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)((2-methyl‑1-oxo‑1‑((tetrahydro‑2H- pyran‑4-yl)oxy)propan‑2-yl)amino)phosphoryl)‑L-phenylalaninate (23) Example 24: Bis(tetrahydro‑2H-pyran‑4-yl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phos- phoryl)bis(azanediyl))(R)‑bis(2-methylpropanoate) (24)

[0395] Synthesis of tetrahydro‑2H-pyran‑4-yl‑2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoate (23a)

[0396] To a mixture of 2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoic acid (1.0 g, 4.92 mmol), tetrahydro‑2H- pyran‑4-ol (0.70 mL, 7.381 mmol), and 1-ethyl‑3‑(3-dimethylaminopropyl)carbodiimide, hydrochloride (1.15 g, 7.381 mmol) in acetonitrile (20mL) was addedDMAP (1.20 g, 9.84mmol). Themixture was stirred at room temperature for 15h, quenchedwithwater, andconcentrated in vacuo.Theobtained residuewaspurifiedbysilicagel chromatography (EtOAc0 to 50% in hexanes) to afford intermediate 23a. 1H NMR (400 MHz, Acetonitrile-d3) δ 5.62 (s, 1H), 4.92 (m, 1H), 3.83 (m, 2H), 3.53 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 1.77‑1.59 (m, 15H). Synthesis of tetrahydro‑2H-pyran‑4-yl‑2-amino‑2-methylpropanoate hydrochloride (23b)

[0397] To a solution of intermediate 23a (490 mg, 1.71 mmol) in DCM (10 mL) was added 4M HCl in dioxane (2 mL) 80 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 slowly at room temperature. The resulting mixture was stirred at room temperature for 15h, concentrated in vacuo, co- evaporated with DCM several times, and dried under high vacuum for 15h to afford intermediate 23b. 1H NMR (400MHz, Acetonitrile-d3) δ 8.48 (bs, 3H), 5.06 (m, 1H), 3.89 (m, 2H), 3.55 (m, 2H), 1.92 (m, 2H), 1.76‑1.59 (m, 8H). Synthesis of hexyl L-phenylalaninate hydrochloride (23c)

[0398] Toamixture of L-phenylalanine (2.5 g, 15.1mmol) and n-hexanol (30mL)was addedSOCl2 (4.4mL, 60.5mmol) slowly at room temperature. The resulting mixture was heated at 80 °C for 15h and concentrated at 65 °C under high vacuum.Upon cooling, the productwas precipitated and filtered. The filter cakewas suspended in ether, stirred overnight, filtered, anddriedunder high vacuum for 24h toafford intermediate23c. 1HNMR (400MHz,Methanol-d4) δ7.42 - 7.29 (m, 3H), 7.28 - 7.22 (m, 2H), 4.29 (t, J=7.0Hz, 1H), 4.17 (m,2H), 3.21 (m,2H), 1.58 (m,2H), 1.35 - 1.25 (m,6H), 0.91(t, J=6.85 Hz, 3H).

[0399] Amixture of PMPA (100mg, 0.348mmol) and intermediate 23b (156mg, 0.696mmol) was flushedwith nitrogen several times and dissolved in pyridine (2 mL). Triphenylphosphine (548mg, 2.09mmol), 2,2’-dipyridyldisulfide (460mg, 2.09 mmol), and triethylamine (0.39 mL, 2.79 mmol) were added. The resulting mixture was heated to 80 °C for 40 min. Intermediate 23c (299 mg, 1.04 mmol) in pyridine (0.5 mL) was added. The mixture was heated at 80 °C for 3h, concentrated in vacuo, and purified by silica gel chromatography (MeOH 0 to 25% in DCM) to two products which were further purified byHPLC (ACN10 to 100% inwater for 12min, ACN100% for 5min for 23 andACN10 to 100% inwater for 17 min for 24) to afford 23 and 24.

[0400] 23: 1H NMR (400 MHz, Acetonitrile-d3) δ 8.27 (s, 0.5H), 8.25 (s, 0.5H), 8.08 (s, 0.5H), 8.03 (s, 0.5H), 7.33 - 7.16 (m, 5H), 6.87‑6.55 (m, 2H), 4.89 (m, 1H), 4.39 - 3.95 (m, 4H), 3.94 - 3.68 (m, 4H), 3.61 (dd, J = 12.8, 8.8 Hz, 0.5H), 3.54 - 3.41 (m, 3.5H), 3.24 (dd, J=12.7, 10.4Hz, 0.5H), 3.15 (d,J=11.3Hz, 0.5H), 3.06‑2.90 (m,1.5H), 2.82 (dd, J=13.5, 8.1Hz, 0.5H), 1.92 - 1.77 (m, 2H), 1.65‑1.46 (m, 4H), 1.43 - 1.19 (m, 12H), 1.11 (t, J=6.0Hz, 3H), 0.92‑0.83 (m, 3H). 31PNMR(162 MHz, Acetonitrile-d3) δ 19.52, 19.39. LCMS: MS m / z = 688.31 [M+1]; tR = 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2%acetonitrile, 1.85min‑2.00min 2%ACNat 1800µl / min. HPLC: tR = 5.57min; HPLCsystem: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; 81 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min.

