WO2023102523A1 - Therapeutic compounds for hiv virus infection - Google Patents

Therapeutic compounds for hiv virus infection Download PDF

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Publication number
WO2023102523A1
WO2023102523A1 PCT/US2022/080813 US2022080813W WO2023102523A1 WO 2023102523 A1 WO2023102523 A1 WO 2023102523A1 US 2022080813 W US2022080813 W US 2022080813W WO 2023102523 A1 WO2023102523 A1 WO 2023102523A1
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Prior art keywords
inhibitors
alkyl
hiv
pharmaceutically acceptable
acceptable salt
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PCT/US2022/080813
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English (en)
French (fr)
Inventor
Gediminas J. Brizgys
Chienhung CHOU
Hang CHU
Julie Farand
Michael Graupe
Tezcan GUNEY
Darryl Kato
Jiayao Li
John O. Link
James B.C. MACK
Dong Min Mun
Scott D. Schroeder
William J. Watkins
Qiaoyin Wu
Jennifer R. Zhang
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority to EP22843973.3A priority Critical patent/EP4440701A1/en
Priority to CA3238270A priority patent/CA3238270A1/en
Priority to JP2024532836A priority patent/JP7736929B2/ja
Priority to AU2022403012A priority patent/AU2022403012B2/en
Priority to CN202280078954.7A priority patent/CN118369316A/zh
Priority to KR1020247021822A priority patent/KR20240113832A/ko
Publication of WO2023102523A1 publication Critical patent/WO2023102523A1/en
Anticipated expiration legal-status Critical
Priority to JP2025142237A priority patent/JP2025172092A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • This disclosure relates generally to novel compounds and pharmaceutical compositions comprising said compounds for use in the prevention or treatment of a Retroviridae viral infection, including an infection caused by the human immunodeficiency virus (HIV). This disclosure also relates to methods of making said compounds and of said compounds.
  • HIV human immunodeficiency virus
  • Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human and animal diseases.
  • Lentivirus HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections.
  • Treating HIV-1 infections with highly active antiretroviral therapies has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S.M., et al.; JAMA 2008, 300: 555-570).
  • these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science 2010, 327:697-701). Therefore, there is a pressing need to discover new antiretroviral agents that are active against emerging drug-resistant HIV variants.
  • HIV therapies and treatments are providing regimens to patients with improved pharmacokinetic properties, including, for example, increased potency, long-acting pharmacokinetics, low solubility, low clearance, and/or other properties.
  • pharmacokinetic properties including, for example, increased potency, long-acting pharmacokinetics, low solubility, low clearance, and/or other properties.
  • current regimens for treating HIV have progressed enough that patients no longer have to take multiple pills multiple times a day, patients today still are required to take a pill every day for the foreseeable span of their life.
  • HIV therapies that require patients take medication less than once a day (e.g. once every couple of days, once a week, once every other week, once a month, and so forth) or take a smaller effective dose of the medication(s) on a daily, weekly, monthly, or longer basis.
  • a compound of Formula I, Formula I or a pharmaceutically acceptable salt thereof wherein X is -C(O)C(O)NR 1 R 1 , -C(O)C(O)OR 2 , -(C1-6 alkyl)OR 3 , -C(O)NR 4 R 5 , -C(O)OR 6 , or -C(O)C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c ; each R 1 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c
  • provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating or preventing a human immunodeficiency virus (HIV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • HAV human immunodeficiency virus
  • provided herein is a method of treating a human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein for use in therapy is provided herein for use in therapy.
  • HIV human immunodeficiency virus
  • HAV human immunodeficiency virus
  • a dash ( ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • R aa in the below structure can be attached to any of the five carbon ring atoms or R aa can replace the hydrogen attached to the nitrogen ring atom: .
  • R aa in the below structure: R aa can be attached to any of the numbered positions shown below: .
  • a solid line coming out of the center of a ring indicates that the point of attachment for the ring system to the rest of the compound can be at any ring atom of the fused, bridged, or spirocyclic ring system.
  • the monocyclic heterocyclyl can be attached to the rest of the compound at any of the numbered positions shown below: .
  • the fused bicyclic heterocyclyl can be attached to the rest of the compound at any of the eight numbered positions shown below: .
  • Cu-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • x-y membered rings wherein x and y are numerical ranges, such as “3 to12- membered heterocyclyl”, refers to a ring containing x-y atoms (i.e., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
  • certain commonly used alternative chemical names may or may not be used.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a compound disclosed herein” or “a compound of the present disclosure” or “a compound provided herein” or “a compound described herein” refers to the compounds of Formula I. Also included are the specific compounds of Examples 1 to 137.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%. In other embodiments, the term “about” includes the indicated amount ⁇ 5%. In certain other embodiments, the term “about” includes the indicated amount ⁇ 1%. Also, the term “about X” includes description of “X”. [0021] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl), or 1 to 2 carbon atoms (i.e., C1-2 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e.
  • Alkenyl refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkylene refers to a divalent and unbranched saturated hydrocarbon chain.
  • alkylene has 1 to 20 carbon atoms (i.e., C1-20 alkylene), 1 to 12 carbon atoms (i.e., C1-12 alkylene), 1 to 8 carbon atoms (i.e., C1-8 alkylene), 1 to 6 carbon atoms (i.e., C1-6 alkylene), 1 to 4 carbon atoms (i.e., C 1-4 alkylene), 1 to 3 carbon atoms (i.e., C 1-3 alkylene), or 1 to 2 carbon atoms (i.e., C1-2 alkylene).
  • alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene.
  • an alkylene is optionally substituted with an alkyl group.
  • substituted alkylene groups include -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 -, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2.
  • Alkoxy refers to the group “alkyl-O-”.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.
  • Hydroalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • acyl examples include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C( ⁇ O)NR y R z and an “N-amido” group which refers to the group -NR y C( ⁇ O)R z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.
  • Amino refers to the group -NR y R z wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.
  • Aryl 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., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
  • Cyano or “carbonitrile” refers to the group -CN.
  • Cycloalkyl 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 includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Bridged refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. [0033] The term “fused” refers to a ring which is bound to an adjacent ring. [0034] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom.
  • spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
  • Halogen or “halo” includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • Examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).
  • Heteroalkylene refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S.
  • a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-20 heteroalkylene); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-8 heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S S (i.e., C1-6 heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-4 heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-3 heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene).
  • -CH2O- is a C1 heteroalkylene
  • -CH2SCH2- is a C 2 heteroalkylene
  • heteroalkylene groups include -CH 2 CH 2 OCH 2 -, -CH2SCH2OCH2-, -CH2O-, and -CH2NHCH2-.
  • a heteroalkylene is optionally substituted with an alkyl group.
  • substituted heteroalkylene groups include -CH(CH 3 )N(CH 3 )CH 2 -, -CH 2 OCH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )S-, -CH 2 NHC(CH 3 ) 2 -, -C(CH 3 ) 2 SCH 2 -, -CH(CH 3 )N(CH 3 )CH(CH 3 )O-, -CH 2 SC(CH 2 CH 3 )(CH 3 )-, and -CH2C(CH2CH3)2NH-.
  • Heteroaryl 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 1 to 20 carbon ring atoms (i.e., C1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); 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. [0038] “Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to a non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl or “heterocyclic ring” or “heterocycle” refer to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to rings that are partially saturated where specified.
  • heterocyclyl or “heterocyclic ring” or “heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond).
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • heterocyclyl has 2 to 20 carbon ring atoms (i.e., C 2-20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C 2-12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2-10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C 3-12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C 3-6 heterocyclyl); having 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, sulfur or oxygen.
  • C 2-20 heterocyclyl having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatom
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • bridged- heterocyclyl refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • bridged- heterocyclyl includes bicyclic and tricyclic ring systems.
