WO2022159387A1 - Substituted pyridotriazine compounds and uses thereof - Google Patents

Substituted pyridotriazine compounds and uses thereof Download PDF

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Publication number
WO2022159387A1
WO2022159387A1 PCT/US2022/012773 US2022012773W WO2022159387A1 WO 2022159387 A1 WO2022159387 A1 WO 2022159387A1 US 2022012773 W US2022012773 W US 2022012773W WO 2022159387 A1 WO2022159387 A1 WO 2022159387A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
halogen
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PCT/US2022/012773
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English (en)
French (fr)
Inventor
Hang CHU
Ana Z. GONZALEZ BUENROSTRO
Hongyan Guo
Xiaochun Han
Anna E. Hurtley
Lan Jiang
Jiayao Li
David W. Lin
Michael L. Mitchell
Devan Naduthambi
Gregg M. SCHWARZWALDER
Suzanne M. SZEWCZYK
Matthew J. VON BARGEN
Qiaoyin Wu
Hong Yang
Jennifer R. Zhang
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority to EP23205202.7A priority Critical patent/EP4321217A3/en
Priority to ES22704452T priority patent/ES2968058T3/es
Priority to KR1020237027739A priority patent/KR20230134529A/ko
Priority to AU2022210247A priority patent/AU2022210247C1/en
Priority to JP2023543136A priority patent/JP7591155B2/ja
Priority to FIEP22704452.6T priority patent/FI4196479T3/fi
Priority to CN202280010649.4A priority patent/CN116745292A/zh
Priority to CA3202957A priority patent/CA3202957A1/en
Priority to PE2023002101A priority patent/PE20231297A1/es
Priority to LTEPPCT/US2022/012773T priority patent/LT4196479T/lt
Priority to EP22704452.6A priority patent/EP4196479B9/en
Priority to DK22704452.6T priority patent/DK4196479T5/da
Priority to MX2023008137A priority patent/MX2023008137A/es
Priority to PE2024001204A priority patent/PE20242099A1/es
Priority to HRP20231654TT priority patent/HRP20231654T2/hr
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to PL22704452.6T priority patent/PL4196479T3/pl
Priority to SI202230013T priority patent/SI4196479T1/sl
Priority to CR20230315A priority patent/CR20230315A/es
Publication of WO2022159387A1 publication Critical patent/WO2022159387A1/en
Priority to ZA2023/06360A priority patent/ZA202306360B/en
Priority to IL304222A priority patent/IL304222A/en
Priority to DO2023000139A priority patent/DOP2023000139A/es
Priority to CONC2023/0009518A priority patent/CO2023009518A2/es
Priority to SA523441639A priority patent/SA523441639B1/ar
Anticipated expiration legal-status Critical
Priority to JP2024165518A priority patent/JP7759459B2/ja
Priority to AU2024223997A priority patent/AU2024223997A1/en
Priority to JP2025030163A priority patent/JP2025087755A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • This disclosure relates generally to certain 2,3-dihydro-1H-pyrido[2,1- f][1,2,4]triazine compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions.
  • Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • reverse transcriptase enzymes which are required for viral replication
  • protease enzymes which are required for viral replication
  • integrase enzymes which are required for viral replication.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains may limit their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D.
  • a goal of antiretroviral therapy is to achieve viral suppression in the HIV infected patient.
  • Current treatment guidelines published by the United States Department of Health and
  • HIV virus is known to mutate in infected subjects (Tang, et al. Drugs
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy;
  • R 1 is H, C 1 -C 3 alkyl or phenyl;
  • R 2 is H or C 1 -C 3 alkyl;
  • R 3 is H or C 1 -C 3 alkyl
  • R 4 and R 5 are each independently H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 6 -C 10 aryl, or six to ten membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 6 -C 10 aryl, or six to ten membered heteroaryl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; or
  • R 4 and R 5 are joined together to form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring comprising one heteroatom selected from N, O, and S;
  • R 6 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl
  • R 7 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, or C 1 -C 6 haloalkyl
  • R 4 and R 5 are joined together to form a 3-6 membered carbocyclic ring or
  • R 8A is C 1 -C 3 alkyl or benzyl
  • R 6 is halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl.
  • the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disclosure provides a kit comprising a compound of
  • the disclosure provides a method of treating an HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the disclosure provides a use of a compound of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating an HIV infection in a human having or at risk of having the infection.
  • the disclosure provides a compound of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof any, for use in a medical therapy.
  • the disclosure provides a compound of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof any, for use in treating an HIV infection.
  • the disclosure provides use of a compound of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection.
  • Amino refers to the -NH 2 radical.
  • a prefix such as “C u-v ” or (C u -C v ) indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl” or ““C 1 -C 6 alkyl” indicates that the alkyl group has from
  • Alkyl refers to a straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms, which is saturated, having from one to twelve carbon atoms (C 1 -
  • C 1-6 alkyl or one to four carbon atoms ( C 1-4 alkyl), and which 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.
  • Alkylene refers to a saturated, branched or straight chain or 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 alkane.
  • an alkylene group can have 1 to 20 carbon atoms 1 to 10 carbon atoms or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 ethyl (-CH(CH 3 )-), 1,2-ethyl (- CH 2 CH 2 -), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3 -propyl (-CH 2 CH 2 CH 2 -
  • Aryl or “aromatic ring” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e.,
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below.
  • Cyano or “carbonitrile” refers to the group -CN.
  • Cycloalkyl or “carbocyclic ring” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Halocycloalkyl refers to a cycloalkyl substituted with one or more halogens.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl group, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl,
  • Heteroaryl or “heteroaromatic ring” refers to an aromatic group having a single ring multiple rings or multiple fused rings with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 5 to 20 ring atoms (5 to 20 membered heteroaromatic ring), 5 to 12 ring atoms (5 to 12 membered heteroaromatic ring), 5 to 10 ring atoms (5 to 10 membered heteroaromatic ring) or 5 to 6 ring atoms (5 to 6 membered heteroaromatic ring); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • 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 selected from the group consisting of nitrogen, oxygen and sulfur and attached to the rest of the molecule by a single bond.
  • heterocyclyl has from three to ten atoms, wherein from one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or from three to seven atoms, wherein from one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heterocyclyl or “heterocyclic 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.