[0401] 24: 1H NMR (400MHz, Acetonitrile-d3) δ 8.23 (s, 1H), 8.05 (s, 1H), 5.99 (s, 2H), 4.92 (m, 2H), 4.34 (dd, J = 14.5, 3.3Hz, 1H), 4.17 (dd, J=14.5, 7.1Hz, 1H), 3.94 (m, 1H), 3.82 (dt, J=10.6, 5.7Hz, 4H), 3.75 (d, J=10.7Hz, 1H), 3.67 (dd, J =12.7, 8.8Hz,1H), 3.59 -3.42 (m,6H), 1.89 (m,4H), 1.62 (m,4H), 1.54 (s, 3H), 1.47 (s, 6H), 1.40 (s, 3H), 1.19 (d,J=6.2Hz, 3H). 31PNMR(162MHz,Acetonitrile-d3)δ17.90.LCMS:MSm / z=626.18 [M+1]; tR=1.21min;LCsystem:ThermoAccela 1250UHPLC;MS system: Thermo LCQFleet; Column: PhenomenexKinetex 2.6µXB-C18 100A, 50 x 3.0mm;Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2%acetonitrile, 1.85min‑2.00min 2%ACNat 1800µl / min. HPLC: tR = 3.81min; HPLCsystem: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 25: Bis(5,5,5-trifluoropentyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bi- s(azanediyl))(R)‑bis(2-methylpropanoate) (25)

[0402] Synthesis of 5,5,5-trifluoropentyl‑2-amino‑2-methylpropanoate hydrochloride (25a)

[0403] To amixture of 2-amino‑2-methylpropanoic acid (600mg, 5.82mmol) and 5,5,5-trifluoropentan‑1-ol (5.0 g, 35.2 mmol) was addedSOCl2 (0.72mL, 9.89mmol)) slowly at room temperature. The resultingmixturewas heated at 80 °C for 15handconcentratedat 70 °Cunder high vacuum.Hexanewasadded to theobtained residuewhichwasstirred for 30min and theprecipitated solid filtered. Thefilter cakewaswashedwith ether several timesanddriedunder high vacuum for 15h to afford intermediate 25a. 1HNMR (400MHz, Acetonitrile-d3) δ 8.69 (bs, 3H), 4.23 (t, J = 6.2 Hz, 2H), 2.25 (m, 2H), 1.86 - 1.73 (m, 2H), 1.72‑1.59 (m, 8H). 19F NMR (376 MHz, Acetonitrile-d3) δ ‑67.50.

[0404] A mixture of PMPA (500 mg, 1.74 mmol), intermediate 25a (1.51 g, 5.74 mmol), 2,2’-dipyridyldisulfide (2.30 g, 10.4mmol), triphenylphosphine (2.74 g, 10.4mmol) was flushedwith nitrogen gas several times, dissolved in pyridine (10 mL), and triethylamine (0.4mL, 2.785mmol) was added. The resultingmixture was heated at 90 °C for 20h, concentrated in vacuo, and purified by silica gel column chromatography (MeOH0 to 20% inDCM) and by prepHPLC (ACN10 to 100% inwater for 12min,ACN100%for5min) toafford the title compound (25). 1HNMR(400MHz,Acetonitrile-d3)δ8.24 (s, 1H), 8.06 (s, 1H), 6.15 (s, 2H), 4.34 (dd, J = 14.4, 3.2 Hz, 1H), 4.22 - 4.03 (m, 5H), 3.94 (m, 1H), 3.77 - 3.61 (m, 2H), 3.56 (d, J = 10.6Hz,1H), 3.44 (dd,J=12.7, 9.8Hz,1H), 2.22 (m,4H), 1.82 -1.56 (m,8H),1.53 (s, 3H), 1.46 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.19 (d, J = 6.3Hz, 3H). 19FNMR (376MHz, Acetonitrile-d3) δ ‑67.52 (d, J = 5.3Hz). 31PNMR (162MHz, Acetonitrile- d3) δ 17.83. LCMS:MSm / z = 706.31 [M+1]; tR = 1.57min; LC system: Thermo Accela 1250UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00min2%ACNat1800µl / min.HPLC: tR=5.53min;HPLCsystem:1290 Infinity II.;Column:Phenomenex2.6µC18 100A,100x4.6mm;Solvents:Acetonitrilewith0.1%TFA,Waterwith0.1%TFA;Gradient: 0min‑8.5min2‑98%ACNat1.5 mL / min. 82 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 Example 26: Bis(trans‑3‑(trifluoromethyl)cyclobutyl) 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy) methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (26)

[0405] Synthesis of trans‑3‑(trifluoromethyl)cyclobutyl‑2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoate (26a)

[0406] To a mixture of trans‑3‑(trifluoromethyl)cyclobutan‑1-ol (1.0 g, 7.14 mmol), 2‑((tert-butoxycarbonyl)amino)‑2- methylpropanoic acid (2.9 g, 14.3 mmol), and DMAP (1.9 g, 15.7 mmol) in acetonitrile (30 mL) was added 1-ethyl‑3‑(3- dimethylaminopropyl)carbodiimide, hydrochloride (2.44 g, 15.7 mmol) at room temperature The mixture was stirred at room temperature for 2hat room temperature, quenchedwithwater, andconcentrated in vacuo.Theobtained residuewas purified by silica gel chromatography (EtOAc 0 to 70% in hexane) to afford intermediate 26a. 1H NMR (400 MHz, Acetonitrile-d3) δ 5.68 (s, 1H), 5.05 (m, 1H), 3.06 (m, 1H), 2.56 (m, 2H), 2.40 (m, 2H), 1.59‑0.92 (m, 15H). 19F NMR (376 MHz,Acetonitrile-d3) δ ‑74.34. LCMS:MSm / z=325.59 [M+1]; tR=1.84min; LCsystem:ThermoAccela1250UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. Synthesis of trans‑3‑(trifluoromethyl)cyclobutyl 2-amino‑2-methylpropanoate hydrochloride (26b)

[0407] To a solution of intermediate 26a (1.96 g, 6.02 mmol) in DCM (10 mL) was added 4M HCl in dioxane (7.53 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 3h, concentrated in vacuo, co- evaporated with DCM several times, suspended in ether, stirred for 5 min, and filtered. The filter cake was washed with ether several times and dried under high vacuum for 15h to afford intermediate 26b. 1H NMR (400MHz, Acetonitrile-d3) δ 8.70 (bs,3H), 5.18 (t,J=6.6Hz,1H), 3.20 (m,1H),2.66‑2.49 (m,2H), 2.40‑2.25 (m,2H),1.74 -1.57 (m,6H).LCMS:MSm / z = 226.02 [M+1-HCl]; tR = 0.96 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: PhenomenexKinetex2.6µXB-C18100A,50x3.0mm;Solvents: acetonitrilewith0.1%formicacid,waterwith0.1%formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2%ACN at 1800µl / min.

