WO2020176505A1 - Protein kinase c agonists - Google Patents

Protein kinase c agonists Download PDF

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Publication number
WO2020176505A1
WO2020176505A1 PCT/US2020/019699 US2020019699W WO2020176505A1 WO 2020176505 A1 WO2020176505 A1 WO 2020176505A1 US 2020019699 W US2020019699 W US 2020019699W WO 2020176505 A1 WO2020176505 A1 WO 2020176505A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
hiv
inhibitors
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PCT/US2020/019699
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French (fr)
Inventor
Yunfeng E. Hu
Jasmine Kaur
Ryan Mcfadden
Jeffrey P. MURRY
Brian E. Schultz
Hoa H. TRUONG
Helen Yu
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Gilead Sciences, Inc.
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Publication of WO2020176505A1 publication Critical patent/WO2020176505A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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 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;
  • 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 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
  • heteroatoms independently selected from N, O, and S, or
  • A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, 2, or 3; and
  • 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
  • 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.
  • 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.
  • 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(CI3 ⁇ 4)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
  • 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 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
  • 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 3-20 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(CH3)N(CH )CH 2 -, -CH 2 OCH(CH3)-, -CH 2 CH(CH 2 CH3)S-, -CH 2 NHC(CH3) 2 -, -C(CH3) 2 SCH 2 -, -CH(CH3)N(CH3)CH(CH 3 )0-, -CH 2 SC(CH 2 CH3)(CH3)-, 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-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 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., C2-20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C2-12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2-10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C3-12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C3-8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C3-6 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 interchangeably.
  • 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.
  • sulfonyl are methylsulfonyl, ethylsulfonyl, phenyl sulfonyl, 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;
  • 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 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
  • heteroatoms independently selected from N, O, and S, or
  • A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, 2, or 3; and
  • n 0, 1, 2, or 3.
  • 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;
  • 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 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
  • heteroatoms independently selected from N, O, and S, or
  • A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, or 2; and
  • 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 independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, pentyl, or hexyl.
  • each R 2 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, pentyl, or hexyl.
  • one, two, or three R 2 is methyl or tert-butyl.
  • one, two, or three R 2 is methyl.
  • one, two, or three R 2 is ethyl.
  • 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. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R 2 is isobutyl.
  • 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 C1-4 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 methyl, ethyl, n-propyl, isopropyl, tert-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 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. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, 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.
  • 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. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, 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 3 and R 4 is H, Ci- 15 alkyl, or C 6-10 aryl
  • 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.
  • one of R 3 and R 4 is H and the other of R 3 and R 4 is Ci- 15 alkyl or C 6-10 aryl, wherein the Ci-is alkyl and the 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.
  • 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 C 6-10 aryl, wherein each Ci- 15 alkyl and the 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.
  • one of R 3 and R 4 is C 6-10 aryl and the other of R 3 and R 4 is Ci- 15 alkyl or C 6-10 aryl, wherein the Ci- 15 alkyl and each C 6-10 aryl are optionally substituted with 1 -3 groups
  • C 5-10 monocyclic cycloalkyl 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
  • the other of R 3 and R 4 is Ci- 12 alkyl or phenyl, wherein the Ci- 12 alkyl is optionally substituted with
  • R 3 and R 4 is H 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 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 Ci- 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 Ci- 12 alkyl or phenyl, wherein the Ci- 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 Ci- 12 alkyl or phenyl, wherein the Ci- 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 Ci- 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 Ci- 12 alkyl or phenyl, wherein the Ci- 12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is H or methyl and the other of R 3 and R 4 is phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • one of R 3 and R 4 is H or methyl and the other of R 3 and R 4 is phenyl, C6-12 alkyl, or a methyl, wherein the methyl is optionally substituted with adamantanyl.
  • 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 phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
  • 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 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 C1-2 alkyl optionally substituted with
  • R 4 is C6-12 alkyl optionally substituted with
  • R 4 is C6-12 alkyl optionally substituted with
  • R 4 is phenyl
  • R 4 is methyl, phenyl
  • R 4 is methyl, phenyl
  • R 4 is
  • 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
  • L is a Ci- 8 alkyl ene optionally substituted with 1-3 R 5 .
  • L is a Ci- 8 alkyl 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 C3-7 monocyclic cycloalkyl.
  • L is a Ci- 6 alkyl ene 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 C1-4 alkylene optionally substituted with 1-3 R 5 .
  • L is a C1-3 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 C1-3 alkylene optionally substituted with two R 5 .
  • 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 .
  • L is methylene, ethylene, propylene, or butylene.
  • -A-L- is -A-m ethylene-, -A-ethylene-,
  • 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 -CFLNH- 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. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R 5 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 5 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, each R 5 is independently methyl or ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a
  • 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. 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 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
  • A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S; or A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S; or A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S; or A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
  • A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, or a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, each of which is optionally substituted with one R 1 .
  • A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, or a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, each of which is optionally substituted with one R 1 .
  • A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, wherein the 9 membered fused bicyclic heteroarylene is optionally substituted with one R 1 .
  • A is a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, wherein the 9-13 membered fused bicyclic or fused tricyclic heterocyclylene is optionally substituted with one R 1 .
  • A is a benzofuranylene, dihydrobenzofuranylene, or indolylene, each of which is optionally substituted with one R 1 .
  • 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.
  • A is benzofuranylene and L is C1-5 alkylene optionally substituted with 1-2 R 5 .
  • A is benzofuranylene and L is C1-3 alkylene optionally substituted with 1-2 R 5 .
  • A is benzofuranylene and L is ethylene optionally substituted with 1-2 R 5 .
  • A is benzofuranylene and L is ethylene optionally substituted with 2 R 5 , wherein the 2 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 cycloalkyl.
  • A is
  • benzofuranylene and L is ethylene 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.
  • A is dihydrobenzofuranylene and L is ethylene 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.
  • A is benzofuranylene and R 3 is H or methyl.
  • A is benzofuranylene and R 4 is phenyl or Ci- 12 alkyl, wherein the Ci- 12 alkyl is optionally substituted with adamantanyl.
  • A is benzofuranylene; R 3 is H or methyl; and R 4 is phenyl or Ci- 12 alkyl, wherein the Ci- 12 alkyl is optionally substituted with
  • the compound of Formula I, II, or Ila is selected from the group consisting of:
  • the compound of Formula I, II, or Ila is:
  • the compound of Formula I, II, or Ila is:
  • the compound of Formula I, II, or Ila is:
  • the compound is:
  • the compound of Formula I, II, or Ila is:
  • the compound is:
  • the compound of Formula I, II, or Ila is:
  • the compound of Formula I, II, or Ila is:
  • the compound is:
  • 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.
  • forms in which the pharmaceutical compositions described herein may be incorporated for 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 solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • 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 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 antagonists, DNA methyl
  • 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.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I,
  • 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
  • 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
  • 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 disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,
  • 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 ®
  • 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).
  • Examples of 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.
  • gpl20 inhibitors examples 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
  • 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 ® DARTs
  • bavituximab examples include bavituximab, UB-421, C2F5, 2G12, C4E10,
  • 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 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 ® 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 ® (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
  • Rh(PPh ) 3 Cl Rhodium(I) tris-triphenylphosphine chloride complex rt room temperature
  • 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.
  • Typical embodiments of compounds disclosed herein may be synthesized using the general reaction schemes described below. It will be apparent to a skilled artisan given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. 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 BHv SMe? (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 Q3B Compound Q3A (45.00 g, 307.92 mmol, 37.19 mL, 1.00 eq) and CH 2 (C0 2 H) 2 (32.04 g, 307.92 mmol, 32.04 mL, 1.00 eq) were added to pyridine (126.00 mL). The reaction was stirred for lh at 80°C. Piperidine (2.10 g, 24.63 mmol, 2.44 mL, 0.08 eq) was added and the reaction was heated to 110°C for lh. The mixture was poured into 450 mL cold water. HC1 (150 mL) was added to the mixture to the point of strong acidity.
  • Compound Q3C A vessel was charged with Pd/C (3.00 g), MeOH (100 mL) and Compound Q3B (10.0 g, 53 mmol, 1.0 eq) under Argon. The reaction was stirred at 50°C for 40 h under H 2 (50 psi). The reaction was filtered and the cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated to obtain Compound Q3C.
  • Compound Q3D A vessel was charged with Compound Q3C (7.00 g, 36.4 mmol, 1 .00 eq), [BnNMesJICh (19.01 g, 54.63 mmol, 1.50 eq), ZnCh (7.45 g, 54.6 mmol, 2.56 mL, 1.50 eq), and CH3COOH (100.00 mL). The reaction was stirred at 15°C for 16 h. The reaction was quenched with H2O (40 mL) and MTBE (25 mL). The system was extracted with DCM (5 x 30 mL).
  • Compound Q3E A vessel was charged with Compound Q3D (8.00 g, 25.15 mmol, 1.00 eq), K2CO3 (6.95 g, 50.30 mmol, 2.00 eq), CH3I (7.14 g, 50.30 mmol, 3.13 mL, 2.00 eq) and DMF (20.0 mL). The system was purged with N2 (3x). The reaction was stirred for 16 h at 15°C. The system was then poured into EtOAc (40 mL). The system was washed with sat. aq LiCl (3x) to remove DMF.
  • Compound Q3F A vessel was charged with Compound Q3E (3.00 g, 9.03 mmol, 1.00 eq), l-ethynyl-4-methyl -benzene (1.08 g, 9.30 mmol, 1.17 mL, 1.03 eq),
  • Compound Q4F To a /tvV-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q4E (24g, 50 mmol) and N-methylmorpholine N-oxide (6.46 g, 55 mmol) was added an aqueous solution of OsCL 4% (1 mL) .
  • Compound Q4 The crude Compound Q4G 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 filter through celite and the filtrate was concentrated under reduced pressur. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q4 (90.9% ee). LCMS ESI + calc’d for C32H30O4 : 479.2 [M+H + ] ; found: does not ionize.
  • Compound Q7 and Compound Q8 A solution of Compound Q3E (1.00 g) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a chiralcel AD (250mm x 30mm x 5 pm) column with gradient elution from 40% MeOH in CO2 upward. Flow rate was 70 mL/min, and 10 injections were conducted. Two peaks were obtained, corresponding to the two enantiomers of Compound Q3E.
  • Compound Q9A A vessel was charged with Compound Q7 (280 mg, 843 umol, 1.00 eq ) and 4-/-butyl-l-ethynylbenzene (138 mg, 876 umol, 1.04 eq) in THF (1.96 mL). Cul (6.42 mg, 33.7 umol, 0.04 eq ), Et3N (123 mg, 1.22 mmol, 170 uL, 1.45 eq ), and
  • Compound Q10A A vessel was charged with Compound Q8 (280 mg, 843 umol, 1.00 eq ) and 4-/-butyl-l-ethynylbenzene (138 mg, 876 umol, 1.04 eq) in THF (1.96 mL). Cul (6.42 mg, 33.7 umol, 0.04 eq ), Et3N (123 mg, 1.22 mmol, 170 uL, 1.45 eq ), and
  • Compound QUA A vessel was charged with Compound Q7 (800 mg, 2.41 mmol, 1.00 eq ) and l-ethynyl-4-methylbenzene (290 mg, 2.51 mmol, 1.04 eq) in THF (5.60 mL). Cul (18.3 mg, 96.3 umol, 0.04 eq), Et3N (353 mg, 3.49 mmol, 1.45 eq), and Pd(PPh3)2Ch (33.8 mg, 48.1 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h.
  • Compound Q12A A vessel was charged with Compound Q8 (800 mg, 2.41 mmol, 1.00 eq ) and l-ethynyl-4-methylbenzene (290 mg, 2.51 mmol, 1.04 eq) in THF (5.60 mL). Cul (18.3 mg, 96.3 umol, 0.04 eq), Et3N (353 mg, 3.49 mmol, 1.45 eq), and Pd(PPh3)2Ch (33.8 mg, 48.1 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h.
  • Compound Q13B To a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13A (20 g, 127.74 mmol, 1.00 equiv), 2-bromo-l,l-di ethoxy ethane (27.6 g, 140.05 mmol, 1.10 equiv), N,N- dimethylformamide (100 mL) and potassium carbonate (19.4 g, 140.37 mmol, 1.10 equiv). The resulting solution was stirred for 16 h at 100°C in an oil bath. The reaction solution was diluted with 300 mL of water.
  • Compound Q13C To a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13B (31 g, 113.67 mmol, 1.00 equiv) and acetic acid (300 mL). The resulting solution was heated at reflux for 16 h in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 150 mL of EA, washed with water (2 x 200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford Compound Q13C. 'H NMR (400 MHz, CDCh) d 9.90 (s, 1H), 7.74 (s, 1H), 7.55-7.45 (m, 3H).
  • Compound Q13E To a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13D (4.7 g, 18.75 mmol, 1.00 equiv), ethyl acetate (300 mL), Palladium on carbon (235 mg, 5%wt) and hydrogen. The resulting mixture was stirred for 30 min at 20°C and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum to afford Compound Q13E.
  • Compound Q13D 4.7 g, 18.75 mmol, 1.00 equiv
  • ethyl acetate 300 mL
  • Palladium on carbon 235 mg, 5%wt
  • Compound Q13F To a 100-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13E (3 g, 11.87 mmol, 1.00 equiv), l-ethynyl-4-m ethylbenzene (4.14 g, 35.64 mmol, 3.00 equiv), N,N- dimethylformamide (30 mL), potassium carbonate (4.9 g, 35.45 mmol, 3.00 equiv), xphos (0.99 g, 0.20 equiv) and Pd 2 (dba) 3 (1.23 g, 1.34 mmol, 0.10 equiv).
  • Compound Q14A A vessel was charged with Compound Q13 (0.95 g, 3.12 mmol, 1.00 eq) in DMF (10 mL). K2CO3 (1.73 g, 12.49 mmol, 4.00 eq) was added to the solution. Mel (553.8 mg, 3.90 mmol, 1.25 eq) was added dropwise to the mixture. The reaction was stirred at 25 °C for 16 h. Water (20 mL) was added to the mixture, which was stirred for 2 min. System was extracted with EtOAc (10 mL + 5.0 mL) and the organic phase was collected. The organic layer was dried over anhydrous INfeSCL, filtered, and the filtrate was concentrated under reduced pressure, providing Compound Q14A.
  • Compound Q14B LiHMDS (1 M, 8.00 mL, 6.37 eq) was added in dropwise fashion to a solution of Compound Q14A (0.400 g, 1.26 mmol, 1.00 eq) in THF (10 mL) at -78 °C under N2. The reaction was stirred at -78 °C for 1 h. Mel (0.535 g, 3.77 mmol, 3.00 eq) was added in dropwise fashion to the solution at -78 °C, which was then stirred at 25 °C for 1 h. The reaction was quenched with sat. NH4CI (30 mL) and extracted with EtOAc (3 x 5.0 mL).
  • Compound Q14 A vessel was charged with Compound Q14B (190 mg, 548.4 pmol, 1.00 eq) in THF (5.0 mL) and H2O (5.0 mL). NaOH (438.7 mg, 10.9 mmol, 20.0 eq) was added to the solution. The reaction was stirred at 50 °C for 16 h. MeOH (2.0 mL) was added to the solution and stirred for 2 h at 75 °C. HC1 (6 N) was added to the mixture to neutralize the NaOH and the system was extracted with EtOAc (10 mL c 2). Combined organic extracts were concentrated under reduced pressure, then triturated with Petroleum Ether/Ethyl Acetate (20: 1 v:v, 30 mL total). Filtration gave a cake, which was dried under reduced pressure, giving
  • Compound Q16 A vessel was charged with Compound Q16C (2.30 g, 7.92 mmol, 1.00 eq) in THF (16.0 mL) and H2O (16.0 mL). NaOH (6.34 g, 158 mmol, 20.0 eq) was added to the mixture. Reaction was stirred at 70°C for 16 h. The reaction was concentrated under reduced pressure to remove the THF. 6M aq HC1 was added to pH ⁇ 3. The system was extracted with DCM (3 x 50.0 mL); combined organic extracts were washed with brine (50.0 mL), dried over Na 2 S0 4 , and filtered.
  • Compound Q17B To a solution of Compound Q17A (518 mg, 2.28 mmol, 1.0 eq.), [PdCh(PPh3)2] (32 mg, 0.046 mmol, 0.02 eq.) and Cul (87 mg, 0.46 mmol, 0.2 eq.) in dry and degassed DMF (23 mL) under a nitrogen atmosphere were successively added l-ethynyl-4- methylbenzene (1.79 mL, 14.1 mmol, 6.2 eq.) followed by Et2NH (1.19 mL, 11.4 mmol, 5.0 eq.). The solution was heated at 115°C for 12h and was then allowed to cool to room
  • Compound Q19B To a 1-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19A (25 g, 146.55 mmol, 1.00 equiv) in ACN/DMF (500/125 mL), Cs 2 C0 3 (95.8 g, 294.03 mmol, 2.01 equiv) and ethyl 2-bromoacetate (29.3 g, 175.45 mmol, 1.20 equiv). The resulting mixture was stirred overnight at 100 °C in an oil bath and then filteredand washed by EA.
  • ACN/DMF 500/125 mL
  • Cs 2 C0 3 95.8 g, 294.03 mmol, 2.01 equiv
  • ethyl 2-bromoacetate 29.3 g, 175.45 mmol, 1.20 equiv
  • Compound Q19D To a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19C (11.2 g, 56.96 mmol, 1.00 equiv) in dichloromethane (150 mL) and Dess-Martin Periodinane (26.7 g, 62.96 mmol, 1.11 equiv). The resulting mixture was stirred for 2 h at room temperature, filtered, and washed by DCM.
  • Compound Q19G To a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19F (3.82 g, 14.32 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), l-ethynyl-4-methylbenzene (5.0 g,
  • Compound Q19 To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution ofCompound Q19G (1.4 g, 4.04 mmol, 1.00 equiv) in tetrahydrofuran/H 2 0 (16/4 mL) and sodium hydroxide (0.84 g, 21.00 mmol, 5.20 equiv). The resulting solution was stirred for 3 h at 50 °C. The resulting mixture was concentrated to 1 ⁇ 4 volume under vacuum. The pH value of the solution was adjusted to 3 with hydrogen chloride (6 N). The solution was filtered and washed by H2O and hexane to afford Compound Q19.
  • Compound Q20B A vessel was charged with Compound Q20A (20.0 g, 156 mmol, 1.00 eq ) and DCM (140 mL). The system was cooled to -70°C. O3 (1.00 eq ) was bubbled into the solution until a pale blue color persisted at -78°C under 15 psi for about 2 h. PPh3 (61.3 g, 234 mmol, 1.50 eq) was added to the mixture. The reaction was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure at 25°C. MTBE (100 mL) was added to the residue. The system was stirred at 25°C for 20 min.
  • Compound Q20D A vessel was charged with Compound Q20C (1.70 g, 5.65 mmol, 1.00 eq) and ACN (17.0 mL). CyiMeN (2.21 g, 11.2 mmol, 2.39 mL, 2.00 eq ), and Pd- Sphos-G2 (406 mg, 564 umol, 0.10 eq) were added. N2 was bubbled through the mixture for 5 mins l-ethynyl-4-m ethylbenzene (1.31 g, 11.2 mmol, 1.43 mL, 2.00 eq) was added. The system was degassed and purged with N2 several times.
  • Compound Q20 A vessel was charged with Compound Q20D (3.00 g, 8.92 mmol, 1.00 eq), MeOH (15.0 mL), THF (15.0 mL), and H 2 0 (15.0 mL). LiOH*H 2 0 (1.12 g,
  • Compound Q21D A vessel containing Compound Q21C (1.80 g, 5.78 mmol,
  • Compound Q21E A vessel was charged with Compound Q21D (3.10 g, 8.95 mmol, 1.00 eq), MeOH (30.0 mL), THF (30.0 mL), and H 2 0 (30.0 mL). NaOH (7.16 g, 178 mmol, 20.0 eq) was added. The reaction was stirred at 70°C for 0.5 hrs. The mixture was poured into water (50.0 mL) and EtOAc (50.0 mL). Aq HC1 (1 N) was added until the pH was 5. The system was extracted with EtOAc (50.0 mL, 20.0 mL). Combined organic layers were washed with sat.
  • Compound Q21 and Compound Q22 A solution of Compound Q21E (900 mg) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALPAK AD column (250mm x 50mm x 10 pm) with isocratic elution at 40% MeOH (doped with 0.1% ammonium hydroxide) in CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q21E. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed (differing from the preparative method): eluent was supercritical CO2 and MeOH (doped with 0.05%
  • Compound Q23B A vessel was charged with Compound Q23A (20.0 g, 99.5 mmol, 1.00 eq), K2CO3 (13.7 g, 99.5 mmol, 1.00 eq), and EtOH (200 mL). The mixture was stirred at 25°C for 1 h. The system was cooled to 0 ⁇ 5°C. Addition of l-chloropropan-2-one (9.21 g, 99.5 mmol, 1.00 eq) was conducted in a dropwise manner. The reaction was stirred at 25°C for 10 min then heated to 80°C for 1 h. The mixture was poured onto ice (500 mL) and stirred for 0.5 h. The slurry was filtered, and the cake dried under reduced pressure, giving
  • Compound Q23D A vessel was charged with Compound Q23C (15.0 g, 50.8 mmol, 1.00 eq), THF (100.0 mL), EtOAc (100.0 mL), and Rh(PPh ) Cl (8.00 g, 8.65 mmol, 0.17 eq). The mixture was sparged with 3 ⁇ 4 several times. The reaction was stirred at 25°C for 96 hrs at 50 psi of 3 ⁇ 4. The reaction was filtered, and the cake was washed with EtOAc (50 mL) and THF (50 mL). The combined filtrate was concentrated under reduced pressure.
  • Compound Q23E A vessel containing Compound Q23D (2.70 g, 9.09 mmol,
  • Compound Q23F A vessel was charged with Compound Q23E (3.70 g, 11.1 mmol, 1.00 eq), MeOH (30.0 mL), THF (30.0 mL), and H 2 0 (30.0 mL). NaOH (8.90 g, 222 mmol, 20.0 eq) was added. The reaction was stirred at 70°C for 1 h. The mixture was poured into water (50.0 mL) and EtOAc (50.0 mL). Aq HC1 (1 N) was added until the pH was 4. The system was extracted with EtOAc (50.0 mL, 20.0 mL, 20.0 mL).
  • Compound Q23 and Compound Q24 A solution of Compound Q23F (900 mg) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALPAK AD column (250mm x 50mm x 10 pm) column with isocratic elution at 27% MeOH (doped with 0.1% ammonium hydroxide) in CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q21E. Stereochemistries of the products were arbitrarily assigned.
  • Compound Q25A To a solution of Compound Q4 (500 mg, 1.04 mmol, 1.0 eq.) in dry THF (4.18 mL) at -78°C under nitrogen atmosphere was added LiHMDS (1M in THF, 1.57 mL, 1.57 mmol, 1.5 eq.) dropwise, and the resulting solution was stirred at -78°C for lh. 2-(adamantan-l-yl)acetaldehyde (373 mg, 2.09 mmol, 2.0 eq.) was then added dropwise, and stirring was pursued at -78°C for another lh. A solution of sat. aq.
  • Compound Q26E A solution of Compound Q26D (57 g) in THF (230 mL) was taken in a round-bottom flask, cooled to -78°C, and Vinyl magnesium bromide (670 mL) was added dropwise at -78°C over a period of lh. The reaction mixture allowed to warm to room temperature and stirred for 3h under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (1 L) and extracted with diethyl ether (2 x 1.2 L).
  • CDCh d 7.49 - 7.35 (m, 6H), 7.34 - 7.26 (m, 8H), 7.25 - 7.16 (m, 6H), 6.83 - 6.76 (m, 1H), 4.56 - 4.47 (m, 2H), 3.58 (s, 2H), 3.32 - 3.27 (m, 1H), 3.20 - 3.15 (m, 1H), 2.75 - 2.67 (m, 1H), 2.63 - 2.55 (m, 1H), 2.19 - 2.11 (m, 2H), 1.78 - 1.69 (m, 1H), 1.30 - 1.14 (m, 4H), 0.96 - 0.77 (m,
  • Compound Q27 To a solution of Compound Q27B (750 mg, 1.14 mmol, 1.0 eq.) in anhydrous dichloromethane (57 mL) under a nitrogen atmosphere was added a 4M solution of HC1 in dioxane (5.7 mL, 22.8 mmol, 20.0 eq.) at room temperature. The resulting solution was stirred at room temperature for 7 min and volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and a sat. aq. solution of NaHCCL (20 mL) was added. The layers were separated and the aqueous layer was washed with brine, dried over MgSCL, filtered and concentrated.
