WO2020176510A1 - Agonistes de protéine kinase c - Google Patents

Agonistes de protéine kinase c Download PDF

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Publication number
WO2020176510A1
WO2020176510A1 PCT/US2020/019704 US2020019704W WO2020176510A1 WO 2020176510 A1 WO2020176510 A1 WO 2020176510A1 US 2020019704 W US2020019704 W US 2020019704W WO 2020176510 A1 WO2020176510 A1 WO 2020176510A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
hiv
inhibitors
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PCT/US2020/019704
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English (en)
Inventor
Yunfeng E. HU
Jasmine Kaur
Ryan Mcfadden
Jeffrey P. MURRY
Hoa H. TRUONG
Lianhong Xu
Helen Yu
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Gilead Sciences, Inc.
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Publication of WO2020176510A1 publication Critical patent/WO2020176510A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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

Definitions

  • This disclosure relates generally to certain diacylglycerol lactone compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions.
  • PKC Protein Kinase C
  • each R 1 is C 1-3 alkyl
  • each R 2 is Ci- 6 alkyl
  • R 3 and R 4 is H, Ci-15 alkyl, or C6-10 aryl, and the other of R 3 and R 4 is Ci-15 alkyl or C6-10 aryl, wherein each C 1 - 15 alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl, or
  • R 3 and R 4 together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl
  • L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene, wherein the Ci-8 alkylene and the Ci-8 heteroalkylene are each optionally substituted with 1-3 R 5 ;
  • each R 5 is independently C1-3 alkyl, or
  • A is a phenylene or naphthalenylene
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • L is Ci- 8 alkylene or C4-8 heteroalkylene, wherein the Ci- 8 alkylene and the C4-8 heteroalkylene are each optionally substituted with 1-3 R 5 .
  • compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a
  • 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.
  • 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, or four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of activating protein kinase C (PKC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the present disclosure provides methods of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the present disclosure provides methods of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of activating T cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -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 a in the below structure can be attached to any of the five carbon ring atoms or R a can replace the hydrogen attached to the nitrogen ring atom:
  • “Ci- 6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
  • a divalent group such as a divalent“alkyl” group, a divalent“aryl” group, etc., may also be referred to as an“alkylene” group or an“alkylenyl” group, or alkylyl group, an “arylene” group or an“arylenyl” group, or arylyl group, respectively.
  • 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, II, Ila, III, IV, and/or V. Also included are the specific compounds of Examples 1 to 195.
  • 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%.
  • the term“about” includes the indicated amount ⁇ 5%.
  • the term“about” includes the indicated amount ⁇ 1%.
  • the term“about X” includes description of“X”.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., Ci-20 alkyl), 1 to 12 carbon atoms (i.e., Ci-12 alkyl), 1 to 8 carbon atoms (i.e., Ci- 8 alkyl), 1 to 6 carbon atoms (i.e., Ci- 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. -(CEh ⁇ CEE), sec-butyl (i.e.
  • -CEhEEyCEhCEb isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CEh ⁇ CEE) and isopropyl (i.e. -CH(CH3)2).
  • 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., C2-20 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).
  • the term“alkynyl” also includes those groups having one triple bond and one double bond.
  • alkylene refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., Ci-20 alkylene), 1 to 12 carbon atoms (i.e., Ci-12 alkylene), 1 to 8 carbon atoms (i.e., Ci- 8 alkylene), 1 to 6 carbon atoms (i.e., Ci- 6 alkylene), 1 to 4 carbon atoms (i.e., C1-4 alkylene), 1 to 3 carbon atoms (i.e., C1-3 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 -,
  • Alkoxy refers to the group“alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.“Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include formyl, acetyl, cylcohexylcarbonyl,
  • 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.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-2 o aryl), 6 to 12 carbon ring atoms (i.e., C 6 -i 2 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 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.
  • 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.
  • the term “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., C 3.2 o cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl),
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Bridged refers to a ring fusion wherein non-adj acent atoms on a ring are j oined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
  • a divalent substituent such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
  • fused refers to a ring which is bound to an adjacent ring.
  • Spiro refers to a ring substituent which is joined by two bonds at the same carbon atom.
  • examples of spiro groups include 1,1 -diethyl cyclopentane, 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 (-CHF2) and tri fluorom ethyl (-CF3).
  • Heteroalkyl ene 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,
  • Ci- 20 heteroalkylene 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., Ci- 8 heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S S (i.e., Ci- 6 heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-4 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., C 1-3 heteroalkylene).
  • -CH 2 O- is a Ci heteroalkylene
  • -CH 2 SCH 2 - is a C 2 heteroalkylene
  • 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 )0-, -CH 2 SC(CH 2 CH 3 )(CH 3 )-, and
  • 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., Ci- 2 o heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3 -i 2 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.
  • 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 2.2 o heterocyclyl), 2 to 12 carbon ring atoms (i.e., C 2 -i 2 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C 2 -io heterocyclyl), 2 to 8 carbon ring atoms (i.e., C 2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C 3 -i 2 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
  • 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.
  • the term“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-l-azaspiro[3.3]heptanyl.
  • the terms“heterocycle”,“heterocyclyl”, and“heterocyclic ring” are used
  • a heterocyclyl is substituted with an oxo group.
  • “Hydroxy” or“hydroxyl” refers to the group -OH.
  • “Sulfonyl” refers to the group -S(0) 2 R C , where R c is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • 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, alkylsulfmyl, sulfonic acid, alkyl sulfonyl, 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.
  • substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • “substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano;“substituted heteroaryl” refers to an heteroaryl group
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is 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. Conventional techniques for the
  • preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • “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), U C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 C1 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.
  • 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, II, or Ila, 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, II, or Ila, 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.
  • 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). Substitution with heavier 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, II, or Ila.
  • 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. Unless otherwise stated, when a position is designated specifically as “H” or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic
  • 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 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.
  • suitable amines include, by way of example only,
  • 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.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (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).
  • prevention or“preventing” 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 decrease a symptom of a disease or condition responsive to activation of protein kinase C (PKC).
  • PKC protein kinase C
  • 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.
  • activation indicates an increase in the baseline activity of a biological activity or process.
  • Activation of PKC or variants thereof refers to an increase in PKC activity as a direct or indirect response to the presence of a compound of the present disclosure relative to the PKC activity in the absence of the compound of the present disclosure.
  • Activation of PKC refers to an increase in PKC activity as a direct or indirect response to the presence of a compound provided herein relative to the PKC activity in the absence of the compound provided herein.
  • the activation of PKC activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
  • an“agonist” is a substance that stimulates its binding partner, typically a receptor. Stimulation is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an“agonist” or an“antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Stimulation may be defined with respect to an increase in a particular effect or function that is induced by interaction of the agonist or partial agonist with a binding partner and can include allosteric effects.
  • an“antagonist” is a substance that inhibits its binding partner, typically a receptor.
  • Inhibition is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an“agonist” or an“antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Inhibition may be defined with respect to a decrease in a particular effect or function that is induced by interaction of the antagonist with a binding partner, and can include allosteric effects.