  • heterocyclyl examples include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N,
  • 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 binding affinity to pharmacologically important site of action.
  • radioactive isotopes tritium, 3 H, and carbon-14, 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium i.e., deuterium
  • 2 H 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.
  • IVa, IVb, V, Va, or Vb can be prepared by techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the methods, compositions, kits and articles of manufacture provided herein use or include compounds (e.g., a compound of Formula I, la, lb, II, Ila, llb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) or pharmaceutically acceptable salts thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule.
  • 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., Foster, “Deuterium Isotope Effects in
  • the embodiments disclosed herein are also meant to encompass the in vivo metabolic 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.
  • “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.
  • “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “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.
  • “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.
  • 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 NX 4 + (wherein X is C 1-4 alkyl).
  • an alkali metal for example, sodium
  • an alkaline earth metal for example, magnesium
  • ammonium and NX 4 + (wherein X is C 1-4 alkyl).
  • 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, camphors,
  • Na + and NX 4 + (wherein X is independently selected from H or a C 1-4 alkyl group).
  • salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e., they will be salts derived from a physiologically acceptable acid or base.
  • 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
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound according to the embodiments disclosed herein.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 or organic sulfonic acids, to basic centers, typically amines.
  • organic and inorganic acids e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 or organic sulfonic acids
  • the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form.
  • 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.
  • Effective amount refers to an amount of a compound according to the embodiments disclosed herein, which when administered to a patient in need thereof, is sufficient to effect treatment of disease-states, conditions, or disorders disclosed herein. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the embodiments disclosed herein which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination, or coincidentally, with the compounds of the embodiments disclosed herein, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • treating and “treatment” as used herein are intended to mean the administration of a compound or composition according to the present embodiments disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and/or to reduce viral load in a patient.
  • the terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the present embodiments disclosed herein to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • treating and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein before the exposure of the individual to the virus (also called pre-exposure prophylaxis or PrEP), to prevent HIV infection from taking hold if the individual is exposed to the virus and/or to keep the virus from establishing a permanent infection and/or to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood.
  • PrEP pre-exposure prophylaxis
  • treatment also encompass the administration of a compound or composition according to the present embodiments disclosed herein both before and after the exposure of the individual to the virus.
  • the terms “preventing” and “prevention” refer to the administration of a compound, composition, or pharmaceutically salt according to the present disclosure pre- or post-exposure of the human to the virus but before the appearance of symptoms of the disease, 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 driven or “on demand” prophylaxis.
  • PrEP pre-exposure prophylaxis
  • PEP post-exposure prophylaxis
  • PEP post-exposure prophylaxis
  • event driven or “on demand” prophylaxis event driven or “on demand” prophylaxis.
  • the terms also refer to prevention of perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • antiviral agent as used herein is intended to mean an agent (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a human being, 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 human being.
  • inhibitor of HIV replication 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.
  • 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)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization.
  • Techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a 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).
  • HPLC high pressure liquid chromatography
  • 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 and mixtures thereof and includes
  • enantiomers which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • compounds disclosed herein may be in the form of a stereoisomer thereof.
  • Partially unsaturated refers to a cyclic group which contains at least one double bond but is not aromatic.
  • Substituents and multivalent groups can be attached to the remainder of the molecule at any position and in any orientation to produce a stable compound.
  • CR 11A R 11B -CR 12A R 12B - include compounds of Formula as well as compounds of Formula II.
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy;
  • R 1 is H, C 1 -C 3 alkyl or phenyl;
  • R 2 is H or C 1 -C 3 alkyl;
  • R 3 is H or C 1 -C 3 alkyl
  • R 4 and R 5 are each independently H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 6 -C 10 aryl, or six to ten membered heteroaryl containing one, two or three heteroatoms selected from
  • C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 6 -C 10 aryl, or six to ten membered heteroaryl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; or
  • R 4 and R 5 are joined together to form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring comprising one heteroatom selected from N, O, and S;
  • R 6 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl
  • R 7 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, or C 1 -C 6 haloalkyl
  • R 8A and R 8B are each independently H, C 1 -C 3 alkyl or benzyl
  • R 9 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy
  • R 10 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy
  • R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 al
  • R 4 and R 5 are joined together to form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one heteroatom; or
  • R 8A is C 1 -C 3 alkyl or benzyl
  • R 6 is halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl.
  • the compounds of Formula I provided herein have a Formula
  • the compounds of Formula I provided herein have a Formula lb:
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-4 halogens.
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Cl and F.
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one heteroatom selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one heteroatom selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy.
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one heteroatom selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy.
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one heteroatom selected from N,
  • Ar is C 6 -C 10 aryl or six to ten membered heteroaryl containing one heteroatom selected from N, O, and S; wherein the C 6 -C 10 aryl or six to ten membered heteroaryl is optionally substituted with 1-3 substituents independently selected from
  • Ar is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy. In some embodiments,
  • Ar is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy. In some embodiments, Ar is phenyl optionally substituted with 1-4 halogens. In some embodiments, Ar is phenyl optionally substituted with 1-3 substituents independently selected from Cl and F. [0059] In some embodiments of the compound of Formula I, Formula la, and Formula lb, Ar is phenyl, optionally substituted with one, two, three, or four substituents independently selected from halogen and C 1 -C 6 alkyloxy.
  • Ar is phenyl substituted with one, two, three, or four substituents independently selected from halo and C 1 -C 4 alkyloxy. In some embodiment, Ar is phenyl substituted with one, two, three, or four substituents independently selected from Cl and F.
  • Ar is: wherein Z is N or CR A ; n is 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy.
  • Z is CH or N. In some embodiments, Z is CH. In some embodiments, Z is N.
  • n is 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkyloxy.
  • Ar is , n is 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl and C 1 -C 6 alkyloxy.
  • Ar is n is 1, 2, 3, or 4; and each R A is independently halogen and C 1 -C 6 alkyloxy. In some embodiments, Ar is n is 1, 2, 3, or 4; and each R A is independently halogen and C 1 -C 4 alkyloxy. In some embodiments,
  • Ar is n is 1, 2, or 3; and each R A is independently fluoro or chloro.
  • n is 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkyloxy.
  • Ar is n is 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl and C 1 -C 6 alkyloxy.