  • Compound Q29B A vessel was charged with Compound Q29A (23.0 g, 76.9 mmol, 1.00 eq) in DMF (161 mL). Pd(PPh3)2Ch (540 mg, 0.769 mmol, 0.01 eq) and Cul (293 mg, 1.54 mmol, 0.02 eq) were added to the mixture. The mixture was purged with N2 for 5 min. Compound Q28 (14.0 g, 76.9 mmol, 1.00 eq) and TEA (23.3 g, 230 mmol, 32.1 mL, 3.00 eq) were added to the mixture. The system was purged with N2 (3x).
  • Compound Q29C A vessel was charged with Compound Q29B (10.0 g, 28.3 mmol, 1.00 eq) in ACN (70.0 mL). Pd(PPh3)2Ch (1.99 g, 2.83 mmol, 0.10 eq) was added to the mixture. The mixture was purged with N2 for 10 min. l-ethynyl-4-m ethylbenzene (9.86 g, 84.9 mmol, 10.7 mL, 3.00 eq) and Cy2NMe (16.5 g, 84.9 mmol, 3.00 eq) were added to the mixture. The reaction was stirred at 80°C for 4.5 h.
  • Compound Q29 A vessel was charged with Compound Q29C (2.00 g, 5.15 mmol, 1.00 eq), NaOH (4.12 g, 102 mmol, 20.0 eq), THF (8.00 mL), H 2 0 (2.00 mL), and MeOH (2.00 mL). The reaction was stirred at 70°C for 12 h. The mixture was concentrated under reduced pressure. Dioxane (8.00 mL) was added to the mixture, and the mixture was heated at 110°C for 12 h with stirring. Aq HC1 (6N, 20.0 mL) was added slowly until the pH was 3. The organic phase was collected, washed with brine (20.0 mL), dried over Na 2 S0 4 , and filtered.
  • Compound Q30 A vessel was charged with LDA (104.9 g, 2 M, 490 mL, 1.26 eq) in THF (700 mL).
  • Compound Q30A (100.0 g, 780 mmol, 107 mL, 1.00 eq ) in THF (700 mL) was added to the mixture dropwise at -70°C over a period of 1.5 h.
  • Propargyl bromide 116.0 g, 780 mmol, 84.0 mL, 1.00 eq
  • THF 700 mL
  • Compound Q31A A vessel was charged with Compound Q29A (39.5 g, 132 mmol, 1.10 eq) in DMF (140 mL). Pd(PPh3)2Ch (4.22 g, 6.02 mmol, 0.05 eq) and Cul (1.15 g, 6.02 mmol, 0.05 eq ), TEA (23.3 g, 230 mmol, 32.1 mL, 3.00 eq), and Compound Q30 (20.0 g, 120 mmol, 1.00 eq) were added to the mixture. The mixture was purged with N2 for 5 min. The system was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h.
  • Compound Q31B A vessel was charged with Compound Q31A (14.0 g, 41.5 mmol, 1.00 eq) in ACN (90.0 mL). The mixture was purged with N2 for 30 min. Pd-Sphos G2 (2.99 g, 4.15 mmol, 0.10 eq), l-ethynyl-4-methylbenzene (9.65 g, 83.0 mmol, 10.5 mL, 2.00 eq) and Cy2NMe (16.2 g, 83.0 mmol, 17.6 mL, 2.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred 80°C for 4 h.

Abstract

The present disclosure relates generally to certain diacylglycerol lactone compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by protein kinase C (PKC) agonists, such as HIV.

Description

PROTEIN KINASE C AGONISTS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No.
62/810,136, filed on February 25, 2019, the entire content of which is hereby incorporated by reference in its entirety.
FIELD
[0002] 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.
BACKGROUND
[0003] Over thirty million people are currently living with HIV infection. Combination antiretroviral therapies (cART) and highly active antiretroviral therapies (HAART) have been able to reduce HIV viral loads, often below 50 copies of HIV RNA/ml of plasma, but no therapy has consistently induced HIV control after therapy is interrupted. This is due to the persistence of HIV-infected cells that contain quiescent virus, commonly referred to as the latent reservoir of HIV. “Kick and kill” strategies have been proposed for reservoir reduction and/or elimination. Compounds with“kick” activity have the potential to reverse latency and increase HIV protein expression in infected cells, making them more susceptible to immune-mediated killing. Compounds with“kill” activity have the potential to enhance killing of HIV-infected cells, e.g. by enhancing immune effector cell function.“Kick” programs have tested various agents, including histone deacetylase inhibitors, disulfiram, therapeutic vaccines, and pattern recognition receptors, as noted in Proviral Latency, Persistent Human Immunodeficiency Virus Infection, and the Development of Latency Reversing Agents, Margolis & Archin, J. Infect. Dis., Vol. 215, No. S3, pp. S111-S118; Targeting the Latent Reservoir for HIV- 1 , Sengupta & Siliciano, Immunity, Vol. 48, No. 5, pp. 872-895.
[0004] There remains a need for new agents and therapies capable of assisting in the activation of the latent HIV-infected cells to enhance the activity of antiretroviral therapies and immune responses. Protein Kinase C (PKC) agonists induce strong expression of latent HIV. When PKCs are activated, they translocate from the cytoplasm to cellular membranes, where they initiate a signaling cascade that leads to activation of NF-KB, P-TEFb and API. Upregulation of these factors induces HIV, as well as markers associated with T cell activation such as CD69. Despite the strong magnitude of latency reversal seen with PKC agonists, clinical trials indicate that dose limiting toxicities occur at levels that have insufficient exposure to induce HIV expression (Gutierrez et al., AIDS, Vol. 30, No. 9, pp. 1385-1392). Thus, there remains a need for PKC agonists with reduced toxicity.
SUMMARY
[0005] In one aspect, provided herein is a compound of Formula I,
Figure imgf000003_0001
Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
each R1 is C1-3 alkyl;
each R2 is Ci-6 alkyl;
one of R3 and R4 is H, Ci-15 alkyl, or C6-10 aryl, and the other of R3 and R4 is Ci-15 alkyl or C6-10 aryl, wherein each Ci-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;
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 R5;
each R5 is independently C 1-3 alkyl, or
two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;
A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
heteroatoms independently selected from N, O, and S, or
A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, 2, or 3; and
m is 0, 1, 2, or 3. [0006] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient or carrier. In some embodiments, 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.
[0007] In some embodiments, 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. In some
embodiments, 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.
[0008] In one aspect, 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.
[0009] In one aspect, 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.
[0010] In one aspect, 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.
[0011] In one aspect, the present disclosure provides methods of reducing the latent HIV reservoir 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. [0012] In one aspect, 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.
[0013] In one aspect, the present disclosure provides methods 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.
[0014] In one aspect, 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.
DETAILED DESCRIPTION
I. Definitions
[0015] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms“a”,“and”, and“the” include plural referents unless the context clearly dictates otherwise. Thus, e.g ., reference to“the compound” includes a plurality of such compounds and reference to“the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.
[0017] As used in the present disclosure, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0018] A dash
Figure imgf000006_0001
that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example, Ra in the below structure can be attached to any of the five carbon ring atoms or Ra can replace the hydrogen attached to the nitrogen ring atom:
Figure imgf000006_0002
[0019] The prefix“Cu-v” indicates that the following group has from u to v carbon atoms.
For example,“Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term“x-y membered” rings, wherein x and y are numerical ranges, such as“3 tol2- membered heterocyclyl”, refers to a ring containing x-y atoms (i.e., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
[0020] Also, certain commonly used alternative chemical names may or may not be used. For example, 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.
[0021] “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.
[0022] Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term“about” includes the indicated amount ± 10%. In other embodiments, the term“about” includes the indicated amount ± 5%. In certain other embodiments, the term“about” includes the indicated amount ± 1%. Also, the term“about X” includes description of“X”. [0023] “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). Examples of 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. When an 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(CI¾)3); and “propyl” includes n-propyl (i.e. -(CEh^CEE) and isopropyl (i.e. -CH(CH3)2).
[0024] “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). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
[0025] “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.
[0026] “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). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, an alkylene is optionally substituted with an alkyl group. Examples of substituted alkylene groups include
-CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-,
-CH(CH3)CH(CH )-, -CH2C(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2.
[0027] “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.
[0028] “Acyl” refers to a group -C(=0)R, wherein 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,
cyclohexylmethyl-carbonyl, and benzoyl.
[0029] “Amido” refers to both a“C-amido” group which refers to the group
-C(=0)NRyRz and an“N-amido” group which refers to the group -NRyC(=0)Rz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.
[0030] “Amino” refers to the group -NRyRz wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.
[0031] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g.
monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of 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.
[0032] “Cyano” or“carbonitrile” refers to the group -CN.
[0033] “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). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl),
3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0034] “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. Quinuclidinyl and admantanyl are examples of bridged ring systems.
[0035] The term“fused” refers to a ring which is bound to an adjacent ring.
[0036] “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.
[0037] “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).
[0038] “Heteroalkyl ene” refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH,
O, and S (i.e., 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., C1-4 heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene). For example, -CH2O- is a Ci heteroalkylene and -CH2SCH2- is a C2 heteroalkylene. Examples of heteroalkylene groups include -CH2CH2OCH2-,
-CH2SCH2OCH2-, -CH2O-, and -CH2NHCH2-. In some embodiments, a heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH3)N(CH )CH2-, -CH2OCH(CH3)-, -CH2CH(CH2CH3)S-, -CH2NHC(CH3)2-, -C(CH3)2SCH2-, -CH(CH3)N(CH3)CH(CH3)0-, -CH2SC(CH2CH3)(CH3)-, and
-CH2C(CH2CH3)2NH-.
[0039] “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. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., Ci-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 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. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.
[0040] “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. As used herein,“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. The term“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. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C2-20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C2-12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2-10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C3-12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C3-8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom
independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“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. As used herein,“bridged- heterocyclyl” includes bicyclic and tricyclic ring systems. Also as used herein, 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. Examples of the spiro- heterocyclyl 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. As used herein, the terms“heterocycle”,“heterocyclyl”, and“heterocyclic ring” are used interchangeably. In some embodiments, a heterocyclyl is substituted with an oxo group.
[0041] “Hydroxy” or“hydroxyl” refers to the group -OH.
[0042] “Oxo” refers to the group (=0) or (O).
[0043] “Sulfonyl” refers to the group -S(0)2RC, where Rc is alkyl, haloalkyl,
heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenyl sulfonyl, and toluenesulfonyl.
[0044] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom(s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.
[0045] The terms“optional” or“optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term“optionally substituted” means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
[0046] The term“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. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, 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. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “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.
[0047] In some embodiments, the term“substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments,“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 having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano and“substituted sulfonyl” refers to a group -S(0)2R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, 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. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
[0048] In some embodiments, 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. For example, in the below moiety, the cyclopropyl is substituted with a methyl group:
Figure imgf000012_0001
[0049] 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). When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein,“scalemic mixture” is a mixture of stereoisomers at a ratio other than 1: 1.
[0050] 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.
[0051] "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.
[0052] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
[0053] 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.
[0054] Some of the compounds provided herein exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, 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.
[0055] 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.
[0056] 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. Examples of 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 2H (deuterium, D), 3H (tritium), UC, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36C1 and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 2H, 3H, 13C and 14C are incorporated, are also provided herein. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
[0057] 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.
[0058] 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 18F 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.
[0059] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure, 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
composition. Accordingly, in the compounds of this disclosure, any atom specifically designated as a deuterium (D) is meant to represent deuterium.
[0060] In many cases, 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.
[0061] The term“pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri (substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, and the like. Specific examples of suitable amines include, by way of example only,
isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0062] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0063] As used herein,“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.
[0064] “Treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (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).
[0065] “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.
[0066] “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. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
[0067] The term“therapeutically effective amount” or“effective amount” of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, 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). 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.
[0068] The term“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. In some embodiments, the activation of PKC activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
[0069] As used herein, 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.
[0070] As used herein, 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.
II. Compounds
[0071] In one aspect, provided herein is a compound of Formula I,
Figure imgf000018_0001
Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
each R1 is C1-3 alkyl;
each R2 is Ci-6 alkyl;
one of R3 and R4 is H, Ci-15 alkyl, or C6-10 aryl, and the other of R3 and R4 is Ci-15 alkyl or C6-10 aryl, wherein each Ci-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;
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 R5;
each R5 is independently C 1-3 alkyl, or
two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;
A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
heteroatoms independently selected from N, O, and S, or
A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, 2, or 3; and
m is 0, 1, 2, or 3.
[0072] In one aspect, provided herein is a compound of Formula I,
Figure imgf000019_0001
Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
each R1 is C1-3 alkyl;
each R2 is Ci-6 alkyl;
one of R3 and R4 is H or C 1-3 alkyl, and the other of R3 and R4 is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl;
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 R5;
each R5 is independently C 1-3 alkyl, or
two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;
A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
heteroatoms independently selected from N, O, and S, or
A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, or 2; and
m is 1 or 2.
[0073] In some embodiments, the compound of Formula I is of Formula II,
Figure imgf000019_0002
Formula II,
or a pharmaceutically acceptable salt thereof.
[0074] In some embodiments, the compound of Formula I or II is of Formula Ila,
Figure imgf000020_0001
Formula Ila,
or a pharmaceutically acceptable salt thereof.
[0075] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, 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.
[0076] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R2 is Ci-6 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R2 is Ci-4 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R2 is independently methyl, 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 R2 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is methyl or tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is methyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is ethyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is n-propyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is isopropyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is n- butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is isobutyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is pentyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R2 is hexyl.
[0077] In some embodiments of the compound of Formula II or Ila, or a
pharmaceutically acceptable salt thereof, R2 is Ci-6 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is C1-4 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula II or Ila, or a
pharmaceutically acceptable salt thereof, R2 is methyl or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is methyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is ethyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is n-propyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is isopropyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is n-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is isobutyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is sec-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is pentyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R2 is hexyl.
[0078] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, one of R3 and R4 is H, Ci-15 alkyl, or C6-10 aryl, and the other of R3 and R4 is Ci-15 alkyl or C6-10 aryl, wherein each Ci-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.
[0079] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R3 and R4 is H and the other of R3 and R4 is Ci- 15 alkyl or C6-10 aryl, wherein the Ci-is 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. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R3 and R4 is Ci-15 alkyl and the other of R3 and R4 is Ci-15 alkyl or C6-10 aryl, wherein each Ci-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. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R3 and R4 is C6-10 aryl and the other of R3 and R4 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 C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl.
[0080] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, one of R3 and R4 is H or C1-3 alkyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is H and the other of R3 and R4 is Ci- 12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is C1-3 alkyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is methyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is ethyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is n-propyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-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, one of R3 and R4 is isopropyl, and the other of R3 and R4 is Ci-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl. [0081] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R3 and R4 is H or methyl and the other of R3 and R4 is phenyl or Ci-12 alkyl, wherein the Ci-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, one of R3 and R4 is H or methyl and the other of R3 and R4 is phenyl, C6-12 alkyl, or a methyl, wherein the methyl is optionally substituted with adamantanyl.
[0082] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, one of R3 and R4 is H or methyl and the other of R3 and R4 is phenyl,
Figure imgf000023_0001
[0083] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, one of R3 and R4 is H and the other of R3 and R4 is
Figure imgf000023_0002
[0084] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R3 is H or methyl and R4 is phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
[0085] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R3 is H, methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R3 is H or methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R3 is H. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R3 is methyl.
[0086] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R4 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, R4 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, R4 is C1-2 alkyl optionally substituted with
adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R4 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, R4 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, R4 is phenyl.
[0087] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R4 is methyl, phenyl,
Figure imgf000024_0001
[0088] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R4 is methyl, phenyl,
Figure imgf000024_0002
[0089] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, R4 is
Figure imgf000024_0003
[0090] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, 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 R5.
[0091] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is a bond.
[0092] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-8 alkyl ene optionally substituted with 1-3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-8 alkyl ene optionally substituted with 1-3 R5, wherein two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-6 alkyl ene optionally substituted with 1-3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-6 alkylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-6 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-6 alkylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-4 alkylene optionally substituted with 1-3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-3 alkylene optionally substituted with one R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-3 alkylene optionally substituted with two R5.
[0093] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is:
Figure imgf000025_0001
[0094] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is:
Figure imgf000025_0002
[0095] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is:
Figure imgf000026_0001
[0096] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is methylene, ethylene, -CH(CH3)CH2-,
-CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, -CH2C(CH2CH3)2-, propylene, or butylene.
[0097] 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, each of which is optionally substituted with 1-3 R5. 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.
[0098] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, -A-L- is -A-m ethylene-, -A-ethylene-,
-A-CH(CH3)CH2-, -A-CH2CH(CH3)-, -A-CH2CH(CH2CH3)-, -A-CH2C(CH3)2-,
-A-C(CH3)2CH2-, -A-CH(CH3)CH(CH3)-, -A-CH2C(CH2CH3)(CH3)-, -A-CH2C(CH2CH3)2-, -A-propylene-, -A-butylene-,
Figure imgf000026_0002
[0099] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, -A-L- is
Figure imgf000026_0003
[0100] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-8 heteroalkyl ene optionally substituted with 1- 3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-8 heteroalkyl ene optionally substituted with 1 -3 R5, wherein two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-6 heteroalkylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-6 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-6 heteroalkylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-5 heteroalkylene optionally substituted with 1 -3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-4 heteroalkylene optionally substituted with 1 -3 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-3 heteroalkylene optionally substituted with one R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C1-3 heteroalkylene optionally substituted with methyl.
[0101] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is:
Figure imgf000027_0001
[0102] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is -CFLNH- or -0¾N(0¾)-.
[0103] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, each R5 is independently C1-3 alkyl or two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R5 is C1-3 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R5 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, each R5 is independently methyl or ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, each R5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R5 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 R5 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 R5 is methyl. In some
embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R5 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 R5 is isopropyl.
[0104] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is optionally substituted with 1-3 R5. 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 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is optionally substituted with two R5. In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is optionally substituted with one R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R5 is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R5 is isopropyl.
[0105] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, L is optionally substituted with two R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is methyl and the other R5 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 R5 is ethyl and the other R5 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 R5 is n-propyl and the other R5 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 R5 is isopropyl and the other R5 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 R5 is methyl and the other R5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is methyl and the other R5 is ethyl.
[0106] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is methyl and the other R5 is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is ethyl and the other R5 is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is n-propyl and the other R5 is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is methyl and the other R5 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is methyl and the other R5 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R5 is ethyl and the other R5 is ethyl.
[0107] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or
cycloheptanyl. In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a cyclopropyl. In some
embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a cyclobutyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R5 are attached to the same carbon, and the two R5, 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 R5 are attached to the same carbon, and the two R5, 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 R5 are attached to the same carbon, and the two R5, together with the carbon to which they are attached, form a
cycloheptanyl.
[0108] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S; or A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I,
II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S; or A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
[0109] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S.
[0110] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, or a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, each of which is optionally substituted with one R1. In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, wherein the 9 membered fused bicyclic heteroarylene is optionally substituted with one R1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, wherein the 9-13 membered fused bicyclic or fused tricyclic heterocyclylene is optionally substituted with one R1.
[0111] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is a benzofuranylene, dihydrobenzofuranylene, or indolylene, each of which is optionally substituted with one R1.
[0112] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is
Figure imgf000031_0001
[0113] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, -A-L- is
Figure imgf000031_0002
[0114] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is
Figure imgf000032_0001
[0115] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is
Figure imgf000032_0002
[0116] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, -A-L- is
Figure imgf000032_0003
[0117] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, -A-L- is
Figure imgf000032_0004
[0118] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, 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.
In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, 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.
[0119] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, each R1 is C 1-3 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R1 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 R1 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R1 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R1 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 R1 is isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R1 is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R1 is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R1 is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R1 is isopropyl.
[0120] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is optionally substituted with one R1. 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 R1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is substituted with one methyl.
[0121] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is benzofuranylene and L is C1-5 alkylene optionally substituted with 1-2 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is benzofuranylene and L is C1-3 alkylene optionally substituted with 1-2 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is benzofuranylene and L is ethylene optionally substituted with 1-2 R5. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is benzofuranylene and L is ethylene optionally substituted with 2 R5, wherein the 2 R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-6 cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is
benzofuranylene and L is ethylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is dihydrobenzofuranylene and L is ethylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0122] In some embodiments of the compound of Formula I, II, or Ila, or a
pharmaceutically acceptable salt thereof, A is benzofuranylene and R3 is H or methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is benzofuranylene and R4 is phenyl or Ci-12 alkyl, wherein the Ci-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, A is benzofuranylene; R3 is H or methyl; and R4 is phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with
adamantanyl.
[0123] In some embodiments of the compound of Formula I, II, or Ila, the compound is selected from the group consisting of:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof.
[0124] In some embodiments of the compound of Formula I, II, or Ila, the compound selected from the group consisting of:
Figure imgf000039_0002
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof.
[0125] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof.
[0126] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000041_0002
or a pharmaceutically acceptable salt thereof.
[0127] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000041_0003
or a pharmaceutically acceptable salt thereof.
[0128] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000041_0004
or a pharmaceutically acceptable salt thereof.
[0129] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof.
[0130] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000042_0002
or a pharmaceutically acceptable salt thereof.
[0131] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof.
[0132] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000042_0004
or a pharmaceutically acceptable salt thereof.
[0133] In some embodiments of the compound of Formula I, II, or Ila, the compound is:
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof.
III. Compositions and Kits
[0134] Compounds provided herein are usually administered in the form of
pharmaceutical compositions. Thus, provided herein are also pharmaceutical 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.
(G.S. Banker & C.T. Rhodes, Eds.).
[0135] In one aspect, provided herein are pharmaceutical 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. In some embodiments, 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.
[0136] In some embodiments, 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. In some
embodiments, 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. [0137] In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for HIV infection. In some embodiments, 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
hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
[0138] 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. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
[0139] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for
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.
[0140] Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (such as a compound provided herein) is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When 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. Thus, 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.
[0141] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof. The pharmaceutical compositions can
additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and
propylhydroxy-benzoates; sweetening agents; and flavoring agents; or any combinations thereof.
[0142] The pharmaceutical 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”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g ., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[0143] For preparing solid compositions such as tablets, 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. 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.
[0144] 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. For example, 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. A variety of materials can be used for such 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.
[0145] Pharmaceutical 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. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, 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.
[0146] In one aspect, provided herein are 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. In some embodiments, the kit further comprises instructions for use. In some embodiments, 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.
[0147] In some embodiments, the kits further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a
pharmaceutically acceptable salt thereof.
[0148] In one aspect, provided herein are articles of manufacture that comprise a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.
IV. Methods
[0149] 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. For example, 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.
[0150] In one aspect, 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.
[0151] In one aspect, 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.
[0152] In one aspect, 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.
[0153] In one aspect, the present disclosure provides methods of reducing the latent HIV reservoir 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.
[0154] In one aspect, 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.
[0155] In one aspect, the present disclosure provides methods 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.
[0156] In some embodiments, the above methods further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a
pharmaceutically acceptable salt thereof.
[0157] In some embodiments, 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 inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
[0158] In some embodiments, 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.
[0159] In some embodiments, 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
pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
[0160] In some embodiments, 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.
[0161] In some embodiments, 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.
[0162] In some embodiments, 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.
[0163] In some embodiments, the one or more additional therapeutic agents is emtricitabine or a pharmaceutically acceptable salt thereof.
[0164] In one aspect, 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.
[0165] In some embodiments, 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.
[0166] In one aspect, provided herein is a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, for use in therapy.
[0167] In one aspect, provided herein is a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, for use in a method of activating PKC in a subject in need thereof.
[0168] In one aspect, provided herein is a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof.
[0169] In one aspect, provided herein is a compound disclosed herein, or 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.
[0170] In one aspect, provided herein is a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, for use in a method of reducing the latent HIV reservoir 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.
[0171] In one aspect, provided herein is a compound disclosed herein, or 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.
[0172] In one aspect, provided herein is a compound disclosed herein, or 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.
[0173] In some embodiments, the above uses further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a
pharmaceutically acceptable salt thereof.
[0174] In some embodiments, 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 antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. [0175] In some embodiments, 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.
[0176] In some embodiments, 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.
[0177] In some embodiments, 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.
[0178] In some embodiments, 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.
[0179] In some embodiments, 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.
[0180] In some embodiments, the above uses further comprise administering
emtricitabine or a pharmaceutically acceptable salt thereof.
[0181] In one aspect, provided herein is a compound disclosed herein, or 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.
[0182] In some embodiments, 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.
V. Administration
[0183] 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.
[0184] 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. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
[0185] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, 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. [0186] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I,
II, Ila, III, IV, or V, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
[0187] 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.
[0188] The compounds of the present disclosure may be administered to an individual
( e.g ., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.
[0189] 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. In some embodiments, 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.
[0190] 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.
[0191] In some embodiments, 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.