  • each R 1 is C 1-3 alkyl
  • each R 2 is Ci- 6 alkyl
  • R 3 and R 4 is H, Ci- 15 alkyl, or C 6-10 aryl, and the other of R 3 and R 4 is Ci- 15 alkyl or C 6-10 aryl, wherein each Ci- 15 alkyl and each C 6-10 aryl are optionally substituted with 1 -3 groups independently selected from C 5-10 monocyclic cycloalkyl, C 5-10 bridged bicyclic cycloalkyl, and C 5-10 bridged tricyclic cycloalkyl, or
  • R 3 and R 4 together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl
  • L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene, wherein the Ci-8 alkylene and the Ci-8 heteroalkylene are each optionally substituted with 1-3 R 5 ;
  • each R 5 is independently C 1-3 alkyl, or
  • A is a phenylene or naphthalenylene
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3; provided that
  • L is Ci- 8 alkylene or C4-8 heteroalkylene, wherein the Ci- 8 alkylene and the C4-8 heteroalkylene are each optionally substituted with 1-3 R 5 .
  • each R 1 is C 1-3 alkyl
  • each R 2 is Ci- 6 alkyl
  • R 3 and R 4 is H or C 1-3 alkyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl, or
  • R 3 and R 4 together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl
  • L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene
  • A is a phenylene or naphthalenylene
  • n 0, 1, or 2;
  • n 1 or 2
  • each R 1 is C 1-3 alkyl
  • each R 2 is Ci- 6 alkyl
  • R 3 and R 4 is H or C 1-3 alkyl, and the other of R 3 and R 4 is Ci- 12 alkyl or phenyl, or R 3 and R 4 , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl;
  • L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene
  • A is a phenylene or naphthalenylene
  • n 0, 1, or 2;
  • n 1 or 2
  • the compound of Formula I is of Formula II
  • the compound of Formula I or II is of Formula Ila,
  • m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 1 or 2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 0. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 1. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 3.
  • each R 2 is Ci- 6 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is Ci- 4 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is C2-4 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, iso-butyl, sec-butyl, pentyl, or hexyl.
  • each R 2 is independently ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is independently ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is independently ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R 2 is
  • one, two, or three R 2 is methyl, n-butyl, or tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is n-butyl or tert- butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is methyl or tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is methyl.
  • one, two, or three R 2 is ethyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is n-propyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is isopropyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is n-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is tert-butyl.
  • one, two, or three R 2 is isobutyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is pentyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is hexyl.
  • R 2 is Ci- 6 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is Ci-4 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is C2-4 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, iso-butyl, sec-butyl, pentyl, or hexyl.
  • R 2 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, or pentyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl.
  • R 2 is ethyl, n-propyl, n-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula II or Ila, or a
  • R 2 is methyl, n-butyl, or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is n-butyl or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is methyl or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is methyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is ethyl.
  • R 2 is n-propyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is isopropyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is n-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is isobutyl.
  • R 2 is sec-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is pentyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R 2 is hexyl.
  • R 2 is ethyl, n-propyl, n- butyl, iso-butyl, sec-butyl, or pentyl.
  • R 2 is not methyl, isopropyl, or tert-butyl.
  • R 3 and R 4 is H, C i-is alkyl, or C6-10 aryl, and the other of R 3 and R 4 is C i-is alkyl or C6-10 aryl, wherein each Ci-is alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl; or R 3 and R 4 , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl.
  • R 3 and R 4 is H and the other of R 3 and R 4 is C i- 15 alkyl or C6-10 aryl, wherein the C i-15 alkyl and the C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl.
  • one of R 3 and R 4 is Ci-15 alkyl and the other of R 3 and R 4 is Ci-15 alkyl or C6-10 aryl, wherein each C i-15 alkyl and the C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl.
  • one of R 3 and R 4 is C6-10 aryl and the other of R 3 and R 4 is Ci-15 alkyl or C6-10 aryl, wherein the Ci-15 alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C 5-10 monocyclic cycloalkyl, C 5-10 bridged bicyclic cycloalkyl, and C 5-10 bridged tricyclic cycloalkyl.
  • R 3 and R 4 is H or C 1-3 alkyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with
  • R 3 and R 4 is H and the other of R 3 and R 4 is C i- 12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is C 1-3 alkyl, and the other of R 3 and R 4 is Ci-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is methyl, and the other of R 3 and R 4 is Ci-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is ethyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is ethyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl.
  • R 3 and R 4 is n-propyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is isopropyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • R 3 and R 4 is H or C 1-3 alkyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl.
  • one of R 3 and R 4 is H and the other of R 3 and R 4 is C i-12 alkyl or phenyl.
  • one of R 3 and R 4 is C 1-3 alkyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl.
  • one of R 3 and R 4 is methyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R 3 and R 4 is ethyl, and the other of R 3 and R 4 is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R 3 and R 4 is n-propyl, and the other of R 3 and R 4 is C M2 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R 3 and R 4 is isopropyl, and the other of R 3 and R 4 is C M2 alkyl or phenyl.
  • R 3 and R 4 is H or methyl and the other of R 3 and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the C 6-12 alkyl is optionally substituted with adamantanyl.
  • R 3 and R 4 is H or methyl and the other of R 3 and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the C 6-12 alkyl is optionally substituted with adamantanyl.
  • R 3 and R 4 is H or methyl and the other of R 3 and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the methyl is optionally substituted with
  • R 3 and R 4 is H or methyl and the other of R 3 and R 4 is methyl, phenyl, or C 6-12 alkyl.
  • R 3 and R 4 are H or methyl and the other of R 3 and R 4 is phenyl,
  • R 3 and R 4 are H and the other of R 3 and R 4 is
  • R 3 is H or methyl and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the C 6-12 alkyl is optionally substituted with adamantanyl.
  • R 3 is H or methyl and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the methyl is optionally substituted with adamantanyl.
  • R 3 is H or methyl and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the methyl is optionally substituted with adamantanyl.
  • R 3 is H or methyl and R 4 is methyl, phenyl, or C 6-12 alkyl, wherein the methyl is optionally substituted with adamantanyl.
  • R 3 is H or methyl and R 4 is methyl, phenyl, or C 6-12 alkyl.
  • R 3 is H, methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 3 is H or methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 3 is H. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 3 is methyl.
  • R 4 is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 4 is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 4 is C 1-3 alkyl optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 4 is C 1-2 alkyl optionally substituted with adamantanyl.
  • R 4 is C6-12 alkyl optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 4 is C6-12 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 4 is phenyl.
  • R 4 is methyl, phenyl
  • R 4 is methyl, phenyl
  • R 4 is methyl, phenyl
  • R 4 is
  • R 3 and R 4 together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclopentyl or cyclohexyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclopropyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclobutyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclopentyl.
  • R 3 and R 4 together with the carbon to which they are attached, form a cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R 3 and R 4 , together with the carbon to which they are attached, form a cycloheptanyl.