  • spiro- heterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl.
  • spiro- heterocyclyl examples include bicyclic and tricyclic ring systems, such as 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably.
  • a heterocyclyl is substituted with an oxo group.
  • “Hydroxy” or “hydroxyl” refers to the group -OH.
  • “Sulfonyl” refers to the group -S(O) 2 R bb , where R bb is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. [0042] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • substituted aryl includes, but is not limited to, “alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and/or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and/or heteroaryl is attached to the rest of the compound.
  • the cyclopropyl is substituted with a methyl group: .
  • 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 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 conventional techniques, for example, chromatography and fractional crystallization.
  • chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s).
  • scalemic mixture is a mixture of stereoisomers at a ratio other than 1:1.
  • 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.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 is a “scalemic” mixture.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.
  • Tautomeric isomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • a “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided.
  • Hydrates of the compounds provided herein are also provided.
  • Any formula or structure provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 2 H, 3 H, 13 C and 14 C are incorporated, are also provided herein.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the present disclosure also includes compounds of Formula I, in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [0055] Deuterium labelled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME).
  • ADME absorption, distribution, metabolism and excretion
  • isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as "H” or "hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • salts of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, and the like.
  • primary, secondary and tertiary amines such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (i.e., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (i.e., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (i.e., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (i.e., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).
  • a) inhibiting the disease or condition i.e., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • a therapeutically effective amount may be an amount sufficient to improve a symptom of a Retroviridae viral infection, including but not limited to HIV infection.
  • the therapeutically effective amount may vary depending on the subject, and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art. II.
  • a compound of Formula I, Formula I or a pharmaceutically acceptable salt thereof wherein X is -C(O)C(O)NR 1 R 1 , -C(O)C(O)OR 2 , -(C 1-6 alkyl)OR 3 , -C(O)NR 4 R 5 , -C(O)OR 6 , or -C(O)C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c ; each R 1 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c
  • X is -C(O)C(O)NR 1 R 1 , -C(O)C(O)OR 2 , -(C 1-6 alkyl)OR 3 , -C(O)NR 4 R 5 , -C(O)OR 6 , or -C(O)C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c ; each R 1 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a ; R 2 is H or C1-6 alky
  • a 4 membered monocyclic heterocyclyl has 1 ring heteroatom selected from N, O, and S.
  • a 5-7 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S.
  • a 5-6 membered monocyclic heteroaryl has 1-4 ring heteroatoms independently selected from N, O, and S.
  • a 8-10 membered fused bicyclic heteroaryl has 1-4 ring heteroatoms independently selected from N, O, and S.
  • X is -C(O)C(O)NR 1 R 1 , -C(O)C(O)OR 2 , -(C 1-6 alkyl)OR 3 , -C(O)NR 4 R 5 , -C(O)OR 6 , or -C(O)C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • X is -C(O)C(O)NR 1 R 1 .
  • each R 1 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • each R 1 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • each R 1 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • one or both R 1 is H.
  • one or both R 1 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or both R 1 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or both R 1 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • one or both R 1 is C1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or both R 1 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or both R 1 is C 1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • one or both R 1 is C 1-6 alkyl.
  • one R 1 is H and one R 1 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • X is -C(O)C(O)OR 2 .
  • R 2 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 2 is H or C1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 2 is H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • R 2 is H, methyl, or ethyl.
  • R 2 is H.
  • R 2 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 2 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 2 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 2 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 2 is C1-3 alkyl, wherein the C1-3 alkyl is substituted with 1-3 groups independently selected from -C(O)OH and R a .
  • R 2 is C 1-6 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 2 is C1-3 alkyl.
  • R 2 is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 2 is methyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 2 is ethyl. [0078] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, X is -(C 1-6 alkyl)OR 3 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, X is -(C1-4 alkyl)OR 3 .
  • X is -CH 2 OR 3 or -CH 2 CH 2 OR 3 .
  • R 3 is -P(O)(OH)2 , -C(O)R 3a , -C(O)OR 3a , -C(O)NR 3b R 3b , -C(O)C(O)OR 3a , -S(O) 2 R 3a , -S(O) 2 NR 3b R 3b , or -S(O) 2 OR 3a .
  • R 3 is -C(O)R 3a , -C(O)C(O)OR 3a , or -P(O)(OH)2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -C(O)R 3a or -C(O)C(O)OR 3a . [0080] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -P(O)(OH)2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -C(O)R 3a .
  • R 3 is -C(O)OR 3a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -C(O)NR 3b R 3b . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -C(O)C(O)OR 3a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -S(O)2R 3a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 3 is -S(O) 2 NR 3b R 3b .
  • R 3 is -S(O) 2 OR 3a .
  • R 3a is H or C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, -C(O)OR 9 , and R a .
  • R 3a is H.
  • R 3a is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -CN, -C(O)OR 9 , and R a .
  • one or both R 3b is R d .
  • R 3 is -P(O)(OH)2
  • X is -C(O)NR 4 R 5 .
  • R 4 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH)2, -CN, halogen, R a , R b , and R c .
  • R 4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH) 2 , -C(O)OR 7 , -C(O)NR 8 R 8 , -S(O)2R 7 , -S(O)2NR 8 R 8 , -S(O)2OR 7 , -NR 8 C(O)R 7 , -NR 8 C(O)NR 8 R 8 , -NR 8 S(O) 2 R 7 , and R a .
  • R 4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-2 groups independently selected from -C(O)OH and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 4 is H or methyl. [0087] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 4 is H.
  • R 4 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH) 2 , -CN, halogen, R a , R b , and R c .
  • R 4 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 4 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH) 2 , -C(O)OR 7 , -C(O)NR 8 R 8 , -S(O) 2 R 7 , -S(O) 2 NR 8 R 8 , -S(O) 2 OR 7 , -NR 8 C(O)R 7 , -NR 8 C(O)NR 8 R 8 , -NR 8 S(O)2R 7 , and R a .
  • R 4 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-2 groups independently selected from -C(O)OH and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 4 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -B(OH) 2 , -CN, halogen, R a , R b , and R c .
  • R 4 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • R 4 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -B(OH)2, -C(O)OR 7 , -C(O)NR 8 R 8 , -S(O)2R 7 , -S(O)2NR 8 R 8 , -S(O)2OR 7 , -NR 8 C(O)R 7 , -NR 8 C(O)NR 8 R 8 , -NR 8 S(O)2R 7 , and R a .
  • R 4 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-2 groups independently selected from -C(O)OH and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 4 is C 1-6 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 4 is methyl.
  • R 5 is H, C1-6 alkyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH)2, -CN, halogen, R a , R b , R c , and R 5a , wherein the 8-10 membered fused bicyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5b .
  • R 5 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5a .
  • R 5 is H.
  • R 5 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -B(OH) 2 , -CN, halogen, R a , R b , R c , and R 5a .
  • R 5 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5a .
  • R 5 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -B(OH)2, -CN, halogen, R a , R b , R c , and R 5a .
  • R 5 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5a .
  • each R 5a independently is 4-7 membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused bicyclic heteroaryl, wherein the 4-7 membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • each R 5a independently is 4-7 membered monocyclic heterocyclyl or phenyl, wherein the 4-7 membered monocyclic heterocyclyl and phenyl are each independently optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 4-7 membered monocyclic heterocyclyl.
  • one or more R 5a is phenyl, wherein the phenyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is phenyl, wherein the phenyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is phenyl.
  • one or more R 5a is naphthalenyl, wherein the naphthalenyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is naphthalenyl, wherein the naphthalenyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is naphthalenyl.
  • one or more R 5a is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 5-6 membered monocyclic heteroaryl.
  • one or more R 5a is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • one or more R 5a is 8-10 membered fused bicyclic heteroaryl.