[0192] When administered orally, the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In some
embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 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.
[0193] In some embodiments, the total daily dosage for a human subject may be about
100 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 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. In some embodiments, 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.
[0194] 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.
In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.
[0195] 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. For example, 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.
[0196] 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. For example, a patient can receive a dose of the compound every other day, or three times per week. Again by way of example, 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.
[0197] 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.
VI. Combination Therapy
[0198] In some embodiments, a compound of the present disclosure, or a
pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
[0199] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
[0200] In some embodiments, 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. [0201] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.
[0202] 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. For example, in some embodiments, 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. Alternatively, in other embodiments, 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. In some embodiments, 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. In other embodiments, 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.
[0203] In some embodiments, 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. In certain embodiments, the tablet can contain another active ingredient for treating a HIV infection. In some embodiments, such tablets are suitable for once daily dosing
[0204] Also provided herein are methods of treatment in which a compound of Formula
I, II, or Ila, or a tautomer or pharmaceutically acceptable salt thereof, is given to a patient in combination with one or more additional therapeutic agents or therapy. In some embodiments, the total daily dosage of a compound of Formula I, II, or Ila, or a tautomer, or a
pharmaceutically acceptable salt thereof, may be about 300 mg/day administered in a single dose for a human subject.
HIV Combination Therapy
[0205] In certain embodiments, a method for treating or preventing an HIV infection in a human or animal having or at risk of having the infection is provided, 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. In one embodiment, a method for treating an HIV infection in a human or animal having or at risk of having the infection is provided, 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.
[0206] In one embodiment, pharmaceutical 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
pharmaceutically acceptable carrier, diluent, or excipient are provided.
[0207] In certain embodiments, 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.
[0208] In certain embodiments, the compounds disclosed herein are formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, 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.
[0209] In certain embodiments, such tablets are suitable for once daily dosing.
[0210] In some embodiments, the additional therapeutic agent may be an anti-HIV agent.
In some embodiments, 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 disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and other HIV therapeutic agents, or any combinations thereof.
[0211] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, 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.
HIV Combination Drugs
[0212] Examples of 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;
lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA K ; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir , ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812, or any combinations thereof.
HIV Protease Inhibitors
[0213] Examples of 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 Reverse Transcriptase Inhibitors
[0214] Examples of 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.
[0215] Examples of 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, doravirine, etravirine, OCR- 5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504 and KP-1461.
HIV Integrase Inhibitors
[0216] Examples of 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- 642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.
[0217] Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.
HIV Entry Inhibitors
[0218] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.
[0219] Examples of 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).
[0220] Examples of 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.
[0221] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.
[0222] Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.
[0223] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV Maturation Inhibitors
[0224] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.
Latency Reversing Agents
[0225] Examples of latency reversing agents 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
(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.
[0226] Examples of HD AC inhibitors include romidepsin, vorinostat, and panobinostat.
[0227] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.
[0228] Examples of GSK3 beta inhibitors include tideglusib, LY2090314, CHIR99021, and AZD1080.
[0229] Examples of SMAC mimetics include birinapant, AZD5582, LCL161, and
AT406.
Capsid Inhibitors
[0230] Examples of 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.
Immune-based Therapies
[0231] Examples of 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; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107;
interleukin-15/Fc fusion protein; normferon; peginterferon alfa-2a; peginterferon alfa-2b;
recombinant interleukin- 15; RPI-MN; GS-9620; STING modulators; RIG-I modulators; NOD2 modulators; and IR-103.
[0232] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-
052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),
US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), US Patent No. 9670205 (Gilead Sciences Inc.),
US20160289229 (Gilead Sciences Inc.), US Patent Application No. 15/692161 (Gilead Sciences Inc.), and US Patent Application No. 15/692093 (Gilead Sciences Inc.).
Phosphatidylinositol 3-kinase (PI3K) Inhibitors
[0233] Examples of 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-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL- 765, and ZSTK-474. alpha-4/beta-7 antagonists
[0234] Examples of 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
[0235] Examples of 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.
[0236] Further examples include bavituximab, UB-421, C2F5, 2G12, C4E10,
C2F 5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDXOIO (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.
[0237] Additional examples of HIV bispecific antibodies include MGD014.
Pharmacokinetic Enhancers
[0238] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.
HIV Vaccines
[0239] Examples of 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]V2.TVl+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV -PT 123 , rAAVl-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM- V101, CombiHIVvac, AD VAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and vims-like particle vaccines such as pseudovirion vaccine,
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 env A/B/C vaccine, DNA.HTI and MVA.HTI.
Additional HIV Therapeutic Agents
[0240] Examples of additional 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
2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).
[0241] 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
[0242] 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.
[0243] Examples of dendritic cell therapy include AGS-004.
Gene Editors
[0244] 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.
[0245] Examples of HIV targeting CRISPR/Cas9 systems include EBT101.
CAR-T cell therapy
[0246] 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. In some embodiments, the immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.
[0247] Examples of HIV CAR-T cell therapy include VC-CAR-T.
TCR-T cell therapy
[0248] TCR-T cell therapy includes T cells engineered to target HIV derived peptides present on the surface of virus-infected cells.
[0249] It will be appreciated by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of those compounds listed in those classes.
[0250] In a specific embodiment, 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. In another specific embodiment, 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. In an additional embodiment, 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. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
[0251] In a particular embodiment, 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);
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); adefovir;
adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ®
(dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine;
raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®;
lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir;
lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfmavir; nelfmavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate;
phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.
[0252] In a particular embodiment, 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.
[0253] In a particular embodiment, 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.
[0254] In a particular embodiment, 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.
[0255] In a particular embodiment, 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.
[0256] 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).
[0257] In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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) may be combined with the agents provided herein in any dosage amount of the compound (i.e., from 1 mg to 500 mg of compound) as if each
combination of dosages were specifically and individually listed.
[0258] In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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) may be combined with the agents provided herein in any dosage amount of the compound (i.e., from 1 mg to 500 mg of compound) as if each combination of dosages were specifically and individually listed.
VII. Compound Preparation
[0259] Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.
[0260] Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography
(HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography.
[0261] During any of the processes for preparation of the compounds provided herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. [0262] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used.
[0263] The methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure.
[0264] Representative syntheses of compounds of the present disclosure are described in the schemes below, and the particular examples that follow.
List of Abbreviations and Acronyms
ACN acetonitrile
AcOH acetic acid
Aq aqueous
aq aqueous
BCh Boron Trichloride
BH SMe2 Borane Dimethyl Sulfide Complex
Bn Benzyl
[BnNMe3]ICl2 B enzyl trim ethyl ammonium di chi oroi odate
BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
brine water saturated with sodium chloride
°C degrees Celsius
calc’d calculated CDI Carbonyl- 1, -dimidazole
CH2CI2 di chi orom ethane
CH3CN acetonitrile
CH3I iodomethane
C02 Carbon dioxide
CS2CO3 Cesium Carbonate
CuBr Copper(I) Bromide
Cul Copper(I) Iodide
CuS04 Copper(II) Sulfate
Cy2MeN Dicyclohexylmethylamine
Cy2NMe Dicyclohexylmethylamine
dba dib enzyli deneacetone
DBU l,8-diazabicyclo[5.4.0]undec-7 -ene
DCC Dicyclohexylcarbodiimide
DCM dichloromethane
Dess-Martin-Periodinane 1,1, 1 -Tris(acetyloxy)- 1 , 1 -dihydro- 1 ,2-benzodioxol-3 -( lH)-one
DMAP 4-(N,N-dimethylamino)-Pyridine
DME 1 ,2-dimethoxym ethane
DMF N,N-dimethylformamide
DIAD Diisopropyl azodi carboxyl ate
DMSO Dimethylsulfoxide
EA Ethyl Acetate
eq equivalents
ESI Electrospray Ionization
Et Ethyl
Et N trimethylamine
Et2NH diethyl amine
Et20 diethyl ether
EtOAc Ethyl Acetate
EtOH Ethanol
GC-MS Gas Chromatography - Mass Spectrometry
H2 Molecular Hydrogen
HC1 Hydrogen Chloride or Hydrochloric Acid
nHex n-Hexane H2O Water
HPLC High Pressure Liquid Chromatography
IBX l-Hydroxy-l,2-benziodoxole-3(lH)-one 1 -oxide
IPA isopropyl alcohol
iPriNEt Diisopropylethylamine
z-PrOH isopropyl alcohol
K2CO3 potassium carbonate
LAH Lithium Aluminum Hydride
LCMS liquid chromatography mass spectrometry
LDA Lithium Diisopropylamide
L1AIH4 Lithium Aluminum Hydride
LiCl Lithium Chloride
LiHMDS Lithium Hexamethyldisilazide
Li OH Lithium Hydroxide
LiOH*H20 Lithium Hydroxide monohydrate
Me Methyl
MeCN Acetonitrile
Mel iodomethane
MgS04 Magnesium Sulfate
MeOH Methanol
Mn02 Manganese (IV) Oxide or Manganese Dioxide
MsCl Methanesulfonyl Chloride
MTBE Methyl, tert-butyl ether
N2 Molecular Nitrogen
Ns Azido group or Azide anion
NaCl Sodium Chloride
NaH Sodium Hydride
NaHCOs Sodium Hydrogen Carbonate or Sodium Bicarbonate
NaI04 Sodium Periodate
NaNs Sodium Azide
NaOH Sodium Hydroxide
Na2S04 Sodium Sulfate
NBS N-bromosuccinimide
NH4C1 Ammonium Chloride «-Hex n-hexane
NH4OH Ammonium Hydroxide
NMR Nuclear Magnetic Resonance
NO2 Nitro group
03 Ozone
0s04 Osmium(VIII) Oxide or Osmium Tetraoxide
PCC Pyridinium Chlorochromate
PDC Pyridinium Dichromate
Pd2(dba)3 bis-Palladium(0)-tris-dibenzylidene acetone
Pd2(dba)3 CHCb bis-Palladium(0)-tris-dibenzylidene acetone chloroform complex
Pd2(PPh3)2Cl2 Palladium(II) bis-triphenylphosphine dichloride complex
Pd2(PPh3)2(OAc)2 Palladium(II) bis-triphenylphosphine diacetate complex
Pd(PtBu3)2 Palladium(O) bis-(tri-tert-butylphosphine) complex
Pd-Sphos-G2 Chloro(2-dicyclohexylphosphino-2,6,-dimethoxy-l, r- biphenyl)[2-(2’ -amino- 1, 1’ -biphenyl)]palladium(II)
Pd-Xphos-G2 Chloro(2-Dicyclohexylphosphino-2’ ,4’ ,6’ -triisopropyl- 1 , G - biphenyl)]palladium(II)
Ph Phenyl
POCh Phosphorus(V) Oxychloride
PPh3 Triphenylphosphine
prep preparative
PhSH Thiophenol
PTFE Polytetrafluoroethyl ene
Pt02 Platinum(IV) Oxide or Platinum Dioxide
p-TsOH para-toluenesulfonic acid
R f Retention Factor
Rh(PPh )3Cl Rhodium(I) tris-triphenylphosphine chloride complex rt room temperature
r.t. room temperature
RT room temperature
SFC Supercritical Fluid Chromatography
Si02 Silicon Dioxide or Silica Gel
SOCb Thionyl Chloride
S-Phos 2-dicyclohexylphosphino-2’ 6’ -dimethoxy- 1,1’ -biphenyl TBAF tetra-n-butylammonium fluoride
/-BuOOH tert-butyl hydroperoxide
TBDPS tert-butyl diphenylsilyl-
TEA Triethylamine
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
TfOH Trifluoromethanesulfonic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TSOH*H20 para-Toluenesulfonic acid monohydrate
v:v volume - to - volume ratio
wt weight
w/w weight-to-weight basis
XPhos 2-Dicyclohexylphosphino-2’ ,4’ , 6’ -trii sopropyl -1, 1’ -biphenyl
3 A MS 3 Angstrohm Molecular Sieves
General Synthetic Schemes
[0265] General Reaction Scheme I is provided as further embodiments of the present disclosure and illustrate general methods which were used to prepare certain compounds of the present disclosure and which can be used to prepare additional compounds of the present disclosure. Each of the variables (e.g. R1, R2, R3, R4) of formulas Cl, C3, FB-C, FBI, FB2, FB3, FB4, and FB5 are as defined herein.
[0266] 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.
[0267] Typical embodiments of compounds disclosed herein may be synthesized using the general reaction schemes described below. It will be apparent to a skilled artisan given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. 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.
[0268] The terms“solvent”,“inert organic solvent”, or“inert solvent” refer 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). Unless specified to the contrary, the 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.
General Reaction Scheme I
Figure imgf000077_0001
Formula 1
[0269] The general scheme depicts general methods to make compounds of Formula 1.
Compound Cl is a molecule in which PG1 and PG2 are each independently a hydrogen atom or protecting group known to those skilled in the art, and wherein PG1 and PG2 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 PG1 and PG2 are different.
Compound Cl is treated with a base followed by a carbonyl-containing Compound C2 having groups R3 and R4 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 PG1, and the additive may also remove or change the identity of PG2 to give Compound FB-C. In cases where both PG1 and PG2 are silyl-type groups, 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 PG1 and PG2 are hydrogen atoms. Separately, Compound FBI, with groups A, L, R1, and alkyl as defined herein is treated with an appropriate R2-containing alkyne
Compound FB2 in the presence of a palladium catalyst and optionally a copper salt promoter or additive such as a trialkylamine base to give Sonogashira product Compound FB3. In cases where the alkyl group of Compound FB3 is methyl or ethyl treatment with a base such as lithium hydroxide or sodium hydroxide in the presence of water and a cosolvent system can provide Compound FB4. Alternatively, when the alkyl group of Compound FB3 is t-butyl group, an acid, such as boron trichloride, may be used to convert Compound FB3 into
Compound FB4. In some but not all cases 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
chlorophosphorane, followed by addition to Compound FB-C optionally in the presence of a base to give Compound FB5. In the cases where PG2 is not a proton, a step is needed to remove PG2 from Compound FB5 and commonly the protecting group itself is removed by treatment with a Lewis Acid such as boron trichloride to give compounds of Formula I. In cases of
Compound FB5 where PG2 is a hydrogen atom, Compound FB5 is effectively a compound of Formula I in and of itself.
VIII. Examples
[0270] Exemplary chemical entities of the present disclosure are provided in the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.
Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. [0271] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.
[0272] In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.
Compound Q1
Figure imgf000079_0001
[0273] Compound Q1B: At -78 °C, to a THF solution (10 mL) of Compound Q1A (2.2 g, 15.5 mmol) was added dropwise vinylmagnesium bromide (31 mL, 1 M in THF). The reaction mixture was allowed to reach RT and stirred for 1 hour. The reaction was quenched by the slow addition of MLCl aq. (15 mL, saturated). The resulting mixture was extracted with Et20 (100 mL) and the combined organic layers were washed with water and brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtO Ac/Hexanes). Compound Q1B. LCMS ESI+ calc’d for C11H22O : 171.2 [M+H+] ; found: compound does not ionize. ¾NMR (400 MHz, chloroform-^) d 5.84 (dd, J= 17.3, 10.8 Hz, 1H), 5.21 (dd, J= 17.3, 1.5 Hz, 1H), 5.09 (dd, J= 10.8, 1.4 Hz, 1H), 1.78 - 1.66 (m, 2H), 1.48 - 1.36 (m, 4H), 0.96 - 0.88 (m, 12H).
[0274] 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 Et20 (200 mL) and stirred at RT for 1 hour. The mixture was filtered over silica and celite and concentrated. The residue was diluted with Et20 (100 mL). The suspension was filtered over silica and Celite, and concentrated. Compound QIC was carried to the next step without further purification. LCMS ESI+ calc’d for C11H20O : 169.2 [M+H+] ; found: compound does not ionize. ¾ NMR (400 MHz, chloroform-7i) d 9.97 (d, J= 8.3 Hz, 1H), 5.92 (d, J= 8.2 Hz, 1H), 2.42 (d, J= 7.4 Hz, 2H), 2.06 (dt, J= 8.5, 4.2 Hz, 2H), 1.86 (dp, J = 13.4, 6.7 Hz, 2H), 0.95 (d, J= 6.6 Hz, 6H), 0.91 (d, 7= 1.6 Hz, 3H), 0.90 (app. s, 3H).
[0275] Compound Ql: Crude Compound QIC (1.8 g, 10.7 mmol) was dissolved in
DCM (20 mL) and to this solution was added Pd/C (360 mg, 10% on charcoal). The reaction was stirred under 1 atm of ¾ for 3 hours. The reaction mixture was filtered and concentrated to give Compound Ql. LCMS ESI+ calc’d for C11H22O : 171.2 [M+H+] ; found: compound does not ionize. ¾ NMR (400 MHz, chloroform-^) d 9.74 (t, J= 2.5 Hz, 1H), 2.29 (dt, J= 6.3, 3.1 Hz, 2H), 2.12 - 2.03 (m, 1H), 1.61 (dp, 7= 19.8, 6.6 Hz, 2H), 1.21 - 1.06 (m, 4H), 0.88 (app. s, 6H), 0.87 (app. s, 3H), 0.85 (app. s, 3H).
Compound Q2
Figure imgf000080_0001
[0276] Compound Q2B: 7¾r/-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. The resulting material was then stirred in 200 mL of MeCN for 30 minutes and collected by filtration. The residue was then dried in vacuo to afford Compound Q2B ¾ NMR (400 MHz, CDCh) d 7.60 - 7.55 (m, 8H), 7.45 - 7.39 (m, 4H), 7.38 - 7.31 (m, 8H), 4.40 (s, 4H), 1.01 (s, 18H). LCMS ESI+ calc’d for CssH^ChSh: 567.3 [M+H+] ; Found:
585.3 [M+H20+H+]
[0277] 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 Et20, 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. The organic layer was dried over sodium sulfate, condensed and purified by column chromatography (0-20% EtOAc in Hexanes, 220g column). Compound Q2C ¾ NMR (400 MHz, CDCh) d 7.69 - 7.60 (m, 8H), 7.45 - 7.38 (m, 4H), 7.38 - 7.30 (m, 8H), 5.83 - 5.67 (m, 1H), 5.08 - 4.95 (m, 2H), 3.63 (ddd, J= 21.5, 9.8, 1.6 Hz, 4H), 2.52 (d, J =
1.3 Hz, 1H), 2.33 (d, J= 7.1 Hz, 2H), 1.03 (s, 18H). LCMS EST calc’d for C20H22O5 :
CssH^ChSh: 607.3 [M-H ] ; Found: 607.7 [M-H ].
[0278] 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 BHv SMe? (2.0 M in THF, 14.8 mL, 29.6 mmol) while being maintained under a blanket of N2. 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. 15 more equivalents of PCC were added and the solution was stirred for 22 hours. 15 more equivalents of PCC were added and the reaction was stirred for 16 hours. The reaction was filtered on a silica pad and washed several time with DCM. The resulting solution was condensed and purified by column chromatography (0-20% EtOAc in hexanes, 220g column) giving Compound Q2D. 1H MR (400 MHz, CDCh) d 7.64 - 7.56 (m, 8H), 7.45 - 7.39 (m, 4H), 7.36 (d, J= 7.5 Hz, 8H), 3.72 (d, J= 10.8 Hz, 2H), 3.64 (d, J= 10.9 Hz, 2H), 2.62 (t, J= 8.5 Hz, 2H), 2.16 (d, J= 8.8 Hz, 2H), 1.01 (s, 18H).
LCMS ESI+ calc’d for C38H4604Si2: 623.3 [M+H+] ; Found: 641.3 [M+H20+H+].
[0279] Compound Q2F: To a solution of Compound Q2D (4.23 g, 6.79 mmol) in 28 mL of THF was added LiHMDS (10.19 mL, 1.0 M in THF 10.19 mmol) dropwise at -78 °C, then the reaction was stirred at the same temperature for 60 min, after which acetone (2.49 mL,
33.95 mmol) was added to the reaction solution slowly. After 30 min, the reaction was quenched with saturated aqueous NH4CI solution (25 mL). The mixture was diluted with 75 mL of EtOAc and 25 mL of a saturated solution of ammonium chloride. The aqueous layer was removed and the organic phase was washed with a saturated solution of ammonium chloride followed by brine. The organic layer was dried and condensed to afford the crude product, Compound Q2E. The crude product was diluted in 27 mL of DCM. Et3N (4.73 mL, 33.95 mmol) was added and the solution was cooled to 0 °C and MsCl (1.05 mL, 13.58 mmol) was added dropwise. The reaction was stirred at this temperature for 30 mins and at room temperature for 90 mins. One equivalent of MsCl was added and the reaction was allowed to stir at room temperature for 30 mins. Another equivalent of MsCl was added and the reaction was stirred at room temperature for 20 minutes. The reaction was cooled to 0 °C and DBU (5.08 mL, 33.95 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with 75 mL of EtOAc and washed twice with a saturated solution of ammonium chloride followed by brine. The organic phase was dried, condensed and purified by flash chromatography to afford crude Compound Q2F. The product was taken as is for the next step. LCMS ESI+ calc’d for C4iH5o04Si2: 663.3 [M+H+] ; found : compound does not ionize.
[0280] Compound Q2: To a crude solution of Compound Q2F (4.502 g, 6.79 mmol) in
THF (136 mL) was added TBAF (13.58 mL, 1 M in THF, 13.58 mmol) at 0 °C, then the reaction was allowed to warm to room temperature for 45 minutes. The reaction mixture was
concentrated and purified by column chromatography (80g column, 0-10 % MeOH in DCM) to afford crude Compound Q2. The mixture was re-purified using a gradient of 50% EtOAc in hexanes to EtOAc (40g column) and Compound Q2 was obtained. ¾ NMR (400 MHz, CDCb) d 3.76 (dd, J= 12.0, 6.8 Hz, 2H), 3.68 (dd, J= 12.0, 6.4 Hz, 2H), 2.73 (dd, J= 2.1, 1.7 Hz, 2H), 2.42 (b s, 1H), 2.25 (t, J= 2.1 Hz, 3H), 1.88 (d, J= 1.3 Hz, 3H), 1.67 (b s, 1H). LCMS ESI+ calc’d for C9H14O4: 187.1 [M+H+] ; found: 187.3 [M+H+]
Compound 03
Figure imgf000083_0001
[0281] Compound Q3B: Compound Q3A (45.00 g, 307.92 mmol, 37.19 mL, 1.00 eq) and CH2(C02H)2 (32.04 g, 307.92 mmol, 32.04 mL, 1.00 eq) were added to pyridine (126.00 mL). The reaction was stirred for lh at 80°C. Piperidine (2.10 g, 24.63 mmol, 2.44 mL, 0.08 eq) was added and the reaction was heated to 110°C for lh. The mixture was poured into 450 mL cold water. HC1 (150 mL) was added to the mixture to the point of strong acidity. After filtration, this gave Compound Q3B. LCMS ESI+ calc’d for CisHnCb : 189.1 [M+H+] ; found 189.1 [M+LL] ¾ NMR (400 MHz, dmso-76) d 7.68 (d, J= 8.0 Hz, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.57 (d, 7=18.8, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.6, 1H), 6.40 (d, J = 16.0, 1H).
[0282] Compound Q3C: A vessel was charged with Pd/C (3.00 g), MeOH (100 mL) and Compound Q3B (10.0 g, 53 mmol, 1.0 eq) under Argon. The reaction was stirred at 50°C for 40 h under H2 (50 psi). The reaction was filtered and the cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated to obtain Compound Q3C. LCMS ESI+ calc’d for CIIHI203 : 193.1 [M+H+] ; found 193.2 [M+H+] ¾ NMR (400 MHz, dmso-76) d 7.14 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.72 (m, J= 7.4 Hz, 1H), 3.22 (dd, J= 15.8, 9.0 Hz, 1H), 2.80 (dd, J = 15.7, 7.6 Hz, 1H), 2.51 - 2.43 (m, 1H), 2.30 (d, broad, J= 6.0 Hz, 2H), 1.95 - 1.76 (m, 2H). [0283] Compound Q3D: A vessel was charged with Compound Q3C (7.00 g, 36.4 mmol, 1 .00 eq), [BnNMesJICh (19.01 g, 54.63 mmol, 1.50 eq), ZnCh (7.45 g, 54.6 mmol, 2.56 mL, 1.50 eq), and CH3COOH (100.00 mL). The reaction was stirred at 15°C for 16 h. The reaction was quenched with H2O (40 mL) and MTBE (25 mL). The system was extracted with DCM (5 x 30 mL). Combined organic phases were washed with aq NaiSiCL (3 x 100 mL), followed by brine (100 mL). The final organic phase was dried over NaiSCL, filtered and concentrated to provide Compound Q3D. LCMS ESI+ calc’d for C11H11IO3 : 319.0 [M+EL]; found 319.0 [M+H+] ¾ NMR (400 MHz, dmso-76) d 7.46 (s, 1H), 7.34 (s, 1H), 6.56 (d, 7 = 8.4 Hz, 1H), 4.82 - 4.70 (m, 1H), 3.25 (dd, 7 = 16.0, 9.0 Hz, 2H), 2.82 (s, 1H), 2.51 - 2.44 (m, 4H), 2.38 - 2.27 (m, 2H), 1.87 - 1.81 (m, 3H).