  • R 3 and R 4 is H, C 2-15 alkyl, or C 6-10 aryl, and the other of R 3 and R 4 is Ci- 15 alkyl or C 6-10 aryl, wherein the C 2-15 alkyl, C 2-15 alkyl, and C 6-10 aryl are each optionally substituted with 1-3 groups independently selected from C 5-10 monocyclic cycloalkyl, C 5-10 bridged bicyclic cycloalkyl, and C 5-10 bridged tricyclic cycloalkyl.
  • R 3 is not methyl.
  • R 4 is not methyl.
  • R 3 is not methyl and R 4 is not methyl.
  • L is a bond, Ci- 8 alkylene, or Ci- 8 heteroalkylene, wherein the Ci- 8 alkylene and the Ci- 8 heteroalkylene are each optionally substituted with 1-3 R 5 .
  • L is a bond, Ci- 8 alkylene, or Ci- 8 heteroalkylene.
  • L is a bond.
  • A is phenylene
  • R 3 is methyl
  • R 4 is methyl
  • L is a Ci- 8 alkylene optionally substituted with 1-3 R 5 .
  • L is a Ci- 8 alkylene optionally substituted with 1-3 R 5 , wherein two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl.
  • L is a Ci- 6 alkylene optionally substituted with 1-3 R 5 .
  • L is a Ci- 6 alkylene optionally substituted with 2 R 5 , wherein the two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a C3-6 monocyclic cycloalkyl.
  • L is a Ci- 6 alkylene optionally substituted with 2 R 5 , wherein the two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • L is a Ci-4 alkylene optionally substituted with 1-3 R 5 .
  • L is a Ci- 3 alkylene optionally substituted with one R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- 3 alkylene optionally substituted with two R 5 .
  • L is a Ci- 8 alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- 6 alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-4 alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- 3 alkylene.
  • L is methylene, ethylene, -CH(CH 3 )CH 2 -,
  • L is methylene, ethylene, propylene, or butylene, each of which is optionally substituted with 1-3 R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is methylene, ethylene, propylene, or butylene.
  • -A-L- is -A-m ethylene-, -A-ethylene-,
  • L is a Ci- 6 alkylene optionally substituted with 2 R 5 , wherein the two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • L is a Ci-4 alkylene optionally substituted with 1-3 R 5 .
  • L is a C 1-3 alkylene optionally substituted with one R 5 .
  • L is a Ci- 8 heteroalkyl ene optionally substituted with 1- 3 R 5 .
  • L is a Ci- 8 heteroalkyl ene optionally substituted with 1-3 R 5 , wherein two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl.
  • L is a Ci- 6 heteroalkylene optionally substituted with 2 R 5 , wherein the two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a C 3-6 monocyclic cycloalkyl.
  • L is a Ci- 6 heteroalkylene optionally substituted with 2 R 5 , wherein the two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • L is a C 1-5 heteroalkylene optionally substituted with 1-3 R 5 .
  • L is a C 1-4 heteroalkylene optionally substituted with 1-3 R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 1-3 heteroalkylene optionally substituted with one R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 1-3 heteroalkylene optionally substituted with methyl.
  • L is a Ci- 8 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- 6 heteroalkyl ene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- 6 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 1-5 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 1-4 heteroalkylene.
  • L is a C 1-3 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 1-2 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C 4-8 heteroalkylene.
  • L is -OCi-8 alkylene, wherein the oxygen is attached to A.
  • L is -OCi-6 alkylene, wherein the oxygen is attached to A.
  • L is -OC 5-8 alkylene, wherein the oxygen is attached to A.
  • L is -OC 4-8 alkylene, wherein the oxygen is attached to A.
  • L is -OC 4-6 alkylene, wherein the oxygen is attached to A.
  • L is -CH2NH- or -03 ⁇ 4N(03 ⁇ 4)-.
  • each R 5 is independently C 1-3 alkyl or two R 5 are attached to the same carbon and the two R 5 , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl.
  • each R 5 is independently C 1-3 alkyl.
  • each R 5 is independently methyl, ethyl, n-propyl, or isopropyl.
  • each R 5 is independently methyl or ethyl.
  • each R 5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R 5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is methyl or ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R
  • one, two, or three R 5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 5 is isopropyl.
  • L is optionally substituted with 1 -3 R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is optionally substituted with 1 -2 R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is optionally substituted with two R 5 . In some embodiments of the compound of Formula I, II, or Ila, or a
  • L is optionally substituted with one R 5 .
  • R 5 is methyl.
  • R 5 is ethyl.
  • R 5 is n-propyl.
  • R 5 is isopropyl.
  • L is optionally substituted with two R 5 .
  • one R 5 is methyl and the other R 5 is methyl, ethyl, n-propyl, or isopropyl.
  • one R 5 is ethyl and the other R 5 is methyl, ethyl, n-propyl, or isopropyl.
  • one R 5 is n-propyl and the other R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 5 is isopropyl and the other R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 5 is methyl and the other R 5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 5 is methyl and the other R 5 is ethyl.
  • R 5 are attached to the same carbon.
  • one R 5 is methyl and the other R 5 is methyl, ethyl, or n-propyl.
  • one R 5 is ethyl and the other R 5 is methyl, ethyl, or n-propyl.
  • one R 5 is n-propyl and the other R 5 is methyl, ethyl, or n-propyl.
  • one R 5 is methyl and the other R 5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 5 is methyl and the other R 5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 5 is ethyl and the other R 5 is ethyl.
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl.
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclopropyl.
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclobutyl.
  • two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclopentyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R 5 are attached to the same carbon, and the two R 5 , together with the carbon to which they are attached, form a
  • A is a phenylene or naphthalenylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a phenylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is
  • A is naphthalenylene.
  • n is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2.
  • n is 0 or 1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 3.
  • each R 1 is C 1-3 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R 1 is independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 1 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 1 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R 1 is n- propyl.
  • R 1 is isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 1 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 1 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 1 is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R 1 is isopropyl.
  • A is optionally substituted with one R 1 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is optionally substituted with one methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is substituted with one R 1 . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is substituted with one methyl.
  • the compound of Formula I, II, or Ila is:
  • the compound of Formula I, II, or Ila is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound of Formula I, II, or Ila is: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, II, or Ila is:
  • the compound of Formula I, II, or Ila is not:
  • compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • the compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g ., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed.
  • compositions comprising a compound provided herein (i.e., a compound of Formula I, II, or IIA), 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.
  • 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 HIV infection.
  • the one or more additional therapeutic agents is selected from the group consisting of: 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil
  • 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.
  • compositions described herein may be incorporated for parenteral, for example, by injection.
  • parenteral for example, by injection.
  • administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient such as a compound provided herein
  • the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof.
  • the pharmaceutical compositions can be 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 be lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl and
  • 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.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • kits that comprise a compound provided herein, (i.e., a compound of Formula I, II, or Ila), 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, II, or Ila), 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.
  • 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
  • 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.
  • 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. In this context, 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 PKC agonist for a given indication, 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 methods of activating PKC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the present disclosure provides methods of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the present disclosure provides methods of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the above methods further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a
  • the one or more additional therapeutic agents is 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, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase
  • PI3K phosphat
  • the one or more additional therapeutic agents is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a
  • the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • the one or more additional therapeutic agents is selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.