[0408] Amixture of PMPA (300mg, 1.04mmol), intermediate 26b (600mg, 2.29mmol), 2,2’-dipyridyldisulfide (768mg, 3.48mmol), and triphenylphosphine (914mg,3.48mmol)wasflushedwithnitrogenseveral timesanddissolved inpyridine 83 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 (5mL). Triethylamine (0.8mL, 5.77mmol) were added. The resultingmixture was stirred at 90 °C for 20h, concentrated in vacuo, co-evaporated with toluene several times, and purified with silica gel chromatography (MeOH 0 to 20% in DCM), and by prep. HPLC (ACN 10 to 100% in water for 12 min, ACN 100% for 5 min) to afford the title compound (26). 1H NMR (400MHz,Acetonitrile-d3)δ8.24 (s, 1H), 8.03 (s, 1H), 5.91 (s, 2H), 5.06 (m,2H), 4.34 (dd,J=14.5, 3.2Hz, 1H), 4.17 (dd,J= 14.5, 7.3Hz, 1H), 3.94 (m,1H), 3.73 -3.63 (m,2H), 3.55 -3.35 (m,2H), 3.11 (m,2H), 2.65 -2.51 (m,2H), 2.51 - 2.36 (m,2H), 1.53 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H). 19F NMR (376MHz, Acetonitrile-d3) δ ‑74.27. 31P NMR (162 MHz, Acetonitrile-d3) δ 18.10. LCMS: MSm / z = 702.22 [M+1]; tR = 1.37 min; LC system: Thermo Accela 1250UHPLC;MS system: Thermo LCQFleet; Column: PhenomenexKinetex 2.6µXB-C18 100A, 50 x 3.0mm;Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2%acetonitrile, 1.85min‑2.00min 2%ACNat 1800µl / min. HPLC: tR = 5.50min; HPLCsystem: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 27: Bis((trans‑4-propylcyclohexyl) 2,2’‑((((((R)‑1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl) phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (27)

[0409] Synthesis of trans‑4-propylcyclohexyl 2‑((tert-butoxycarbonyl)amino)‑2-methylpropanoate (27a)

[0410] To a mixture of trans‑4-propylcyclohexan‑1-ol (1.0 g, 7.03 mmol), 2‑((tert-butoxycarbonyl)amino)‑2-methylpro- panoic acid (2.14 g, 10.5 mmol), and DMAP (1.72 g, 14.1 mmol) in acetonitrile (30 mL) was added 1-ethyl‑3‑(3- dimethylaminopropyl)carbodiimide, hydrochloride (2.18 g, 14.1 mmol) at room temperature The mixture was stirred at room temperature for 15h at room temperature, quenched with water, and concentrated in vacuo. The obtained residue was dissolved inEtOAc,washedwith brine, driedwith sodiumsulfate, and concentrated in vacuo,and purified by silica gel chromatography (EtOAc 0 to 70%hexane) to afford intermediate 27a. 1HNMR (400MHz, Acetonitrile-d3) δ 5.58 (bs, 1H), 4.61 (m, 1H), 1.96 - 1.83 (m, 2H), 1.85 - 1.73 (m, 2H), 1.45‑1.14 (m, 22H), 1.05 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LCMS:MS m / z = 327.77 [M+1]; tR = 1.98 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: PhenomenexKinetex2.6µXB-C18100A,50x3.0mm;Solvents: acetonitrilewith0.1%formicacid,waterwith0.1%formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2%ACN at 1800µl / min. Synthesis of trans‑4-propylcyclohexyl 2-amino‑2-methylpropanoate hydrochloride (27b)

[0411] Toa solution of intermediate 27a (1.46 g, 4.46mmol) inDCM (10mL)was added 4MHCl in dioxane (6mL) slowly at room temperature. The resultingmixture was stirred at room temperature for 4h, concentrated in vacuo, co-evaporated with DCM several times, suspended in ether, stirred for 5 min, and filtered. The filter cake was washed with ether several times and dried under high vacuum for 15h to afford intermediate 27b. 1H NMR (400MHz, Chloroform‑d) δ 8.98 (bs, 3H), 4.76 (m,1H), 2.02 (m,2H), 1.80 (m,2H), 1.72 (s, 6H), 1.48 (m, 2H), 1.38 - 1.12 (m,5H), 0.99 (m,2H), 0.89 (t, J=7.2Hz, 3H). LCMS: MSm / z = 227.89 [M+1-HCl]; tR = 1.19 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water 84 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min.

[0412] Amixture of PMPA (300mg, 1.04mmol), intermediate 27b (600mg, 2.27mmol), 2,2’-dipyridyldisulfide (768mg, 3.49mmol) and triphenylphosphine (914mg, 3.49mmol)was flushedwith nitrogenseveral timesanddissolved in pyridine (5mL). Triethylamine (0.8mL, 5.77mmol) were added. The resultingmixture was stirred at 90 °C for 20h, concentrated in vacuo, co-evaporated with toluene several times, and purified with silica gel (MeOH 0 to 15% in DCM) to afford the title compound (27). 1H NMR (400 MHz, Acetonitrile-d3) δ 8.24 (s, 1H), 8.06 (s, 1H), 6.01 (s, 2H), 4.62 (m, 2H), 4.34 (dd, J = 14.5, 3.2Hz, 1H), 4.17 (dd, J =14.5, 7.0Hz, 1H), 3.94 (m, 1H), 3.74 (d, J=10.6Hz, 1H), 3.66 (dd, J=12.7, 8.9Hz, 1H), 3.55 (d, J = 10.7Hz, 1H), 3.46 (dd, J = 12.6, 9.8Hz, 1H), 1.96 - 1.87 (m, 4H), 1.85 - 1.72 (m, 4H), 1.57 - 0.95 (m, 33H), 0.91 (t, J = 7.3Hz,6H). 31PNMR(162MHz,Acetonitrile-d3)δ17.59.LCMS:MSm / z=706.37 [M+1]; tR=1.89min;LCsystem:Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8min 2‑100%acetonitrile, 1.8 min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00min 2%ACNat 1800µl / min. HPLC: tR = 7.84min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 28: Dihexyl 2,2’‑(((((1‑(6-acetamido‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (28)