  • R 5 is C1-6 alkyl.
  • R 5 is methyl, .
  • R 5 is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5b .
  • R 5 is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and R 5b .
  • R 5 is 8-10 membered fused bicyclic heteroaryl.
  • each R 5b independently is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • each R 5b independently is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • each R 5b independently is C 1-6 alkyl.
  • X is -C(O)OR 6 .
  • R 6 is C 1-10 alkyl or C 3-7 monocyclic cycloalkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C 2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 6 is C1-10 alkyl or C3-7 monocyclic cycloalkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C 2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR 8 R 8 , and R a .
  • R 6 is C1-10 alkyl or C3-5 monocyclic cycloalkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O) 2 OR 7 , -(O(C 1-4 alkyl)) n OR 7a , -NR 8 R 8 , R a , -OC(O)(C2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C 3-5 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR 8 R 8 , and R a .
  • R 6 is C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C 2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl.
  • R 6 is C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl.
  • R 6 is C 1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O)2OR 7 , -(O(C1-4 alkyl))nOR 7a , -NR 8 R 8 , R a , -OC(O)(C2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl.
  • R 6 is C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O) 2 OR 7 , -(O(C 1-4 alkyl))nOR 7a , -NR 8 R 8 , R a , -OC(O)(C2-6 alkenylene)C(O)OR 9 , 5-6 membered monocyclic heterocyclyl, and 6 membered monocyclic heteroaryl.
  • 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O) 2 OR 7 , -(O(C 1-4 alkyl))nOR 7a , -NR 8 R 8 , R a , -OC(O)(C2-6 alkenylene)C(O)OR 9 , 5-6 membered monocyclic heterocyclyl, and
  • R 6 is C 1-10 alkyl, wherein the C 1-10 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl.
  • R 6 is C1-10 alkyl, wherein the C1-10 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , R c , and -OC(O)(C2-6 alkenylene)C(O)OR 9 , 4- 7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl.
  • R 6 is C1-10 alkyl, wherein the C1-10 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O) 2 OR 7 , -(O(C 1-4 alkyl)) n OR 7a , -NR 8 R 8 , R a , -OC(O)(C 2-6 alkenylene)C(O)OR 9 , 4-7 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl.
  • R 6 is C 1-10 alkyl, wherein the C 1-10 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 7 , -S(O) 2 OR 7 , -(O(C 1-4 alkyl)) n OR 7a , -NR 8 R 8 , R a , -OC(O)(C2-6 alkenylene)C(O)OR 9 , 5-6 membered monocyclic heterocyclyl, and 6 membered monocyclic heteroaryl.
  • R 6 is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one -(O(C1-4 alkyl))nOR 7a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 6 is C1-10 alkyl. [0111] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, n is 1, 2, 3, 4, or 5. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, n is 2.
  • n is 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, n is 4. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, n is 5. [0112] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 6 is methyl,
  • R 6 is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one -(O(C 1-4 alkyl))nOR 7a and wherein n is 1, 2, or 3.
  • R 6 is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with pyridinyl or morpholinyl.
  • R 6 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 6 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR 8 R 8 , and R a .
  • R 6 is C3-5 monocyclic cycloalkyl, wherein the C3-5 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR 8 R 8 , and R a .
  • R 6 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • R 6 is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR 8 R 8 , and R a .
  • R 6 is C 3-5 monocyclic cycloalkyl, wherein the C 3-5 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR 8 R 8 , and R a .
  • R 6 is C 3-7 monocyclic cycloalkyl.
  • R 6 is C3-5 monocyclic cycloalkyl, wherein the C3-5 monocyclic cycloalkyl is substituted with 1-2 groups independently selected from -C(O)OH, -NR 8 R 8 , and R a .
  • R 6 is cyclobutyl, wherein the cyclobutyl is substituted with one -NR 8 R 8 .
  • X is -C(O)C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • X is -C(O)C1-10 alkyl, wherein the C1-10 alkyl is substituted with one 4-7 membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R b , and R c .
  • X is -C(O)C1-10 alkyl.
  • each R a independently is -P(O)(OH)2 or -OP(O)(OH)2.
  • one or more R a is -P(O)(OH) 2 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R a is -OP(O)(OH)2.
  • one or more R b is -C(O)R 7 .
  • one or more R b is -S(O) 2 R 7 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R b is -S(O)2NR 8 R 8 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R b is -S(O) 2 OR 7 .
  • one or more R c is -OR 7 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -OC(O)R 7 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -OC(O)C(O)OR 7 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -(O(C 1-4 alkyl)) n OR 7a .
  • one or more R c is -NR 8 R 8 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -N + R 8 R 8 R 8a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -NR 8 C(O)R 7 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R c is -NR 8 C(O)NR 8 R 8 .
  • each R 7 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • each R 7 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 9 , -NR 10 R 10 , and R a .
  • each R 7 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -NR 10 R 10 , and R a .
  • one or more R 7 is H.
  • one or more R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 9 , -NR 10 R 10 , and R a .
  • one or more R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -NR 10 R 10 , and R a .
  • one or more R 7 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 7 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 9 , -NR 10 R 10 , and R a .
  • one or more R 7 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1- 3 groups independently selected from -OH, -NR 10 R 10 , and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 7 is C 1-6 alkyl.
  • each R 7a independently is H, -P(O)(OH) 2 , or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • each R 7a independently is H or -P(O)(OH)2.
  • one or more R 7a is H.
  • one or more R 7a is -P(O)(OH)2.
  • one or more R 7a is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 7a is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 7a is C1-6 alkyl.
  • each R 8 independently is H, R d , or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • each R 8 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 8 is H.
  • one or more R 8 is R d .
  • one or more R 8 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 8 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 8 is C 1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 9 , and R a .
  • one or more R 8 is C 1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, C(O)OH, and R a .
  • one or more R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1- 3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 8 is C1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, R a , R d , and R e .
  • one or more R 8 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR 9 , and R a .
  • one or more R 8 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, C(O)OH, and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 8 is C 1-6 alkyl. [0136] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R 8 is H or . [0138] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R 8 is .
  • each R 8a independently is H or C 1-3 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 8a independently is H or methyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 8a is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 8a is C 1-3 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 8a is methyl.
  • one or more R d is -C(O)R 9 .
  • one or more R d is -S(O)2R 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R d is -S(O) 2 NR 10 R 10 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R d is -S(O) 2 OR 9 .
  • one or more R e is -OR 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -OC(O)R 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -OC(O)C(O)OR 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -NR 10 R 10 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -N + R 10 R 10 R 10a .
  • one or more R e is -NR 10 C(O)R 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -NR 10 C(O)NR 10 R 10 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -NR 10 C(O)OR 9 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R e is -NR 10 C(O)C(O)OR 9 .
  • each R 9 independently is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • each R 9 independently is H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • each R 9 independently is H or C1-3 alkyl.
  • one or more R 9 is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 9 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from CN, halogen, R a , R f , and R g . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 9 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • one or more R 9 is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • one or more R 9 is C 1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from CN, halogen, R a , R f , and R g .
  • one or more R 9 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • one or more R 9 is C 1-3 alkyl, wherein the C 1-3 alkyl is substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and R a .
  • one or more R 9 is C1-6 alkyl.
  • one or more R 9 is C 1-3 alkyl.
  • each R 10 independently is H, R f , or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R f , and R g .
  • each R 10 independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • each R 10 independently is H or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • each R 10 independently is H or C1-3 alkyl.
  • one or more R 10 is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 10 is R f . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 10 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, R a , R f , and R g .
  • one or more R 10 is C1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or more R 10 is C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or more R 10 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1- 3 groups independently selected from -CN, halogen, R a , R f , and R g .
  • one or more R 10 is C 1- 6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or more R 10 is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and R a .