  • Ar is n is 1, 2, 3, or 4; and each R A is independently halogen and C 1 -C 6 alkyloxy. In some embodiments, Ar is n is 1, 2, 3, or 4; and each R A is independently halogen and C 1 -C 4 alkyloxy. In some embodiments,
  • Ar is n is 1, 2, or 3; and each R A is independently fluoro or chloro.
  • n 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy.
  • n 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkyloxy.
  • the compound of Formula I, Formula lb, and Formula II disclosed herein have a Formula llb:
  • Formula llb wherein n is 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkyloxy.
  • -X-Y- is
  • each R 9 , R 10 , R 13A and R 13B are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy; or R 13A and R 13B are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy; and R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -
  • each R 9 and R 10 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy; or R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • -CR 9 CR 10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • R 9 and R 10 together with the carbons to which they are attached form a phenyl or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3
  • the 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyloxy.
  • R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, or C 1 -C 6 alkyloxy.
  • R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, or methoxy.
  • R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, fluoro, or methoxy.
  • R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, fluoro, or methoxy.
  • the compounds of Formula I, Ia, Ib, II, IIa, and IIb have a Formula III: Formula III; wherein m is 0, 1, 2, or 3; and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyloxy.
  • Formula IlIa wherein m is 0, 1, 2, or 3; and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyloxy.
  • Formula Illb wherein m is 0, 1, 2, or 3; and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyloxy.
  • m is 0, 1, or 2.
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy. In some embodiments, each R B is independently halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments, each R B is independently halogen or C 1 -C 3 alkyl. In some embodiments, each R B is independently halogen.
  • m is 0, 1, or 2 and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • m is 0, 1, or 2 and each R B is independently halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • m is 0, 1, or 2 and each R B is independently halogen or C 1 -C 3 alkyl.
  • m is 0, 1, or 2, and each R B is independently halogen.
  • m is 0 or 1
  • each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • m is 0 or 1
  • each R B is independently halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • m is 0 or 1
  • each R B is independently halogen or C 1 -C 3 alkyl.
  • m is 0 or 1, and each R B is independently halogen.
  • m is 1 or 2, and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • m is 1 or 2
  • each R B is independently halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • m is 1 or 2
  • each R B is independently halogen or C 1 -C 3 alkyl.
  • m is 1 or 2, and each R B is independently halogen.
  • m is 1, and R is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • R is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • m is, and
  • R B is halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments, m is 1, and R B is halogen or C 1 -C 3 alkyl. In some embodiments, m is 1, and R B is halogen.
  • m is 2, and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • m is 2, and each R B is independently halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • m is 2, and each R B is independently halogen or C 1 -C 3 alkyl.
  • m is 2, and each R B is independently halogen.
  • -CR 9 CR 10 -, wherein each R 9 and R 10 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyloxy.
  • -X-Y- is -
  • CR 9 CR 10 -, wherein each R 9 and R 10 is independently H, halogen, or C 1 -C 6 alkyl.
  • each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl; or each R 11A and R 12A is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, or C 1 -C 6 haloalkyl; and R 11B and R 12B together with the carbons to which they are attached form a 3-6 membered carbocyclic ring; wherein the 3-6 membered carbocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.
  • -CR 11A R 11B -CR 12A R 12B - wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyl.
  • -X-Y- is -CR 11A R 11B - CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen orC 1 -C 6 alkyl.
  • -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H or halogen.
  • -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H or F.
  • -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is H.
  • -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A and R 12A is independently H, halogenC, 1 -C 6 alkyl, C 1 -C 6 alkyloxy, or C 1 -C 6 haloalkyl; and R 11B and R 12B together with the carbons to which they are attached form a 3-6 membered carbocyclic ring; wherein the 3-6 membered carbocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl
  • z’ is 1. In some embodiments z’ is 2.
  • R 8A is H and R 8B is H, C 1 -C 3 alkyl or benzyl. In some embodiments, R 8A is H and R 8B is H or C 1 -C 3 alkyl. In some embodiments, R 8A is H and R 8B is H or benzyl. In some embodiments, R 8A is H and R 8B is C 1 -C 3 alkyl or benzyl. In some embodiments, R 8A is H and R 8B is C 1 -C 3 alkyl. In some embodiments, R 8A is H and R 8B is benzyl. In some embodiments, both R 8A and R 8B are H.
  • R 8A is C 1 -C 3 alkyl and R 8B is H, C 1 -C 3 alkyl or benzyl. In some embodiments, R 8A is C 1 -C 3 alkyl and R 8B is H or C 1 -C 3 alkyl. In some embodiments, R 8A is C 1 -C 3 alkyl and R 8B is H or benzyl. In some embodiments, R 8A is C 1 -C 3 alkyl and R 8B is C 1 -C 3 alkyl or benzyl. In some embodiments, R 8A is C 1 -C 3 alkyl and R 8B is H. In some embodiments, R 8A is C 1 -C 3 alkyl and R 8B is benzyl. In some embodiments, both R 8A and R 8B are independently C 1 -C 3 alkyl.
  • R 8A is benzyl and R 8B is H, C 1 -C 3 alkyl or benzyl. In some embodiments, R 8A is benzyl and R 8B is H or C 1 -C 3 alkyl. In some embodiments, R 8A is benzyl and R 8B is H or benzyl. In some embodiments, R 8A is benzyl and R 8B is C 1 -C 3 alkyl or benzyl.
  • R 8A is benzyl and R 8B is C 1 -C 3 alkyl. In some embodiments, R 8A is benzyl and R 8B is H. In some embodiments, both R 8A and R 8B are benzyl.
  • R 1 is H, C 1 -C 3 alkyl or phenyl and R 2 is H. In some embodiments, R 1 is H or phenyl and R 2 is H. In some embodiments, R 1 is H or C 1 -C 3 alkyl and R 2 is H. In some embodiments, R 1 is C 1 -C 3 alkyl or phenyl and R 2 is H. In some embodiments, both R 1 and R 2 are H. In some embodiments, R 1 is C 1 -C 3 alkyl and R 2 is H. In some embodiments, R 1 is phenyl and R 2 is H.