[0413]

[0414] To a solution of 1 (100 mg, 0.210 mmol) in pyridine (1 mL) was added acetic anhydride (0.03 mL, 0.320 mmol). The resultingmixturewas stirred at room temperature for 2h and purified by prep. HPLC (ACN10‑100% inwater for 8min, ACN100%for18min) toafford the title compound (28). 1HNMR(400MHz,Acetonitrile-d3)δ9.13 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 4.43 (dd, J=14.5, 3.2Hz, 1H), 4.26 (dd, J=14.5, 7.1Hz, 1H), 4.17 - 4.01 (m, 4H), 3.97 (m, 1H), 3.75 (d, J=10.8Hz, 1H), 3.69 (dd, J=12.8, 8.6Hz, 1H), 3.59 (d, J=10.8Hz, 1H), 3.45 (dd, J=12.7, 9.8Hz, 1H), 2.48 (s, 3H), 1.62 (m, 4H), 1.52 (s, 3H), 1.45 (s, 6H), 1.42 -1.23 (m,15H), 1.20 (d,J=6.3Hz, 3H), 0.95 -0.88 (m,6H). 31PNMR(162MHz,Acetonitrile-d3) δ 17.75. LCMS:MSm / z = 668.42 [M+1]; tR = 1.90min; LC system: Thermo Accela 1250 UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 6.66 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µC18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 85 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 mL / min. Example 29: Dihexyl 2,2’‑(((((1‑(6-butyramido‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azane- diyl))(R)‑bis(2-methylpropanoate) (29)

[0415]

[0416] To a solution of 1 (100 mg, 0.210 mmol) in pyridine (1 mL) was added butyryl chloride (0.033 mL, 0.320 mmol). The resultingmixturewas stirred at room temperature for 2h and purified by prep. HPLC (ACN10‑100% inwater for 8min, 100% for 15min) to afford the title compound (29). 1HNMR (400MHz, Acetonitrile-d3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 4.43 (dd,J=14.5, 3.1Hz,1H),4.25 (dd,J=14.5, 7.2Hz,1H), 4.17 -4.01 (m,4H),3.96 (m,1H),3.78 -3.64 (m,2H),3.57 (d, J = 10.8 Hz, 1H), 3.44 (dd, J = 12.7, 9.9 Hz, 1H), 2.77 (t, J = 7.4 Hz, 2H), 1.74 (m, 2H), 1.63 (m, 4H), 1.52 (s, 3H), 1.48‑1.42 (m, 6H), 1.43 - 1.23 (m, 15H), 1.20 (d, J = 6.2 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H), 0.96 - 0.84 (m, 6H). 31PNMR (162 MHz, Acetonitrile-d3) δ 17.756. LCMS: MSm / z = 696.31 [M+1]; tR = 2.02 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 7.02 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 30: Dihexyl 2,2’‑(((((1‑(6-dodecanamido‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azane- diyl))(R)‑bis(2-methylpropanoate) (30)

[0417]

[0418] To a solution of 1 (100mg, 0.210mmol) in pyridine (1mL) was added lauryl chloride (0.07mL, 0.320mmol). The resulting mixture was stirred at room temperature for 2h, quenched by adding methanol, concentrated in vacuo, and purified by silica gel chromatography (MeOH 0‑15% in DCM) to afford the title compound (30). 1H NMR (400 MHz, Acetonitrile-d3) δ 8.96 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.30 - 4.23 (m, 1H), 4.17 - 4.01 (m, 4H), 3.96 (m, 1H), 3.77 - 3.64 (m,2H), 3.54 (d, J=10.8Hz, 1H), 3.43 (dd, J=12.7, 9.9Hz, 1H), 2.78 (t, J=7.5Hz, 2H), 1.78 - 1.53 (m,6H),1.52 (s, 3H), 1.46‑1.40 (m,6H), 1.40 -1.25 (m,31H), 1.20 (d,J=6.2Hz,3H), 0.93‑0.83 (m,9H). 31PNMR(162 MHz, Acetonitrile-d3) δ 17.71. LCMS: MSm / z = 808.83 [M+1]; tR = 2.58 min LC system: : Dionex Ultimate 3000 UHPLC; Column: PhenomenexKinetex 2.6µC18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% 86 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 formic acid; Gradient: 0 min‑0.2 min 40% acetonitrile, 0.2 min‑1.55 min 40%‑100% acetonitrile, 1.55 min‑2.80 min 100% acetonitrile, 2.80‑2.81 min 100%‑40% acetonitrile at 1100µl / min. HPLC: tR = 8.92 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 31: Dihexyl 2,2’‑(((((1‑(6‑((propoxycarbonyl)amino)‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphor- yl)bis(azanediyl))(R)‑bis(2-methylpropanoate) (31)

[0419]

[0420] To a solution of 1 (200 mg, 0.32 mmol) in pyridine (1 mL) was added propyl chloroformate (118 mg, 0.96 mmol). The resultingmixturewas stirred at room temperature for 2h and the reaction quenched by addingwater. Themixturewas concentrated and purified by prep HPLC (ACN 10 to 100% in water for 5 min and ACN 100% for 18 min) to afford the title compound (31). 1HNMR (400MHz,Acetonitrile-d3) δ8.88 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 4.43 (dd, J=14.5, 3.2Hz, 1H), 4.25 (dd, J = 14.5, 7.2 Hz, 1H), 4.20 - 4.01 (m, 6H), 4.01 - 3.91 (m, 1H), 3.75 (d, J = 10.9 Hz, 1H), 3.69 (dd, J = 12.8, 8.6 Hz, 1H),3.58 (d,J=10.9Hz,1H), 3.44 (dd,J=12.8,9.9Hz,1H),1.73 (m,2H),1.69 -1.58 (m,4H), 1.52 (s, 3H), 1.45 (s, 6H), 1.41 - 1.26 (m, 15H), 1.20 (d, J = 6.2 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H), 0.93 - 0.83 (m, 6H). 31PNMR (162MHz, Acetonitrile-d3) δ 17.86. LCMS:MSm / z = 712.31 [M+1]; tR = 1.84min; LC system: ThermoAccela 1250UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µXB-C18 100A, 50 x 3.0mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8min‑1.85min 100%‑2%acetonitrile, 1.85min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 7.12 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µC18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 32: Dihexyl 2,2’‑(((((1‑(6‑(((pentyloxy)carbonyl)amino)‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phos- phoryl)bis(azanediyl))(R)‑bis(2-methylpropanoate) (32)