  • one or more R 10 is C1-6 alkyl.
  • one or more R 10 is C 1-4 alkyl.
  • one or more R 10 is C1- 3 alkyl.
  • each R 10a independently is H or C1-3 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 10a independently is H or methyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 10a is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 10a is C1-3 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 10a is methyl.
  • one or more R f is -C(O)R 11 .
  • one or more R f is -S(O)2R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R f is -S(O)2NR 11 R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R f is -S(O)2OR 11 .
  • one or more R g is -OR 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -OC(O)R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -OC(O)C(O)OR 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -NR 11 R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -N + R 11 R 11 R 11a .
  • one or more R g is -NR 11 C(O)R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -NR 11 C(O)NR 11 R 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -NR 11 C(O)OR 11 . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R g is -NR 11 C(O)C(O)OR 11 .
  • one or more R 11 is H. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 11 is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -COOH, and R a . In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R 11 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -OH, CN, halogen, -COOH, and R a .
  • one or more R 11 is C1-6 alkyl.
  • each R 11a independently is H or C1-3 alkyl.
  • each R 11a independently is H or methyl.
  • one or more R 11a is H.
  • one or more R 11a is C 1-3 alkyl.
  • one or more R 11a is methyl.
  • a compound selected from the group consisting of: , or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.
  • a compound selected from the group consisting of: , or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of: , , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I is a compound that is: , or a pharmaceutically acceptable salt thereof.
  • a compound that is: , or a pharmaceutically acceptable salt thereof In some embodiments of the compound of Formula I, provided herein is a compound that is: , or a pharmaceutically acceptable salt thereof.
  • a compound that is: , or a pharmaceutically acceptable salt thereof In some embodiments of the compound of Formula I, provided herein is a compound that is: , or a pharmaceutically acceptable salt thereof.
  • a compound that is: , or a pharmaceutically acceptable salt thereof is a compound that is: , or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound that is: , or a pharmaceutically acceptable salt thereof.
  • a compound that is: , or a pharmaceutically acceptable salt thereof is provided herein.
  • the dosing of the compounds of Formula I results in the formation of lenacapavir, which is known to be active against HIV, as disclosed, for example, in U.S. Patent No. 10,071,985.
  • the compounds of Formula I are converted to lenacapavir in the gastrointestinal tract.
  • the compounds of Formula I are more soluble than lenacapavir and thus are administered orally at a lower effective dose than the required oral effective dose for lenacapavir to achieve the same level of exposure of lenacapavir in vivo.
  • Compositions and Kits [0166] Compounds provided herein, or pharmaceutically acceptable salts thereof, are usually administered in the form of pharmaceutical compositions.
  • 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, or pharmaceutically acceptable salts thereof 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 (i.e., a compound of Formula I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • 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 (i.e., 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 (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the one or more additional therapeutic agents include agents that are therapeutic for an HIV virus infection.
  • the one or more additional therapeutic agents is an anti-HIV agent.
  • the one or more additional therapeutic agents is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, 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, autolog
  • the additional therapeutic agent or agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and any combinations thereof.
  • 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 any combinations thereof.
  • the additional therapeutic agent or agents are chosen from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, T cell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and any combinations thereof.
  • the additional therapeutic agent or agents are chosen from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent or agents are chosen from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and any combinations thereof, or a pharmaceutically acceptable salt thereof.
  • combination drugs include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); dar
  • compositions comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents.
  • the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell
  • the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are 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, bispecific antibodies, “antibody-like” therapeutic proteins, or any combinations thereof.
  • additional therapeutic agents are 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
  • the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fum
  • 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 transdermal routes.
  • the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • One mode for administration is parenteral, for example, by injection.
  • the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein are administered by subcutaneous injection.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • the sterile injectable preparation disclosed herein may also be a sterile injectable solution or suspension prepared from a reconstituted lyophilized powder in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the suspension is a microsuspension. In certain embodiments the suspension is a nanosuspension.
  • formulations suitable for parenteral administration will include one or more excipients.
  • Excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. Examples of suitable excipients are well known to the person skilled in the art of parenteral formulation and may be found e.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.
  • solubilizing excipients in a parenteral formulation include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207).
  • a parenteral formulation e.g., an SC or IM formulation
  • polysorbates such as polysorbate 20 or 80
  • poloxamers such as poloxamer 338, 188, or 207.
  • the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein are administered with implants.
  • Oral administration may be another route for administration of the compounds provided herein or pharmaceutically acceptable salts thereof. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient (such as a compound provided herein) 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.
  • 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; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”).
  • 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.
  • Such 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.
  • 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 provided herein or pharmaceutically acceptable salts thereof 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.
  • 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, (i.e., a compound of Formula I), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging.
  • the kit further comprises instructions for use.
  • the kit comprises a compound provided herein (i.e., a compound of Formula I), 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.
  • the kits further comprise one or more (i.e., 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. IV. Methods [0197] The methods provided herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof.
  • the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the present disclosure may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound as disclosed herein for a given cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • the present disclosure provides a method of treating or preventing a human immunodeficiency virus (HIV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • the methods provided herein further comprise administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the one, two, three, or four additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/C
  • the one, two, three, or four additional therapeutic agents are 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, bispecific antibodies, and “antibody-like” therapeutic proteins, or any combinations thereof.
  • the one, two, three, or four additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • the present disclosure provides a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein for use in therapy.
  • the present disclosure provides a compound provided herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition provided herein for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
  • HIV human immunodeficiency virus
  • the present disclosure provides a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein for use in a method of treating a human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
  • the uses provided herein further comprise administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the one, two, three, or four additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non- nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, 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
  • the one, two, three, or four additional therapeutic agents are 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, bispecific antibodies, and “antibody- like” therapeutic proteins, or any combinations thereof.
  • the one, two, three, or four additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.
  • the patient is a human. V.
  • the compounds of the present disclosure or pharmaceutically acceptable salts thereof 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, or pharmaceutically acceptable salts thereof, is that they are orally bioavailable and can be dosed orally.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof 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, or a pharmaceutically acceptable salt thereof is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • a dosage may be expressed as a number of milligrams of a compound provided herein, or a pharmaceutically acceptable salt thereof, 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.
  • 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 dosage may also be described as a total amount of a compound described herein, or a pharmaceutically acceptable salt thereof, administered per dose.
  • the dosage or dosing frequency of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compounds of the present disclosure, or pharmaceutically acceptable salts thereof may be administered to an individual (e.g., a human) in a therapeutically effective amount.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once daily, once weekly, once monthly, once every two months, once every three months, or once every six months.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once daily.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once weekly.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once monthly.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once every two months.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered once every three months. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once every six months. [0218]
  • the compounds provided herein, or pharmaceutically acceptable salts thereof, 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, or a pharmaceutically acceptable salt thereof may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day.
  • a therapeutically effective amount of the compounds provided herein, or pharmaceutically acceptable salts thereof 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 ⁇ g to about 30 mg per day, or from about 30 ⁇ g to about 300 ⁇ g per day.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof (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 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose, or such as from about 1 mg per dose to about 1000 mg per dose.
  • Other therapeutically effective amounts of the compound of Formula I, or a pharmaceutically acceptable salt thereof are about 50, 100, 125, 150, 175, 200, 225, 250, 275, or 300 mg per dose.
  • Other therapeutically effective amounts of the compound of Formula I, or pharmaceutically acceptable salts thereof are about 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 1 mg to about 1000 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 900 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 800 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 700 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 600 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 1 mg to about 500 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 400 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 300 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 200 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 100 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 1 mg to about 75 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 50 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 25 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 20 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 15 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 1 mg to about 10 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 5 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1050 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 5 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 100 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 250 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 350 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 400 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 450 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 550 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 600 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 650 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 700 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 750 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 800 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 850 mg.