[0284] Compound Q3E: A vessel was charged with Compound Q3D (8.00 g, 25.15 mmol, 1.00 eq), K2CO3 (6.95 g, 50.30 mmol, 2.00 eq), CH3I (7.14 g, 50.30 mmol, 3.13 mL, 2.00 eq) and DMF (20.0 mL). The system was purged with N2 (3x). The reaction was stirred for 16 h at 15°C. The system was then poured into EtOAc (40 mL). The system was washed with sat. aq LiCl (3x) to remove DMF. The final organic phase was concentrated to obtain a residue, which was purified by gel column (S1O2, Petroleum ether/Ethyl acetate=0/l to 4: 1). Next, the product was purified using prep-HPLC (TFA modified eluent). Finally the product was purified by SFC to obtain Compound Q3E. LCMS ESI+ calc’d for C12H13IO3 : 333.0 [M+H+]; found 333.1 [M+H+] 1H MR (400 MHz, dmso-76) d 7.46 (s, 1H), 7.34 (d, 7 = 8.0 Hz, 1H), 6.56 (d, 7 = 8.4 Hz, 1H), 4.76 (m, 1H), 3.56 (s, 3H), 3.25 (dd, 7 = 16.0, 9.0 Hz, 1H), 2.83 (dd, 7 = 16.2, 7.4 Hz, 1H), 2.32 (dt, 7 = 7.6, 3.6, 2H), 1.91 - 1.87 (m, 2H).
[0285] Compound Q3F: A vessel was charged with Compound Q3E (3.00 g, 9.03 mmol, 1.00 eq), l-ethynyl-4-methyl -benzene (1.08 g, 9.30 mmol, 1.17 mL, 1.03 eq),
Pd(PPh )2Cl2 (126 mg, 180 umol, 0.02 eq), Et N (1.37 g, 13.5 mmol, 1.88 mL, 1.50 eq), Cul (68.8 mg, 361 pmol, 0.04 eq), and THF (30.0 mL). The mixture was purged with N2 (3x). The reaction was stirred for 16 h at 15°C. The reaction was filtered and washed with THF (2 x 20 mL). The filtrate was concentrated and purified by gel column (S1O2, Petroleum ether/Ethyl acetate=0/l to 5: l)to give Compound Q3F. 1H MR (400 MHz, chloroform-7) d 7.37 (d, 7 = 8.0 Hz, 2H), 7.30 (m, 1H), 7.29 (s, 1H), 7.11 (d, 7 = 8.0Hz, 2H), 6.69 (d, 7 = 8.4 Hz, 1H), 4.84 (m, 1H), 3.67 (s, 3H), 3.31 (m, 7= 15.6 Hz, 1H), 2.54 (m, 7= 15.8 Hz, 1H), 2.51 (d, 7= 8.0 Hz, 2H), 2.34 (s, 3H), 2.04 (q, 7= 7.4 Hz, 2H), 1.53(s, 1H).
[0286] Compound Q3: A vessel was charged with Compound Q3F (2.75 g, 8.58 mmol, 1.00 eq) in THF (20.00 mL) and H20 (5.00 mL). Then NaOH (1.37 g, 34.3 mmol, 4.00 eq) was added. The reaction was stirred for 16 h at 70°C. DCM (25 mL) was added to the mixture. The system was filtered and the cake was suspended in DCM (100 mL) and TbO (100 mL). 6M HC1 was added until the pH = 3. The mixture was filtered, and the resulting cake was dried under reduced pressure, giving Compound Q3. LCMS ESI+ calc’d for C20H18O3 : 307.1 [M+H+]; found 307.1 [M+H+] Ή NMR (400 MHz, chloroform-r/) d 7.32 (d, ./ = 8.0 Hz, 2H), 7.24 (m, 2H), 7.06 (d, J= 8.0 Hz, 2H), 6.64 (d, J= 8.0 Hz, 1H), 4.80 (m, 1H), 3.27 (dd, J= 15.7, 9.0 Hz, 1H), 2.80 (dd, J= 15.8, 7.4 Hz, 1H), 2.51 (m, J= 3.2, 7.4 Hz, 2H), 2.28 (s, 3H), 2.00 (q, J= 7.4 Hz, 2H).
Compound 04
Figure imgf000085_0001
[0287] Compound Q4B: At 0 °C, to a solution of Compound Q4A (50 g, 567 mmol) and Et3N (158.19 mL, 1.13 mmol) in CH2CI2 (350 mL) was added trityl chloride (158.19 g, 567 mmol). The reaction was stirred at 0 °C for 1 hour and warmed up to room temperature and stirred for an additional 1 hour. The reaction mixture was diluted with EtOAc (200 mL) and the precipitate was removed by filtration. The filtrate was then washed with H2O (2 x 210 mL).
The aqueous phases were combined and extracted once with EtOAc ( 300 mL). The combined organic layers were washed with brine (200 mL), dried over MgS04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1 kg) with
EtOAc:hexanes (10-25%) as eluent to give Compound Q4B. LCMS ESI+ calc’d for C23H22O2 : 331.2 [M+H+] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.48-7.43 (m, 6H), 7.34-7.21 (m, 9H), 5.26 (dd, = 1.5, 0.7 Hz, 1H), 5.18 (dd, 7= 2.4, 1.1 Hz, 1H), 4.17-4.12 (m, 2H), 3.70 (s, 2H), 1.69 (t, J= 6.2 Hz, 1H). [0288] Compound Q4C: In an oven dried round bottom flask equipped with a magnetic stir bar and a nitrogen inlet was charged dry CH2CI2 (75 mL). The flask was then cooled to -20° C and (+)-diethyl L-tartrate (1.86 mL, 10.9 mmol) and Ti[OCH(CH3)2]4 (2.69 ml, 9.1 mmol) were added sequentially and stirred for 40 min. While still at -20°C, /-BuOOH (5.5 M in nonane, 33 mL, 181 mmol) was added dropwise over 15 minutes and the reaction mixture was stirred for an additional 40 min. A solution of Compound Q4B (30 g, 91 mmol) in CH2CI2 (75 mL) was then added dropwise over 20 min and stirring was continued for 90 min at -20°C (around 75% conversion by LCMS). The reaction mixture was then treated with a 3M NaOH (300 mL) solution saturated with sodium chloride under vigorous stirring. After 1 h, the reaction mixture was diluted with H2O (1 L) and stirred for 1 h. The mixture was diluted with DCM (500 mL) and the water phase was decanted. The DCM phase was filtered over celite. The filtrate was transferred in a seperatory funnel. The layers were separated and the aqueous phase was washed with CH2CI2 (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSCL, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc:hexanes (20-60%) as eluent to give Compound Q4C. LCMS ESI+ calc’d for C23H22O4 : 347.2 [M+EL] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.47-7.38 (m, 6H), 7.35-7.19 (m, 9H), 3.93 (dd, J= 12.3, 4.7 Hz, 1H), 3.80-3.71 (m, 1H), 3.33-3.24 (m, 2H), 2.88 (t, J= 6.7 Hz, 1H), 2.72 (d, J= 4.8 Hz, 1H), 1.77-1.69 (m, 1H).
[0289] Compound Q4D: To a 0 °C solution of Compound Q4C (25.14 g, 72.6 mmol) in dry DMF (130 mL) was added NaH (3.48 g, 87.1 mmol) in one portion. The solution was stirred for 20 minutes. Benzyl bromide (9.1 mL, 76.2 mmol) was added dropwise at 0 °C over 5 min. The reaction was then stirred at room temperature for 20 min, diluted slowly with water (500 mL) and the organic material was extracted with ethyl acetate (3 x 200 mL). All organic phases were combined and washed with brine (2 x 200 mL). The organic phase was dried over MgSCL, filtered and purified using column chromatography eluting with EtOAc:hexanes (5- 30%) to afford Compound Q4D (90.4% ee). LCMS ESI+ calc’d for C30H28O3 : 437.2 [M+H+] ; found: does not ionize. ¾ NMR: (CDCI3, 400 MHz): d 7.43 (ddd, J= 4.7, 3.7, 0.2 Hz, 6H), 7.33-7.19 (m, 14H), 4.57-4.47 (m, 2H), 3.73 (q, 7= 11.0 Hz, 2H), 3.29 (dd, J= 28.6, 10.2 Hz, 2H), 2.76 (dd, J= 19.3, 5.0, 2H).
[0290] Compound Q4E: A solution of Compound Q4D (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). The combined organic extracts were washed with brine (l x 200 mL), dried over MgSCC, and filtered. The solvent was removed under reduced pressure to afford crude Compound Q4E (92.6% ee) that was used without any further purification for the next step. LCMS ESI+ calc’d for C33H34O3 : 479.3 [M+H+] ; found: does not ionize. 1H NMR: (CDCI3, 400 MHz): d 7.41 (ddd, J= 4.8, 3.8, 2.1 Hz, 6H), 7.36-7.19 (m, 14H), 5.96-5.65 (m, 1H), 5.20-5.08 (m, 1H), 4.98-4.81 (m, 2H), 4.61-4.49 (m, 2H), 3.66-3.46 (m, 2H), 3.13 (q, J = 8.7 Hz, 2H), 2.03-1.81 (m, 2H), 1.61 (ddd, J= 10.4, 7.8, 4.6 Hz, 2H).
[0291] Compound Q4F: To a /tvV-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q4E (24g, 50 mmol) and N-methylmorpholine N-oxide (6.46 g, 55 mmol) was added an aqueous solution of OsCL 4% (1 mL) . The reaction mixture was stirred for 12 h and diluted with EtOAc (500 mL) before being washed with sodium thiosulfate (2 x 250 mL), NH4CI (250 mL, saturated aqueous solution), NaHCCC (250 mL, saturated aqueous solution), brine (250 mL), dried over MgSCC, filtered and concentrated under reduced pressure. Purification using a pad of silica eluting with EtOAc/Hexanes (50-100%) afforded Compound Q4F. LCMS ESI+ calc’d for C33H36O5 : 513.3 [M+H+] ; found: does not ionize. ¾ NMR: (CDCC, 400 MHz): d 7.43-7.37 (m, 6H), 7.37-7.19 (m, 14H), 4.54 (t, J= 6.0 Hz, 2H), 3.66 (dd, J= 8.9, 4.9 Hz, 1H), 3.57 (ddd, J= 11.6, 7.5, 3.8 Hz, 1H), 3.53-3.46 (m, 2H), 3.38-3.28 (m, 1H), 3.21-3.08 (m, 2H), 2.90-2.84 (m, 1H), 2.78 (d, J= 3.8 Hz, 1H), 1.96-1.87 (m, 1H), 1.71-1.62 (m, 2H), 1.40-1.27 (m, 2H).
[0292] Compound Q4G: To a solution of the Compound Q4F (22.3 g, 43.5 mmol) in
CH3CN/W ater (1 : 1, 250 mL) at 0 °C, was added NalCL (11.2 g, 52.2 mmol). After 90 min, the reaction was diluted with brine (400 mL) and the organic material was extracted with EtOAc (2 X 300 mL). The organic layers were combined, dried over MgS04, filtered and concentrated under reduced pressure to afford Compound Q4G that was used without any further
purification in the next step. LCMS ESC calc’d for C32H32O5 : 481.2 [M+H+] ; found: does not ionize. ¾ NMR: (CDCC, 400 MHz): d 7.47-7.39 (m, 6H), 7.37-7.19 (m, 14H), 5.53-5.38 (m, 1H), 4.67-4.45 (m, 2h), 3.71 (d, J= 8.4 Hz, 1H), 3.57 (dd, J= 25.8, 9.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.32-3.24 (m, 1H), 3.04 (dd, = 25.9, 9.2 Hz, 1H), 2.15-2.04 (m, 1H), 2.04-1.74 (m, 3H).
[0293] Compound Q4: The crude Compound Q4G 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 filter through celite and the filtrate was concentrated under reduced pressur. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q4 (90.9% ee). LCMS ESI+ calc’d for C32H30O4 : 479.2 [M+H+] ; found: does not ionize. 1H NMR: (CDCb, 400 MHz): d 7.43-7.39 (m, 6H), 7.35-7.21 (m, 14H), 4.58-4.46 (m, 2H), 3.59 (dd, = 44.8, 10.3 Hz, 2H), 3.23 (dd, 7= 45.1, 9.9 Hz, 2H), 2.69-2.54 (m, 2H), 2.14 (ddd, J= 12.9, 9.9, 7.1 Hz, 1H), 2.08-1.93 (m, 1H).
Compound 05
Figure imgf000088_0001
Q4 Q5A
[0294] Compound Q5A: To a solution of Compound Q4 (500 mg, 1.04 mmol) in THF
(4.2 mL) was added LiHMDS (1.56 mL, 1.0 M in THF 1.56 mmol) dropwise at -78 °C, then the reaction was stirred at this temperature for 60 min. Acetone (0.38 mL, 5.20 mmol) was then added slowly to the reaction. After 45 min, the reaction was quenched at -78 °C with saturated aqueous NH4CI solution (15 mL) and diluted with EtOAc (25 mL). The aqueous layer was removed and the organic phase was washed with NH4CI sat. aq. solution followed by brine. The organic layer was dried with NaiSCL filtered and concentrated under reduced pressure to afford the crude product. This residue was dissolved in Pyridine (5 mL) and cooled to 0 °C, and then POCI3 (0.29 mL, 3.12 mmol) was added. The resulting solution was heated to 50 °C and stirred for 1 hour. The reaction mixture was cooled to 0 °C, diluted with Et20 (20 mL) and quenched with 10% CuSC>4 solution (10 mL). The layers were separated and the organic layer was washed twice with 10% CuSCL solution (10 mL) followed by water (10 mL) and brine (10 mL). The organic phase was dried over Na2SC>4 , filtered and concentrated under reduce pressure to afford Compound Q5A. The product was used without any further purification for the next step. LCMS ESI+ calc’d for C35H34O4 : 519.3 [M+H+] ; found 519.2 [M+H+]
[0295] Compound Q5: To a solution of Compound Q5A (485 mg, 0.94 mmol) in
DCM (3.75 mL) at ambient temperature was added formic acid (1 mL) and the reaction was stirred for 24 hours. The reaction was cooled to 0 °C and quenched by the slow addition of an aqueous saturated solution of NaHCCL. The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over Na2SC>4, filtered, concentrated under reduced pressure and purified by column chromatography (0-70% EtOAc in hexanes, 40 g column) giving Compound Q5. LCMS ESI+ calc’d for C16H20O4 : 277.1 [M+H+] ; found 277.1 [M+H+]
Compound 06
Figure imgf000089_0001
[0296] Compound Q6A: To a solution of Compound Q4 (1.00 g, 2.09 mmol) in anhydrous tetrahydrofuran (8.4 mL) cooled to -78 °C under a nitrogen atmosphere was added dropwise a lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 3.14 mL, 3.14 mmol) and the reaction was stirred at -78 °C for 1 h. Compound Q1 (0.71g, 4.18 mmol) was then added to the mixture and the mixture was stirred for an additional 1 h at -78 °C. The reaction was then quenched at -78 °C with saturated aqueous ammonium chloride (25 mL) and the mixture was diluted with ethyl acetate (45 mL). The layers were separated and the organic layer was dried over sodium sulfate, concentrated in vacuo and purified by normal-phase chromatography (0 - 20% ethyl acetate in hexanes) to give Compound Q6A. LCMS ESI+ calc’d for C43H52O5 : 648.4 [M+H+] ; found: 666.3 [M+H20+H+]
[0297] Compound Q6B: To a solution of Compound Q6A (1.28 g, 1.97 mmol) in anhydrous toluene (19.7 mL) was added DCC (611 mg, 2.97 mmol) followed by CuBr (29 mg, 0.20 mmol) and the reaction was stirred at reflux for 4 hours. The solution was cooled to room temperature, filtered through celite, concentrated in vacuo and purified by normal-phase chromatography (0 - 20% ethyl acetate in hexanes) to give Compound Q6B. LCMS ESI+ calc’d for C43H50O4 : 630.4 [M+H+] ; found: 648.3 [M+H20+H+]
[0298] Compound Q6: To a solution of Compound Q6B (0.885 g, 1.40 mmol) in dry dichloromethane (70 mL) was added hydrogen chloride (4.0 M solution in dioxane, 2700 mL, 28.00 mmol) at it and the mixture was stirred for 5 min. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was then dried over sodium sulfate, concentrated in vacuo and purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give Compound Q6. LCMS ESI+ calc’d for C24H36O4 : 389.3 [M+H+] ; found: 389.1 [M+H+] 1H NMR: (CDCh, 400 MHz): d 7.39 - 7.32 (m, 2H), 7.30 (t, 7 = 5.4 Hz, 3H), 6.81 - 6.73 (m, 1H), 4.62 - 4.51 (m, 2H), 3.77 (d, 7 = 12.0 Hz, 1H), 3.68 (d, 7 = 12.1 Hz, 1H), 3.61 (d, 7 = 9.9 Hz, 1H), 3.54 (d, 7= 9.9 Hz, 1H), 2.86 - 2.59 (m, 2H), 2.11 (t, 7= 6.7 Hz, 2H), 1.87 (s, 1H), 1.74 - 1.57 (m, 3H), 1.13 - 1.03 (m, 4H), 0.86 (d, 7= 6.5 Hz, 12H).
Compound 07 and Compound 08
Figure imgf000090_0001
[0299] Compound Q7 and Compound Q8: A solution of Compound Q3E (1.00 g) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a chiralcel AD (250mm x 30mm x 5 pm) column with gradient elution from 40% MeOH in CO2 upward. Flow rate was 70 mL/min, and 10 injections were conducted. Two peaks were obtained, corresponding to the two enantiomers of Compound Q3E. An analytical chiral SFC method was developed (differing from the preparative method): eluent was supercritical CO2 and MeOH (doped with 0.05% isopropylamine) on a chiralcel OJ-H (5 pm, 0.46cm id x 25 length) column with gradient elution from 10-40% MeOH(doped with 0.05% isopropylamine). This provided Compound Q7 (second to elute using analytical method): LCMS ESI+ calc’d for C12H13IO3 : 333.0 [M+H+] ; found 333.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.44 (s, 1H), 7.38 (d, 7 =
8.4 Hz, 1H), 6.54 (d, 7 = 8.4 Hz, 1H), 4.81 (m, 1H), 3.71 (s, 3H), 3.21 (dd, 7 = 16.0, 9.0 Hz, 1H), 2.87 (dd, 7 = 16.2, 7.4 Hz, 1H), 2.52 (dt, 7 = 7.6, 3.6 Hz, 2H), 2.04 (t, 2H); and Compound Q8 (first to elute using analytical method): LCMS ESI+ calc’d for C12H13IO3 : 333.0 [M+H+] ; found 333.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.43 (s, 1H), 7.38 (d, 7= 8.0 Hz, 1H), 6.53 (d, 7 = 8.4 Hz, 1H), 4.82 (m, 1H), 3.70 (s, 3H),3.30 (dd, 7= 16.0, 9.0 Hz, 1H), 2.88 (dd, 7= 16.2, 7.4 Hz, 1H), 2.53 (dt, 7= 7.6, 3.6 Hz, 2H), 2.04 (t, 2H). Absolute stereochemistries of the products were arbitrarily assigned. Compound 09
Figure imgf000091_0001
[0300] Compound Q9A: A vessel was charged with Compound Q7 (280 mg, 843 umol, 1.00 eq ) and 4-/-butyl-l-ethynylbenzene (138 mg, 876 umol, 1.04 eq) in THF (1.96 mL). Cul (6.42 mg, 33.7 umol, 0.04 eq ), Et3N (123 mg, 1.22 mmol, 170 uL, 1.45 eq ), and
Pd(PPh3)2Ch (11.8 mg, 16.8 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h. The reaction was filtered and the cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified via column chromatography on silica gel (Petroleum ether/Ethyl acetate = 100/1 to 20/1) giving Compound Q9A. 1H NMR (400 MHz, CDCb) d 7.43 (d, J= 8.4 Hz, 2H), 7.36-7.29 (m, 4H), 6.71 (d, J= 8.0 Hz, 1H), 4.87- 4.82 (m, 1H), 3.70 (s, 3H), 3.33-3.30 (m, 1H), 2.56-2.52 (m, 2H), 2.09-2.04 (m, 2H), 1.33 (s, 9H).
[0301] Compound Q9: A vessel was charged with Compound Q9A (310 mg, 855 umol, 1.00 eq) in THF (2.50 mL) and H2O (2.50 mL). NaOH (684 mg, 17.1 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was washed with DCM (2.0 mL), and filtered. The cake was treated with H2O (10 mL) and acidified to pH = 3 using 6.0 M aq HC1. The system was filtered and the resulting cake was washed with de-ionized H2O (50 mL). The final cake was dried under reduced pressure, providing Compound Q9. LCMS ESI+ calc’d for C23H24O3 : 349.2 [M+H+] ; found 349.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.43 (d, J= 8.4 Hz, 2H), 7.36-7.30 (m, 4H), 6.72 (d, J= 8.0 Hz, 1H), 4.91-4.84 (m, 1H), 3.37-3.33 (m, 1H), 2.90-2.88 (m, 1H), 2.63-2.59 (m, 2H), 2.10-2.05 (m, 2H), 1.48 (s, 9H). Compound Q10
Figure imgf000092_0001
[0302] Compound Q10A: A vessel was charged with Compound Q8 (280 mg, 843 umol, 1.00 eq ) and 4-/-butyl-l-ethynylbenzene (138 mg, 876 umol, 1.04 eq) in THF (1.96 mL). Cul (6.42 mg, 33.7 umol, 0.04 eq ), Et3N (123 mg, 1.22 mmol, 170 uL, 1.45 eq ), and
Pd(PPh3)2Ch (11.8 mg, 16.8 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h. The reaction was filtered and the cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified via column chromatography on silica gel (Petroleum ether/Ethyl acetate = 100/1 to 20/1) giving Compound Q10A. 'H NMR (400 MHz, CDCb) d 7.43 (d, J= 8.4 Hz, 2H), 7.36-7.29 (m, 4H), 6.71 (d, J= 8.0 Hz, 1H), 4.89- 4.82 (m, 1H), 3.70 (s, 3H), 3.36-3.32 (m, 1H), 2.57-2.52 (m, 2H), 2.09-2.04 (m, 2H), 1.33 (s, 9H).
[0303] Compound Q10: A vessel was charged with Compound Q10A (150 mg, 413 umol, 1.00 eq) in THF (1.00 mL) and H2O (1.00 mL). NaOH (331 mg, 8.28 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was washed with DCM (2.0 mL), and filtered. The cake was treated with H2O (10 mL) and acidified to pH = 3 using 6.0 M aq HC1. The system was filtered and the resulting cake was washed with de-ionized H2O (50 mL). The final cake was dried under reduced pressure, providing Compound Q10. LCMS ESI+ calc’d for C23H24O3 : 349.2 [M+H+] ; found 349.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.43 (d, J= 8.4 Hz, 2H), 7.36-7.30 (m, 4H), 6.72 (d, J= 8.0 Hz, 1H), 4.92-4.86 (m, 1H), 3.37-3.33 (m, 1H), 2.90-2.89 (m, 1H), 2.64-2.59 (m, 2H), 2.11-2.05 (m, 2H), 1.33 (s, 9H). Compound Oil
Figure imgf000093_0001
[0304] Compound QUA: A vessel was charged with Compound Q7 (800 mg, 2.41 mmol, 1.00 eq ) and l-ethynyl-4-methylbenzene (290 mg, 2.51 mmol, 1.04 eq) in THF (5.60 mL). Cul (18.3 mg, 96.3 umol, 0.04 eq), Et3N (353 mg, 3.49 mmol, 1.45 eq), and Pd(PPh3)2Ch (33.8 mg, 48.1 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h. The reaction was filtered and the cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified via column chromatography on silica gel (Petroleum ether/Ethyl acetate = 100/1 to 20/1) giving Compound QUA.