[0421]

[0422] To a solution of 1 (200 mg, 0.32 mmol) in pyridine (1 mL) was added pentyl chloroformate (144 mg, 0.96 mmol). The resultingmixture was stirred at room temperature for 2h and the reaction was quenched by adding water and purified byprepHPLC(ACN10 to100% inwater for 5minandACN100%for18min) toafford the title compound (32). 1HNMR(400 MHz,Acetonitrile-d3) δ8.74 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 4.43 (dd, J=14.5, 3.1Hz, 1H), 4.30 - 4.17 (m, 3H), 4.17 - 4.01 (m, 4H), 3.96 (m, 1H), 3.74 (d, J = 10.8Hz, 1H), 3.68 (dd, J = 12.8, 8.6 Hz, 1H), 3.56 (d, J = 10.8 Hz, 1H), 3.43 (dd, J = 12.7, 87 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 9.9Hz,1H), 1.77 -1.56 (m,6H), 1.52 (s, 3H), 1.47 -1.26 (m,25H), 1.20 (d,J=6.2Hz, 3H), 0.98 -0.85 (m,9H). 31PNMR(162 MHz, Acetonitrile-d3) δ 17.80. LCMS:MSm / z=740.39 [M+1]; tR = 1.96min; LCsystem: ThermoAccela 1250UHPLC;MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min‑1.8 min 2‑100% acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 7.61 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 33: Dihexyl 2,2’‑(((((1‑(6‑((((5-methyl‑2-oxo‑1,3-dioxol‑4-yl)methoxy)carbonyl)amino)‑9H-purin‑9-yl) propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)‑bis(2-methylpropanoate) (33)

[0423]

[0424] To a mixture of 1 (200 mg, 0.32 mmol) and triphosgene (38 mg, 0.128 mmol) in DCM (4 mL) was added DMAP (234mg, 1.92mmol) slowly portionwise at room temperature The resultingmixturewas stirred at room temperature for 15 min and 4‑(hydroxymethyl)‑5-methyl‑1,3-dioxol‑2-one (60mg, 0.46mmol) was added at room temperature The resulting mixture was stirred for 2h, concentrated in vacuo, and purified by silica gel column chromatography (MeOH 0 to 15% in DCM) and by prep HPLC (ACN 10 to 100% in water for 8 min, ACN 100% for 15 min) to afford the title compound (33). 1H NMR (400MHz, Acetonitrile-d3) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 5.02 (s, 2H), 4.44 (dd, J = 14.5, 3.2 Hz, 1H), 4.26 (dd, J = 14.5, 7.2 Hz, 1H), 4.16‑4.02 (m, 4H), 3.96 (m, 1H), 3.79 - 3.61 (m, 2H), 3.55 (d, J = 10.7 Hz, 1H), 3.44 (dd, J = 12.7, 9.8 Hz, 1H), 2.21 (s, 3H), 1.70 - 1.55 (m, 4H), 1.52 (s, 3H), 1.45 (s, 6H), 1.42 - 1.26 (m, 15H), 1.20 (d, J = 6.2Hz, 3H), 0.95 - 0.83 (m, 6H). 31P NMR (162 MHz, Acetonitrile-d3) δ 17.63. LCMS: MS m / z = 782.17 [M+1]; tR = 2.00 min; LC system: ThermoAccela1250UHPLC;MSsystem:ThermoLCQFleet;Column:PhenomenexKinetex2.6µXB-C18100A, 50x3.0 mm;Solvents: acetonitrilewith 0.1% formic acid,waterwith 0.1% formic acid;Gradient: 0min‑1.8min 2‑100%acetonitrile, 1.8 min‑1.85 min 100%‑2% acetonitrile, 1.85 min‑2.00 min 2% ACN at 1800µl / min. HPLC: tR = 7.05 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6µ C18 100A, 100 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min‑8.5 min 2‑98% ACN at 1.5 mL / min. Example 34: Dicyclopentyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azane- diyl))(R)‑bis(2-methylpropanoate) (34)

[0425] Synthesis of cyclopentyl 2-amino‑2-methyl-propanoate hydrochloride (34a)

[0426] 2-Amino‑2-methyl-propanoic acid (1.0 g, 9.70 mmol) was suspended in cyclopentanol (17.6 mL, 194 mmol). Thionyl chloride (1.4 mL, 19.4 mmol) was added over slowly over 3 minutes. The mixture was heated at 70 °C for 3 days. Themixturewasdilutedwith ethyl acetate / hexanes (1:1, 20mL) andwater (20mL). Theorganic phasewasextractedwith water (20mL). Thecombinedaqueousphaseswerewashedwith ethyl acetate / hexanes (1:1, 3 x20mL), diethyl ether (3 x 20 mL) and dichloromethane (3 x 20 mL). Any residual solvent in the aqueous phase was removed under reduced pressure. The volumewas reduced to 20ml under reduced pressure. The aqueous phasewas dilutedwith acetonitrile (10 mL) and subjected to lyophilization. The solid was washed stirred with hexanes for 15 minutes and isolated by filtration, 88 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 providing intermediate 34a. 1HNMR (400MHz,DMSO-d6) δ 8.54 (s, 3H), 5.18 (m, 1H), 1.94 - 1.78 (m, 2H), 1.76 - 1.62 (m, 4H), 1.62 - 1.52 (m, 2H), 1.45 (s, 6H).