  • a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof is about 900 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 950 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1000 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is about 1050 mg.
  • the total weekly dosage for a human subject may be between about 1 mg and 1,000 mg/week, between about 10-500 mg/week, between about 50- 300 mg/week, between about 75-200 mg/week, or between about 100-150 mg/week. In some embodiments, the total weekly dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/week administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 100 mg administered in a single dose.
  • the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 150 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 200 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 250 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 300 mg administered in a single dose.
  • the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 350 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 400 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 450 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 500 mg administered in a single dose.
  • the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be between about 500 mg and 1,000 mg/month, between about 600-900 mg/month, or between about 700-800 mg/month.
  • the total weekly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/week administered in a single dose.
  • the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 500 mg administered in a single dose.
  • the total monthly dosage for a human subject may be about 550 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 600 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 650 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 700 mg administered in a single dose.
  • the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 750 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 800 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 850 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 900 mg administered in a single dose.
  • the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof may be about 950 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 1000 mg 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 provided herein, or a pharmaceutically acceptable salt thereof is administered once daily in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered twice daily in a method disclosed herein. [0225] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once daily in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once weekly in a method disclosed herein.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is administered once monthly in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once every two months in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once every three months in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once every six months in a method disclosed herein. [0226] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 100 mg once weekly.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is administered orally in a single dose of about 150 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 200 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 250 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 300 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 350 mg once weekly.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is administered orally in a single dose of about 400 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 450 mg once weekly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 500 mg once weekly. [0227] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 500 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 550 mg once monthly.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is administered orally in a single dose of about 600 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 650 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 700 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 750 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 800 mg once monthly.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is administered orally in a single dose of about 850 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 900 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 950 mg once monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1000 mg once monthly.
  • the frequency of dosage of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof will be determined by the needs of the individual patient and can be, for example, once per day, once per week, once per month, once per every two months, once per every three months, or once per every six months.
  • Administration of the compound, or a pharmaceutically acceptable salt thereof continues for as long as necessary to treat the Retroviridae infection, including an HIV infection, or any other indication described herein.
  • a compound, or a pharmaceutically acceptable salt thereof can be administered to a human suffering from a Retroviridae infection, including an HIV infection, for the duration of the human’s life.
  • 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, or a pharmaceutically acceptable salt thereof, followed by a period of several or more days during which a patient does not receive a daily dose of the compound or a pharmaceutically acceptable salt thereof.
  • a patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, every other day, or three times per week.
  • a patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound, or a pharmaceutically acceptable salt thereof.
  • a subsequent period e.g., from 1 to 14 days
  • Alternating periods of administration of the compound, or a pharmaceutically acceptable salt thereof, followed by non-administration of the compound, or a pharmaceutically acceptable salt thereof can be repeated as clinically required to treat the patient.
  • the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds, or pharmaceutically acceptable salts thereof, 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 for Retroviridae infections, including an HIV infection. In some embodiments, treatment cycles are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. VI.
  • one aspect of the disclosure is a method of treating an HIV infection comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more compounds useful for the treatment of an HIV infection to a subject, particularly a human subject, in need thereof.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents 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. [0233]
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof 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 the present disclosure, or a pharmaceutically acceptable salt thereof is co-administered with one or more additional therapeutic agents.
  • Co-administration includes administration of unit dosages of the compounds provided herein, or pharmaceutically acceptable salts thereof, before or after administration of unit dosages of one or more additional therapeutic agents.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof 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 provided herein, or a pharmaceutically acceptable salt thereof, within seconds or minutes.
  • a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof is administered first, followed, after a period of hours (i.e., 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 (i.e., 1-12 hours), by administration of a unit dose of a compound provided herein or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is formulated as a tablet, which may optionally contain one or more other compounds useful for treating the disease being treated.
  • the tablet can contain another active ingredient for treating a Retroviridae infection, including an HIV infection.
  • such tablets are suitable for once daily dosing.
  • such tablets are suitable for once weekly dosing.
  • such tablets are suitable for once monthly dosing.
  • such tablets are suitable for once every two months dosing.
  • such tablets are suitable for once every three months dosing.
  • such tablets are suitable for once every six months dosing.
  • the total daily dosage of a compound of Formula I, or a tautomer, or a pharmaceutically acceptable salt thereof may be about 1 to about 500 mg administered in a single dose for a human subject.
  • HIV Combination Therapy [0239]
  • the additional therapeutic agent or agents may be an anti-HIV agent.
  • the additional therapeutic agent can be HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non- catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, 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, engineered B cells
  • the additional therapeutic agent or agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.
  • 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.
  • the additional therapeutic agent or agents are chosen from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, T cell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.
  • HIV protease inhibitors HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase
  • the additional therapeutic agent or agents any are chosen from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.
  • combination drugs include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvit
  • HIV Drugs examples include, but are not limited to, aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-beta-D- arabinose nucleic acid (FANA)-modified antisense oligon
  • HIV Protease Inhibitors examples include, but are not limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09 + ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL- 008, MK-8122, TMB-607, GRL-02031, and TMC-310911.
  • HIV Gag Protein Inhibitors examples include, but are not limited to, HRF- 10071.
  • HIV Ribonuclease H Inhibitors [0248] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC- 727447.
  • HIV Nef Inhibitors [0249] Examples of HIV Nef inhibitors include, but are not limited to, FP-1.
  • HIV Reverse Transcriptase Inhibitors examples include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained release oral, HIV infection), elsulfavirine (long acting injectable nanosuspension, HIV infection), and elsulfavirine (VM-1500).
  • non- nucleoside or non-nucleotide inhibitors of reverse transcriptase include the compounds disclosed in U.S. Patent No. 10,548,898.
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX- 1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abac
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.
  • HIV Integrase Inhibitors examples include, but are not limited to, elvitegravir, elvitegravir (extended-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives
  • HIV integrase inhibitors include the compounds disclosed in U.S. Patent No. 11,084,832.
  • Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442.
  • HIV Viral Infectivity Factor Inhibitors [0255] Examples of HIV viral infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives, and Irino-L.
  • HIV Entry Inhibitors examples include, but are not limited to, AAR- 501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.
  • CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO- 140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc and vMIP (Haimipu).
  • Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, birithsin (gp41/gp120/gp160 inhibitor), BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT- 31, Cl3hmAb, lipuvirtide, PIE-12 trimer and sifuvirtide.
  • Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.
  • Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicide, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.
  • Examples of gp160 inhibitors include, but are not limited to, fangchinoline.
  • Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT- 1188, N15 peptide, and vMIP (Haimipu).
  • HIV Maturation Inhibitors examples include, but are not limited to, BMS- 955176, GSK-3640254 and GSK-2838232.
  • Latency Reversing Agents examples include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917,
  • PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactones.
  • TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.
  • TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.
  • Histone Deacetylase HDAC
  • the agents as described herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734).
  • histone deacetylase 1 histone deacetylase 1
  • HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ- 26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL- 001), vorinostat, tinostamustine, remetinostat, and entinostat.
  • capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacapavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, HIV- 1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK WO2019/087016).
  • NCp7 HIV nucleocapsid p7
  • GS-6207 HIV nucleocapsid p7
  • GS-CA1 HIV nucleocapsid protein inhibitors
  • GS-6207 GS-CA1
  • AVI-621 AVI-621
  • AVI-101 AVI-101
  • AVI-201 AVI-301
  • AVI-CAN1-15 series PF-
  • RNA polymerase modulators examples include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264.
  • the agents as described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors.
  • Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells.
  • Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics.
  • the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2016) 37:110).
  • the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2016) 18(11):671-688).
  • immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co- stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily
  • T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD- L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG,
  • T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155).