  • R 1 is H, C 1 -C 3 alkyl or phenyl and R 2 is C 1 -C 3 alkyl. In some embodiments, R 1 is H or phenyl and R 2 is C 1 -C 3 alkyl. In some embodiments, R 1 is H or C 1 -C 3 alkyl and R 2 is C 1 -C 3 alkyl. In some embodiments, R 1 is C 1 -C 3 alkyl or phenyl and R 2 is C 1 -C 3 alkyl.
  • R 1 is H and R 2 is C 1 -C 3 alkyl. In some embodiments, each R 1 and R 2 is independently C 1 -C 3 alkyl. In some embodiments, R 1 is phenyl and R 2 is Ci- C 3 alkyl. In some embodiments, each R 1 and R 2 is independently H or C 1 -C 3 alkyl. [0103] In some embodiments of the compounds of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb,
  • each R 4 and R 5 is independently H, or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy.
  • R 4 is H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H or C 1 - C 6 alkyl.
  • R 4 is H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H.
  • R 4 is halogen or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H, halogen, or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy.
  • R 4 is halogen or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H, halogen, or C 1 -C 6 alkyl.
  • R 4 is halogen or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one two or three groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H.
  • each R 4 and R 5 is independently H, Me, OMe, or CF 2 F. In some embodiments, R 4 is H, Me, OMe, or CF 2 F and R 5 is H. [0106] In some embodiments of the compounds of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb,
  • R 4 and R 5 are joined together to form a 4-6 membered heterocyclic ring comprising one heteroatom selected from N, O, and S.
  • R 4 and R 5 are joined together to form a 3-6 membered carbocyclic ring.
  • R 6 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 6 is H, halogen or C 1 -C 6 alkyl. In some embodiments, R 6 is halogen or C 1 -C 6 alkyl. In some embodiments, R 6 is C 1 -C 6 alkyl. In some embodiments, R 6 is H.
  • R 7 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 7 is H, halogen, or C 1 -C 6 alkyl. In some embodiments, R 7 is halogen or C 1 -C 6 alkyl. In some embodiments, R 7 is C 1 -C 6 alkyl. In some embodiments, R 7 is H.
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of: [0111]
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of: and
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of: [0118]
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is selected from the group consisting of:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is: [0123]
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is: [0127]
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is:
  • IV, IVa, IVb, V, Va, or Vb is: III. Compositions and Kits
  • compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • the compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art.
  • compositions comprising a compound provided herein (e.g., a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV,
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical compositions may be administered by various methods including, for example, rectal, buccal, intranasal and transderm al routes.
  • the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient such as a compound provided herein
  • the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof.
  • the pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents; or any combinations thereof.
  • compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient (such as a compound provided herein) after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770;
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • kits that comprise a compound provided herein,
  • the kit further comprises instructions for use.
  • the kit comprises a compound provided herein (e.g, a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • a compound provided herein e.g, a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb
  • a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof e.g, a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb
  • kits further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • articles of manufacture that comprise a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.
  • methods of treating an HIV (e.g, HIV-1 and/or HIV-2) infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV,
  • IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, are provided.
  • the methods further comprise administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents.
  • the additional therapeutic agent or agents are anti-HIV agents.
  • the additional therapeutic agent or agents are HIV protease inhibitors,
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase HIV nucleoside or nucleotide inhibitors of reverse transcriptase
  • HIV capsid inhibitors HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.
  • the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent or agents are lenacapavir, islatravir.
  • the additional therapeutic agent is lenacapavir.
  • the additional therapeutic agent is islatravir.
  • IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, for treating an HIV (e.g.,
  • HIV-1 and/or HIV-2) infection in a human having or at risk of having the infection is provided.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in medical therapy is provided.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human one, two, three, or four additional therapeutic agents.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, T
  • the one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latency reversing agents, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, Ma, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, Ma, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, Ma, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.
  • a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.
  • IV, IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.
  • a method of using a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb in therapy is provided.
  • a method of treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal is provided, comprising administering to the mammal a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • composition comprising a compound of Formula I, la, lb,
  • IVa, IVb, V, Va, or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in preventing HIV infection.
  • IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof is provided for use in pre- exposure prophylaxis (PrEP), i.e., before the exposure of the individual to the HIV virus to prevent HIV infection from taking hold if the individual is exposed to the virus and/or to keep the virus from establishing a permanent infection and/or to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood.
  • PrEP pre- exposure prophylaxis
  • an article of manufacture comprising a composition effective to treat an HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by HIV is disclosed.
  • exemplary compositions comprise a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting the replication of HIV comprises exposing the virus to an effective amount of the compound of
  • a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb to inhibit the activity of the HIV integrase enzyme is disclosed.
  • the compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated.
  • Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
  • An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.
  • a compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • a dosage level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg).
  • Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about
  • 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • Daily dosage of a compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to
  • 1,000 mg/day between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compounds of the present disclosure may be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.
  • the compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration.
  • Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about
  • a therapeutically effective amount of the compounds provided herein include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 pg to about 30 mg per day, or from about 30 pg to about 300 pg per day.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound).
  • Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about
  • Other therapeutically effective amounts of the compound of Formula I, la, lb, II, Ila, llb, III, IlIa, IIIb, IV, IVa, IVb, V, Va, or Vb are about 1 mg per dose, or about 2,
  • therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450,
  • the methods described herein comprise administering to the subject an initial daily dose of about 1 to 500 mg of a compound p herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose.
  • the dosage can be increased daily, every other day, twice per week, once per week, once every two weeks, once every three weeks, or once a month.
  • the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500,
  • the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg/day administered in a single dose.
  • the total daily dosage for a human subject may be about 100 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about
  • the total daily dosage for a human subject may be about 500 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg/day administered in a single dose.
  • the total daily dosage for a human subject may be about 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about
  • the total daily dosage for a human subject may be about 1000 mg/day administered in a single dose.
  • a single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours.
  • a single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days.
  • a single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks.
  • a single dose can be administered once every week.
  • a single dose can also be administered once every month.
  • a compound disclosed herein is administered once daily in a method disclosed herein.
  • a compound disclosed herein is administered twice daily in a method disclosed herein.
  • a compound disclosed herein is administered once every 10 days. In some embodiments, a compound disclosed herein is administered once every 15 days.