[0305] Compound Qll: A vessel was charged with Compound QUA (650 mg, 2.03 mmol, 1.00 eq) in THF (5.00 mL) and H2O (5.00 mL). NaOH (1.62 g, 40.5 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was washed with DCM (2.0 mL), and filtered. The cake was treated with H2O (10 mL) and acidified to pH = 3 using 6.0 M aq HC1. The system was filtered and the resulting cake was washed with de-ionized H2O (50 mL). The final cake was dried under reduced pressure, providing Compound Q9. LCMS ESI+ calc’d for C20H18O3 : 307.1 [M+H+] ; found 307.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.39 (d, J= 8.0 Hz, 2H), 7.32 (d, J= 12.4 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 6.72 (d, J= 8.0 Hz, 1H), 4.92-4.84 (m, 1H), 3.37-3.33 (m, 1H), 2.88-2.80 (m, 1H), 2.63-2.59 (m, 2H), 2.36 (s, 3H) ,2.10- 2.05 (m, 2H). Compound 012
Figure imgf000094_0001
[0306] Compound Q12A: A vessel was charged with Compound Q8 (800 mg, 2.41 mmol, 1.00 eq ) and l-ethynyl-4-methylbenzene (290 mg, 2.51 mmol, 1.04 eq) in THF (5.60 mL). Cul (18.3 mg, 96.3 umol, 0.04 eq), Et3N (353 mg, 3.49 mmol, 1.45 eq), and Pd(PPh3)2Ch (33.8 mg, 48.1 umol, 0.02 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25 °C under N2 for 16 h. The reaction was filtered and the cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified via column chromatography on silica gel (Petroleum ether/Ethyl acetate = 100/1 to 20/1) giving Compound Q12A.
[0307] Compound Q12: A vessel was charged with Compound Q12A (680 mg, 2.12 mmol, 1.00 eq) in THF (5.00 mL) and H2O (5.00 mL). NaOH (1.70 g, 42.4 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was washed with DCM (2.0 mL), and filtered. The cake was treated with H2O (10 mL) and acidified to pH = 3 using 6.0 M aq HC1. The system was filtered and the resulting cake was washed with de-ionized H2O (50 mL). The final cake was dried under reduced pressure, providing Compound Q12. LCMS ESI+ calc’d for C20H18O3 : 307.1 [M+H+] ; found 307.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.39 (d, J= 8.0 Hz, 2H), 7.32 (d, J= 12.4 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 6.72 (d, J= 8.0 Hz, 1H), 4.91-4.84 (m, 1H), 3.37-3.33 (m, 1H), 2.88-2.80 (m, 1H), 2.63-2.59 (m, 2H), 2.36 (s, 3H) ,2.10- 2.05 (m, 2H). Compound 013
Figure imgf000095_0001
[0308] Compound Q13B: To a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13A (20 g, 127.74 mmol, 1.00 equiv), 2-bromo-l,l-di ethoxy ethane (27.6 g, 140.05 mmol, 1.10 equiv), N,N- dimethylformamide (100 mL) and potassium carbonate (19.4 g, 140.37 mmol, 1.10 equiv). The resulting solution was stirred for 16 h at 100°C in an oil bath. The reaction solution was diluted with 300 mL of water. The resulting mixture was extracted with ethyl acetate (2 x 100 mL) and the organic layers were combined, washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford Compound Q13B.
[0309] Compound Q13C: To a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13B (31 g, 113.67 mmol, 1.00 equiv) and acetic acid (300 mL). The resulting solution was heated at reflux for 16 h in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 150 mL of EA, washed with water (2 x 200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford Compound Q13C. 'H NMR (400 MHz, CDCh) d 9.90 (s, 1H), 7.74 (s, 1H), 7.55-7.45 (m, 3H).
[0310] Compound Q13D: To a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (20 mL) and sodium hydride (1.77 g, 0.44 mmol, 1.60 equiv, 0.6%) followed by the addition of a solution of ethyl 2-(diethoxyphosphoryl)acetate (9.3 g, 41.48 mmol, 1.50 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0°C in 10 min. To this was added a solution of Compound Q13C (5 g, 27.69 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 0°C in 10 min.
The resulting solution was stirred for 3 h at 0-25°C in a water/ice bath. The reaction was then quenched by the addition of 200 mL of water/ice. The resulting solution was extracted with ethyl acetate (3 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1 :8) to afford Compound Q13D. 1H NMR (400 MHz, CDCh) d 7.53-7.47 (m, 2H), 7.39-7.26 (m, 3H), 6.84 (s, 1H) , 6.59-6.53 (m, 1H), 4.29-4.22 (m, 2H), 1.35-1.30 (m, 3H).
[0311] Compound Q13E: To a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13D (4.7 g, 18.75 mmol, 1.00 equiv), ethyl acetate (300 mL), Palladium on carbon (235 mg, 5%wt) and hydrogen. The resulting mixture was stirred for 30 min at 20°C and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum to afford Compound Q13E. 'H NMR (400 MHz, CDCh) d 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.19-7.15 (m, 1H), 6.38 (s, 1H), 4.20-4.13 (m, 2H), 3.14-3.09 (m, 2H), 2.78-2.73 (m, 2H), 1.29-1.23 (m, 3H).
[0312] Compound Q13F: To a 100-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Compound Q13E (3 g, 11.87 mmol, 1.00 equiv), l-ethynyl-4-m ethylbenzene (4.14 g, 35.64 mmol, 3.00 equiv), N,N- dimethylformamide (30 mL), potassium carbonate (4.9 g, 35.45 mmol, 3.00 equiv), xphos (0.99 g, 0.20 equiv) and Pd2(dba)3 (1.23 g, 1.34 mmol, 0.10 equiv). The resulting mixture was stirred for 16 h at 100°C in an oil bath. The resulting smixture was filtered and the filtrate was diluted with 100 mL of EA. The resulting mixture was washed with 5x200 mL of 5%NaCl(aq), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1 : 10) to afford Compound Q13F. 1H NMR (400 MHz, CDCh) d 7.64 (dd, J = 1.5, 0.8 Hz, 1H), 7.46 - 7.28 (m, 4H), 7.18 - 7.08 (m, 2H), 6.39 (t, J = 1.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.15 - 3.03 (m, 2H), 2.74 (dd, J = 8.2, 6.9 Hz, 2H), 2.35 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).
[0313] Compound Q13: To a 100-mL 3-necked round-bottom flask, was placed
Compound Q13F (2 g, 6.02 mmol, 1.00 equiv), tetrahydrofuran (16 mL), water(4 mL) and sodium hydroxide (1.2 g, 30.00 mmol, 5.00 equiv). The resulting solution was stirred for 4 h at 50°C in an oil bath. The reaction mixture was cooled to 0°C with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (6 N). The mixture was filtered and washed with 3x30 mL of water to afford Compound Q13. LCMS ESI+ calc’d for C43H52O6 : 303.1 [M-H ] ; found 303.3 [M-H ]. ¾ NMR (400 MHz, DMSO-de) d 12.32 (s, 1H), 7.74 (s, 1H), 7.55-7.53 (m, 1H), 7.45-7.40 (m, 3H), 7.24-7.22 (m, 2H), 6.63 (s, 1H), 3.04-3.0 (m, 2H), 2.79-2.67 (m, 2H), 2.17 (s, 3H).
Compound 014
Figure imgf000097_0001
[0314] Compound Q14A: A vessel was charged with Compound Q13 (0.95 g, 3.12 mmol, 1.00 eq) in DMF (10 mL). K2CO3 (1.73 g, 12.49 mmol, 4.00 eq) was added to the solution. Mel (553.8 mg, 3.90 mmol, 1.25 eq) was added dropwise to the mixture. The reaction was stirred at 25 °C for 16 h. Water (20 mL) was added to the mixture, which was stirred for 2 min. System was extracted with EtOAc (10 mL + 5.0 mL) and the organic phase was collected. The organic layer was dried over anhydrous INfeSCL, filtered, and the filtrate was concentrated under reduced pressure, providing Compound Q14A.
[0315] Compound Q14B: LiHMDS (1 M, 8.00 mL, 6.37 eq) was added in dropwise fashion to a solution of Compound Q14A (0.400 g, 1.26 mmol, 1.00 eq) in THF (10 mL) at -78 °C under N2. The reaction was stirred at -78 °C for 1 h. Mel (0.535 g, 3.77 mmol, 3.00 eq) was added in dropwise fashion to the solution at -78 °C, which was then stirred at 25 °C for 1 h. The reaction was quenched with sat. NH4CI (30 mL) and extracted with EtOAc (3 x 5.0 mL). The organic phase was collected and dried over anhydrous MgS04, then filtered. The filtrate was concentrated and the resulting residue purified by prep-HPLC (column: Nano-micro Kromasil C18 100 x30mm 5um; mobile phase: [water (0.1%TFA)-ACN]; B%: 80%-90%,10 min), providing Compound Q14B.
[0316] Compound Q14: A vessel was charged with Compound Q14B (190 mg, 548.4 pmol, 1.00 eq) in THF (5.0 mL) and H2O (5.0 mL). NaOH (438.7 mg, 10.9 mmol, 20.0 eq) was added to the solution. The reaction was stirred at 50 °C for 16 h. MeOH (2.0 mL) was added to the solution and stirred for 2 h at 75 °C. HC1 (6 N) was added to the mixture to neutralize the NaOH and the system was extracted with EtOAc (10 mL c 2). Combined organic extracts were concentrated under reduced pressure, then triturated with Petroleum Ether/Ethyl Acetate (20: 1 v:v, 30 mL total). Filtration gave a cake, which was dried under reduced pressure, giving
Compound Q14. LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.0 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 7.75 (s, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.23 (d, J= 8.0 Hz, 2H) 6.62 (s, 1H), 3.00 (s, 2H), 2.33 (s, 3H), 1.17 (s, 6H).
Compound 015
Figure imgf000098_0001
[0317] Compound Q15B: A 3-necked round-bottom flask was charged with
Compound Q15A (50.0 g, 186 mmol, 1.00 eq ) and THF (250 mL). The mixture was cooled to 0°C. The mixture was degassed with N2 (3x). LAH (7.08 g, 186 mmol, 1.00 eq) was added to the mixture slowly in 3 portions. After addition was completed, the reaction was stirred at 20°C for 12 h. H2O (7.0 mL) and 15% w/w NaOH (7.0 mL) and H2O (7.0 mL) were added to the mixture in that specific order. H2O (100 mL) and EtOAc (200 mL) were added to the mixture, which was subsequently filtered via Buchner funnel. The organic layer was washed with brine (50.0 mL), dried over INfeSCL, filtered (Buchner funnel), and concentrated. The crude residue was washed with Petroleum Ether: EtOAc (5: 1, v:v, 100 mL total). The resulting mixture was filtered (Buchner funnel) giving Compound Q15B.
[0318] Compound Q15C: A single-necked round-bottomed flask was charged with
Compound Q15B (20.0 g, 88.5 mmol, 1.00 eq) along with DME (100 mL). Mn02 (38.5 g, 442 mmol, 5.00 eq) was introduced to the mixture in one portion. The mixture was stirred at 70°C for 12 h. The mixture was filtered (Buchner funnel). The filtrate was concentrated under reduced pressure. The resulting residue was washed with Petroleum Ether: EtOAc (3: 1, v:v, 100 mL total). Filtration then gave a cake to provide Compound Q15C. ¾ NMR (400 MHz, CDCb) d 9.86 (s, 1H), 9.07 (s, 1H), 7.91 (s, 1H), 7.49 (d, J= 8.8 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 7.22 (s, 1H).
[0319] Compound Q15D: A single-necked round-bottom flask was charged with triethyl phosphosphonoacetate (10.5 g, 46.8 mmol, 1.05 eq) and THF (80.0 mL). The mixture was cooled to 0°C. NaOH (1.96 g, 49.1 mmol, 1.10 eq) was added to the mixture in one portion. The system was stirred at 0°C for 0.5 h. Compound Q15C (10.0 g, 44.6 mmol, 1.00 eq) was added to the mixture in one portion. The reaction was stirred at 20°C for 11.5 h. Saturated aq NaHC03 (250 mL) and EtOAc (250 mL) were added to the mixture. The phases were separated and the organic layer was washed with brine (2 x 100 ml). The organic layer was dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure, providing
Compound Q15D. LCMS ESI+ calc’d for Ci3Hi2BrN02 : 294.1, 296.1 [M+H+] ; found 293.9, 295.9 [M+H+]
[0320] Compound Q15E: A single-necked round-bottom flask was charged with
Compound Q15D (9.00 g, 30.6 mmol, 1.00 eq) and EtOAc (100 mL). Rh(PPli3)3Cl (l.OOg, 1.08 mmol, 0.03 eq) was added to the mixture in one portion. The mixture was sparged with ¾ for (3x). The reaction was stirred at 20°C under ¾ (30 psi) for 12 h. The system was carefully concentrated to dryness under reduced pressure. The residue was purified by column
chromatography on silica gel (Petroleum ether: Ethyl acetate = 5: 1 to 2: 1), giving Compound
Q15E. LCMS ESI+ calc’d for Ci3Hi4BrN02 : 296.1, 298.1 [M+H+] ; found 295.9, 297.9 [M+H+] ¾ NMR (400 MHz, CDCb) d 8.66 (s, 1H), 7.64 (s, 1H), 7.18 (s, 2H), 6.18 (s, 1H), 4.22-4.18 (m, 2H), 3.08-3.04 (m, 2H), 2.74-2.71 (m, 2H), 1.29-1.25 (m, 3H).
[0321] Compound Q15F: A single-necked round-bottom flask was charged with
Compound Q15E (3.00 g, 10.1 mmol, 1.00 eq ) and ACN (30.0 mL). l-ethynyl-4- methylbenzene (2.35 g, 20.3 mmol, 2.00 eq), Sphos-G2 (730 mg, 1.01 mmol, 0.10 eq), and CyiMeN (3.96 g, 20.3 mmol, 2.00 eq) were added to the mixture. The mixture was degassed with N2 (3x). The reaction was stirred at 80°C for 12 h. H2O (100 mL) was added to the mixture, which was extracted with EtOAc (3x 100 mL). The organic layer was washed with brine (3x 100 mL). The organic layer was dried over NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 25: 1 to 5: 1). The resulting product-containing fractions were combined and concentrated. The residue was washed with Petroleum Ether: EtOAc (5: 1, v:v, 50 mL total), followed by Petroleum Ether: EtOAc (2: 1, v:v, 30 mL total). Filtration gave a cake to provide Compound Q15F. LCMS ESI+ calc’d for C22H21NO2 : 332.2 [M+H+] ; found 332.0 [M+H+]
[0322] Compound Q15: A single-necked round-bottom flask was charged with
Compound Q15F (2.40 g, 7.24 mmol, 1.00 eq), MeOH (20.0 mL), THF (20.0 mL), and H20 (20.0 mL). NaOH (5.79 g, 144.8 mmol, 20.0 eq) was added to the mixture in one portion. The reaction was stirred at 70°C for 12 h. The reaction was concentrated to dryness under reduced pressure. EtOAc (100 mL) and H2O (100 mL) were added. Layers were separated and the aq phase was extracted with EtOAc (50.0 mL). All organic phases were combined, washed with brine (50.0 mL), dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1 : 1 to pure Ethyl acetate) giving Compound Q15. LCMS ESI+ calc’d for C20H17NO2 : 304.1 [M+H+] ; found 304.0 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.2 (s, broad, 1H), 11.17 (s, 1H), 7.62 (s, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.29 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.0 Hz, 2H), 7.15 (d, J= 10.0 Hz, 1H), 6.18 (s, 1H), 2.95 (t, J= 7.2 Hz, 2H), 2.66 (t, J= 7.2 Hz, 2H), 2.32 (s, 3H). Compound 016
Figure imgf000101_0001
[0323] Compound Q16B: A vessel was charged with Compound Q16A (10.0 g, 41.4 mmol, 1.00 eq ) in MeOH (100 mL). SOCh (39.4 g, 331 mmol, 24.0 mL, 8.00 eq ) was added dropwise to the mixture at 0°C. The reaction was stirred at 70°C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (200 mL). The system was washed with aq. NaHCCL (200 mL) and brine (200 mL). The organic phase was separated, dried with NaiSCL, and filtered. The filtrate was concentrated under reduced pressure to give Compound Q16B. LCMS ESI+ calc’d for C19H14O3 : 291.1 [M+H+] ; found 291.0
[MALL] ¾ NMR (400 MHz, CDCh) d 7.87 (s, 1H), 7.61 (d, J= 8.8 Hz, 1H), 7.56 (d, J= 8.8 Hz, 2H), 7.52 (s, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 3.99 (s, 3H), 2.38 (s, 3H).
[0324] Compound Q16C: A single-necked round-bottom flask was charged with
Compound Q16B (7.50 g, 29.4 mmol, 1.00 eq) and l-ethynyl-4-methylbenzene (6.83 g, 58.8 mmol, 7.46 mL, 2.00 eq) and Dioxane (55.0 mL). Cul (448 mg, 2.35 mmol, 0.08 eq), Pd(PtBu3)2 (601 mg, 1.18 mmol, 0.04 eq), and Et3N (4.31 g, 42.6 mmol, 5.93 mL, 1.45 eq) were added. The mixture was degassed with N2 (3x). The reaction was stirred at 90°C for 16 h. The reaction was filtered. The filtrate was treated with H2O (100 mL) and extracted with EtOAc (3 x 100 mL).
The organic layer was washed with brine (100 mL). The organic layer was dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100: 1 to l : l)to give Compound Q16C. LCMS ESI+ calc’d for C19H14O3 : 291.1 [M+H+] ; found 291.0 [M+H+]
[0325] Compound Q16: A vessel was charged with Compound Q16C (2.30 g, 7.92 mmol, 1.00 eq) in THF (16.0 mL) and H2O (16.0 mL). NaOH (6.34 g, 158 mmol, 20.0 eq) was added to the mixture. Reaction was stirred at 70°C for 16 h. The reaction was concentrated under reduced pressure to remove the THF. 6M aq HC1 was added to pH ~ 3. The system was extracted with DCM (3 x 50.0 mL); combined organic extracts were washed with brine (50.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, THF/MeOH = 50/1), giving Compound Q16. LCMS ESC calc’d for CI8HI203 : 277.1 [M+fC] ; found 277.0 [M+fC] ¾ NMR (400 MHz, DMSO-de) d 7.87 (s, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.67-7.64 (m, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H) 2.34 (s, 3H).
Compound 017
Figure imgf000102_0001
[0326] Compound Q17B: To a solution of Compound Q17A (518 mg, 2.28 mmol, 1.0 eq.), [PdCh(PPh3)2] (32 mg, 0.046 mmol, 0.02 eq.) and Cul (87 mg, 0.46 mmol, 0.2 eq.) in dry and degassed DMF (23 mL) under a nitrogen atmosphere were successively added l-ethynyl-4- methylbenzene (1.79 mL, 14.1 mmol, 6.2 eq.) followed by Et2NH (1.19 mL, 11.4 mmol, 5.0 eq.). The solution was heated at 115°C for 12h and was then allowed to cool to room
temperature. Water (50 mL) was added and the mixture was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine twice, dried over MgS04, filtered and concentrated. Purification by silica gel chromatography (0 to 50% EtOAc/nHex) afforded
Compound Q17B. LCMS ESI+ calc’d for CI8HI402 : 263.1 [M+H+] ; found 263.0 [M+H+]
[0327] Compound Q17C: To a solution of Compound Q17B (317 mg, 1.21 mmol, 1.0 eq.) in dry DCM (4.8 mL) cooled to 0°C under a nitrogen atmosphere was added SOCh (0.13 mL, 1.7 mmol, 1.4 eq.) dropwise. After stirring for lh at 0°C, the reaction was concentrated to dryness and the residue was dissolved in DMSO (6.4 mL). NalNri (395 mg, 6.04 mmol, 5.0 eq.) was added and the mixture was stirred at 70°C for 2 min and at room temperature for 2h. A solution of sat. aq. NaHCCL (5 mL) was then added and the mixture was extracted with dichloromethane (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSCri, filtered and concentrated to give pure Compound Q17C. LCMS ESI+ calc’d for C 18H13N3O : 260.1 [M-N2+H+] ; found 260.0 [M-N2+H+]
[0328] Compound Q17: To a solution of Compound Q17C (248 mg, 0.86 mmol, 1.0 eq.) in dry THF (8.6 mL) cooled to 0°C under a nitrogen atmosphere was added powder L1AIH4 (69 mg, 1.73 mmol, 2.0 eq.) in one portion. The resulting suspension was stirred at 0°C for 30 min and a solution of sat. aq. NH4CI (0.3 mL) was added, followed by a 6N solution of NaOH (5 mL). The mixture was extracted with dichloromethane (3 x 5 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. A quick filtration on silica gel (50% EtOAc/nHex to remove impurities, then 10% MeOH/EtOAc) afforded
Compound Q17. LCMS ESI+ calc’d for CisHisNO : 245.1 [M-NH +H+] ; found 245.6 [M- NH3+H+].
Compound 018
Figure imgf000103_0001
[0329] Compound Q18: To a solution of Compound Q17B (100 mg, 0.38 mmol, 1.0 eq.), N-methyl-2-nitrobenzenesulfonamide (91 mg, 0.42 mmol, 1.1 eq.) and PPI13 (170 mg, 0.65 mmol, 1.7 eq.) in dry THF (1.9 mL) cooled to 0°C under a nitrogen atmosphere was added DIAD (130 pL, 0.65 mmol, 1.7 eq.) dropwise. The resulting solution was stirred at room temperature for the night and volatiles were removed under reduced pressure. Partial purification by silica gel chromatography (0 to 30% Acetone/nHex) afforded crude Compound Q18A.
Crude Compound Q18A was used without further purification and was dissolved in DMF (0.4 mL) and K2CO3 (169 mg, 1.22 mmol, 3.2 eq.) was added, followed by PhSH (92 pL, 0.88 mmol, 2.3 eq.). The resulting mixture was stirred at 40°C for the night and then allowed to cool temperature. A 6N solution of NaOH (5 mL) was added and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 10% MeOH/CHCh) afforded Compound Q18. LCMS ESI+ calc’d for C19H17NO : 245.1 [M- CH NH2+H+] ; found 245.0 [M-CH NH2+H+]
Compound 019
Figure imgf000104_0001
[0330] Compound Q19B: To a 1-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19A (25 g, 146.55 mmol, 1.00 equiv) in ACN/DMF (500/125 mL), Cs2C03 (95.8 g, 294.03 mmol, 2.01 equiv) and ethyl 2-bromoacetate (29.3 g, 175.45 mmol, 1.20 equiv). The resulting mixture was stirred overnight at 100 °C in an oil bath and then filteredand washed by EA. The filtrate was concentrated under vacuum and then quenched by the addition of 200 mL of water, the mixture was extracted with EtOAc (3x 200 mL) and the organic layers were combined, washed with brine (2x 200 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0~1 :60) to afford Compound Q19B. ¾ NMR (400 MHz, CDCh) d 7.63 (d, J= 2.1 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.42 (dd, J= 8.8, 2.1 Hz, 1H), 4.48 (q, J= 7.1 Hz, 2H), 2.59 (s, 3H), 1.47 (t, = 7.1 Hz, 3H).
[0331] Compound Q19C: To a 1-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of L1AIH4 (2.3 g, 60.61 mmol, 0.80 equiv) in tetrahydrofuran (180 mL) followed by addition of Compound Q19B (18 g, 75.42 mmol, 1.00 equiv) in several batches at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was then quenched by addition of 20 mL of potassium carbonate (cone.) at 0 °C, filtered, and extracted with 3x20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to afford Compound Q19C. ¾ NMR (400 MHz, CDCh) d 7.46 (d, J= 2.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.30 - 7.19 (m, 1H), 4.75 (d, J= 2.4 Hz, 2H), 2.23 (s, 3H), 1.8 ( m, 1H).
[0332] Compound Q19D: To a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19C (11.2 g, 56.96 mmol, 1.00 equiv) in dichloromethane (150 mL) and Dess-Martin Periodinane (26.7 g, 62.96 mmol, 1.11 equiv). The resulting mixture was stirred for 2 h at room temperature, filtered, and washed by DCM. The resulting solution was diluted with 100 mL of H2O, extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with 20 mL of brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0-1 :50) to afford Compound Q19D. ¾ NMR (400 MHz, CDCh) d 10.04 (s, 1H), 7.67 (dd, J= 1.8, 1.0 Hz, 1H), 7.48 (t, J= 1.5 Hz, 2H), 2.61 (s, 3H).
[0333] Compound Q19E: To a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (2.1 g, 52.50 mmol, 1.62 equiv) in tetrahydrofuran (60 mL) followed by addition of a solution of triethyl phosphonoacetate (10.9 g, 51.86 mmol, 1.60 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0 °C in 10 min. To this was added Compound Q19D (6.3 g, 32.37 mmol, 1.00 equiv) in several batches at 0 °C. The resulting mixture was stirred for 3 h at 0 °C in a water/ice bath. The reaction was then quenched by addition of water/ice, extracted with 3x30 mL of ethyl acetate and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1 : 100-1 :60) to afford Compound Q19E. 1H NMR (400 MHz, CDCh) d 7.61 (d, J= 15.6 Hz, 1H), 7.48 (d, J= 2.0 Hz, 1H), 7.40 - 7.23 (m, 2H), 6.53 (d, 7= 15.5 Hz, 1H), 4.29 (q, 7= 7.1 Hz, 2H), 2.33 (s, 3H), 1.35 (t, J= 7.1 Hz, 3H).