  • T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible
  • the agents as described herein are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors.
  • Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94).
  • NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol.
  • the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.
  • the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.
  • the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181.
  • the small molecule inhibitor of CTLA4 comprises BPI-002.
  • inhibitors of CTLA4 include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC- 392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).
  • inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co- administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS- 936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (
  • the agents as described herein are combined with anti- TIGIT antibodies, such as BMS-986207, RG-6058, and AGEN-1307.
  • TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators [0281]
  • the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604),
  • TNFRSF1A NC
  • anti-TNFRSF4 (OX40) antibodies examples include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.
  • anti-TNFRSF5 (CD40) antibodies examples include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.
  • the anti-TNFRSF7 (CD27) antibody varlilumab (CDX- 1127) is co-administered.
  • anti-TNFRSF9 (4-1BB, CD137) antibodies examples include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.
  • anti-TNFRSF18 (GITR) antibodies examples include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.
  • an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered.
  • Such antibodies are described, e.g., in WO2017096179 and WO2018089628.
  • NK-Cell Engagers are combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor Fc ⁇ R (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS
  • the anti-CD16 binding bi-specific molecules may or may not have an Fc.
  • Illustrative bi-specific NK-cell engagers that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKEs and TriKEs are described, e.g., in Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54.
  • Examples of trispecific NK cell engagers include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.
  • Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors [0288] In various embodiments, the agents as described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620).
  • IDO1 inhibitors include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV- 1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.
  • TLR Toll-Like Receptor Agonists
  • the agents as described herein are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793).
  • TLR1 NCBI Gene ID: 7096
  • TLR2 NCBI Gene ID: 7097
  • TLR3 NCBI Gene ID: 7098
  • TLR4 NCBI Gene ID: 7099
  • TLR5 NCBI Gene ID: 7100
  • TLR6 NCBI Gene ID: 10333
  • TLR7 NC
  • Example TLR7 agonists that can be co-administered include without limitation AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analog, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M- 051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen),
  • TLR7/TLR8 agonists include without limitation NKTR-262, telratolimod and BDB-001.
  • TLR8 agonists include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M- 052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Vent
  • TLR9 agonists include without limitation AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO- 8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042.
  • TLR3 agonist examples include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH- 33, MCT-465, MCT-475, and ND-1.1.
  • TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.
  • CDK inhibitors or antagonists [0290] In some embodiments, the agents described herein are combined with an inhibitor or antagonist of CDK. In some embodiments, the CDK inhibitor or antagonist is selected from the group consisting of VS2-370. STING agonists, RIG-I and NOD2 modulators [0291] In some embodiments, the agents described herein are combined with a stimulator of interferon genes (STING).
  • the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di- AMP.
  • the agents described herein are combined with a RIG-I modulator such as RGT-100, or NOD2 modulator, such as SB-9200, and IR-103.
  • the agents as described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.
  • an anti-TIM-3 antibody such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.
  • the antibodies or antigen-binding fragments described herein are combined with an anti LAG-3 (Lymphocyte-activation) antibody, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.
  • Interleukin agonists are combined with an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI- 101, Neo-2/15; examples of IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated Il- 15), P-22339, and a IL-15 -PD-1 fusion protein N-809
  • an interleukin agonist such as IL
  • Examples of additional immune-based therapies that can be combined with an agent of this disclosure include, but are not limited to, interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma; FLT3 agonists such as CDX- 301, GS-3583, gepon, normferon, peginterferon alfa-2a, peginterferon alfa-2b, and RPI-MN.
  • FLT3 agonists such as CDX- 301, GS-3583, gepon, normferon, peginterferon alfa-2a, peginterferon alfa-2b, and RPI-MN.
  • Phosphatidylinositol 3-kinase (PI3K) Inhibitors include, but are not limited to, idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117,
  • alpha-4/beta-7 Antagonists examples include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.
  • HPK1 Inhibitors examples include, but are not limited to, ZYF-0272, and ZYF-0057.
  • HIV Targeting Antibodies examples include, but are not limited to, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB- 360, TMB-370, and those targeting HIV gp120 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, gp120 bispecific monoclonal antibody, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibody, camelid derived anti-CD18 antibodies, camelid-derived anti- ICAM-1 antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ibalizuma
  • bNAbs may be used. Examples include, but are not limited to, those described in U.S. Patent No. 8673307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014/063059, WO2012/158948, WO2015/117008, and PCT/US2015/41272, and WO2017/096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195.
  • Additional examples include, but are not limited to, those described in Sajadi et al., Cell. (2016) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427): 118-22 (2012), Horwitz et al., Proc Natl Acad Sci U S A, 110(41): 16538-43 (2013), Scheid et al., Science, 333: 1633-1637 (2011), Scheid et al., Nature, 458:636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P
  • Examples of additional antibodies include, but are not limited to, bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (elipovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT- 130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (ipilimum), CAP
  • HIV bispecific and trispecific antibodies include without limitation MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01/PGDM-1400/10E8v4, 10E8.4/iMab, 10E8v4/PGT121-VRC01.
  • in vivo delivered bNAbs include without limitation AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01; and engineered B-cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).
  • Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir. Additional Therapeutic Agents [0306] Examples of additional therapeutic agents include, but are not limited to, the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer
  • HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccine, CD4-derived peptide vaccines, vaccine combinations, adenoviral vector vaccines (an adenoviral vector such as Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus i.e.
  • adenoviral vector vaccines an adenoviral vector such as Ad5, Ad26 or Ad35
  • simian adenovirus chimpanzee, gorilla, rhesus i.e.
  • adeno-associated virus vector vaccines Chimpanzee adenoviral vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackieviruses based vaccines, enteric virus based vaccines, Gorilla adenovirus vaccines, lentiviral vector based vaccine, arenavirus vaccines (such as LCMV, Pichinde), bi-segmented or tri-segmented arenavirus based vaccine, trimer-based HIV-1 vaccine, measles virus based vaccine, flavivirus vector based vaccines, tobacco mosaic virus vector based vaccine, Varicella- zoster virus based vaccine, Human parainfluenza virus 3 (PIV3) based vaccines, poxvirus based vaccine (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipo
  • vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40.Env- gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triplex vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B/E (gp120), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX- 2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rA
  • the agents described herein are combined with a birth control or contraceptive regimen.
  • Therapeutic agents used for birth control (contraceptive) include without limitation 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, ulipristal acetate, and any combinations thereof.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alaf
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with a first additional therapeutic agent chosen from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir and a second additional therapeutic agent chosen from emtricitabine and lamivudine.
  • an agent disclosed herein, or a pharmaceutical composition thereof is combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel , dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone , misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene , segestersone acetate, ulipristal acetate, and any combinations thereof.
  • a contraceptive selected from the group consisting of cyproterone acetate, desoges
  • Gene therapy and cell therapy include without limitation 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 cell therapy include without limitation LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX- B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell based therapy.
  • Examples of dendritic cell therapy include without limitation AGS-004.
  • CCR5 gene editing agents include without limitation SB-728T, SB-728-HSPC.
  • CCR5 gene inhibitors include without limitation Cal-1, and lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy- transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection/HIV-related lymphoma).
  • C34-CCR5/C34-CXCR4 expressing CD4-positive T-cells are co-administered with one or more multi-specific antigen binding molecules.
  • the agents described herein are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy.
  • Gene Editors [0315] In certain embodiments, the agents described herein are combined with a gene editor, e.g., an HIV targeted gene editor.
  • the genome editing system can be selected from the group consisting of: a CRISPR/Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonucleases complex, and a meganuclease complex.
  • An illustrative HIV targeting CRISPR/Cas9 system includes without limitation EBT-101.
  • CAR-T Cell Therapy [0316]
  • the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain.