  • the one or more additional therapeutic agents is emtricitabine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of activating T-cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof i.e., a compound of Formula I, II, or Ila
  • the methods described herein comprise administering a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in a method of activating PKC in a subject in need thereof.
  • a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • a pharmaceutically acceptable salt thereof for use in a method of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • a pharmaceutically acceptable salt thereof for use in a method of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof for use in a method of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • the above uses further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a
  • the above uses further comprise administering one or more additional therapeutic agents 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, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3 -kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor
  • the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse
  • the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifum
  • the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
  • the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.
  • the above uses further comprise administering
  • emtricitabine or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt thereof for use in a method of activating T-cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein i.e., a compound of Formula I, II, or Ila
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
  • the uses described herein comprise administering a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated.
  • Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
  • An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.
  • a compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compounds of the present disclosure may be administered to an individual
  • the compound is administered once daily.
  • the compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration.
  • Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 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 include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 pg to about 30 mg per day, or from about 30 pg to about 300 pg per day.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound).
  • Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 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, II, Ila, III, IV, or V are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.
  • Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 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.
  • the methods described herein comprise administering to the subject an initial daily dose of about 1 to 500 mg of a compound p herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose.
  • the dosage can be increased daily, every other day, twice per week, once per week, once every two weeks, once every three weeks, or once a month.
  • the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In some
  • the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg/day administered in a single dose.
  • the total daily dosage for a human subject may be about
  • the total daily dosage for a human subject may be about 150 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg/day administered in a single dose.
  • the total daily dosage for a human subject may be about 450 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg/day administered in a single dose.
  • the total daily dosage for a human subject may be about 750 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 1000 mg/day administered in a single dose.
  • a single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks.
  • a single dose can be administered once every week.
  • a single dose can also be administered once every month.
  • a compound disclosed herein is administered once daily in a method disclosed herein.
  • a compound disclosed herein is administered twice daily in a method disclosed herein.
  • the frequency of dosage of the compound of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection, HIV infection, cancer, hyper-proliferative disease, or any other indication described herein.
  • a compound can be administered to a human being infected with HBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.
  • Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound.
  • a patient can receive a dose of the compound every other day, or three times per week.
  • a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound.
  • Alternating periods of administration of the compound, followed by non-administration of the compound can be repeated as clinically required to treat the patient.
  • the compounds of the present disclosure or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer
  • chemotherapy and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles.
  • the treatment cycles in other embodiments, may also be continuous.
  • 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.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents.
  • 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.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • a compound of the present disclosure 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 is co-administered with one or more additional therapeutic agents.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents.
  • the compounds disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (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 disclosed herein.
  • a compound of Formula I, II, or Ila 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 HIV infection.
  • such tablets are suitable for once daily dosing.
  • pharmaceutically acceptable salt thereof may be about 300 mg/day administered in a single dose for a human subject.
  • a method for treating or preventing an HIV infection in a human or animal having or at risk of having the infection comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents.
  • a method for treating an HIV infection in a human or animal having or at risk of having the infection comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents, and a
  • the present disclosure provides a method for treating an
  • HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • the compounds disclosed herein are formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse
  • transcriptase HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, or any combinations thereof.
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is selected from the group consisting of HIV combination drugs, 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), latency reversing agents, compounds that target the HIV capsid (including capsid inhibitors), immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein
  • 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, or any combinations thereof.
  • combination drugs include ATRIPLA ® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ® (EVIPLERA ® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine);
  • ODEFSEY® tenofovir alafenamide, emtricitabine, and rilpivirine
  • GENVOYA® tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir
  • BIKTARVY® bictegravir
  • emtricitabine tenofovir alafenamide
  • darunavir tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat
  • efavirenz lamivudine, and tenofovir disoproxil fumarate
  • HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfmavir, nelfmavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL- 100), T-169, BL-008, and TMC-310911.
  • HIV non -nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM- 1500.
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX ® and VIDEX EC ® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravi
  • HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives, integrase- LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC
  • NICKI HIV non-catalytic site, or allosteric, integrase inhibitors
  • HIV entry (fusion) inhibitors examples include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.
  • CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).
  • gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.
  • CD4 attachment inhibitors include ibalizumab and CADA analogs.
  • Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.
  • CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).
  • HIV maturation inhibitors include BMS-955176 and GSK-2838232.
  • latency reversing agents examples include histone deacetylase (HD AC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA
  • AM-0015 (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, GSK-343, GSK3beta inhibitors, SMAC mimetics, and Gal 9.
  • HD AC inhibitors examples include romidepsin, vorinostat, and panobinostat.
  • PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.
  • GSK3 beta inhibitors examples include tideglusib, LY2090314, CHIR99021, and AZD1080.
  • SMAC mimetics examples include birinapant, AZD5582, LCL161, and
  • capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CANl-15 series.
  • NCp7 HIV nucleocapsid p7
  • immune-based therapies include toll-like receptors modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd- Ll) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12
  • interleukin-15/Fc fusion protein normferon
  • peginterferon alfa-2a peginterferon alfa-2b
  • normferon peginterferon alfa-2a
  • peginterferon alfa-2b peginterferon alfa-2b
  • interleukin- 15 recombinant interleukin- 15; RPI-MN; GS-9620; STING modulators; RIG-I modulators; NOD2 modulators; and IR-103.
  • TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-
  • PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK- 2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP- 6530, RV-1729, SAR-245409, SAR-260
  • Integrin alpha-4/beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.
  • HIV antibodies, bispecific antibodies, and“antibody-like” therapeutic proteins include DARTs ® , DUOBODIES ® , BITES ® , XmAbs ® , TandAbs ® , Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti -Rev antibody, camelid derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, and MB-66.
  • DARTs ® , DU
  • bavituximab examples include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F 5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060- 00-AB, MGD-014 and VRC07.
  • HIV bispecific antibodies include MGD014.
  • Examples of pharmacokinetic enhancers include cobicistat and ritonavir.
  • HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gpl20) (RV144), monomeric gpl20 HIV-1 subtype C 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), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), gpl40[delta]
  • CombiVICHvac LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i- key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71 -deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gpl20, Vacc- 4x + romidepsin, variant gpl20 polypeptide vaccine, rAd5 gag-pol
  • HIV therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/1300
  • Examples of other drugs for treating HIV include acemannan, alisporivir,
  • BanLec deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV- 205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.
  • Gene therapy and cell therapy include 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; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.
  • Examples of dendritic cell therapy include AGS-004.
  • Examples of gene editing systems include a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system.
  • HIV targeting CRISPR/Cas9 systems examples include EBT101.
  • CAR-T cell therapy examples include EBT101.
  • CAR-T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain.
  • the HIV antigens include an HIV envelope protein or a portion thereof, gpl20 or a portion thereof, a CD4 binding site on gpl20, the CD4-induced binding site on gpl20, N glycan on gpl20, the V2 of gpl20, and 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.