[0334] Compound Q19F: To a 250-mL tank, was placed a solution of Compound
Q19E (4.96 g, 18.74 mmol, 1.00 equiv) in ethyl acetate (100 mL) and Palladium carbon (0.25 g). ¾ (g) was then introduced (60 atm) to the reaction. The resulting mixture was stirred for 30 min at room temperature, filtered, and washed by EA. The resulting filtrate was concentrated under vacuum to afford Compound Q19F. ¾ NMR (400 MHz, CDCh) d 7.41 (d, J= 2.1 Hz, 1H), 7.34 - 7.25 (m, 1H), 7.23 - 7.13 (m, 1H), 4.16 (q, J= 7.1 Hz, 2H), 3.08 (t, J= 7.5 Hz, 2H), 2.74 (t, J= 7.5 Hz, 2H), 2.18 (s, 3H), 1.26 (t, 7= 7.1 Hz, 3H).
[0335] Compound Q19G: To a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Compound Q19F (3.82 g, 14.32 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), l-ethynyl-4-methylbenzene (5.0 g,
43.04 mmol, 3.01 equiv), potassium carbonate (4.16 g, 30.10 mmol, 2.10 equiv), Xphos (960 mg, 2.01 mmol, 0.14 equiv) and Pd2(dba)3 CHCh (1.04 g, 1.00 mmol, 0.07 equiv). The resulting mixture was stirred overnight at 100 °C in an oil bath. After cooled to room temperature, the mixture was filtered and the filtrate was diluted with 50/100 mL of H2O/EA. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers were combined, washed with 3x20 mL of brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0-1 :80) to afford Compound Q19G. ¾ NMR (400 MHz, CDCh) d 7.64 (d, J= 1.6 Hz, 1H), 7.51 - 7.37 (m, 3H), 7.35 (d, J= 8.4 Hz, 1H), 7.18 (d, J= 7.9 Hz, 2H), 4.17 (q, 7= 7.1 Hz, 2H), 3.09 (t, J= 7.5 Hz, 2H), 2.76 (t, J= 7.5 Hz, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 1.27 (t, J= 7.1 Hz, 3H).
[0336] Compound Q19: To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution ofCompound Q19G (1.4 g, 4.04 mmol, 1.00 equiv) in tetrahydrofuran/H20 (16/4 mL) and sodium hydroxide (0.84 g, 21.00 mmol, 5.20 equiv). The resulting solution was stirred for 3 h at 50 °C. The resulting mixture was concentrated to ¼ volume under vacuum. The pH value of the solution was adjusted to 3 with hydrogen chloride (6 N). The solution was filtered and washed by H2O and hexane to afford Compound Q19. LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 319.2 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.26 (s, 1H), 7.69 (d, 7= 1.6 Hz, 1H), 7.53 - 7.32 (m, 4H), 7.22 (d, J= 7.9 Hz, 2H), 2.98 (t, J= 7.3 Hz, 2H), 2.60 (t, J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H).7.3 Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H). Compound 020
Figure imgf000107_0001
[0337] Compound Q20B: A vessel was charged with Compound Q20A (20.0 g, 156 mmol, 1.00 eq ) and DCM (140 mL). The system was cooled to -70°C. O3 (1.00 eq ) was bubbled into the solution until a pale blue color persisted at -78°C under 15 psi for about 2 h. PPh3 (61.3 g, 234 mmol, 1.50 eq) was added to the mixture. The reaction was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure at 25°C. MTBE (100 mL) was added to the residue. The system was stirred at 25°C for 20 min. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 20/1), giving Compound Q20B. ¾ NMR (400 MHz, CDCb) d 9.82 (s, 1H), 4.18-4.11 (m, 2H), 2.80 (t, J= 6.8 Hz, 2H), 2.62 (t, J= 6.4Hz, 2H), 1.26 (t, J= 7.2 Hz, 3H).
[0338] Compound Q20C: A vessel was charged with 4-bromobenzene-l,2-diol (1.94 g,
10.2 mmol, 1.00 eq) and TsOH»H20 (194 mg, 1.02 mmol, 0.10 eq) in toluene (19.4 mL).
Compound Q20B (2.00 g, 15.3 mmol, 1.50 eq) was added to the mixture. The system was degassed with N2 (3x). The reaction was stirred at 120°C for 3 h. Ethyl acetate (60.0 mL) and H2O (60.0 mL) were added to the mixture. The system was filtered. The organic phase of the filtrate was collected and washed with brine (2 x 80 mL). The organic phase was dried over Na2SC>4, and filtered. The filtrate was collected and concentrated under reduced pressure.
Purification by silica gel chromatography (S1O2, Petroleum ether/Ethyl acetate = 20/1 to 15/1) gave Compound Q20C. ¾ NMR (400 MHz, CDCb) d 6.91 (d, J= 3.2 Hz, 2H), 6.64 (d, J= 8.4 Hz, 1H), 6.25 (s, 1H), 4.16 (d, J= 6.8 Hz, 2H), 2.53 (t, J= 8.0 Hz, 2H), 2.31-2.29 (m, 2H), 1.26 (t, 7= 7.2 Hz, 3H). [0339] Compound Q20D: A vessel was charged with Compound Q20C (1.70 g, 5.65 mmol, 1.00 eq) and ACN (17.0 mL). CyiMeN (2.21 g, 11.2 mmol, 2.39 mL, 2.00 eq ), and Pd- Sphos-G2 (406 mg, 564 umol, 0.10 eq) were added. N2 was bubbled through the mixture for 5 mins l-ethynyl-4-m ethylbenzene (1.31 g, 11.2 mmol, 1.43 mL, 2.00 eq) was added. The system was degassed and purged with N2 several times. The reaction was heated to 70°C for 12 h. MTBE (40.0 mL) and H2O (40.0 mL) were added to the mixture. The mixture was filtered and the organic phase of the filtrate was collected. The organic phase was washed with brine (2 x 50 mL), dried over INfeSCL, and filtered once more. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 70/1) giving Compound Q20D. ¾ NMR (400 MHz, CDCh) d 7.40 (d, J = 8.0 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 7.03 (d, J= 8.4 Hz, 1H), 6.92 (s, 1H), 6.73 (d, J= 8.0 Hz, 1H), 6.26 (t, J= 4.0 Hz, 1H), 4.19-4.13 (m, 2H), 2.55 (t, J= 7.2 Hz, 2H), 2.37 (s, 3H), 2.33-1.30 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H).
[0340] Compound Q20: A vessel was charged with Compound Q20D (3.00 g, 8.92 mmol, 1.00 eq), MeOH (15.0 mL), THF (15.0 mL), and H20 (15.0 mL). LiOH*H20 (1.12 g,
26.7 mmol, 3.00 eq) was added. The reaction was stirred at 25°C for 6 h. The reaction was concentrated to dryness under vacuum. Ethyl acetate (25.0 mL) and H2O (25.0 mL) were added to the mixture. Next, aq HC1 (1.0 M) was added until the pH was 1-3. The system was extracted with EtOAc. Concentration of the organic phase gave a residue, which was purified by silica gel chromatography (S1O2, Dichloromethane/Methanol= 1/0 to 10/1). This gave Compound Q20. LCMS ESC calc’d for CiHLeCh : 309.1 [M+H+] ; found 309.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.40 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H), 7.03 (d, J= 8.0 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.74 (d, J= 8.0 Hz, 1H), 6.27 (t, J= 4.4 Hz, 1H), 2.63 (d, J= 8.0 Hz, 2H), 2.37 (s, 3H), 2.35-2.32 (m, 2H).
Compound 021 and Compound 022
Figure imgf000109_0001
[0341] Compound Q17A: A round-bottom flask was charged with 5-bromobenzofuran-
2-carboxylic acid (18.0 g, 74.6 mmol, 1.00 eq ) and THF (130 mL). The system was cooled to 0°C. Borane-dimethylsulfide (10.0 M in THF, 11.2 mL, 1.50 eq) was added dropwise at 0°C.
The reaction was warmed to 25°C and stirred for 16 h. The reaction was poured into aq HC1 (IN, 200.0 mL) and stirred for 30 min. The quenched reaction was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with sat. aq NaHCCL (30.0 mL) and brine (30.0 mL), dried over NaiSCL , and filtered. The filtrate was concentrated, giving Compound Q17A. 1H MR (400 MHz, CDCh) d 8.16 (d, J= 2.0 Hz, 1H), 7.39 (dd J= 2.0 Hz, J= 8.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 6.62 (s, 1H), 4.78 (s, 2H).
[0342] Compound Q21A: A round-bottom flask was charged with Compound Q17A
(16.0 g, 70.4 mmol, 1.00 eq) and DME (112 mL). MnCh (55.1 g, 634.2 mmol, 9.00 eq) was added. The reaction was stirred at 80°C for 15 hrs. The mixture was poured into EtOAc (100.0 mL) and stirred for 0.5 hr. The mixture was filtered, and the filtrate concentrated under reduced pressure, giving Compound Q21A. ¾ NMR (400 MHz, CDCh) d 9.88 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.74-7.72 (m, 2H).
[0343] Compound Q21B: A three-necked round-bottom flask was charged with triethyl-(2-phosphono)-propanoate (9.67 g, 40.6 mmol, 8.87 mL, 1.05 eq ) and THF (52.0 mL). The system was degassed and sparged with N2 (3x) then cooled to 0°C. NaOH (1.70 g, 42.5 mmol, 1.10 eq) was added. Reaction was stirred at 0°C for 0.5 hrs. Compound Q21A (8.70 g, 38.6 mmol, 1.00 eq) was added. Reaction was stirred at 20°C for 1 hr. The mixture was poured into sat. aq NaHCCb (50.0 mL). The system was extracted with EtOAc (50 mL, then 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaiSCL , and filtered. The filtrate was concentrated, giving Compound Q21B.
[0344] Compound Q21C: A vessel was charged with Compound Q21B (10.9 g, 35.2 mmol, 1.00 eq), THF (50.0 mL), and EtOAc (50.0 mL). Rh(PPh3)3Cl (1.96 g, 2.12 mmol, 0.06 eq) was added. The mixture was sparged with ¾ several times. The reaction was stirred at 25°C for 72 hrs and then concentrated under vacuum. Purification of the residue by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 20/1 to 10/1) provided Compound Q21C.
[0345] Compound Q21D: A vessel containing Compound Q21C (1.80 g, 5.78 mmol,
I .00 eq) was treated with Cy2NMe (14.0 mL). Pd-Sphos G2 (416.8 mg, 578 umol, 0.10 eq) was introduced. The system was degassed with N2 several times l-ethynyl-4-methylbenzene (1.34 g,
I I .5 mmol, 1.47 mL, 2.00 eq) was added, and the mixture was degassed and purged with N2 several times. The reaction was stirred at 80°C for 15 hrs. Water (100.0 mL) and EtOAc (100.0 mL) were added to the mixture. pH was adjusted to 5 with 0.5 N HC1. The mixture was extracted with EtOAc (100.0 mL, 50.0 mL). Combined organic phases were washed with aq. NH4CI (100.0 mL) and brine (100.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated, giving a residue that was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 20/1 ~ 10/l)followed by Prep. HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HC1)-ACN]; B%: 58%-88%, 20 min). This gave
Compound Q21D. ¾ NMR (400 MHz, DMSO-de) d 7.73 (s, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.38-7.44 (m, 3H), 7.22 (d, J= 8.4 Hz, 2H), 6.63 (s, 2H), 4.03-4.08 (m, 2H), 2.95-3.32 (m, 1H), 2.86-2.93 (m, 2H), 2.32 (s, 3H), 1.09-1.19 (s, 6H).
[0346] Compound Q21E: A vessel was charged with Compound Q21D (3.10 g, 8.95 mmol, 1.00 eq), MeOH (30.0 mL), THF (30.0 mL), and H20 (30.0 mL). NaOH (7.16 g, 178 mmol, 20.0 eq) was added. The reaction was stirred at 70°C for 0.5 hrs. The mixture was poured into water (50.0 mL) and EtOAc (50.0 mL). Aq HC1 (1 N) was added until the pH was 5. The system was extracted with EtOAc (50.0 mL, 20.0 mL). Combined organic layers were washed with sat. NH4CI (30.0 mL) and brine (30.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving Compound Q21E. LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 319.1 [M+H+]
Figure imgf000111_0001
[0347] Compound Q21 and Compound Q22: A solution of Compound Q21E (900 mg) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALPAK AD column (250mm x 50mm x 10 pm) with isocratic elution at 40% MeOH (doped with 0.1% ammonium hydroxide) in CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q21E. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed (differing from the preparative method): eluent was supercritical CO2 and MeOH (doped with 0.05%
isopropylamine) on a chiralcel AD-3 (5 pm, 0.46cm id x 5 cm length) column with gradient elution from 10-40% MeOH (doped with 0.05% isopropylamine). This provided Compound Q22 (first to elute on analytical method): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 319.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 7.73 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8Hz, 2H), 7.38 (d, J= 7.2 Hz, 1H), 7.23 (d, J= 8 Hz, 2H), 6.63(s, 1H), 3.06-3.11 (m, 1H), 2.77-2.87 (m, 2H), 2.33 (s, 3H), 1.13 (d, J= 6.4 Hz, 3H) and Compound Q21 (second to elute on analytical method): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 319.0 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 7.71 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.37 (d, J= 7.2 Hz, 1H), 7.22 (d, J= 8.0 Hz, 2H), 6.61 (s, 1H), 3.06-3.11 (m, 1H), 2.70-2.80 (m, 2H), 2.33 (s, 3H), 1.10 (d, J= 6.4 Hz, 3H). Compound 023 and Compound 024
Figure imgf000112_0001
[0348] Compound Q23B: A vessel was charged with Compound Q23A (20.0 g, 99.5 mmol, 1.00 eq), K2CO3 (13.7 g, 99.5 mmol, 1.00 eq), and EtOH (200 mL). The mixture was stirred at 25°C for 1 h. The system was cooled to 0 ~ 5°C. Addition of l-chloropropan-2-one (9.21 g, 99.5 mmol, 1.00 eq) was conducted in a dropwise manner. The reaction was stirred at 25°C for 10 min then heated to 80°C for 1 h. The mixture was poured onto ice (500 mL) and stirred for 0.5 h. The slurry was filtered, and the cake dried under reduced pressure, giving
Compound Q23B. LCMS ESI+ calc’d for CioH7Br02 : 239.0, 241.0 [M+H+] ; found 239.0, 240.9 [M+EE]. ¾ NMR (400 MHz, DMSO-de) d 8.06 (d, J= 1.6 Hz, 1H), 7.84 (s, 1H), 7.65- 7.73 (m, 2H), 2.56 (s, 3H).
[0349] Compound Q23C: A three-necked round-bottom flask was charged with triethylphosphonoacetate (9.60 g, 52.7 mmol, 7.62 mL, 1.05 eq) and THF (85.0 mL). The system was degassed and sparged with N2 (3x) and then cooled to 0°C. NaOH (2.21 g, 55.2 mmol, 1.10 eq) was added. Reaction was stirred at 0°C for 0.5 hrs. Compound Q23B (12.0 g, 50.2 mmol, 1.00 eq) was added. Reaction was stirred at 25°C for 1 hr. The reaction was poured into EtOAc (50 mL) and H2O (100 mL). The organic phase was collected and the aq phase extracted with EtOAc (2 x 50 mL). Combined organic layers were washed with sat. aq NaHC03 (50.0 mL) followed by brine (50.0 mL). The organic layer was dried over Na2S04 and filtered. The filtrate was concentrated, giving Compound Q23C. The product was found to be a mixture of E/Z isomers based on NMR data. ¾ NMR (400 MHz, CDCh) d 7.71-7.72 (m, 2H), 7.39-7.44 (m, 3H), 7.33-7.35 (m, 2H), 6.93 (s, 1H), 6.64 (s, 1H), 5.98 (s, 1H), 3.77 (s, 6H), 2.53 (s, 3H), 2.29 (s, 3H).
[0350] Compound Q23D: A vessel was charged with Compound Q23C (15.0 g, 50.8 mmol, 1.00 eq), THF (100.0 mL), EtOAc (100.0 mL), and Rh(PPh ) Cl (8.00 g, 8.65 mmol, 0.17 eq). The mixture was sparged with ¾ several times. The reaction was stirred at 25°C for 96 hrs at 50 psi of ¾. The reaction was filtered, and the cake was washed with EtOAc (50 mL) and THF (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting residues was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 30/1) and then triturated with Petroleum Ether: Ethyl Acetate (50: 1, v:v, 50 mL total). Filtration provided a filtrate that was concentrated under reduced pressure, giving Compound Q23D. LCMS ESC calc’d for Ci3Hi Br03 : 297.0, 299.0 [M+H+] ; found 297.0, 299.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.61 (d, J= 1.6 Hz, 1H), 7.32 (dd, J= 8.4 Hz, J= 1.6 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 6.37 (s, 1H), 3.69 (s, 3H), 3.48-3.54 (m, 1H), 2.81-2.86 (m, 1H), 2.54-2.62 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H).
[0351] Compound Q23E: A vessel containing Compound Q23D (2.70 g, 9.09 mmol,
I.00 eq) was treated with Cyi Me (17.0 mL). Pd-Sphos G2 (654.0 mg, 908 umol, 0.10 eq) was introduced. The system was degassed with N2 several times l-ethynyl-4-methylbenzene (1.34 g,
I I.5 mmol, 1.47 mL, 2.00 eq) was added, and the mixture was degassed and purged with N2 several times. The reaction was stirred at 80°C for 12 hrs. Water (100.0 mL) and EtOAc (100.0 mL) were added to the mixture. pH was adjusted to 5 with 1.0 N HC1. The mixture was extracted with EtOAc (200 mL). Combined organic phases were washed with brine (100.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated, giving a residue that was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 50/l)followed by Prep. HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (0.05% HC1)- ACN]; B%: 57%-87%, 20 min). This gave Compound Q23E. LCMS ESI+ calc’d for C22H2o03 : 333.1 [M+H+] ; found 333.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.67 (d, J= 0.8 Hz, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.36-7.41 (m, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.41 (s, 1H), 3.70 (s, 3H), 3.46-3.52 (m, 1H), 2.83-2.89 (m, 1H), 2.55-2.60 (m, 1H), 2.38 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H).
[0352] Compound Q23F: A vessel was charged with Compound Q23E (3.70 g, 11.1 mmol, 1.00 eq), MeOH (30.0 mL), THF (30.0 mL), and H20 (30.0 mL). NaOH (8.90 g, 222 mmol, 20.0 eq) was added. The reaction was stirred at 70°C for 1 h. The mixture was poured into water (50.0 mL) and EtOAc (50.0 mL). Aq HC1 (1 N) was added until the pH was 4. The system was extracted with EtOAc (50.0 mL, 20.0 mL, 20.0 mL). Combined organic layers were washed with brine (30.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, and the resulting material was triturated with Petroleum Ether (30.0 mL) for 30 min. Filtration gave a cake that was dried under reduced pressure, providing Compound Q23F. ¾ NMR (400 MHz, CDCb) d 12.31 (s, 1H), 7.74 (d, J= 1.2 Hz, 1H), 7.55 (d, J= 8.8 Hz, 1H), 7.38-7.45 (m, 3H), 7.23 (d, J= 8.0 Hz, 2H), 6.63 (s, 1H), 3.36-3.41 (m, 1H), 2.70-2.76 (m, 1H), 2.52-2.56 (m, 1H), 2.33 (s, 3H), 1.32 (d, J= 7.2 Hz, 3H).
Figure imgf000114_0001
[0353] Compound Q23 and Compound Q24: A solution of Compound Q23F (900 mg) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALPAK AD column (250mm x 50mm x 10 pm) column with isocratic elution at 27% MeOH (doped with 0.1% ammonium hydroxide) in CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q21E. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed (differing from the preparative method): eluent was supercritical CO2 and EtOH(doped with 0.05% isopropylamine) on a chiralcel AD-3 (3 pm, 0.46cm id x 10 cm length) column with gradient elution from 10- 40% EtOH(doped with 0.05% isopropylamine). This provided Compound Q23 (first to elute on analytical method): LCMS ESI calc’d for C21H18O3 : 317.1 [M-H ] ; found 317.1 [M-H ] ¾ NMR (400 MHz, Methanol-d4) d 7.65 (d, J= 1.2 Hz, 1H), 7.34-7.41 (m, 4H), 7.18 (d, J= 7.6 Hz, 2H), 6.52 (s, 1H), 3.41-3.50 (m, 1H), 2.77-2.83 (m, 1H), 2.52-2.58 (m, 1H), 2.35 (s, 3H), 1.40 (d, J= 7.2 Hz, 3H) and Compound Q24 (second to elute on analytical method): LCMS ESI+ calc’d for C21H18O3 : 317.1 [M-H ] ; found 317.0 [M-H ]. ¾ NMR (400 MHz, Methanol- d4) 5 7.65 (d, 7= 1.2 Hz, 1H), 7.36-7.41 (m, 4H), 7.18 (d, J= 8.0 Hz, 2H), 6.51 (s, 1H), 3.42- 3.48 (m, 1H), 2.78-2.84 (m, 1H), 2.53-2.59 (m, 1H), 2.35 (s, 3H), 1.40 (d, J= 6.8 Hz, 3H). Compound 025
Figure imgf000115_0001
[0354] Compound Q25A: To a solution of Compound Q4 (500 mg, 1.04 mmol, 1.0 eq.) in dry THF (4.18 mL) at -78°C under nitrogen atmosphere was added LiHMDS (1M in THF, 1.57 mL, 1.57 mmol, 1.5 eq.) dropwise, and the resulting solution was stirred at -78°C for lh. 2-(adamantan-l-yl)acetaldehyde (373 mg, 2.09 mmol, 2.0 eq.) was then added dropwise, and stirring was pursued at -78°C for another lh. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 0 to 20% EtOAC7//-Hex) afforded Compound Q25A as a 1 : 1 mixture of diastereoisomers. LCMS ESI+ calc’d for C44H48O5 : 657.4 [MALL] ; found: does not ionize.
[0355] Compound Q25B: To a solution of Compound Q25A (596 mg, 0.91 mmol, 1.0 eq.) in dry toluene (9.07 mL) under a nitrogen atmosphere was added CuBr (13 mg, 0.091 mmol, 0.1 eq.) followed by DCC (284 mg, 1.36 mmol, 1.5 eq.). The reaction was refluxed for 4h and then allowed to cool to room temperature. The reaction was filtered on a PTFE filter and volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography chromatography (0 to 20% EtOAc/nHex), affording Compound Q25B. LCMS ESI+ calc’d for C44H46O4 : 639.3 [M+H+] ; found: 639.3 [M+H+]
[0356] Compound Q25: To a solution of Compound Q25B (473 mg, 0.0.74 mmol, 1.0 eq.) in dry DCM (37 mL) under a nitrogen atmosphere at room temperature was added a 4N solution of HC1 in dioxane (3.7 mL, 14.8 mmol, 20 eq.). The reaction was stirred at room temperature for 5 minutes and volatiles were removed under reduced pressure. The residue was treated with a sat. aq. solution of NaHCCh (20 mL) and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSCh, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 to 60% EtOAc/nHex), affording Compound Q25. LCMS ESI+ calc’d for C25H32O4 : 397.2 [M+EC] ; found: 397.2 [M+H+] 1H NMR: (CDCh, 400 MHz): d 7.39 - 7.27 (m, 5H), 6.89 - 6.82 (m, 1H), 4.63 - 4.51 (m, 2H), 3.73 (dd, 7 = 34.4, 12.1 Hz, 2H), 3.59 (dd, 7 = 25.4, 10.0 Hz, 2H), 2.75 (qd, 7= 17.0, 1.4 Hz, 1H), 1.94 (m, 6H), 1.66 (dd, 7= 36.9, 12.1 Hz, 6H), 1.53 (s, 6H).
Compound 026
Figure imgf000116_0001
[0357] Compound Q26C: A solution of Compound Q26A (150.0 g) in TFAA: TfOH
(95:5, 1.2945 L) was heated to 65°C and stirred for 2.5 h. The reaction mixture was cooled to room temperature and concentrated at below 30°C to obtain crude Compound Q26B, to which was added crushed ice (300 g) followed by cold water (1.5 L, 10 Volumes relative to
Compound Q26A). The mixture was stirred for 30 min, filtered, and dried under vacuum for 30 min to afford Compound Q26C. ¾ NMR (300 MHz, CDCh) d 9.08 - 9.88 (m, broad, 2H), 3.50 (s, 1H), 2.56 (d, 7= 15.9 Hz, 1H), 2.41 (d, 7= 15.6 Hz, 1H), 1.14 - 1.09 (m, 9H), 1.03 (s, 9H).