  • a compound disclosed herein is administered once every 20 days. In some embodiments, a compound disclosed herein is administered once every 10-15 days. In some embodiments, a compound disclosed herein is administered once every 15-20 days. In some embodiments, a compound disclosed herein is administered once every 10-20 days. In some embodiments, a compound disclosed herein is administered once every month. In some embodiments, a compound disclosed herein is administered once every 2 months. In some embodiments, a compound disclosed herein is administered once every 3 months. In some embodiments, a compound disclosed herein is administered once every 4 months. In some embodiments, a compound disclosed herein is administered once every 5 months. In some embodiments, a compound disclosed herein is administered once every 6 months. In some embodiments, a compound disclosed herein is administered once every 8 months. In some embodiments, a compound disclosed herein is administered once every 10 months. In some embodiments, a compound disclosed herein is administered once every year.
  • the frequency of dosage of the compound of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection, HIV infection, cancer, hyper-proliferative disease, or any other indication described herein.
  • a compound can be administered to a human being infected with HBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.
  • Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound.
  • a patient can receive a dose of the compound every other day, or three times per week.
  • a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound.
  • Alternating periods of administration of the compound, followed by non-administration of the compound can be repeated as clinically required to treat the patient.
  • the compounds of the present disclosure or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about
  • the treatment cycles in other embodiments, may also be continuous.
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more
  • a method for treating an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.
  • the present disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically 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.
  • a compound disclosed herein is administered with one or more additional therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one or more 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.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of the one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • 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 or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g.,
  • a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • a compound of Formula I is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as 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, pharmacokinetic enhancers, and combinations thereof.
  • the additional therapeutic agent may be an anti-HIV agent.
  • 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, 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 T cell therapies), latency reversing agents, compounds that target the HIV capsid
  • 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, 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.
  • combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); 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,
  • Examples of other drugs for treating HIV include acemannan, alisporivir, astodrimer,
  • HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfmavir, nelfmavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17,
  • TMB-657 PPL- 100
  • T-169 T-169
  • BL-008 MK-8122
  • TMB-607 TMC-310911.
  • HIV non -nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-
  • VM-1500 elsulfavirine
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC®
  • tenofovir disoproxil orotate fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504,
  • HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of
  • 3,5-dicaffeoylquinic acid 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir,
  • NCINI HIV non-catalytic site, or allosteric, integrase inhibitors
  • HIV entry (fusion) inhibitors examples include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gpl20 inhibitors, and
  • CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO- 140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB -66, polypeptide C25P, TD-0680, and vMIP (Haimipu).
  • gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2,
  • CD4 attachment inhibitors include ibalizumab and CADA analogs.
  • Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.
  • CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).
  • HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-
  • Latency Reversing Agents examples include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, and ixazomib citrate, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343.
  • HDAC histone deacetylase
  • PLC protein kinase C
  • Smyd2 inhibitors Smyd2 inhibitors
  • BET-bromodomain 4 (BRD4) inhibitors ionomycin
  • PMA protein kinase C
  • SAHA suberoyl, anilide, and hydrox
  • HDAC inhibitors include romidepsin, vorinostat, and panobinostat.
  • PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.
  • capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and AVI- CAN1-15 series.
  • immune-based therapies include toll-like receptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin;polymer polyethylene
  • TLR agonists examples include vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531.
  • vesatolimod GS-9620
  • GS-986 examples include lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531.
  • Phosphatidylinositol 3-kinase (PI3K) Inhibitors examples include 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-76
  • Integrin alpha-4/beta-7 antagonists examples include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.
  • HIV Antibodies, Bispecific Antibodies, and “Antibody-like” Therapeutic Proteins examples include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41, antibody- recmiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB vims C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti -Rev antibody, camelid derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41 -based HIV therapeutic antibodies, human recombinant
  • Examples of those targeting HIV in such a manner include bavituximab, UB-421,
  • HIV bispecific antibodies include
  • Example of in vivo delivered bnABs such as AAV8-VRC07; mRNA encoding anti-
  • Examples of pharmacokinetic enhancers include cobicistat and ritonavir.
  • Examples of additional therapeutic agents include the compounds disclosed in WO
  • HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines using viral vectors such as arenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus, modified vaccinia Ankara virus (MV A), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV) and Chimpanzee adenovirus (ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccine combinations,
  • viral vectors such as arenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus, modified vaccinia Ankara virus (MV A), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV) and Chimpanzee adenovirus (ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccine combinations,
  • gpl20 (RV144), monomeric gpl20 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir,
  • Ad4-Envl45NFL Ad5-ENVA-48, HB-500, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5,
  • Vacc-CRX, VVX-004, VAC-3 S multi clade DNA recombinant adenovirus-5 (rAd5), rAd5 gag- pol env A/B/C vaccine, Pennvax-G, Pennvax-GP/MVA-CMDR, HIV-TriMix-mRNA vaccine,
  • HIV-LAMP-vax Ad35
  • Ad35-GRIN Ad35-GRIN
  • NAcGM3/VSSP ISA-51 NAcGM3/VSSP ISA-51
  • poly-ICLC adjuvanted vaccines
  • Tatlmmune GTU-multiHIV (FIT-06), gpl40[delta]V2.TVl+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2,
  • NYVAC-HIV-PT 1 NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41- FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01
  • STRIBILD® elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine
  • TRUVADA® tenofovir disoproxil fumarate and emtricitabine; TDF +FTC
  • tenofovir alafenamide and emtricitabine tenofovir alafenamide and emtricitabine
  • ODEFSEY® tenofovir alafenamide, emtricitabine, and rilpivirine
  • GEN VO Y A® tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir
  • ALETVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine;
  • 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; nelfmavir; nelfmavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
  • a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate
  • a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.
  • a compound as disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula I (e.g., from 1 mg to 500 mg of compound).
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 1 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound as disclosed herein e.g., a compound of Formula I
  • kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
  • Birth control (contraceptive) combination therapy Therapeutic agents used for birth control (contraceptive) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate,
  • Gene Therapy and Cell Therapy including the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient’s own immune system to enhance 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 dendritic cell therapy include AGS-004.
  • AGT- 103 -transduced autologous T cell therapy [0239] AGT- 103 -transduced autologous T cell therapy.
  • the genome editing system is selected from the group consisting of: a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system.
  • HIV targeting CRISPR/Cas9 systems examples include EBT-101.