  • HIV CAR-T cell therapy examples include VC-CAR-T.
  • TCR-T cell therapy includes T cells engineered to target HIV derived peptides present on the surface of virus-infected cells.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more 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);
  • ATRIPLA ® efavirenz, tenofovir disoproxil fumarate, and emtricitabine
  • COMPLERA ® EVIPLERA ®
  • STRIBILD ® elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine
  • TRUVADA K tenofovir disoproxil fumarate and emtricitabine; TDF +FTC
  • DESCOVY® tenofovir alafenamide and emtricitabine
  • ODEFSEY® tenofovir alafenamide, emtricitabine, and rilpivirine
  • GENVOYA® tenofovir alafenamide, emtricitabine, cobicistat
  • elvitegravir elvitegravir
  • BIKTARVY® bictegravir, emtricitabine, tenofovir alafenamide
  • adefovir elvitegravir
  • adefovir dipivoxil cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ ®
  • dolutegravir dolutegravir, abacavir, and lamivudine
  • dolutegravir dolutegravir, abacavir sulfate, and lamivudine
  • raltegravir raltegravir and lamivudine
  • maraviroc enfuvirtide
  • enfuvirtide ALUVIA K (KALETRA ® ;
  • COMBIVIR ® zidovudine and lamivudine; AZT+3TC
  • EPZICOM ® LIVEXA ® ; abacavir sulfate and lamivudine; ABC+3TC
  • TRIZIVIR ® abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
  • a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir
  • a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudi
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.
  • a compound as disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compound (e.g., from 1 mg to 500 mg of compound).
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound as disclosed herein i.e., a compound of Formula I, II, or IIA
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound as disclosed herein i.e., a compound of Formula I, II, or Ila
  • Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.
  • HPLC high performance liquid 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 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.
  • 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.
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • PhI(OAc) 2 (Diacetoxyiodo)benzene or iodosobenzene diacetate
  • FB3, FB4, and FB5 are as defined herein.
  • the compounds of the present disclosure may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent to a skilled artisan given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.
  • the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments disclosed in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.
  • 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 di chi orom ethane), diethyl ether, methanol, and the like).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • chloroform chloroform
  • methylene chloride or di chi orom ethane
  • diethyl ether methanol, and the like.
  • solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.
  • Compound Cl is a molecule in which PG 1 and PG 2 are each independently a hydrogen atom or protecting group known to those skilled in the art, and wherein PG 1 and PG 2 may be the same or different.
  • Compound Cl may be racemic or enantioenriched to a degree, having R or S stereochemistry in the lactone ring as shown in cases where PG 1 and PG 2 are different.
  • Compound Cl is treated with a base followed by a carbonyl-containing Compound C2 having groups R 3 and R 4 as defined herein.
  • Activation of the intermediate aldol addition product commonly with dicyclohexylcarbodiimide and a copper salt promoter, or alternatively with a sulfonyl chloride is followed by elimination to give aldol condensation product Compound C3.
  • Compound C3 is treated with an additive, commonly an acid, to remove PG 1 , and the additive may also remove or change the identity of PG 2 to give Compound FB-C.
  • the fluoride source such as tetra -//-butyl a monium fluoride may be used to remove both silyl groups from Compound C3, giving a version of Compound FB-C where both PG 1 and PG 2 are hydrogen atoms.
  • Compound FBI with groups A, L, R 1 , and alkyl as defined herein is treated with an appropriate R 2 -containing alkyne
  • Compound FB4 may be subjected to chiral chromatography to give enantioenriched and or diastereomerically enriched versions of
  • Compound FB4 The terminal carboxylic acid group of Compound FB4 is activated, commonly with oxalyl chloride (giving an intermediate acid chloride) or with a
  • Compound FB5 where PG 2 is a hydrogen atom, Compound FB5 is effectively a compound of Formula I in and of itself.
  • Compound QIC A stirred solution of PCC (6.8 g, 31.8 mmol) in DCM (50 mL, dried over 3 A MS) was stirred at RT and to the solution was slowly added Compound Q1B (1.8 g, 10.6 mmol, 10 mL DCM solution). The reaction mixture was stirred at RT overnight. The mixture was diluted with Et 2 0 (200 mL) and stirred at RT for 1 hour. The mixture was filtered over silica and celite and concentrated. The residue was diluted with Et 2 0 (100 mL). The suspension was filtered over silica and Celite, and concentrated. Compound QIC was carried to the next step without further purification.
  • Compound Q2B 73 ⁇ 4r/-butylchlorodiphenylsilane (63.5 mL, 244 mmol) was added over a period of 1 h to an ice-cooled solution of Compound Q2A (10.0 g, 111 mmol) and DMAP (3.39 g, 27.8 mmol) in dry pyridine (140 mL). The reaction mixture was allowed to warm to rt, and stirred for 16 hours. The reaction mixture was poured into ice-water (600 mL) and stirred for 1 hour. The precipitated solid was filtered and washed with 400 mL of water followed by 200 mL of MeCN.
  • Compound Q2C A stirred solution of Compound Q2B (10.00 g, 17.64 mmol) in dry THF (90 mL) at 0 °C was added dropwise to a solution of allylmagnesium bromide (1.0 M in Et 2 0, 26.5 mL, 123 mmol) over a period of 10 min. The reaction mixture was stirred at 0 °C for an additional 1 h, the reaction was quenched with IN HC1 (50 mL). 100 mL of EtOAc was added and the aqueous layer was removed. The organic extract was washed 2 times with water and once with brine.
  • Compound Q2D A stirred solution of Compound Q2C (9.02 g, 14.8 mmol) in dry THF (99 mL) at -78 °C was treated dropwise with a THF solution of B3 ⁇ 4 SMe 2 (2.0 M in THF, 14.8 mL, 29.6 mmol) while being maintained under a blanket of N 2 . The reaction mixture was stirred at rt for 6 h after the addition, and then it was concentrated in vacuo. The residue obtained was dissolved in dry DCM (400 mL) and treated with pyridinium dichlorochromate (79.8 g, 370 mol). The mixture was stirred at rt for 24 h.
  • Compound Q3C A vessel was charged with Compound Q3A (20.0 g, 90.9 mmol, 1.00 eq ) in DMF (308 mL). Compound Q3B (18.4 g, 94.5 mmol, 1.04 eq ) and CS2CO3 (44.4 g, 136 mmol, 1.50 eq) were added to the solution. The reaction was stirred at 25°C for 16 h. Reaction was diluted with H2O (200 mL). System was extracted with EtOAc (3 x 200 mL), and the organic layers dried over Na 2 SC> 4. The solution was concentrated under reduced pressure to provide crude Compound Q3C (30.0 g, crude).
  • Compound Q3D A vessel was charged with Compound Q3C (5.00 g, 14.9 mmol, 0.98 eq ), 4-ethynyl-l-tButyl benzene (2.42 g, 15.2 mmol, 1.00 eq ), and THF (50.0 mL). Pd(PPh3)2Ch (214 mg, 0.305 mmol, 0.02 eq), Cul (116 mg, 0.610 mmol, 0.04 eq) and Et3N (2.24 g, 22.1 mmol, 1.45 eq) were added to the solution. The system was degassed and purged with N2 a total of 3 times. Reaction was stirred at 25°C under N2 for 16 h.