[0427] PMPA (100 mg, 0.384 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2’-dipyridyl disulfide (307 mg, 1.39 mmol) and intermediate34a (289mg,1.39mmol)were suspended in pyridine (4mL)under argon.Triethylamine (0.38mL, 2.79mmol) was added. The reaction was heated at 75 °C for 3 days. The pyridine was removed under reduced pressure. The residue was co-evaporated with toluene (2 x 10 mL). The residue was subjected to a silica plug using an ISCO solid loading cartridge with 40% then 100% ethyl acetate / hexanes. Thematerial remaining on the solid loading cartridge was subjected to flashchromatography (0 - 20%methanol / dichloromethane). The fractions containingproductwere combined and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 uM, NX-C18, 110 Å 250 x 30 mm column, 40%‑100% acetonitrile / water gradient over 20 minutes). The fractions containing product were combined and subjected to lyophilization, providing the title compound (34). 1H NMR (400 MHz, Metha- nol‑d4) δ 8.30 (s, 1H), 8.23 (s, 1H), 5.20 (m, 1H), 5.15 (m, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.34 (d, J = 11.9 Hz, 0.39H), 4.27 (dd, J = 14.5, 7.4 Hz, 1H), 4.12 (s, 0.24H), 4.08 - 3.96 (m, 1H), 3.80 (dd, J = 12.8, 8.5 Hz, 1H), 3.55 (dd, J = 12.8, 10.2 Hz, 1H), 1.89 (m, 5H), 1.82 - 1.69 (m, 6H), 1.66 (m, 5H), 1.55 (s, 3H), 1.47 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H). 31PNMR (162MHz,Methanol‑d4) δ 20.98 - 20.75 (m). LCMS:MSm / z=594.58 [M+1]; tR = 1.145min; LC system: ThermoAccela1250UHPLC;MSsystem:ThermoLCQFleet;Column:PhenomenexKinetex2.6µXB-C18100A, 50x3.0 mm;Solvents: Acetonitrilewith 0.1% trifluoroacetic acid, waterwith 0.1% trifluoroacetic acid;Gradient: 0min‑0.2min 10% acetonitrile, 0.2min‑1.85min 10%‑100%acetonitrile, 1.85min‑2.14min 100%acetonitrile, 2.14min‑2.15min 100%‑10% acetonitrile, 2.15min‑2.25min 10% acetonitrile at 1.8 mL / min. HPLC: tR = 2.706min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: A = Acetonitrile with 5% water and 0.1% TFA, B =Water with 5 % acetonitrile 0.1%TFA;Gradient: 0min‑4.0min2‑95%B, 4.0min‑5.0min95%B, 5.0min‑5.25min95‑98%B,5.25‑5.50min 98%‑2% B at 2 mL / min. Example 35: Diisobutyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (35)

[0428] Synthesis of isobutyl 2-amino‑2-methyl-propanoate hydrochloride (35a)

[0429] 2-Amino‑2-methylpropanoic acid (2.5 g, 24.2 mmol) was suspended in 2-methylpropan‑1-ol (22 mL, 282mmol) anda solution of hydrogen chloride in 1,4-dioxane (4N, 60mL, 242mmol). Themixturewasheatedat 65 °C for 5 days. The 1,4-dioxanewas removed under reduced pressure. Themixturewas dilutedwith ethyl acetate / hexanes (1: 1, 50mL) and water (50 mL). The organic phase was extracted with water (50 mL). The combined aqueous phases were washed with ethyl acetate / hexanes (1:1, 3 x 50mL), diethyl ether (3 x 50mL) and dichloromethane (3 x 50mL). Any residual solvent in the aqueous phase was removed and the volume was reduced to 50 mL, under reduced pressure. The aqueous phase was diluted with acetonitrile (20mL) andwater (10mL) and subjected to lyophilization. The solid was stirredwith hexanes (20mL) and isolated by filtration with hexaneswashing to provide intermediate 35a. 1HNMR (400MHz, DMSO‑d6) δ 8.56 89 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55 (s, 3H), 3.98 (d, J = 6.5 Hz, 2H), 1.93 (m, 1H), 1.49 (s, 6H), 0.92 (d, J = 6.7 Hz, 6H).

[0430] PMPA (100 mg, 0.384 mmol), triphenylphosphine (341 mg, 1.74 mmol), 2,2’-dipyridyl disulfide (307 mg, 1.39 mmol) and intermediate 35a (289 mg, 1.39 mmol) were suspended in pyridine (4 mL) under argon. Triethylamine (0.475 mL, 3.48 mmol) was added. The reaction was heated at 90 °C for 18 hours. The pyridine was removed under reduced pressure. The residue was co-evaporated with toluene (3 x 10 mL). The residue was subjected to a silica plug using an ISCO solid loading cartridge with 40% then 100% ethyl acetate / hexanes. The material remaining on the solid loading cartridge was subjected to flash chromatography (0 - 20%methanol / dichloromethane). The fractions containing product were combined and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 uM, NX-C18, 110 Å 250 x 30 mm column, 40%‑100% acetonitrile / water gradient over 20 minutes). The fractions containing product were combined and subjected to lyophilization, providing the title compound (35). 1H NMR (400 MHz, Methanol‑d4) δ 8.34 (s, 1H), 8.28 (s, 1H), 4.45 (dd, J = 14.5, 3.0 Hz, 1H), 4.29 (dd, J = 14.5, 7.4 Hz, 1H), 4.05 - 3.88 (m, 5H), 3.88 - 3.75 (m, 1H), 3.55 (dd, J=12.8, 10.2Hz, 1H), 2.03 - 1.90 (m, 2H), 1.59 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H), 1.02 - 0.92 (m, 12H). 31P NMR (162 MHz, Methanol‑d4) δ 20.78 (t, J = 9.3 Hz). LCMS: MSm / z = 570.14 [M+1]; tR = 1.350 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: Acetonitrile with 0.1% trifluoroacetic acid, water with 0.1% trifluoroacetic acid;Gradient: 0min‑0.2min10%acetonitrile, 0.2min‑1.85min10%‑100%acetonitrile, 1.85min‑2.14 min 100% acetonitrile, 2.14 min‑2.15 min 100%‑10% acetonitrile, 2.15 min‑2.25 min 10% acetonitrile at 1.8 mL / min. HPLC: tR = 2.673 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: A = Acetonitrile with 5% water and 0.1% TFA, B = Water with 5 % acetonitrile 0.1% TFA; Gradient: 0 min‑4.0 min 2‑95% B, 4.0min‑5.0 min 95% B, 5.0 min‑5.25 min 95‑98% B, 5.25‑5.50 min 98%‑2% B at 2 mL / min. Example 36: Dipropyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (36)