  • the HIV antigen include an HIV envelope protein or a portion thereof, gpl20 or a portion thereof, a CD4 binding site on gpl20, the CD4-induced binding site on gpl20, N glycan on gpl20, the V2 of gpl20, the membrane proximal region on gp41.
  • the immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. Cells can be autologous or allogeneic.
  • HIV CAR-T examples include VC-CAR-T, anti-CD4 CART cell therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide.
  • TCR-T cell therapy TCR-T cells are engineered to target HIV derived peptides present on the surface of virus-infected cells. VII. Examples Exemplary chemical entities of the present disclosure are provided in the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.
  • Step 1 Preparation of 1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2- b][1,2,5]triazonine-2,14-dione (2-a) and 1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13- methanobenzo[g]pyrido[1,2-b ][ 1, 2, 5 ]triazonine-2, 14-dione (2-b )
  • Step 2 Preparation of 1 -(benzyloxy)-10-fluoro-3-iodo-7,12-dihydro-6, 13- methanobenzo[g]pyrido[1,2-b] [1,2,5]triazonine-2, 14-dione (3-a) and 1-(benzyloxy)-9-fluoro-3- iodo- 7, 12-dihydro-6, 13-methanobenzo[g]pyrido[ 1, 2-b ][ 1, 2, 5 ]triazonine-2, 14-dione (3-b):
  • NIS(114 mg, 0.51 mmol) were added sequentially. Reaction vial was sealed and heated from rt to 80°C for 30 min. Additional m-CPBA (77%) (114 mg, 0.51 mmol) and NIS(114 mg, 0.51 mmol) were added sequentially. Reaction mixture was heated again at 80 °C for 30 min.
  • Step 3 Preparation of: (6R)-1-(benzyloxy)-10-fluoro-2, 14-dioxo-N-(2,4,6-trifluorobenzyl)-
  • Step 1 Synthesis of methyl 1-(allyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6- trifluorobenzyl) carbamoyl) -1, 4-dihydropyridine-2-carboxylate (5):
  • Step 2 Synthesis of tert-butyl N-allyl-N-[3-benzyloxy-2- [[(1S)- 1-methylallyl] carbamoyl] -4-oxo-
  • Step 3 Synthesis of 1-allyl-5-hydroxy-3-[(lS)-1-methylallyl]-4,6-dioxo-N-[(2,4,6- trifluor ophenyl)methyl]-2H-pyrido [2, 1-f][ 1,2, 4]triazine-7 -carboxamide (8) and 1-allyl-5- benzyloxy-3-[ ( lS)-1-methylallyl ] — 4, 6-dioxo-N-[ ( 2, 4, 6-trifluorophenyl)methyl ]-2H-pyrido[ 2,1- f][ 1, 2, 4 ]triazine- 7 -carboxamide (9):
  • the reaction was capped and heated for another 30 min.
  • the reaction was cooled to rt, diluted with EtOAc, basified to pH ⁇ 7 with sat. NaHCO 3 , organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step 4 Synthesis of (10S)-6-benzyloxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl] ⁇
  • Step 5 Synthesis of (10S)-6-hydroxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl] ⁇
  • Step 1 Synthesis of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6- trifluorobenzyl) carbamoyl) -1, 4-dihydropyridine-2-carboxylate :
  • Step 2 Synthesis of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6- trifluorobenzyl) carbamoyl) -1, 4-dihydropyridine-2-carboxylic acid:
  • Step 3 Synthesis of tert-butyl (3-(benzyloxy)-2-carbamoyl-4-oxo-5-((2,4,6- trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate:
  • Step 4 Synthesis of 1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4- dihydropyridine-2, 5-dicarboxamide :
  • Step 6 Synthesis of 13-benzyl-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5, 7,9- hexahydro-1, 6-methanopyrido[ 1, 2-b ][ 1, 2, 5 ]triazonine-10-carboxamide:
  • Step 7 Synthesis of 13-benzyl-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5, 7,9- hexahydro-1, 6-methanopyrido[ 1, 2-b ][ 1, 2, 5 ]triazonine-10-carboxamide (C6):
  • Example 7 Preparation of (1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6- trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11- carboxamide (C7):
  • Step 1 Synthesis of methyl (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4- oxo-5-( (2, 4, 6-trifluorobenzyl)carbamoyl)-1 , 4-dihydropyridine-2-carboxylate (7 A):
  • Step 2 Synthesis of (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5- ((2,4, 6-trifluorobenzyl)carbamoyl) -1, 4-dihydropyridine-2-carboxylic acid (7B):
  • Step 3 Synthesis of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6- trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((R)-pent-4-en-2-yl)carbamate (7C):
  • Step 4 synthesis of tert-butyl (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-11-((2,4,6- trifluorobenzyl) carbamoyl) -2, 3, 6, 7, 8, 10-hexahydro-1H-pyrido [ 1, 2-b ][ 1, 2, 5 ]triazecine-1- carboxylate (7D):
  • Step 5 Synthesis of (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)- 2, 3, 6, 7, 8, 10-hexahydro-1H-pyrido[ 1, 2-b ][ 1, 2, 5 ]triazecine-11-carboxamide (7E):
  • Step 6 Synthesis of (lS,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)- 3, 4, 5, 6, 8, 10-hexahydro-2H-1 , 7-methanopyrido[ 1, 2-b ][ 1, 2, 5 ]triazecine-11-carboxamide (7F) :
  • Step 7 Synthesis (lS,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)- 3, 6, 8, 10-tetrahydro-2H-1, 7-methanopyrido[ 1, 2-b ][ 1, 2, 5 ]triazecine-11-carboxamide (C7):
  • Example 8 Preparation of (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6- trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11- carboxamide (C8):
  • Peak 1 (1R,2R.Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8. 10-dioxo-3.6.8. 10- tetrahydro-2H-1.7-methanopyrido[1.2-b][.2.51triazecine-11-carboxamide (C10): MS (m/z):
  • Peak 2 (1S.2R.Z)-N-(2.4-difluorobenzyl)-9-hvdroxv-2-methvl-8.10-dioxo-3.6.8.10- tetrahvdro-2H-1.7-methanopyridor[1.2-b][1,2,5]triazecine-11-carboxamide (C11): MS (m/z):
  • Example 12 Preparation of (1R,2S,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6- trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-1l- carboxamide (02):
  • Compound 12 was prepared in a manner similar to (1S,2R,6S,Z)-9-hydroxy-2,6- dimethyl-8, 10-dioxo-N-(2, 4, 6-trifluorobenzyl)-3, 6,8, 10-tetrahydro-2H-1, 7-methanopyrido[1, 2- b] [1 ,2, 5]triazecine- 11 -carboxamide (C7 in example 7) using (2R)-pent-4-en-2-ol instead of (2S)- pent-4-en-2-ol in step 1 and using (2R)-but-3-en-2-amine;hydrochloride instead of (2S)-but-3- en-2-amine;hydrochloride in step 3.