[0358] Compound Q26D: To a solution of Compound Q26C (89 g) in acetic acid
(1260 mL) was added water (756 mL) and sulphuric acid (138 mL) at rt, the resulting reaction mixture was stirred at reflux for 6 h. The reaction mixture was cooled to rt and extracted with DCM (1 L). The DCM layer was washed with water (1 L), saturated sodium bi carbonate (500 mL) and water (1 L). The separated organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude Compound Q26D. ¾ NMR (400 MHz, CDCh) d 2.27 (s, 4H), 1.00 (s, 18H). [0359] Compound Q26E: A solution of Compound Q26D (57 g) in THF (230 mL) was taken in a round-bottom flask, cooled to -78°C, and Vinyl magnesium bromide (670 mL) was added dropwise at -78°C over a period of lh. The reaction mixture allowed to warm to room temperature and stirred for 3h under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (1 L) and extracted with diethyl ether (2 x 1.2 L).
The separated the organic layer was washed with brine (500 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford a crude Compound Q26E. ¾ NMR (400 MHz, DMSO-de) d 5.93 (dd, J= 17.4, 10.8 Hz, 1H), 5.24 (dd, J= 17.4,
2.4 Hz, 1H), 4.94 (dd, J= 10.8, 2.4 Hz, 1H), 3.85 (s, 1H), 1.58 - 1.33 (m, 4H), 0.94 - 0.86 (m, 18H).
[0360] Compound Q26F: To a solution of Compound Q26E (55.0 g) in DCM (1100 mL) was added PCC (239 g) at room temperature under nitrogen atmosphere and stirred at rt for 18 h. The reaction mixture was filtered through the celite pad and washed with DCM (1 L).
The filtrate was concentrated under reduced pressure and purified by flash column
chromatography using silica gel (100-200 mesh) eluted with 3% EtO Ac/hexane to obtain
Compound Q26F. ¾ NMR (400 MHz, CDCh) d 9.87 (d, J= 8 Hz, 1H), 5.96 (d, J= 8.4 Hz, 1H), 2.52 (s, 2H), 2.13 (s, 2H), 1.00 - 0.90 (m, 18H).
[0361] Compound Q26: To a stirred solution of Compound Q26F (16 g) in DCM(160 mL) was added 10% Pd/C (8 g) carefully and stirred under hydrogen balloon pressure at rt for 48 h. The reaction mixture was filtered through celite bed, washed with additional amount of DCM (500mL) and the filtrate was concentrated under vacuum at room temperature to afford a crude residue. The crude residue was purified by column chromatography using neutral alumina and eluted with 0-1% EtOAc/hexaneto obtain Compound Q26, which was immediately used in the next reaction. ¾ NMR (300 MHz, CDCh) d 9.75 (t, J= 2.4 Hz, 1H), 2.44 (dd, J= 5.6, 2.4 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.40 - 1.30 (m, 2H), 1.24 - 1.12 (m, 2H), 0.97 - 0.91 (m, 18H).
Compound 027
Figure imgf000118_0001
[0362] Compound Q27A: To a solution of Compound Q4 in dry THF at -78 °C under nitrogen atmosphere was added LiHMDS (1M in THF) dropwise over a period of 15 min and the resulting solution was stirred at -78 °C for 1 h. Then Compound Q26 in THF (2 mL) was then added dropwise at -78°C for 10 min and stirred at same temperature for another 1 h. The reaction mixture was quenched with a sat. aq. NH4CI solution (30 mL) and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with sat. aq. NaCl, dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography by using silica gel (100-200 mesh) and eluted with EtO Ac/Hexane to obtain Compound Q27A. ¾ NMR (300 MHz, DMSO-d6) d 11.99 - 11.93 (m, 1H), 7.48 - 7.07 (m, 20H), 4.92 - 4.68 (m, 1H), 4.53 - 4.42 (m, 2H), 3.78 - 3.71 (m, 1H), 3.68 - 3.51 (m, 2H), 3.14 - 2.93 (m, 2H), 2.20 - 2.14 (m, 1H), 2.09 - 1.90 (m, 2H), 1.68 - 1.54 (m, 2H), 1.27 - 1.17 (m, 3H), 1.15 - 1.00 (m, 3H), 1.00 - 0.69 (m, 18H).
[0363] Compound Q27B: To a solution of Compound Q27A (2g) in dry toluene (30 mL) under a nitrogen atmosphere was added CuBr (127 mg) followed by DCC (2.134 g). The reaction stirred at reflux for 48 h. The reaction mixture was allowed to cool to room
temperature, filtered, and washed with toluene (30 mL). The filtrate was evaporated under reduced pressure and was purified by flash column chromatography by using silica gel (100-200 mesh) and eluted with 3% EtO Ac/Hexane to afford Compound Q27B. ¾NMR (400 MHz,
CDCh) d 7.49 - 7.35 (m, 6H), 7.34 - 7.26 (m, 8H), 7.25 - 7.16 (m, 6H), 6.83 - 6.76 (m, 1H), 4.56 - 4.47 (m, 2H), 3.58 (s, 2H), 3.32 - 3.27 (m, 1H), 3.20 - 3.15 (m, 1H), 2.75 - 2.67 (m, 1H), 2.63 - 2.55 (m, 1H), 2.19 - 2.11 (m, 2H), 1.78 - 1.69 (m, 1H), 1.30 - 1.14 (m, 4H), 0.96 - 0.77 (m,
18H).
[0364] Compound Q27: To a solution of Compound Q27B (750 mg, 1.14 mmol, 1.0 eq.) in anhydrous dichloromethane (57 mL) under a nitrogen atmosphere was added a 4M solution of HC1 in dioxane (5.7 mL, 22.8 mmol, 20.0 eq.) at room temperature. The resulting solution was stirred at room temperature for 7 min and volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and a sat. aq. solution of NaHCCL (20 mL) was added. The layers were separated and the aqueous layer was washed with brine, dried over MgSCL, filtered and concentrated. Purification by silica gel chromatography (0 to 20% Acetone/nHexane) afforded Compound Q27. LCMS ESI+ calc’d for C26H40O4 : 417.6 [M+H+] ; found 417.3 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.37 - 7.27 (m, 4H), 6.82 - 6.76 (m, 1H), 4.62 - 4.50 (m, 2H), 3.72 (dd, J= 36.2, 12.0 Hz, 2H), 3.57 (dd, J= 28.0, 10.0 Hz, 2H), 2.83 - 2.65 (m, 2H), 2.24 - 2.16 (m, 2H), 1.97 (s, broad, 1H), 1.80 - 1.69 (m, 1H), 1.31 - 1.15 (m, 4H), 0.90 (d, J= 1.2 Hz, 18H).
Compound 028
Figure imgf000119_0001
[0365] Compound Q28: A vessel was charged with THF (100 mL) and purged with N2 for 5 min. The system was cooled to -78°C, and LDA (2 M, 69.3 mL, 1.00 eq ) was added dropwise to the mixture. In a dropwise manner, Compound Q28A (20.0 g, 138 mmol, 1.00 eq) was added to the mixture. The reaction was stirred at -78°C for 1 h. Propargyl bromide (18.1 g, 152 mmol, 1.10 eq) was added to the mixture. Reaction was stirred at 15°C for 16 h. After cooling to 0°C, dropwise addition of aq. NH4CI (50.0 mL) was done to quench the reaction. The mixture was extracted with EtOAc (50.0 mL). The organic phase was washed with brine (50.0 mL), dried over NaiSCL, and filtered. The organic phase was concentrated under reduced pressure. The crude product was distilled in vacuum (oil bath: 125°C, distilling head: 90°C, water pump). This gave Compound Q28. 1H NMR (400 MHz, CDCb) d 4.15 (q, J= 8.0 Hz, 2H), 2.50 (d, J= 4.0 Hz, 2H), 1.93 (s, 1H), 1.70 (q, J= 8.0 Hz, 4H), 1.25 (t, J= 8.0 Hz, 3H), 0.81 (t, J= 8.0 Hz, 6H).
Figure imgf000120_0001
[0366] Compound Q29B: A vessel was charged with Compound Q29A (23.0 g, 76.9 mmol, 1.00 eq) in DMF (161 mL). Pd(PPh3)2Ch (540 mg, 0.769 mmol, 0.01 eq) and Cul (293 mg, 1.54 mmol, 0.02 eq) were added to the mixture. The mixture was purged with N2 for 5 min. Compound Q28 (14.0 g, 76.9 mmol, 1.00 eq) and TEA (23.3 g, 230 mmol, 32.1 mL, 3.00 eq) were added to the mixture. The system was purged with N2 (3x). The reaction was stirred at 60°C for 14 h. Water (100 mL) was added to the mixture. The organic phase was washed with brine (100 mL x 2), dried over INfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 0/1), giving Compound Q29B. LCMS ESI+ calc’d for CnfLiBrCL : 353.1, 355.1 [M+H+] ; found 353.1, 355.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.60 (s, 1H), 7.29 (t, J= 8.0 Hz,
1H), 7.24 (s, 1H), 6.37 (s, 1H), 4.22-4.14 (m, 2H), 3.07 (s, 2H), 1.66-1.59 (m, 2H), 1.28-1.25 (m, 3H), 0.92-0.88 (m, 6H).
[0367] Compound Q29C: A vessel was charged with Compound Q29B (10.0 g, 28.3 mmol, 1.00 eq) in ACN (70.0 mL). Pd(PPh3)2Ch (1.99 g, 2.83 mmol, 0.10 eq) was added to the mixture. The mixture was purged with N2 for 10 min. l-ethynyl-4-m ethylbenzene (9.86 g, 84.9 mmol, 10.7 mL, 3.00 eq) and Cy2NMe (16.5 g, 84.9 mmol, 3.00 eq) were added to the mixture. The reaction was stirred at 80°C for 4.5 h. The reaction was filtered; EtOAc (50.0 mL) and water (50.0 mL) were added to the filtrate. The organic phase was washed with brine (50.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 0/1), giving Compound Q29C. LCMS ESI+ calc’d for C26H28O3 : 389.2 [M+H+] ; found 389.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.69 (s, 1H), 7.67 (d, 7= 1.2 Hz, 2H), 7.45-7.36 (m,
2H), 7.16 (d, J= 7.6 Hz, 2H), 6.41 (s, 1H), 4.23-4.14 (m, 2H), 3.09 (s, 2H), 2.38 (s, 3H), 1.65 (q, J= 8.0 Hz, 4H), 1.29 (t, J= 6.4 Hz, 3H), 0.92 (t, J= 8.0 Hz, 6H).
[0368] Compound Q29: A vessel was charged with Compound Q29C (2.00 g, 5.15 mmol, 1.00 eq), NaOH (4.12 g, 102 mmol, 20.0 eq), THF (8.00 mL), H20 (2.00 mL), and MeOH (2.00 mL). The reaction was stirred at 70°C for 12 h. The mixture was concentrated under reduced pressure. Dioxane (8.00 mL) was added to the mixture, and the mixture was heated at 110°C for 12 h with stirring. Aq HC1 (6N, 20.0 mL) was added slowly until the pH was 3. The organic phase was collected, washed with brine (20.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 1/0 to 0/1). This gave Compound Q29. LCMS ESI+ calc’d for C24H2403 : 361.2 [M+H+] ; found 361.1 [M+H+] 1H NMR (400 MHz, DMSO-de) d 12.45 (s, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.44 (d, J= 8.0 Hz, 1H), 7.39 (d, 7= 1.6 Hz, 1H), 6.65 (s, 1H), 3.02 (s, 2H), 2.33 (s, 3H), 1.57-1.48 (m, 4H), 0.87 (t, J= 1.6 Hz, 6H).
Compound 030
Figure imgf000121_0001
[0369] Compound Q30: A vessel was charged with LDA (104.9 g, 2 M, 490 mL, 1.26 eq) in THF (700 mL). Compound Q30A (100.0 g, 780 mmol, 107 mL, 1.00 eq ) in THF (700 mL) was added to the mixture dropwise at -70°C over a period of 1.5 h. Propargyl bromide (116.0 g, 780 mmol, 84.0 mL, 1.00 eq) in THF (700 mL) was added to the mixture dropwise at - 70°C over a period of 2.5 h. Addition of sat. aq NH4C1 (600 mL) to the mixture was conducted to quench the reaction. The mixture was extracted with MTBE (3 x 600 mL). Combined organic extracts were washed with brine (3 x 100 mL), dried over Na2S04, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (100 ~ 200 mesh, petroleum ether: ethyl acetate = 20: 1 to 0: 1) giving Compound Q30. ¾NMR (400 MHz, CDCh) d 4.19-4.07 (m, 3H), 2.60 (p, J= 2.4 Hz, 2H), 2.42 (p, J= 12 Hz 2H), 2.06-2.01 (m,
3H), 1.95-1.92 (m, 2H), 1.27-1.21 (m, 4H), 0.85-0.80 (m, 1H). Compound 031
Figure imgf000122_0001
[0370] Compound Q31A: A vessel was charged with Compound Q29A (39.5 g, 132 mmol, 1.10 eq) in DMF (140 mL). Pd(PPh3)2Ch (4.22 g, 6.02 mmol, 0.05 eq) and Cul (1.15 g, 6.02 mmol, 0.05 eq ), TEA (23.3 g, 230 mmol, 32.1 mL, 3.00 eq), and Compound Q30 (20.0 g, 120 mmol, 1.00 eq) were added to the mixture. The mixture was purged with N2 for 5 min. The system was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The reaction was filtered. Water (100 mL) was added to the filtrate, and the reaction was extracted with EtOAc (3 x 200 mL). Combined organic phase was washed with brine (200 mL), dried over lNfeSCri, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 0/1), giving Compound Q31A. LCMS ESC calc’d for CieHivBrCri : 337.1, 339.1 [M+H+] ; found 337.1, 339.1 [M+H+]
[0371] Compound Q31B: A vessel was charged with Compound Q31A (14.0 g, 41.5 mmol, 1.00 eq) in ACN (90.0 mL). The mixture was purged with N2 for 30 min. Pd-Sphos G2 (2.99 g, 4.15 mmol, 0.10 eq), l-ethynyl-4-methylbenzene (9.65 g, 83.0 mmol, 10.5 mL, 2.00 eq) and Cy2NMe (16.2 g, 83.0 mmol, 17.6 mL, 2.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred 80°C for 4 h. The reaction was filtered; water (50.0 mL) was added to the filtrate, and the system was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 0/1), giving Compound Q31B. ¾ NMR (400 MHz, CDCh) d 7.65 (s, 1H), 7.41 (d, J= 8.0 Hz, 1H), 6.37 (s, 1H), 4.20-4.14 (m, 2H), 3.27 (s, 2H), 2.55-2.52 (m, 2H), 2.14-2.12 (m, 2H), 1.98-1.94 (m, 2H), 1.22 (t, J= 7.2 Hz, 3H).
[0372] Compound Q31: A vessel was charged with Compound Q31B (4.00 g, 10.7 mmol, 1.00 eq), THF (15.0 mL), MeOH (5.00 mL), and H20 (8.00 mL). NaOH (8.59 g, 214 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 5 h. Aq HC1 was added until the pH was 1. The system was extracted with EtOAc (3 x 10 mL). Combined organic phases were collected, washed with brine (10.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (Si02, THF). This gave Compound Q31. LCMS ESI+ calc’d for C23H2o03 : 345.1 [M+H+] ; found: does not ionize. ¾ NMR (400 MHz, DMSO-de) d 12.4 (s, 1H), 7.74 (s, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8.0 Hz, 2H), 7.38 (d, J= 8.4 Hz, 1H), 7.22 (d, J= 8.4 Hz, 2H), 6.55 (s, 1H), 3.24 (s, 1H), 2.39-2.33 (m, 5H), 2.06-2.04 (m, 2H), 1.95-1.85 (m, 2H).
Compound 032
Figure imgf000123_0001
[0373] Compound Q32B: A vessel was charged with EtOH (700 mL). Sodium Metal
(22.4 g, 975 mmol, 23.1 mL (in molten form), 1.00 equiv) was carefully added to the mixture at 0°C. The reaction was stirred at 0°C for 1 h. The solution was warmed to 60°C. Diethylmalonate (156.1 g, 975 mmol, 147 mL, 1.00 eq ) was added to the mixture. After 1 h, Compound Q32A (100.0 g, 975 mmol, 109 mL, 1.00 eq) was added to the mixture. The reaction was stirred at 60°C for 14 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with 6 N HC1 slowly until the pH was 1. The mixture was extracted with EtOAc (3 x 300 mL). Combined organic phases were washed with brine (300 mL), dried over Na2S04 , filtered, and concentrated. Purification by vacuum distillation (with oil pump, distillation head: 90-110°C, oil bath: 120-145°C) provided Compound Q32B. ¾ NMR (400 MHz, CDCh) 5 4.15-4.10 (m, 4H), 3.36 (s, 1H), 2.12 (s, 1H), 1.37 (s, 6H), 1.19 (t, 7= 7.6 Hz, 6H).
[0374] Compound Q32: A vessel was charged with Compound Q32B (85.0 g, 375 mmol, 1.00 eq) in DMSO (550 mL). H2O (16.9 g, 939 mmol, 16.9 mL, 2.50 eq) was added to the mixture. NaCl (65.8 g, 1.13 mol, 3.00 eq) was added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 150°C for 3 days. Extraction with EtOAc (500 mL) gave an organic phase that was then washed with brine (3 x 500 mL), dried over Na2SC>4, and filtered. This gave Compound Q32. ¾ NMR (400 MHz, CDCh) d 4.09-3.39 (m, 4H), 2.39 (s, 1H), 2.15 (s, 1H), 1.30 (s, 6H), 1.22 (t, 7= 8.1 Hz, 3H).
Compound 033
Figure imgf000124_0001
[0375] Compound Q33A: A vessel was charged with Compound Q32 (25.0 g, 162 mmol, 1.00 eq) in DMF (150 mL). The reaction was purged with N2 for 30 min. Pd(PPh3)2Ch (1.14 g, 1.62 mmol, 0.01 eq), Cul (617 mg, 3.24 mmol, 0.02 eq), Compound Q29A (58.1 g, 194 mmol, 1.20 eq) , and TEA (32.8 g, 324 mmol, 45.1 mL, 2.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The reaction was filtered. Water (100 mL) was added to the fitlrate, and the reaction was extracted with EtOAc (3 x 150 mL). Combined organic phase was washed with brine (100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), giving Compound Q33A. ¾ NMR (400 MHz, CDCh) d 7.58 (s, 1H), 7.27 (d, J = 4.0 Hz, 2H), 6.34 (s, 1H), 4.01-3.96 (m, 2H), 2.67 (s, 2H), 1.45 (s, 6H), 1.05 (t, J = 7.2 Hz, 3H).
[0376] Compound Q33B: A vessel was charged with Compound Q33A (10.0 g, 30.7 mmol, 1.00 eq) in ACN (70.0 mL). The mixture was purged with N2 for 30 min. Pd-Sphos G2 (2.22 g, 3.08 mmol, 0.10 eq), Cy2NMe (12.0 g, 61.5 mmol, 13.0 mL, 2.00 eq) and l-ethynyl-4- methylbenzene (4.29 g, 36.9 mmol, 4.68 mL, 1.20 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for 4.5 h. The reaction was filtered; water (50.0 mL) was added to the filtrate, and the system was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 tol/1), giving Compound Q33B. LCMS ESI+ calc’d for C24H24O3 : 361.2 [M+H+] ; found 361.2 [M+H+]
[0377] Compound Q33: A vessel was charged with Compound Q33B (2.00 g, 5.55 mmol, 1.00 eq), THF (5.00 mL), MeOH (5.00 mL) and H20 (4.00 mL). NaOH (4.44 g, 110 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 60°C for 5 h. Aq HC1 (6N) was added until the pH was about 3. The system was extracted with EtOAc (3 x 10 mL).
Combined organic phases were collected, washed with brine (10.0 mL), dried over Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (S1O2, THF). This gave Compound Q33. LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found: 333.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 9.88 (s, 1H), 7.69 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.40 (d, J= 6.8 Hz, 1H), 7.28 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.44 (s, 1H), 2.78 (s, 2H), 2.39 (s, 3H), 1.53 (s, 6H).
Compound 034
Figure imgf000125_0001
[0378] Compound Q34: A vessel was charged with LDA (2 M, 196 mL, 1.40 eq) in
THF (60 mL) at -70°C under N2. Compound Q34A (40.0 g, 281 mmol, 1.00 eq) in THF (60 mL) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1.5 h. Compound Q34B (59.1 g, 309 mmol, 50.5 mL, 1.10 eq) in THF (60 mL) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 2.5 h. Addition of sat. aq NH4CI to the mixture was conducted to quench the reaction; the final pH was about 8. The mixture was extracted with EtOAc (3 x 150 mL). Combined organic extracts were washed with brine (150 mL), dried over Na2S04, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), giving Compound Q34C. ¾ NMR (400 MHz, CDCb) d 2.69 (s, 2H), 1.43 (s, 9H), 1.12-1.09 (m, 2H), 0.92-0.89 (m, 2H), 0.13 (s, 9H).
[0379] Compound Q34: A vessel was charged with Compound Q34C (8.00 g, 31.6 mmol, 1.00 eq ) in MeOH (40.0 mL). K2CO3 (13.1 g, 95.0 mmol, 3.00 eq ) was added to the mixture. Reaction was stirred at 25°C for 2 h. H2O was added (50.0 mL) to the mixture. The system was extracted with EtOAc (3 x 50 mL). Combined organic extracts were washed with brine (50 mL), dried over INfeSCL, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), giving Compound Q34. ¾NMR (400 MHz, CDCh) d ): 2.63 (s, 2H), 2.02 (s, 1H), 1.42 (s, 9H), 1.13-1.12 (m, 2H), 0.90-0.89 (m, 2H).
Compound 035
Figure imgf000126_0001
[0380] Compound Q35A: A vessel was charged with Compound Q29A (9.12 g, 30.5 mmol, 1.10 eq) in DMF (35 mL). The mixture was purged with N2 for 30 min. Pd(PPh3)2Ch (1.95 g, 2.77 mmol, 0.10 eq), Cul (528 mg, 2.77 mmol, 0.10 eq), TEA (5.61 g, 55.4 mmol, 7.72 mL, 2.00 eq), and Compound Q34 (5.00 g, 27.7 mmol, 1.00 eq) were added to the mixture. The mixture was purged with N2 (3x). Reaction was stirred at 60°C for 15.5 h. The reaction was filtered. Water (30 mL) was added to the filtrate, and the reaction was extracted with EtOAc (3 x 30 mL). Combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate = 100: 1 to 1 : 1), giving Compound Q35A.
[0381] Compound Q35B: A vessel was charged with Compound Q35A (4.70 g, 13.3 mmol, 1.00 eq) in ACN (30.0 mL). The mixture was purged with N2 for 30 min. Pd-Sphos G2 (964.2 mg, 1.34 mmol, 0.10 eq), CyiNMe (5.23 g, 26.7 mmol, 5.68 mL, 2.00 eq), and 1-ethynyl- 4-methylbenzene (2.02 g, 17.4 mmol, 2.21 mL, 1.30 eq) were added to the mixture. The reaction was stirred at 80°C for 4.5 h. The reaction was filtered; water (15.0 mL) was added to the filtrate, and the system was extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (15 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate = 100: 1 to 1 : 1), giving Compound Q35B. ¾ NMR (400 MHz, CDCb) d 7.67 (s, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 4.0 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.45 (s, 1H), 3.05 (s, 2H), 2.37 (s, 3H), 1.39 (s, 3H), 1.29-1.28 (m, 2H), 0.89-0.87 (m, 2H).
[0382] Compound Q35: A vessel was charged with Compound Q35B (1.30 g, 3.36 mmol, 1.00 eq), and DCM (9.00 mL). BCh (1 M, 33.6 mL, 10.0 eq) was added to the mixture at -70°C. Reaction was stirred at 25°C for 5 h. The reaction was quenched with MeOH (9.0 mL). The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 250*50mm* 10 um;mobile phase: [water(0.1%TFA)- ACN];B%: 55%-85%,20min), giving Compound Q35. LCMS ESI+ calc’d for C22H18O3 : 331.1 [M+H+] ; found 331.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.28 (s, 1H), 7.75 (s, 1H), 7.54 (d, J= 7.6 Hz, 4H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 7.6 Hz, 4H), 7.24 (d, J= 8.0 Hz, 2H), 6.62 (s, 1H), 3.06 (s, 2H), 2.34 (s, 3H), 1.22-1.20 (m, 2H), 0.97-0.94 (m, 2H).