[0431] Synthesis of 2-amino‑2-methyl-propanoate hydrochloride (36a)

[0432] 2-Amino‑2-methylpropanoic acid (1 g, 9.7 mmol) was suspended in propan‑1-ol (17.6 mL, 278 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4N, 12.1 mL, 48.5 mmol). The mixture was heated at 40 °C for 5 days. The 1,4-dioxanewas removed under reduced pressure. Themixture was diluted with ethyl acetate / hexanes (1:1, 50mL) and water (50 mL). The organic phase was extracted with water (50 mL). The combined aqueous phases were washed with ethyl acetate / hexanes (1:1, 3 x 50mL), diethyl ether (3 x 50mL) and dichloromethane (3 x 50mL). Any residual solvent in the aqueous phase was removed and the volume was reduced to 50 mL, under reduced pressure. The aqueous phase was diluted with acetonitrile (20mL) andwater (10mL) and subjected to lyophilization. The solid was stirredwith hexanes (20mL) and isolatedby filtrationwith hexaneswashing, providing intermediate36a. 1HNMR(400MHz,DMSO‑d6) δ8.76 - 8.33 (m, 3H), 4.14 (t, J = 6.5 Hz, 2H), 1.64 (m, 2H), 1.49 (s, 6H), 0.92 (t, J = 7.4 Hz, 3H). 90 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0433] PMPA (100 mg, 0.384 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2’-dipyridyl disulfide (307 mg, 1.39 mmol) and intermediate 36a (341 mg, 1.88 mmol) were suspended in pyridine (4 mL) under Argon. Triethylamine (0.475 mL, 3.48mmol)wasadded. The reactionwasheatedat 90 °C for 16h. Thepyridinewas removedunder reducedpressure. The residue was co-evaporated with toluene (3 x 10 mL). The residue was subjected to a silica plug using an ISCO solid loading cartridge with 40% then 100% ethyl acetate / hexanes. Thematerial remaining on the solid loading cartridge was subjected to flashchromatography (0 - 20%methanol / dichloromethane). The fractions containingproductwere combined and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 uM, NX-C18, 110 Å 250 x 30 mm column, 40%‑100% acetonitrile / water gradient over 20 minutes). The fractions containing product were combined and subjected to lyophilization, providing the title compound (36). 1H NMR (400 MHz, Metha- nol‑d4) δ 8.35 (s, 1H), 8.29 (s, 1H), 4.45 (dd, J = 14.5, 3.1Hz, 1H), 4.29 (dd, J = 14.5, 7.5Hz, 1H), 4.21 - 4.03 (m, 4H), 4.03 - 3.96 (m, 1H), 3.81 (dd, J = 12.8, 8.4 Hz, 1H), 3.55 (dd, J = 12.8, 10.2Hz, 1H), 1.77 - 1.63 (m, 4H), 1.57 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H), 1.26 (d, J=6.2Hz, 3H), 1.03 - 0.92 (m,6H). 31PNMR(162MHz,Methanol‑d4) δ20.76. LCMS:MS m / z = 542.11 [M+1]; tR = 1.240 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: Acetonitrile with 0.1% trifluoroacetic acid, water with 0.1% trifluoroacetic acid;Gradient: 0min‑0.2min10%acetonitrile, 0.2min‑1.85min10%‑100%acetonitrile, 1.85min‑2.14 min 100% acetonitrile, 2.14 min‑2.15 min 100%‑10% acetonitrile, 2.15 min‑2.25 min 10% acetonitrile at 1.8 mL / min. HPLC: tR = 2.402 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µ C18 110A, 50 x 4.6 mm; Solvents: A = Acetonitrile with 5% water and 0.1% TFA, B = Water with 5 % acetonitrile 0.1% TFA; Gradient: 0 min‑4.0 min 2‑95% B, 4.0min‑5.0 min 95% B, 5.0 min‑5.25 min 95‑98% B, 5.25‑5.50 min 98%‑2% B at 2 mL / min. Example 37: Bis(cyclobutylmethyl) 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bi- s(azanediyl))(R)‑bis(2-methylpropanoate) (37)

[0434] Synthesis of cyclobutylmethyl 2-amino‑2-methylpropanoate hydrochloride (37a)

[0435] 2-Amino‑2-methylpropanoic acid (1.0 g, 9.7mmol)was suspended in cyclobutylmethanol (8.8mL, 97mmol) and asolutionof hydrogenchloride in1,4-dioxane (4N,24.2mL,97mmol). Themixturewasheatedat65 °C for 3days.The1,4- dioxane was removed under reduced pressure. The mixture was diluted with ethyl acetate / hexanes (1: 1, 100 mL) and water (100mL). The organic phasewas extractedwithwater (100mL). The combined aqueous phaseswerewashedwith ethyl acetate / hexanes (1:1, 3x100mL), diethyl ether (3x100mL)anddichloromethane (3x100mL).Any residual solvent in the aqueous phase was removed and the volumewas reduced to 50mL, under reduced pressure. The aqueous phase was diluted with acetonitrile (20 mL) and water (10 mL) and subjected to lyophilization, providing intermediate 37a. 1H NMR (400MHz, DMSO‑d6) δ 8.52 (s, 3H), 4.16 (d, J = 6.4 Hz, 2H), 2.71 - 2.56 (m, 1H), 2.07 - 1.95 (m, 2H), 1.95 - 1.70 (m, 4H), 1.48 (s, 6H). 91 EP 4 667 477 A2 5 10 15 20 25 30 35 40 45 50 55