  • Acetonitrile-d3) ⁇ 10.43 (s, 1H), 8.42 (s, 1H), 6.94 - 6.81 (m, 2H), 5.75 - 5.60 (m, 2H), 5.20 (q,
  • Compound 13 was prepared in a manner similar to (1S,2R,6S)-9-hydroxy-2,6- dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11 -carboxamide (C8) in example 8 using (1S,2R,Z)-N-
  • Compound 14 was prepared in a manner similar to (1S,2R,6S)-9-hydroxy-2,6- dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (C8) in example 8 using (1R,2S,6R,Z)-
  • Compound 15 was prepared in a manner similar to (1R,2R,Z)-N-(2,4- difluorobenzyl)-9-hydroxy-2-methyl-8, 10-dioxo-3,6,8, 10-tetrahydro-2H- 1,7- methanopyrido[l 2 b][l 2 5]triazecine l l carboxamide (C8) in example 8 using (1R,2R,Z)-N- (2, 4-difluorobenzyl)-9-hydroxy-2-m ethyl-8, 10-dioxo-3 ,6, 8, 10-tetrahydro-2H- 1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (10) instead of (2R,6S,Z)-9-
  • Compound 17 was prepared in a manner similar to (1S,2R,6S)-9-hydroxy-2,6- dimethyl-8, 10-dioxo-N-(2, 4, 6-trifluorobenzyl)-3, 4, 5, 6,8,10-hexahydro-2H- 1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (C8) in example 8 using (1S,2R,Z)-9- hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (16) instead of (2R,6S,Z)-9-
  • Example 19 and 20 Preparation of (1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N- (2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine- 11-carboxamide (C19) and (1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6- trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-1l- carboxamide (C20):
  • Peak 1 (1 R.2S.6S.Z )-9-hydroxy-2, 6-dim ethyl -810-dioxo-N-(2.4.6-trif1uorobenzyl )-
  • Compound 23 was prepared in a manner similar to (1S,2R,6S)-9-hydroxy-2,6- dimethyl-8, 10-dioxo-N-(2, 4, 6-trifluorobenzyl)-3, 4, 5, 6,8,10-hexahydro-2H- 1,7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (C8) in example 8 using (1S,2S,6S,Z)-9- hydroxy-2, 6-dimethyl-8,10-dioxo-N-(2, 4, 6-trifluorobenzyl)-3, 6,8,10-tetrahydro-2H-1, 7- methanopyrido[1, 2-b][1, 2, 5]triazecine-11-carboxamide (C20): instead of (2R,6S,Z)-9-
  • Step 1 Preparation of methyl 3-(benzvloxv)-1-((tert-butoxvcarbonyl)amino)-4-oxo-5-((2,4.6- trifluorobenzvl)carbamovl)-1,4-dihvdropvridine-2-carboxvlate
  • Step 2 Preparation of methyl 3-(benzvloxv)-1-(but-3-en-2-vl(tert-butoxvcarbonyl)amino)-4-oxo-
  • Step 3 Preparation of 3-(benzvloxv)-1-(but-3-en-2-vl(tert-butoxvcarbonvl)amino)-4-oxo-5-
  • Step 4 Preparation of tert-butyl (3-(benzvloxv)-2-(((S)-but-3-en-2-vl)carbamoyl)-4-oxo-5 -
  • Step 5 Preparation of 3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-
  • Step 6 Preparation of 5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4.6- trifluorobenzyl)-2, 3, 4, 6-tetrahydro-1H-pyridol[21-f][ 1, 2, 41 triazine-7 -carboxamide
  • reaction mixture was then concentrated to dryness to remove all solvents and acids.
  • the resulting crude material was then dissolved in DMF (17 mL).
  • K 2 CO 3 (2.76 g, 20 mmol) and benzyl bromide (2.56 g, 15 mmol) were added sequentially.
  • the reaction mixture was then heated at 100 °C for 3 hrs.
  • Reaction mixture was then diluted with EtOAc (100 mL) and was then treated with NaHCO 3 (saturated aqueous solution) (100 mL) and water (100 mL).
  • Step 7 Preparation of (1S,2R,5S)-8-(benzvloxv)-2,5-dimethyl-7,9-dioxo-N-(2,4.6- trifluorobenzyl)-2, 5, 7, 9-tetrahydro-1, 6-methanopyridof l, 2-b][ 1,2,5 ltriazonine-10-carboxamide
  • Example 27 Preparation of (1S,2S,5S )-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6- trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10- carboxamide (C27)
  • Example 28 Preparation of (1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6- trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10- carboxamide (C28)
  • Step 1 Preparation of methyl 3-(benzvloxv)-1-((tert-butoxvcarbonvl)amino)-5-((2,4- difluorobenzvl)carbamovl)-4-oxo-1,4-dihvdropvridme-2-carboxylate
  • BocNHNH 2 (5 g, 37.8 mmol) and NaHCO 3 (5.87 g, 69.9 mmol) were added at room temperature. Reaction mixture was then stirred at 55 °C for 16 hours. The reaction mixture was placed under vacuum to remove the most MeOH. The resulting residue was diluted with
  • Step 2 Preparation of methyl 3-(benzvloxv)-1-(but-3-en-2-vl(tert-butoxvcarbonyl)amino)-4-oxo- 5-( (2, 4-difluorobenzvl)carbamoyl)-1 , 4-dihvdropyridine-2-carboxvlate
  • Methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4- difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (10.5 g, 19.3 mmol) was dissolved in THF (200 mL) at rt.