  • Compound Q4A A vessel was charged with Compound Q3C (5.00 g, 14.9 mmol, 0.98 eq), ethynylbenzene (1.56 g, 15.2 mmol, 1.00 eq), and THF (50.0 mL). Pd(PPh3)2Ch (214 mg, 0.305 mmol, 0.02 eq ), Cul (116 mg, 0.610 mmol, 0.04 eq) and Et3N (2.24 g, 22.1 mmol, 1.45 eq) were added to the solution. The system was degassed and purged with N2 a total of 3 times. Reaction was stirred at 25°C under N2 for 16 h. Reaction was filtered and the organic phase of the filtrate was concentrated. The resulting residue was purified by column
  • Compound Q5B Compound Q5A (12.3 g, 105 mmol, 1.00 eq) was placed in a vessel and 4-iodophenol (22.8 g, 103 mmol, 0.98 eq) in THF (370 mL) was added. Cul (806 mg, 4.24 mmol, 0.04 eq), Pd(PPh 3 ) 2 Ch (1.49 g, 2.12 mmol, 0.02 eq) and Et3N (15.5 g, 153 mmol,
  • Compound Q5C A vessel was charged with Compound Q5B (6.00 g, 28.8 mmol, 1.00 eq) and DMF (95.0 mL). Ethyl 6-bromohexanoate (6.69 g, 29.9 mmol, 1.04 eq) and CS2CO3 (14.0 g, 43.2 mmol, 1.50 eq) were added. Reaction was stirred at 25°C under N2 for 16 h. Reaction was diluted with H2O (200 mL) and extracted with EtOAc (3x 200 mL). Combined organic layers were dried over Na 2 SC> 4 , filtered, and concentrated.
  • Compound Q6A A vessel was charged with Compound Q5B (4.70 g, 22.5 mmol, 1.00 eq ) and DMF (75.0 mL). Compound Q3B (4.58 g, 23.4 mmol, 1.04 eq ) and CS2CO3 (11.0 g, 33.8 mmol, 1.50 eq) were added. Reaction was stirred at 25°C under N2 for 16 h.
  • Compound Q8B A vessel was charged with Compound Q8A (10.0 g, 56.1 mmol, 1.00 eq), HIO 4 (2.56 g, 11.2 mmol, 2.56 mL, 0.20 eq), and I 2 (5.70 g, 22.4 mmol, 4.52 mL, OAOeq). A solution of H 2 SO 4 (2.50 mL), AcOH (82.0 mL) and H 2 O (18.0 mL) was added to the mixture. The system was degassed and purged by N2 (3x). The reaction was stirred at 75°C for 16 h. The reaction was cooled to room temperature.
  • Deionized water (50.0 mL) was added to the solution, which was filtered to give a cake.
  • the cake was treated with DCM (100 mL) then washed with deionized water (2 x 50.0 mL) and sodium thiosulfate (2 x 50.0 mL).
  • the organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to provide crude Compound Q8B.
  • Compound Q8C A vessel was charged with Compound Q8B (12.0 g, 39.4 mmol, 1.00 eq) and MeOH (80.0 mL). The solution was cooled to 0 °C in an ice bath. SOCb (7.04 g, 59.1 mmol, 4.29 mL, 1.50 eq) was added dropwise. Reaction was stirred at 20 °C for 2 h. The reaction was concentrated in vacuo, and the resulting residue was dissolved in DCM (50.0 mL). The system was washed with H2O (2 x 20.0 mL), dried over Na 2 SC> 4 , and filtered. The filtrate was concentrated to obtain Compound Q8C.
  • Compound Q8D A vessel was charged with Compound Q8C (5.00 g, 15.7 mmol, 1 eq) and Compound Q5A (1.90 g, 16.3 mmol, 1.04 eq) in THF (35.0 mL). Cul (119 mg, 628 umol, 0.04 eq), Pd(PPh ) 2 Cl 2 (220 mg, 314 umol, 0.02 eq) and Et N (2.31 g, 22.7 mmol, 3.17 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N 2 (3X). The reaction mixture was stirred at 25°C under N 2 for 16 h. The mixture was filtered.
  • Compound Q9B A vessel was charged with Compound Q9A (10.0 g, 63.2 mmol, 1 eq ) and Compound Q3A (12.5 g, 56.8 mmol, 0.90 eq ) in THF (100 mL). Cul (240 mg, 1.26 mmol, 0.02 eq ), Pd(PPh3)2Ch (1.77 g, 2.53 mmol, 0.04 eq), and Et3N (9.27 g, 91.6 mmol, 12.7 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N2 (3x). The reaction mixture was stirred at 25°C under N2 for 16 h.
  • Compound Q9C A vessel was charged with Compound Q9B (4.00 g, 15.9 mmol, 1.00 eq) in DMF (40.0 mL). Next, Compound Q3B (3.01 g, 16.6 mmol, 1.04 eq) and CS2CO3 (7.81 g, 23.9 mmol, 1.50 eq) were added to the solution. The reaction mixture was stirred at 25°C for 16 h. H2O (50.0 mL) was added to the mixture, which was extracted with Ethyl acetate (3 x 50.0 mL). Combined organic extracts were washed with brine (50.0 mL), dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure.
  • Compound Q10A A vessel was charged with Compound Q5B (4.00 g, 19.2 mmol, 1.00 eq ) in DMF (40.0 mL). Methyl 5-bromopentanoate (3.90 g, 19.9 mmol, 2.86 mL, 1.04 eq) and CS2CO3 (9.39 g, 28.8 mmol, 1.50 eq) were added to the solution. Reaction was stirred at 25°C for 16 h. Mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (3 x 50.0 mL).
  • Compound Q13D A vessel was charged with Compound Q13C (5.60 g, 17.3 mmol, 1.00 eq) and Compound Q5A (2.09 g, 18.0 mmol, 1.04 eq) in THF (40.0 mL). Cul (66.0 mg, 346 umol, 0.02 eq), Pd(PPh3)2Ch (486 mg, 693 umol, 0.04 eq) and Et3N (2.54 g, 25.1 mmol, 3.50 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N2 (3x). The reaction was stirred at 75 °C under N2 for 16 h.
  • Compound Q14E A solution of Compound Q14D (23 g, 53 mmol) in anhydrous THF (250 mL) was cooled to 0 °C and a solution (2M in THF) of allylmagnesium chloride (66 mL, 131.7 mmol) was added slowly over 30 min, keeping the internal temperature between 2 °C to 5 °C. The reaction was stirred at 2 °C for an extra 1 hour. The reaction was quenched with the addition of saturated aqueous ammonium chloride (400 mL). The aqueous layer was extracted with ethyl acetate (3 x 200 mL).
  • Compound Q14F To a tert-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q14E (24g, 50 mmol) and N-methylmorpholine N-oxide (6.46 g, 55 mmol) was added an aqueous solution of OsCri 4% (1 mL) .