[0436] PMPA (100 mg, 0.384 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2’-dipyridyl disulfide (307 mg, 1.39 mmol) and intermediate 37a (341 mg, 1.64 mmol) were suspended in pyridine (4 mL) under Argon. Triethylamine (0.475 mL, 3.48 mmol) was added. The reaction was heated at 105 °C for 19 hours. The pyridine was removed under reduced pressure. The residue was co-evaporated with toluene (3 x 10 mL). The residue was subjected to a silica plug using an ISCO solid loading cartridge with 40% then 100% ethyl acetate / hexanes. The material remaining on the solid loading cartridge was subjected to flash chromatography (0 - 20%methanol / dichloromethane). The fractions containing product were combined and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 uM, NX-C18, 110 Å 250 x 30 mm column, 40%‑100% acetonitrile / water gradient over 20 minutes). The fractions containing product were combined and subjected to lyophilization, providing the title compound (37). 1H NMR (400 MHz, Methanol‑d4) δ 8.29 (s, 1H), 8.23 (s, 1H), 4.46 - 4.35 (m, 2H), 4.33 - 4.24 (m, 1H), 4.11 (m, 5H), 4.02 - 3.94 (m, 1H), 3.81 (dd, J = 12.8, 8.4 Hz, 1H), 3.54 (dd, J = 12.8, 10.3Hz, 1H), 2.77 - 2.56 (m, 2H), 2.16 - 2.02 (m, 4H), 2.02 - 1.88 (m, 4H), 1.88 - 1.74 (m, 4H), 1.58 (s, 3H), 1.50 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H). 31P NMR (162MHz, Methanol‑d4) δ 20.87 (t, J = 9.4 Hz). LCMS: MS m / z = 594.54 [M+1]; tR = 1.203 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18 100A, 50 x 3.0 mm; Solvents: Acetonitrile with 0.1% trifluoroacetic acid, water with 0.1% trifluoroacetic acid; Gradient: 0 min‑0.2 min 10% acetonitrile, 0.2min‑1.85min 10%‑100%acetonitrile, 1.85min‑2.14min 100%acetonitrile, 2.14min‑2.15min 100%‑10%acetonitrile, 2.15 min‑2.25 min 10% acetonitrile at 1.8 mL / min. HPLC: tR = 2.811 min; HPLC system: Agilent 1100 series.; Column: Gemini 5µC18 110A, 50 x 4.6mm; Solvents: A =Acetonitrile with 5%water and 0.1%TFA, B =Water with 5%acetonitrile 0.1%TFA;Gradient: 0min‑4.0min 2‑95%B, 4.0min‑5.0min 95%B, 5.0min‑5.25min 95‑98%B, 5.25‑5.50min 98%‑2%B at 2 mL / min. Example 38: Dibutyl 2,2’‑(((((1‑(6-amino‑9H-purin‑9-yl)propan‑2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (R)‑bis(2-methylpropanoate) (38)

[0437] Synthesis of butyl 2-amino‑2-methylpropanoate hydrochloride (38a)

[0438] 2-Amino‑2-methylpropanoic acid (2...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently chosen from C1-12alkyl, aryl-C1-4alkylene, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkylene, aryl-C3-7cycloalkylene, C7-12spirocycloalkyl, C7-12spirocycloalkyl-C1-4alkylene, bridged C5-10bicycloalkyl, bridged C5-10bicycloalkyl-C1-4alkylene, fused C5-10bicycloalkyl, C10-16dispirocycloalkyl, C10-16dispirocycloalkyl-C1-4alkylene, bridged C9-12tricycloalkyl, bridged C9-12tricycloalkyl-C1-4alkylene, C3-7cycloalkyl-C3-7cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1-12alkyl, aryl-C1-4alkylene, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkylene, aryl-C3-7cycloalkylene, C7-12spirocycloalkyl, and C7-12spirocycloalkyl-C1-4alkylene is optionally substituted with from one to three Ra; R3, R4, R5, and R6 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; or optionally: R3 and R4 together with the carbon atom to which they are attached form a 3-to 6- membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; or R3 and R4 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3- to 6- membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; or R3 and R4 together with the carbon atom to which they are attached form a 3-to 6- membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3- to 6- membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; B is R7 is hydrogen or R8; R8 is -L1-(L2)m-(L3)n-R8a; L1 is chosen from a bond, -C(O)-, and -C(O)O-; L2 is C1-6alkylene; L3 is -C(O)O- or R8a is chosen from C1-12alkyl, aryl, -C(O)-aryl, -C(O)-C1-4alkyl, -S-C(O)-C1-4alkyl, wherein aryl and -C(O)-aryl are optionally substituted with one or two Rc; each Ra is independently chosen from C1-4alkyl, halo, C1-4haloalkyl, and -O-C1-4alkyl; each Rb is independently C1-4alkyl; each Rc is independently C1-4alkyl or -OC(O)-C1-4alkyl; m and n are independently 0 or 1; and p is 0, 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently chosen from 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are the same and chosen from and 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, and R6 are each independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein (a) R3 and R5 are the same, optionally wherein R3 and R5 are both methyl; or (b) R4 and R6 are the same, optionally wherein R4 and R6 are both ethyl or both benzyl; or (c) R3 and R4 are the same, optionally wherein R3 and R4 are both methyl; or (d) R5 and R6 are the same, optionally wherein R5 and R6 are both methyl.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein (a) R3 and R4 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb; and R5 and R6 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb, optionally wherein R5 and R6 are independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb; or (b) R3 and R4 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb, optionally wherein R3 and R4 are independently chosen from methyl, ethyl, cyclopropyl, and benzyl, wherein each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with from one to three Rb; or (c) R3 and R4 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, wherein the cyclopropane ring or the cyclobutane ring is optionally substituted with from one to three Rb.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently methyl or ethyl.

8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, and R6 are the same, optionally wherein R3, R4, R5, and R6 are each methyl or cyclopropyl, or wherein R3, R4, R5, and R6 are each methyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, having the formula (II):

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, having the formula (III):

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen.

12. The compound of claim 1, wherein the compound is selected from: or or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is selected from: or or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.