  • Step 3 Preparation of 3-(benzvloxv)-1-(but-3-en-2-vl(tert-butoxvcarbonvl)amino)-4-oxo-5-
  • Step 5 Preparation of 3-(benzvloxv)-N2-((S)-but-3-en-2-vl)-1-(but-3-en-2-vlamino)-4-oxo-N5- (2, 4-difluorobenzyl)-1, 4-dihydropyridine-2, 5 -dicarboxamide
  • Step 6 Preparation of 5-(benzvloxv)-3-((S)-but-3-en-2-vl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4- difluorobenzvl)-2, 3, 4, 6-tetrahydro-1H-pwido[2, 1-flf l, 2, 4 ltriazine- 7 -carboxamide
  • Step 7 Preparation of (1S.2R,5S)-8-(benzyloxy)-2.5-dimethyl-7.9-dioxo-N-(2.4-difluorobenzyl)- 2, 5, 7, 9-tetrahydro-1, 6-methanopyridof l, 2-b 1 [1,2,5 ltriazonine- 10-carboxamide and (1S, 2S, 5S) ⁇ 8-(benzyloxv)-2, 5 -dimethyl- 7, 9-dioxo-N-(2, 4-difluorobenzyl)-2, 5, 7, 9-tetrahydro-1, 6- methanoyyridoi 1, 2-bJf 1, 2, 5]triazonine-10-carboxamide
  • Step 8 Preparation of (1S.2R,5S)-8-hvdroxv-2,5-dimethvl-7,9-dioxo-N-(2,4-difluorobenzyl)-
  • Example 32 Preparation of (1S,2R,3R,4S,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9- dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2- b] [1,2,5]triazonine-10-carboxamide: (C32) Preparation of (1S, 2R, 3R, 4S, 5S)-8-(benzyloxy)-3, 4-dihydroxy-2, 5-dimethyl- 7, 9-dioxo-N-(2, 4, 6- trifluorobenzyl)-2, 3, 4, 5, 7, 9-hexahydro-1, 6-methanopyridoi l, 2-b][ 1,2,5 ltriazonine-10- carboxamide :
  • step 7, A (140 mg, 0.26 mmol) was dissolved in acetone (8 mL) and water (1 mL) mixture, then was cooled down to 0 °C in ice- water bath.
  • 4-Methylmorpholine N-oxide (50% in water, 0.1 mL, 2 eq.) was slowly added into above reaction solution.
  • 2.5% osmium tetr oxide (0.01 mL, 4% eq.) was added.
  • the mixture was stirred at 0 °C and warm up to r.t. for 2 days.
  • the reaction was quenched by adding aqueous 10% sodium sulfite solution.
  • reaction mixture was extracted using (1 : 1) EtOAc:n-BnOH .
  • organic layer was concentrate down, and purified via silica column (eluting with 0-10% MeOH/DCM) to give (1S,2R,3S,4R,5S)-8-
  • methyl iodide (diluted with DCM to 100 times dilute, 1 mL, 1.3 eq.) was added. The mixture was stirred at 0 °C for 30 minutes. LC-MS showed bis-Me product, and two mono-Me products, and some starting material. The reaction was quenched by adding aqueous saturated sodium bicarbonate solution. The reaction mixture was extract using ethyl acetate. The organic layer was concentrated down, and purified via preparative HPLC, eluting 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give
  • Example 33 Preparation of (1S,2R,4R,5S)-8-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo- N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine- 10-carboxamide
  • C33 Preparation of (1S,2R,4R.5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4.6- trifluorobenzyl)-2, 3, 4, 5, 7, 9-hexahydro-1, 6-methanopyrido[ l, 2-bl[ 1,2,5 ltriazonine-10- carboxamide and (1S, 2R, 3S , 5S)-8-(benzyloxv)-3-hydroxy-2, 5 -dimethyl- 7, 9-dioxo-N
  • N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10- carboxamide (10 mg, 0.018 mmol) was dissolved in DMF (1 mL), then was cooled down to 0 °C in ice-water bath. Sodium hydride (60%, 1.4 mg, 2 eq.) was added into above reaction solution.
  • Example 38 Preparation of (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4,5-difluoro-9-hydroxy- 2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine- 11-carboxamide (C38):
  • Step 1 Synthesis of (1S.2R,4S.5R)-9-(benzvloxv)-N-(2,4-difluorobenzvl)-4,5-dihydroxv-2- methyl-8, 10-dioxo-3, 4, 5, 6, 8, 10-hexahydro-2H-1, 7-methanopwidof l, 2-b][ 1,2,5 ltriazecine-11- carboxamide (15 A) :
  • Step 2 Synthesis of (1S,2R,4R.5S)-N-(2,4-difluorobenzvl)-4,5-difluoro-9-hvdroxv-2-methvl- 8, 10-dioxo-3, 4, 5, 6, 8, 10-hexahydro-2H-1, 7-methanopwidof l, 2-b][ l, 2, 51triazecine-11- carboxamide (C38):
  • Step 1 Synthesis of (1S,2R,4S,5R)-9-(bemyloxy)-N-(2,4-difluorobemyl)-5-hydroxy-4-methoxy- 2-methyl-8, 10-dioxo-3,4,5, 6,8, 10-hexahydro-2H-1, 7-methanovwido[l,2-bl [l,2,51triazecine-11- carboxamide and (1S, 2R, 4S, 5R)-9-(benzyloxy)-N-(2, 4-difluorobenzyl)-4, 5-dimethoxy-2-methyl-
  • Step 2 Synthesis of ( 1S,2R,4S,5R)-N-(2,4-difluorobenzvl)-9-hvdroxv-4,5-dimethoxv-2-methvl -
  • Step 1 Synthesis of tert-butyl ( tert-butoxycarbonyl) (prop-2-yn-1-vDcarbamate :
  • Step 2 Synthesis of tert-butyl (R,Z)-(tert-butoxvcarbonvl)(5-hvdroxyhex-2-en-1-vl)carbamate:
  • reaction mixture was stirred at this temperature for 4 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution and water. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated NaHCO 3 solution and brine, dried over Na 2 SO 4 and evaporated to obtain crude which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain tert-butyl (R)-(tert-butoxycarbonyl)(5 -hydroxyhex-2-yn- 1 -yl)carbamate as a colorless liquid.

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