  • CAR chimeric antigen receptor
  • the HIV antigen include an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, the CD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120, the membrane proximal region on gp41.
  • the immune effector cell is a T-cell or an NK cell.
  • 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 A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CART-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T-cells, dual anti-CD4 CART-T cell therapy (CD4 CAR+C34-CXCR4 T-cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide.
  • TCR T-cell Therapy the agents described herein are combined with a population of TCR-T-cells.
  • TCR-T-cells are engineered to target HIV derived peptides present on the surface of virus-infected cells, for example, ImmTAV.
  • B-cell Therapy the antibodies or antigen-binding fragments described herein are combined with a population of B cells genetically modified to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019.
  • 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.
  • the additional therapeutic agent or agents of the kit is an anti- HIV agent, selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV 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), compounds that target the HIV capsid, latency reversing agents, HIV bNAbs, immune-based therapies, phosphatid
  • the additional therapeutic agent or agents of the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase and an HIV capsid inhibitor.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three or four HIV bNAbs.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs and an HIV capsid inhibitor.
  • the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase.
  • HIV Long acting Therapy Examples of drugs that are being developed as long acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, doravirine, raltegravir, and long acting dolutegravir. VII.
  • Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.
  • Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography.
  • the final compounds provided herein were isolated as mono- or bis- trifluoracetic acid salts.
  • the methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure.
  • Representative syntheses of compounds of the present disclosure are described in the schemes below, and the particular examples that follow.
  • Typical embodiments of compounds disclosed herein may be synthesized using the general reaction schemes described below. It will be apparent to a skilled artisan given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection.
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • chloroform chloroform
  • methylene chloride or dichloromethane
  • Intermediate 5 or Intermediate 5E can be reacted with a compound of formula A1 under various conditions to give a compound of formula A2.
  • Non-limiting exemplary coupling conditions include the use of common coupling reagents such as HATU, COMU, TCFH, or EDC under appropriate solvent and temperature conditions in the presence of a base.
  • a compound of formula A2 after optional deprotection of a protecting group, can be converted to a compound of formula A4 by employing various conditions known in the art for alkylation or acylation using a compound with a compound of formula A3.
  • Compounds of formula A1 and A3 can be obtained commercially, or readily synthesized from known materials and reagents in one or more steps by those skilled in the art.
  • Compounds of formula B1 can be obtained commercially, or readily synthesized from known materials and reagents in one or more steps by those skilled in the art.
  • General Synthetic Scheme 3. [0338] Compounds of formulas C1 and C3 can be prepared according to General Synthetic Scheme 3, wherein M is R a as defined herein, -OH, or C 1-6 alkyl; G is a general leaving group including but not limited to -Cl, -Br, -I, or -F; J is -OC(O)R 9 or -OC(O)C(O)OR 9 , wherein R 9 is as defined herein; and L is 1, 2, 3, 4, 5, or 6.
  • Intermediate 5 or Intemediate 5E can be reacted under a variety of conditions to give a compound of formula C1.
  • Non-limiting exemplary coupling conditions include di-tert-butyl chloromethyl phosphate, trimethylsilyl chloride and paraformaldehyde, or other electrophilic reagents.
  • a compound of formula C1 can be reacted with neutral or deprotonated H-J under various basic conditions to provide a compound of formula C3 after optional deprotection in cases where H-J contains protected functionality.
  • Intermediate 5 or Intemediate 5E can be converted directly to a compound of formula C3 through reaction with a compound of formula C2 under a variety of basic conditions.
  • a compound of formula D1 can be reacted with 32A under basic conditions to give a compound of formula D2 following optional deprotection and/or functionalization with various electrophilic reagents, including but not limited to di-tert-butyl N,N-diisopropylphosphoramidite, phosphoryl chloride, or N,N′-di-Boc-1H-pyrazole-1-carboxamidine with an optional second deprotection.
  • electrophilic reagents including but not limited to di-tert-butyl N,N-diisopropylphosphoramidite, phosphoryl chloride, or N,N′-di-Boc-1H-pyrazole-1-carboxamidine with an optional second deprotection.
  • Compounds of formula D1 can be obtained commercially, or readily synthesized from known materials and reagents in one or more steps by those skilled in the art.
  • General Synthetic Scheme 5 5.
  • Compounds of formula E2 can be prepared according to General Synthetic Scheme 5, wherein R 5 is as defined herein.
  • a compound of formula E1 can be reacted with 32A under basic conditions to give a compound of formula E2 following optional deprotection and/or functionalization with various electrophilic reagents, including but not limited to di-tert-butyl N,N-diisopropylphosphoramidite, phosphoryl chloride, or N,N′-di-Boc-1H-pyrazole-1-carboxamidine with an optional second deprotection.
  • the organic phase was solvent exchanged into toluene, distilling to a final volume of 3 ml/g before diluting with toluene (224 mL).
  • N-acetyl-D- leucine 43.3 mmol
  • zinc oxide 6.25 mmol
  • 2-pyridinecarboxaldehyde 1.6 mmol
  • the mixture was agitated at 35 °C for 157 h prior to cooling to 20 °C.
  • the mixture was treated with a solution of NaOH (45 mmol) in water (75 mL) and then filtered through celite (7.5 g), rinsing forward toluene (30 mL).
  • Lithium hexamethyldisilazide (1.0 M solution in THF, 4.5 g) was charged over about 60 minutes and the reaction was agitated until complete. A solution of sulfuric acid (2.0 g) in water (5.6 mL) was charged, then the reaction was warmed to about 20 °C and agitated for about 20 minutes. Layers were separated and the aqueous layer was extracted twice with 2- methyltetrahydrofuran (5.3 mL). The combined organic layers were concentrated and N,N- diisopropylamine (0.5 g) was charged. The product was crystallized by the addition of heptane (11 ml).
  • N-Acetyl-L-cysteine (19.5 g), water (202 g), NaOH (6.5 g), and EtOH (48.7 g) were added and the mixture was stirred for 1 h.
  • the aqueous phase was removed and the organic phase was washed with a mixture of N-acetyl-L-cysteine (19.5 g), water (429 g), NaOH (6.5 g), and EtOH (48.8 g) followed by a solution of water (293 g) and sodium dihydrogen phosphate (32.5 g).
  • the aqueous phase was discarded and the organic phase was washed twice with a solution of sodium carbonate 38 mmol, 2.1 equiv) and sodium chloride (4.0 g) in water (200 g).
  • the organic phase was azeotropically distilled with additional 2-methyltetrahydrofuran, followed by distillation to a volume of about 3 ml/g. Additional 2-methyltetrahydrofuran (240 g) was added, the temperature was adjusted to 10 °C, and triethylamine (112 mmol, 6.3 equiv) and methanesulfonyl chloride (52 mmol, 2.9 equiv) were added. After 1.5 h, the mixture was washed with water (100 g).
  • the resultant solution was transferred to a reactor containing water (15 g) over about 1 hour.
  • the resultant slurry was further agitated for about one hour, and was filtered.
  • the filter cake was washed with water (2 x 5 g), deliquored, and dried at about 60 °C under vacuum to provide title compound Intermediate 5, which is also known as lenacapavir.
  • oxalyl chloride (0.21 mmol) was dissolved in dichloromethane (1.0 mL) and cooled to 0 o C and treated with a solution of Intermediate 5E (0.10 mmol) in dichloromethane (1.0 mL) at 0 o C followed by diisopropylethylamine (0.12 mmol). The resulting reaction mixture was stirred at 0 °C for 30 min. Once oxamoyl chloride formation was observed by LCMS, the reaction was treated with freshly prepared bis(trimethylsilyl) (2-aminoethyl)phosphonate solution. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC.
  • Triethylamine (1.55 mmol) was then added, followed by 2-bromoethanol (0.929 mmol).