  • Compound Q14 The crude Compound Q14G was diluted with DCM (250 mL), and PDC (32.7 g, 108.8 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature for 48 h and the mixture was diluted with DCM (200 mL). The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q14 (90.9%). LCMS ESI + calc’d for C32H30O4 : 479.2 [M+H + ] ; found: does not ionize.
  • Compound Q16C A solution of Compound Q16B (27 g, 61.9 mmol) in anhydrous THF (270 mL) was cooled to 0 °C and a solution (2M in THF) of allylmagnesium chloride (77.3 mL, 154.6 mmol) was added slowly over 30 min, keeping the internal
  • Compound Q16D To a /t V-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q16C (29g, 60.6 mmol) and N-methylmorpholine N-oxide (7.8 g, 66.6 mmol) was added an aqueous solution of OsCb 4% (1.25 mL).
  • Compound Q16 The crude Compound Q16E was diluted with DCM (300 mL), and PDC (44 g, 117 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature for 48 h and the mixture was diluted with DCM (200 mL). The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q16. LCMS ESI + calc’d for C32H30O4 : 479.2 [M+H + ] ; found: does not ionize.
  • Compound Q19B A vessel was charged with Compound Q19A (14 g, 57.5 mmol, 1.00 eq) in MeOH (60 mL). H2SO4 (5.65 g, 57.5 mmol, 3.07 mL, 1.00 eq ) was added to the mixture under N2 . The reaction was stirred at 85 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and the reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with brine (70, 50mL). The final organic phase was concentrated under reduced pressure to give crude Compound Q19B that was used in the next step without further purification.
  • Compound Q19C A vessel was charged with Compound Q19B (13.4 g, 52.1 mmol, 1.00 eq) and Compound Q5A (7.26 g, 62.5 mmol, 7.93 mL, 1.20 eq) in dioxane (90 mL). Cul (397 mg, 2.09 mmol, 0.04 eq ), Pd(PPh3)2Ch (731 mg, 1.04 mmol, 0.02 eq) and Et3N (7.65 g, 75.6 mmol, 10.5 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 90°C under N2 for 16 h.
  • Compound Q20B A vessel was charged with Compound Q20A (10 g, 36.2 mmol, 1.00 eq ) in MeOH (60 mL). H2SO4 (3.55 g, 36.2 mmol, 1.93 mL, 1.00 eq ) was added to the mixture under N2 . The reaction was stirred at 85 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and the reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with brine (70, 50mL). The final organic phase was concentrated under reduced pressure to give crude Compound Q20B, which was used without further purification.
  • Compound Q20C A vessel was charged with Compound Q20B (10 g, 34.4 mmol, 1.00 eq) and Compound Q5A (4.80 g, 41.3 mmol, 5.25 mL, 1.20 eq) in THF (70 mL). Cul (262 mg, 1.38 mmol, 0.04 eq), Pd(PPh3)2Ch (483 mg, 689 pmol, 0.02 eq) and Et3N (5.06 g, 49.9 mmol, 6.96 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 25°C under N2 for 16 h.
  • Compound Q21C A vessel was charged with Compound Q21B (6.8 g, 24.6 mmol, 1.00 eq) and Compound Q5A (3.43 g, 29.5 mmol, 3.74 mL, 1.20 eq) in THF (50 mL). Cul (187 mg, 985 pmol, 0.04 eq), Pd(PPh3)2Ch (345 mg, 492 pmol, 0.02 eq) and Et3N (3.61 g, 35.7 mmol, 4.97 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 90°C under N2 for 16 h.
  • Compound Q22B A vessel was charged with Compound Q22A (5.00 g, 18.8 mmol, 1.00 eq ) and Compound Q5A (4.38 g, 37.7 mmol, 4.78 mL, 2.00 eq) in dioxane (70.0 mL). Cul (287 mg, 1.51 mmol, 0.08 eq ), Pd(t-Bu3P)2 (385 mg, 754 umol, 0.04 eq) and Et3N (2.77 g, 27.3 mmol, 3.81 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 for (3x). The reaction was stirred at 90°C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by column
  • Compound Q22 A vessel was charged with Compound Q22B (2.20 g, 7.32 mmol, 1.00 eq), THF (10.0 mL), and H2O (10.0 mL). NaOH (5.86 g, 146 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70°C for 16 h. The reaction was concentrated under reduced pressure to give a residue. The material was washed with DCM (100 mL) and then filtered. The cake was diluted with H2O (100 mL), and 6M aq. HC1 was added until the pH was ⁇ 3. Filtration gave another cake, which was dried under reduced pressure.
  • Compound Q23B A vessel was charged with Compound Q23A (24.0 g, 83.9 mmol, 1.00 eq ) in DMF (160 mL). 3,3-dimethoxyprop-l-ene (9.00 g, 88.1 mmol, 10.4 mL, 1.05 eq), TBAC (24.5 g, 88.2 mmol, 24.6 mL, 1.05 eq), and TEA (13.5 g, 134 mmol, 18.6 mL, 1.60 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25°C for 0.5 h.
  • Compound Q23C A vessel was charged with Compound Q23B (2.50 g, 8.53 mmol, 1.00 eq) in ACN (25.0 mL).
  • Compound Q5A (1.98 g, 17.0 mmol, 2.16 mL, 2.00 eq ), Cy2NMe (3.33 g, 17.0 mmol, 3.62 mL, 2.00 eq), and Pd Sphos G2 (614 mg, 852 umol, 0.10 eq) were added to the mixture.
  • the system was degassed and purged with N2 (3x). The reaction was stirred at 80°C for 4 h. The reaction was filtered, and H2O (100 mL) was added to the mixture.
  • Compound Q24B To a stirred solution of Compound Q24A (232 mg, 2.00 mmol) in anhydrous Pentane:DCM ( 9: 1, 10.00 mL) at ambient temperature was added TEMPO (32 mg, 0.200 mmol) followed by PhI(OAc)2 (709 mg, 2.20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of an aqueous saturated solution of NaHC0 3 (10 mL). The layers were separated, the aqueous layer was extracted with DCM, the combined organic phases were dried over Na 2 S0 4 , filtered and kept as a stock solution of desired aldehyde with iodobenzene due to volatility.
  • Example Al A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound El A (102 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-40% EtOAc in Hexanes, 12 g column) giving crude Example Al. This sample of crude Example Al was purified a second time using 0-50% EtOAc in Hexane, giving purified Example Al.
  • Example A2 A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E2A (87 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-10% EtOAc in DCM, 12 g column) giving crude Example A2. The crude Example A2 was purified a second time using 0-50% EtOAc in Hexane giving Example A2.
  • Example A3 A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E3A (98 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-60% EtOAc in hexanes, 12 g column) giving Example A3.
  • the organic layer was dried and condensed in vacuo to afford the crude product.
  • the crude product was dissolved in 3 mL of pyridine and POCI3 (0.18 mL, 1.92 mmol) was added dropwise at 0°C. The solution was stirred at 50°C overnight.
  • the reaction was dissolved with 20 mL of Et 2 0 and washed twice with a 10% CuS0 4 solution followed by water and brine.