  • the vessel was sealed and the mixture was stirred at rt for 1h then 45 °C for 1 day.
  • the mixture was partitioned between ethyl acetate and water and the organic phase was separated and washed with 5% LiCl aqueous and brine, and the resulting organic fraction was dried over MgSO4, filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography eluting with ethyl acetate / hexane to afford title compound 18 as a mixture of atropisomers.
  • reaction mixture was stirred at rt for 15 minutes and quenched by addition of saturated aqueous NH4Cl solution and stirring for 5 minutes.
  • the organic layer was next washed with brine and dried over Na2SO4.
  • the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes to afford an atropisomeric mixture of title compound 19A, which was used without further purification.
  • reaction mixture was stirred at rt for 2 h and quenched with methanol and then partitioned between sat'd aq. NH4Cl and ethyl acetate. The organic layer was separated, dried over MgSO 4 , filtered and concentrated. The residue was purified by reverse phase HPLC. Fractions containing the product were pooled and lyophilized to give title compound 19 as a mixture of atropisomers.
  • Example 23 [0383] Synthesis of di-tert-butyl ((N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro- 3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1- yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1- yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)methylsulfonamido)methyl) phosphate (23A): To a solution of Intermediate 5 (0.207 mmol) in 0.5 mL of DMF was added di-tert-butyl chloromethyl
  • reaction mixture was stirred at room temperature for 10 minutes then at 70 °C for 24 hours. Upon completion, the reaction was partitioned between 5 % LiCl and ethyl acetate, and then the organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate /hexane to afford an atropisomeric mixture of title compound 23A. MS (m/z) 1189.51 [M+H] + .
  • Trifluoroacetic acid (6.530 mmol) was then added with a further 10 mins stirring at which time the reaction was diluted with 1:1 H2O:MeCN (1 mL). The reaction contents were then transferred to a separatory funnel with DCM (15 mL) and washed once with 1M HCl (20 mL). The organic fraction was collected, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse phase HPLC. Fractions containing the product were pooled and lyophilized to give title compound 37 as a mixture of atropisomers.
  • Trifluoroacetic acid (6.530 mmol) was then added with a further 10 mins stirring at which time the reaction was diluted with 1:1 H2O:MeCN (1 mL). The reaction contents were then transferred to a separatory funnel with DCM (15 mL) and washed once with 1M HCl (20 mL). The organic fraction was collected, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse phase HPLC. Fractions containing the product were pooled and lyophilized to give title compound 60 as a mixture of atropisomers.
  • the reaction was sealed, heated to 40 °C, and stirred for 1 hour. Then 50% H2O2 (11.1 mmol) was added to the reaction. The reaction was sealed, heated to 40 °C, and stirred for 1 hour. Upon completion, the reaction was diluted with water (95 mL) and quenched with sat. Na 2 SO 3 (1 mL). The solution was transferred to a separatory funnel and extracted 3x with 1:1 EtOAc/Hexanes (60 mL). The organic fraction was collected, washed with 0.1M HCl (120 mL), 5% LiCl (120 mL), sat. NaCl (60 mL), dried over Na 2 SO 4 , concentrated, and purified with silica chromatography.
  • Trifluoroacetic acid (6.530 mmol) was then added with a further 10 mins stirring at which time the reaction was diluted with 1:1 H 2 O:MeCN (1 mL). The reaction contents were then transferred to a separatory funnel with DCM (15 mL) and washed once with 1M HCl (20 mL). The organic fraction was collected, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse phase HPLC. Fractions containing the product were pooled and lyophilized to give the title compound 77 as a mixture of atropisomers.
  • reaction contents were transferred to a separatory funnel using 50 mL of dichloromethane and 10 mL of H 2 O.
  • the organic layer was washed with 1M aqueous HCl (3 x 50 mL), dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by silica gel chromatography. Fractions containing the product were pooled and concentrated under reduced pressure to yield title compound 84A.
  • the reaction mixture was heated at 65 °C for 2 hours.
  • the crude mixture was purified by silica gel column chromatography (eluent: hexanes/ethyl acetate) followed by reverse phase HPLC (eluent: water/acetonitrile containing 0.1% v/v TFA) to provide title compound 92 as a mixture of atropisomers.
  • Trifluoroacetic acid (6.530 mmol) was then added with a further 10 mins stirring at which time the reaction was diluted with 1:1 H 2 O:MeCN (1 mL). The reaction contents were then transferred to a separatory funnel with DCM (15 mL) and washed once with 1M HCl (20 mL). The organic fraction was collected, dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by reverse phase HPLC. Fractions containing the product were pooled and lyophilized to give the title compound 122 as a mixture of atropisomers.
  • Example 125 [0543] Synthesis of di-tert-butyl 3-hydroxypentanedioate (125A): To a solution of di- tert-butyl 3-oxopentanedioate (1.35 mmol) in EtOH (5 mL) at -10 °C, was added portionwise sodium borohydride (2.03 mmol, 1.5 equiv). Upon completion, the reaction was concentrated under reduced pressure and the residue partitioned between 1M aqueous NaOH (5 mL) and EtOAc (50 mL). The organic fraction was collected, dried over Na 2 SO 4 , and concentrated under reduced pressure to yield the title compound 125A, which was used without purification.
  • Example 137 [0578] Synthesis of 2-(benzyloxy)ethan-1-amine (137A): To a stirred solution of 2- (benzyloxy)ethan-1-amine (66.1 mmol) in CH 2 Cl 2 (60 mL) at 0 °C was added chloromethyl chloroformate (66.1 mmol). The reaction mixture was stirred at 0 °C and monitored by TLC and LCMS. After completion, the reaction mixture was washed with sat. aq. solutions of NH4Cl and brine. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The crude mixture was purified by column chromatography (10% to 50% EtOAc in hexanes) to afford title compound 137A.
  • FaSSIF fasted state simulated intestinal fluid
  • FeSSIF fed state simulated intestinal fluid
  • tubes were vortexed for approximately 10 seconds to re-suspend any solids and returned to the vial mixer at 25 °C and 1400 rpm until the next predetermined timepoint.
  • samples were removed from the freezer, equilibrated to ambient temperature, and analyzed by reversed-phase UPLC to determine the concentration of compound in the supernatant at each timepoint. Results are presented in the second column of Table 1 below. 2.
  • the 1X PBS buffer (pH 7.4) was prepared by adding 50 mL of phosphate buffered saline solution 10X, PBS (Fisher Bioreagent part number BP399-500) to approximately 450 mL HPLC grade H 2 O. The volume of the solution was then adjusted to 500mL for a total dilution factor of 1:10 and a final PBS concentration of 1X. The pH of the final solution was measured and found to be 7.4. 3.
  • Oral Bioavailability PK Samples [0587] Oral dose (suspension and solution vehicle) of the compound being tested was administered via gavage in rat (Sprague Dawley) and dog (Beagle). Serial blood samples were collected via jugular vein into pre-chilled K2EDTA with 2 mM dichlorvos (final concentration) for up to 168h. Whole blood was processed into plasma by centrifuge (3000 rpm for 10 minutes at 5C) within 30 minutes of collection. [0588] Plasma samples were analyzed by direct protein precipitation with acetonitrile and further dilution with water before injecting onto Sciex API 5500 LC/MS/MS system for analysis.
  • the reported values in the fourth and fifth columns of Table 1 are based on observed exposure of Intermediate 5 in plasma.
  • the suspension vehicle was 0.5% hydroxypropyl methylcellulose, high viscosity and 99.5% water with final pH of 2.0.
  • the solution vehicles used were 1) 5 % ethanol, 20% propylene glycol, and 75 % water and 2) 30% 10 mM HCl, 5% ethanol, 45% polyethylene glycol 300, and 20% propylene glycol. Table 1.

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