  • the organic phase was dried and condensed in vacuo to afford the crude product.
  • the crude product was dissolved in THF (13 mL) and a TBAF solution (1.92 mL, 1.0 M in THF, 1.92 mmol) was added dropwise at 0°C. The reaction was stirred at room temperature for 1 hour.
  • the reaction was condensed in vacuo and purified by column chromatography using 50-100% EtOAc in hexanes giving
  • Example A4 A stirred solution of Compound E4A (70.0 mg, 0.31 mmol) and pyridine (75 pL, 0.93 mmol) in dry DCM (4.75 mL) at 0 °C was added dropwise a solution of Compound E4B (147 mg, 0.47 mmol) in 1.50 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-50% EtOAc in hexanes, 12 g column) giving crude Example A4. The crude Example A4 was purified a second time using 0-50% EtOAc in Hexane giving Example A4.
  • Example A5 Example A6, Example A7, and Example A8:
  • the solution was then diluted with diethyl ether (25 mL) and the solution was washed with 10% aqueous copper sulfate solution (2 c 25 mL), then with water (2 c 25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • the oil was then dissolved in di chi orom ethane (33 mL), cooled to 0 °C under a nitrogen atmosphere, and a solution of tetrabutyl ammonium fluoride (1 M in tetrahydrofuran, 14.9 mL, 14.9 mmol) was added. The reaction was stirred at rt over the weekend.
  • Example A5, Example A6, Example A7, and Example A8 The mixture was subjected to chiral SFC and each enantiomer of each olefin isomer was obtained individually, for a total of 4 compounds.
  • Semi-preparative SFC conditions for chiral analysis and purification were as follows: Column ChiralPack IA 10 x 250 mm, 5pm, isocratic 30% isopropanol, 10 mL/min, 100 bar, 35 °C.
  • Example A5 (First Peak to Elute): LCMS ESI + calc’d for C29H24O5: 453.2
  • Example A6 (Second Peak to Elute): LCMS ESI + calc’d for C29H24O5: 453.2
  • Example A7 (Third Peak to Elute): LCMS ESI + calc’d for C29H24O5: 453.2
  • Example A9 To a solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in anhydrous DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E9A (96 mg, 0.29 mmol) in DCM (1.25 mL). The reaction mixture was warmed to ambient temperature and stirred for an additional hour. The reaction was
  • Compound E10A A stirred solution of Compound Q9 (101.0 mg, 0.30 mmol) and pyridine (1 drop) in dry DCM (1.00 mL) at 0 °C was added dropwise a solution of oxalyl chloride. The reaction mixture was stirred at room temperature for an additional 30 minutes. The reaction was condensed to afford the desired Compound E10A. This material was used without further purification.
  • Example A10 Compound E10A (102 mg, 0.29 mmol) in DCM (1.25 mL) was added dropwise to an ice-cooled solution of Compound Q2 (35 mg, 0.19 mmol), pyridine (46 pL, 0.57 mmol) and di chi orom ethane (2.50 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 30 mins. The reaction was condensed in vacuo and purified by column chromatography (0-60% EtOAC in hexanes, 12g column) giving Example A10.
  • the reaction was quenched at the same temperature with saturated aqueous ammonium chloride (15 mL) and the mixture was diluted with ethyl acetate (30 mL). The phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the intermediate alcohol.
  • the crude alcohol was dissolved in pyridine (3.28 mL) and cooled to 0 °C. To this solution was added phosphorus(V) oxychloride (0.23 mL, 2.46 mmol) dropwise and the mixture was then heated to 50 °C and stirred overnight.
  • the purified material was then dissolved in dichloromethane (1.75 mL) and to this solution was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.31 mL, 1.31 mmol) at 0 °C and the solution was slowly allowed to attain room temperature and stirred overnight.
  • Example All To a solution Compound E11A (0.022 g, 0.104 mmol) and pyridine (0.025 mL, 0.311 mmol) in dichloromethane (1.7 mL) under a nitrogen atmosphere was added a solution of Compound E4B (0.036 g, 0.114 mmol) in dichloromethane (0.4 mL) dropwise at 0 °C. The reaction was then warmed to rt and stirred for 30 min. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase
  • Example A12 To a solution of Compound Q2 (0.030 g, 0.161 mmol) and pyridine (0.039 mL, 0.483 mmol) in dichloromethane (2.5 mL) was added a solution of
  • Example A13 Compound E4B (24 mg, 0.80 mmol) in DCM (0.3 mL) was added dropwise to an ice-cooled solution of Compound Qll (12 mg, 0.05 mmol), pyridine (12 pL, 0.15 mmol) and di chi orom ethane (0.70 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 mins. The reaction was condensed in vacuo and purified by column chromatography (0-60% EtOAc in hexanes, 12g column) giving Example A13.
  • Example A14 To a solution Compound Q12 (0.030 g, 0.101 mmol) and pyridine (0.024 mL, 0.302 mmol) in dichloromethane (1.5 mL) was added a solution of
  • Example A15 Compound E4B (28 mg, 0.09 mmol) in DCM (0.50 mL) was added dropwise to an ice-cooled solution of Compound Q24 (15 mg, 0.06 mmol), pyridine (16 pL, 0.18 mmol) and di chi orom ethane (0.80 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 30 min. The reaction was condensed in vacuo and purified by column chromatography on silica (0-60% EtOAc in hexanes, 12g column) giving Example A15.
  • the solution was then diluted with diethyl ether (20 mL) and washed with 10% aqueous copper sulfate solution (2 x 10 mL) followed by water (2 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced 1. The residue was passed through a silica pad using 10% EtOAC in hexanes.
  • the crude product was then dissolved in THF (5 mL), cooled to 0 °C under a nitrogen atmosphere, and treated with a tetrabutyl ammonium fluoride solution (1 M in tetrahydrofuran, 0.72 mL, 0.72 mmol). The reaction was stirred at room temperature for 30 minutes and was condensed under reduced pressure.
  • Example A16 and Example A17 To a solution of a mixture of Compound
  • Example A16 was obtained (first to elute) and Example A17 was also obtained (second to elute):
  • Example A16 LCMS ESI + calc’d for C33H32O6 : 525.2 [M+H + ] ; found 525.1
  • Example A17 LCMS ESI + calc’d for C33H32O6 : 525.2 [M+H + ] ; found 524.9
  • Example A18 To a solution Compound Q2 (0.032 g, 0.172 mmol) and pyridine

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Abstract

La présente invention concerne de manière générale certains composés de diacylglycérol lactone, des compositions pharmaceutiques comprenant lesdits composés, et des procédés de fabrication et d'utilisation desdits composés et compositions pharmaceutiques. Les composés et les compositions de l'invention peuvent être utilisés pour le traitement ou la prévention de maladies, de troubles ou d'infections pouvant être modifiées par des agonistes de protéine kinase C (PKC), tels que le VIH.
PCT/US2020/019704 2019-02-25 2020-02-25 Agonistes de protéine kinase c WO2020176510A1 (fr)

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