Compound 036
Figure imgf000127_0001
[0383] Compound Q36: A vessel was charged with Compound Q36A (20.0 g, 156 mmol, 1.00 eq) in THF (140 mL). The reaction was cooled to -70°C by using a dry ice-EtOH bath. LDA (2.00 M, 101 mL, 1.30 eq) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1 h. Propargyl bromide (25.5 g, 172 mmol, 18.5 mL, 1.10 eq) in THF (130 mL) was added to the mixture dropwise at -70°C. Reaction was stirred at -70-20°C for 12 h. Reaction was poured into sat. aq NH4CI (500 mL) to quench the reaction. The mixture was treated with brine (700 mL) and extracted with EtOAc (300 mL, 100 mL, 100 mL). Combined organic extracts were washed with brine (3 x 300 mL), dried over NaiSCL, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (100-200 mesh, petrol ether/ethyl acetate = 100/1 to 0/1), giving Compound Q36. ¾ NMR (400 MHz, CDCb) d 3.70 (s, 3H), 2.50 (d, J= 2.4 Hz, 2H), 2.10-2.08 (m, 2H), 1.94 (t, J= 2.8 Hz, 1H), 1.71-1.68 (m, 6H).
Figure imgf000128_0001
[0384] Compound Q37A: A vessel was charged with Compound Q36 (7.58 g, 45.6 mmol, 1.00 eq) in DMF (105 mL). Pd(PPh3)2Ch (1.60 g, 2.28 mmol, 0.05 eq ), Cul (434.4 mg, 2.28 mmol, 0.05 eq ), TEA (13.8 g, 136 mmol, 19.0 mL, 3.00 eq) and Compound Q29A (15.0 g, 50.1 mmol, 1.10 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 14.5 h. The reaction was filtered. Water (150 mL) was added to the filtrate, and the reaction was extracted with EtOAc (200 mL). Combined organic phase was washed with sat. aq NH4CI (3 x 200 mL), dried over INfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 30/1), giving Compound Q37A. 'H NMR (400 MHz, CDCb) d 7.60 (d, J= 2.0 Hz, 1H), 7.31 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.26 (d, J= 9.6 Hz, 1H), 6.35 (d, J= 0.4 Hz, 1H), 3.70 (s, 3H), 3.11 (s, 2H), 2.19-2.12 (m, 2H), 1.72-1.68 (m, 6H).
[0385] Compound Q37B: A vessel was charged with Compound Q37A (8.00 g, 23.7 mmol, 1.00 eq) in ACN (56.0 mL). The mixture was purged with N2 for 30 min. Cy2NMe (9.27 g, 47.4 mmol, 10.0 mL, 2.00 eq) and l-ethynyl-4-methylbenzene (5.51 g, 47.4 mmol, 6.02 mL, 2.00 eq) were added to the mixture. Pd-Sphos G2 (1.71 g, 2.37 mmol, 0.10 eq) was introduced. The reaction was stirred at 80°C for 5 h. The reaction was filtered; water (100 mL) was added to the filtrate, and the system was extracted with EtOAc (100 mL). The organic phases were washed with sat. aq NH4CI (3 x lOOmL), brine (50.0 mL), dried over NaiSCri, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 30/1) and triturated with
Petroleum ether/Ethyl acetate (5: 1, v:v, 20 mL total). The system was filtered, and the cake was dried under reduced pressure, giving Compound Q37B. LCMS ESI+ calc’d for C25H24O3 : 373.2 [M+EC] ; found 373.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (d, J= 1.2 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.8 Hz, 7= 1.6 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 6.39 (s, 1H), 3.71 (s, 3H), 3.12 (s, 2H), 2.38 (s, 3H), 2.19-2.16 (m, 2H), 1.76-1.71 (m, 6H).
[0386] Compound Q37: A vessel was charged with Compound Q37B (2.30 g, 6.18 mmol, 1.00 eq), THF (15.0 mL), MeOH (8.00 mL), and H20 (10.00 mL). NaOH (4.94 g, 123 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 5 h. H2O (20 mL) and ethyl acetate (30 mL) were added. Aq HC1 (6N) was added until the pH of the aq phase was about 3. The organic phase was collected, washed with brine (2 x 30.0 mL), dried over INfeSCL, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 0/1). This gave Compound Q37. LCMS ESP calc’d for C24H22O3 : 357.2 [M-H ] ; found: 357.1 [M-H ]. ¾ NMR (400 MHz, DMSO-de) d 12.36 (s, J = 8.0 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.38 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.23 (d, J= 8.4 Hz, 2H), 6.59 (s, 1H), 3.10 (s, 2H), 2.33 (s, 3H), 2.04-1.98 (m, 2H), 1.64-1.62 (m, 6H).
Compound 038
Figure imgf000129_0001
[0387] Compound Q38: A vessel was charged with Compound Q38A (20.0 g, 140 mmol, 20.1 mL, 1.00 eq) in THF (140 mL). The reaction was purged several times with N2. The reaction was cooled to -70°C. LDA (2 M, 88.6 mL, 1.26 eq) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1 h. Propargyl bromide (25.1 g, 168 mmol, 18.1 mL, 80% in toluene, 1.20 eq) was added to the mixture dropwise at -70°C. Reaction was stirred at 20°C for 12 h. Reaction was treated slowly with sat. aq NH4CI (100 mL) to quench the reaction. The mixture was extracted with EtOAc (3 x 50 mL). Combined organic extracts were washed with H2O (50.0 mL), brine (50 mL), dried over INfeSCri, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (SiCh, 100-200 mesh, Petroleum ether/Ethyl acetate = 100/1 to 30/1), giving Compound Q38. 'H NMR (400 MHz, CDCb) d 3.71 (s, 3H), 2.40 (d, J= 2.8 Hz, 2H), 2.05-2.09 (m, 2H), 2.00 (d, J= 2.8 Hz, 1H), 1.56 (m, 3H), 1.43 (m, 4H), 1.24-1.27 (m, 2H).
Figure imgf000130_0001
[0388] Compound Q39A: A vessel was charged with Compound Q29A (15.0 g, 50.1 mmol, 1.10 eq ) in DMF (100 mL). Compound Q38 (8.22 g, 45.6 mmol, 1.00 eq), Cul (434.0 mg, 2.28 mmol, 0.05 eq ), Pd(PPh3)2Cl2 (1.60 g, 2.28 mmol, 0.05 eq ), and TEA (13.8 g, 136 mmol, 19.0 mL, 3.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 16 h. The mixture was poured onto H2O (200 mL) and extracted with EtOAc (4 x 50.0 mL). Combined organic layers were washed with sat.MLCl (4 x 20.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (S1O2, 100-200 mesh, Petroleum ether/Ethyl acetate = 50/1 to 10/1), giving Compound Q39A.
[0389] Compound Q39B: A vessel was charged with Compound Q39A (8.00 g, 22.7 mmol, 1.00 eq) in ACN (50.0 mL). The mixture was purged with N2 for 30 min. l-ethynyl-4- methylbenzene (5.29 g, 45.5 mmol, 5.78 mL, 2.00 eq) , Pd-Sphos G2 (1.64 g, 2.28 mmol, 0.10 eq ), and Cy2NMe (8.90 g, 45.5 mmol, 9.66 mL, 2.00 eq) were added. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for 4 h. More l-ethynyl-4-methylbenzene (5.29 g,
45.5 mmol, 5.78 mL, 2.00 eq) and Pd-Sphos G2 (820.6 mg, 1.14 mmol, 0.05 eq) were added.
The mixture was purged with N2 (3x). The reaction was stirred at 80°C for another 4 h. The reaction was poured into water (150 mL), and the system was extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, 100-200 mesh, Petroluem ether/Ethyl acetate = 1/0 to 20/1 and triturated with Petroleum ether. The system was filtered, and the cake was dried under reduced pressure, giving Compound Q39B.
[0390] Compound Q39: A vessel was charged with Compound Q39B (2.00 g, 5.17 mmol, 1.00 eq ), THF (7.0 mL), MeOH (3.00 mL), and H20 (4.00 mL). NaOH (4.14 g, 103 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 12 h. EtOH (10.0 mL) was added. The reaction was stirred at 90°C for 4 h. The reaction was concentrated under reduced pressure to remove most of the solvent. Aq HC1 (6N) was added until the pH of the aq phase was about 3. The system was extracted with EtOAc (3 x 10 mL). The combined organic phases were collected, washed with brine (10.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column
chromatography (Si02, pure EtOAc). This gave Compound Q39. LCMS ESP calc’d for C25H2403 : 371.2 [M-H ] ; found: 371.0 [M-H ]. ¾NMR (400 MHz, DMSO-de) d 12.41 (s, 1H), 7.75 (d, J= 1.2 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8.0 Hz, 2H), 7.38 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.23 (d, J= 8.0 Hz, 2H), 6.60 (s, 1H), 2.97 (s, 2H), 2.33 (s, 3H), 1.95-1.98 (m, 2H), 1.48-1.56 (m, 3H), 1.15-1.32 (m, 5H).
Compound 040
Figure imgf000131_0001
[0391] Compound Q40: A vessel was charged with LDA (2 M, 473 mL, 1.10 eq) in
THF (700 mL). The system was cooled to -70°C. Compound Q40A ((100 g, 860 mmol, 114 mL, 1.00 eq) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1 h. Propargyl bromide (166 g, 1.12 mol, 120 mL, 80.0% purity, 1.30 eq) was added to the mixture dropwise at -70°C. Reaction was stirred at -70°C for 2.5 h, then warmed to 20°C and stirred for 12 h. Petroleum ether (2 L) and H20 (500 mL) were added to the reaction. Reaction was washed with brine (500 mL). The organic phase was dried over Na2S04, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (Si02, Petroleum ether/Ethyl acetate=10/l), giving Compound Q40. 'H NMR (400 MHz, CDCh) d 4.17-4.08 (m, 2H), 2.48-2.46 (m, 2H), 2.01-1.95 (m, 1H), 1.68-1.67 (m, 2H), 1.23 (t, J= 7.6 Hz, 3H), 0.90 (t, J= 7.6 Hz, 3H).
Figure imgf000132_0001
[0392] Compound Q41A: A vessel was charged with Compound Q40 (20.0 g, 129 mmol, 1.00 eq ) in DMF (140 mL). The mixture was purged with N2 (3x). Compound Q29A (42.6 g, 142 mmol, 1.10 eq), Cul (1.24 g, 6.48 mmol, 0.05 eq), Pd(PPh3)2Cl2 (4.55 g, 6.48 mmol, 0.05 eq), and TEA (39.3 g, 389 mmol, 54.1 mL, 3.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The mixture was poured onto H2O (500 mL) and Petroleum Ether (1 L). The organic layer was washed with brine (500 mL), dried over Na2S04, and filtered. The filtrate was concentrated, and the residue was purified by column (S1O2, Petroleum ether/Ethyl acetate=10/l), giving Compound Q41A. 'H NMR (400 MHz, CDCh) d 7.59 (s, 1H), 7.31-7.24 (m, 2H), 6.36 (s, 1H), 4.16-4.10 (m, 2H), 3.13-3.08 (m, 1H), 2.93-2.87 (m, 1H), 1.72-1.60 (m, 2H), 1.19 (t, J= 7.2 Hz, 3H), 0.95 (t, J = 7.6 Hz, 3H).
[0393] Compound Q41B: A vessel was charged with Compound Q41A (10.0 g, 30.7 mmol, 1.00 eq) in ACN (65.0 mL). The mixture was purged with N2 for 30 min. l-ethynyl-4- methylbenzene (7.14 g, 61.5 mmol, 7.80 mL, 2.00 eq), Pd-Sphos G2 (2.22 g, 3.08 mmol, 0.10 eq), and Cy2NMe (12.0 g, 61.5 mmol, 13.0 mL, 2.00 eq) were added. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for 4 h. The reaction was poured into water (200 mL), and the system was extracted with EtOAc (800 mL). The organic phase was washed with brine (200 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, 100-200 mesh, Petroluem ether/Ethyl acetate = 1/0 to 20/1), giving Compound Q41B. ¾ NMR (400 MHz, CDCb) d 7.66 (s, 1H), 7.45-7.35 (m, 4H), 7.16 (d, J= 8.0 Hz, 2H), 6.42 (s, 1H), 4.14 (t, J= 7.2 Hz, 2H), 3.10- 3.13 (m, 1H), 2.95-2.90 (m, 1H), 2.83-2.81 (m, 1H), 2.38 (s, 3H), 1.74-1.65 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.97 (t, J= 7.6 Hz, 3H).
[0394] Compound Q41: A vessel was charged with Compound Q41B (3.00 g, 8.32 mmol, 1.00 eq), THF (11.0 mL), MeOH (4.00 mL), and H20 (6.00 mL). NaOH (6.66 g, 166 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 12 h. Aq HC1 (6N) was added until the pH of the aq phase was about 3. The system was extracted with EtOAc (500 mL). The organic phase was washed with brine (200 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l). This gave Compound Q41. 'H NMR (400 MHz, DMSO-de) d 12.36 (s, broad, 1H), 7.74 (d, J= 1.2 Hz, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.40-7.43 (m, 3H), 7.23 (d, J= 8.0 Hz, 2H), 6.63 (s, 1H), 3.04-3.02 (m, 1H), 2.95-2.93 (m, 1H), 2.69-2.67 (m, 1H), 2.50-2.33 (s, 3H), 1.60-1.56 (m, 2H), 0.90 (t, J= 7.6 Hz, 3H).
Compound 042 and Compound 043
Figure imgf000133_0001
[0395] Compound Q42 and Compound Q43: A solution of Compound Q41 (900 mg) was subjected to preparative chiral SFC. Two peaks were obtained, corresponding to the two enantiomers of Compound Q41. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed: eluent was supercritical C02 and MeOH(doped with 0.05% isopropylamine) on a chiralcel AD-3 (3 pm, 0.46cm id x 15 cm length) column with isocratic elution at 40% MeOH (doped with 0.05% isopropylamine). This provided Compound Q42 (first to elute on analytical method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 331.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.35 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.46-7.39 (m, 3H), 7.24 (d, J= 8.0 Hz, 2H), 6.64 (s, 1H), 3.04-2.95 (m, 2H), 2.70- 2.68 (m, 1H), 2.34 (s, 3H), 1.62-1.58 (m, 2H), 0.91 (t, J= 7.6 Hz, 3H) and Compound Q43 (second to elute on analytical method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.34 (s, 1H), 7.74 (s, 1H), 7.54 (d, 7= 8.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.23 (d, J= 8.0 Hz, 2H), 6.63 (s, 1H), 3.00-2.93 (m, 2H), 2.67-2.66 (m, 1H), 2.33 (s, 3H), 1.61-1.57 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H).
Compound 044
Figure imgf000134_0001
[0396] Compound Q44: A vessel was charged with LDA (2 M, 473 mL, 1.10 eq) in
THF (700 mL). The system was cooled to -70°C and stirred for 30 min. Compound Q44A (100 g, 860 mmol, 1.00 eq) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1.5 h. Propargyl bromide (166 g, 1.12 mol, 120 mL, 80.0% purity, 1.30 eq) was added to the mixture dropwise at -70°C. Reaction was stirred at -70°C for 2.5 h, then warmed to 15°C and stirred for 12 h. Petroleum ether (2 L) and LLO (500 mL) were added to the reaction. Reaction was washed with brine (500 mL). The organic phase was dried over Na2SC>4, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column (SiCh, Petroleum ether/Ethyl acetate=10/l), giving Compound Q44. 1H NMR (400 MHz, CDCh) d 3.67 (s, 2H), 2.46-2.41 (m, 2H), 1.97-1.96 (m, 1H), 1.69-1.61 (m, 2H),
1.24 (s, 3H), 0.85-0.80 (m, 3H).
Figure imgf000135_0001
[0397] Compound Q45A: A vessel was charged with Compound Q44 (20.0 g, 129 mmol, 1.00 eq ) in DMF (140 mL). The mixture was purged with N2 (3x). Compound Q29A (42.6 g, 142 mmol, 1.10 eq), Cul (1.24 g, 6.48 mmol, 0.05 eq), Pd(PPh3)2Cl2 (4.55 g, 6.48 mmol, 0.05 eq), and TEA (39.3 g, 389 mmol, 54.1 mL, 3.00 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The mixture was poured onto H2O (500 mL) and Petroleum Ether (1 L). The organic layer was washed with brine (500 mL), dried over Na2S04, and filtered. The filtrate was concentrated, and the residue was purified by column (S1O2, Petroleum ether/Ethyl acetate=10/l), giving Compound Q45A. 'H NMR (400 MHz, CDCh) d 7.60 (s, 1H), 7.32-7.24 (m, 2H), 6.36 (s, 1H), 3.71 (s, 3H), 3.15 (d, J = 14.8 Hz, 1H), 2.90 (d, J= 14.8 Hz, 1H), 1.79-1.74 (m, 1H), 1.59-1.53 (m, 1H), 1.19 (s, 1H), 0.90 (t, 7= 7.2 Hz, 3H).
[0398] Compound Q45B: A vessel was charged with Compound Q45A (15.0 g, 46.1 mmol, 1.00 eq) in ACN (97.0 mL). The mixture was purged with N2 for 30 min. l-ethynyl-4- methylbenzene (10.7 g, 92.2 mmol, 11.7 mL, 2.00 eq), Pd-Sphos G2 (3.32 g, 4.61 mmol, 0.10 eq), and Cy2NMe (18.0 g, 92.2 mmol, 19.5 mL, 2.00 eq) were added. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for 4 h. The reaction was poured into water (200 mL), and the system was extracted with EtOAc (800 mL). The organic phase was washed with brine (200 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/l), giving Compound Q45B. ¾ NMR (400 MHz, CDCh) d 7.66 (s, 1H), 7.44-7.34
(m, 4H), 7.16 (d, 7 = 8.0 Hz, 2H), 6.40 (s, 1H), 3.72 (s, 3H), 3.16 (t, 7 = 14.8 Hz, 1H), 2.92 (d, 7 = 14.8 Hz, 1H), 2.37 (s, 1H), 1.81-1.76 (m, 1H), 1.61-1.55 (m, 1H), 1.21 (s, 3H), 0.91 (t, J= 7.6 Hz, 3H).
[0399] Compound Q45: A vessel was charged with Compound Q45B (5.00 g, 13.8 mmol, 1.00 eq), THF (20.0 mL), MeOH (5.00 mL), and H20 (10.00 mL). NaOH (11.1 g, 277 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 5 h. Aq HC1 (6N, 100 mL) was added. The system was extracted with EtOAc (500 mL). The organic phase was washed with brine (200 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l). This gave Compound Q45. ¾ NMR (400 MHz, DMSO-d6) d 12.4 (s, 1H), 7.76 (d, J= 1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.40-7.38 (m, 1H), 7.23 (d, J= 8.0 Hz, 2H), 6.62 (s, 1H), 3.08 (d, J= 14.8 Hz, 1H), 2.92 (t, d= 14.8 Hz, 1H), 2.33 (s, 3H), 1.69-1.63 (m, 1H), 1.52-1.47 (m, 1H), 1.09 (s, 3H), 0.86 (t, J= 7.6 Hz, 3H).
Compound 046 and Compound 047
Figure imgf000136_0001
[0400] Compound Q46 and Compound Q47: A solution of Compound Q45 (900 mg) was subjected to preparative chiral SFC. Two peaks were obtained, corresponding to the two enantiomers of Compound Q45. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed: eluent was supercritical C02 and EtOH(doped with 0.05% isopropylamine) on a chiralcel AD-3 (3 pm, 0.46cm id x 15 cm length) column with gradient elution from 10 to 40% EtOH (doped with 0.05% isopropylamine). This provided
Compound Q46 (first to elute on analytical method): LCMS ESI+ calc’d for C23H22C>3 : 347.2 [M+H+] ; found 347.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12.43 (s, 1H), 7.77 (s, 1H),
7.53 (d, J= 8.8 Hz, 1H), 7.46-7.44 (m, 2H), 7.41-7.39 (m, 1H), 7.25-7.23 (m, 2H), 6.63 (s, 1H), 2.95-2.67 (m, 2H), 2.34 (s, 3H), 1.66-1.50 (m, 2H), 1.10 (s, 3H), 0.87 (t, J= 7.6 Hz, 3H) and Compound Q47 (second to elute on analytical method): LCMS ESI calc’d for C23H22O3 : 345.2 [M-H ] ; found 345.1 [M-H ]. ¾ NMR (400 MHz, DMSO-de) d 12.42 (s, 1H), 7.76 (s, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.51-7.45 (m, 2H), 7.43-7.40 (m, 1H), 7.38-7.22 (m, 2H), 6.62 (s, 1H), 3.32- 2.90 (m, 2H), 2.33 (s, 3H), 1.69-1.47 (m, 2H), 1.09 (s, 3H), 0.86 (t, J= 7.6 Hz, 3H).
Compound 048 and Compound 049
Figure imgf000137_0001
[0401] Compound Q48 and Compound Q49: A vessel was charged with NaH (7.53 g,
188.2 mmol, 60.0% purity, 1.50 eq ) and THF (100 mL). A solution of triethyl 2- phosphonopropanoate (44.8 g, 188.2 mmol, 41.1 mL, 1.50 eq) in THF (100 mL) was added dropwise to the mixture. The reaction was stirred at 15°C for 1 h. The system was cooled to 0°C, and Compound Q23B (30.0 g, 125.4 mmol, 1.00 eq) in THF (100.0 mL) was added to the mixture. The reaction was stirred at 15°C for 16 h. Aq. NH4CI (100.0 mL) was added to the reaction followed by EtOAc (200.0 mL). The organic layer was collected and washed with brine (200.0 mL), dried over INfeSCL, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 0/1), giving: Compound Q48: ¾NMR (400 MHz, CDCb) d 7.37-7.36 (m,
1H), 7.34-7.33 (m, 1H), 6.69 (d, J= 5.2 Hz, 1H), 4.34-4.26 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.38-1.34 (m, 3H); and Compound Q49: ¾ NMR (400 MHz, CDCb) d 7. .65 (s, 1H), 7.35- 7.33 (m, 1H), 7.25-7.22 (m, 1H), 6.60 (d, J= 5.2 Hz, 1H), 4.25-4.20 (m, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 1.21-1.16 (m, 3H). Relative E/Z olefin geometries of the products were arbitrarily assigned. Structures derived from this assignment in subsequent reactions took this into consideration. Compound 050
Figure imgf000138_0001
[0402] Compound Q50A: (relative stereochemistry of this product is inferred based on the arbitrary E-olefin geometry of the starting material). A vessel was charged with Compound Q48 (13.0 g, 40.2 mmol, 1.00 eq ) and Pt02 (0.91 g, 4.02 mmol, 0.10 eq ) in EtOAc (91.0 mL). The system was sparged with Eh and placed under an atmosphere of Eh (50 psi) with stirring at 25°C for 24 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 1/0 to 0/1) to give Compound Q50A as a racemate. LCMS ESI+ calc’d for
CisHivBrCh : 325.0, 327.0 [M+H+] ; found 325.0, 327.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.68 (s, 1H), 7.67 (s, 1H), 7.61-7.59 (m, 4H), 6.69 (s, 1H), 6.37 (s, 1H), 4.29-4.08 (m, 4H), 3.50- 3.30 (m, 1H), 3.30-3.10 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.70 (m, lH), 2.26-2.24 (m, 4H), 1.35- 1.05 (m, 2H).
[0403] Compound Q50B: A vessel was charged with Compound Q50A (10.0 g, 30.7 mmol, 1.00 eq) in ACN (70.0 mL). l-ethynyl-4-m ethylbenzene (10.7 g, 92.2 mmol, 11.7 mL, 3.00 eq), Pd-Sphos G2 (2.22 g, 3.08 mmol, 0.10 eq), and Cy2NMe (12.0 g, 61.5 mmol, 13.0 mL, 2.00 eq) were added. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for 16 h. The reaction was filtered. The filtrate was poured into water (50 mL), and the system was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/l), giving Compound Q50B as a racemate. LCMS ESI+ calc’d for C24H24O3 : 361.2 [M+H+] ; found 361.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.68 (d, J= 1.6 Hz, 1H), 7.46-7.36 (m, 4H), 7.16 (d, J= 7.6 Hz, 1H), 6.43 (d, J= 4.8 Hz, 1H), 4.20-4.10 (m, 2H), 3.43-3.28 (m, 1H), 3.26- 2.98 (m, 1H), 2.38 (s, 3H), 1.38-1.27 (m, 3H), 1.17-1.15 (m, 3H), 1.11-1.09 (m, 3H).
[0404] Compound Q50: A vessel was charged with Compound Q50B (3.50 g, 9.71 mmol, 1.00 eq), THF (10.5 mL), MeOH (7.00 mL), and H20 (7.00 mL). NaOH (3.88 g, 97.1 mmol, 10.0 eq) was added. The reaction was stirred at 60°C for 2 h. The reaction was concentrated under reduced pressure. Aq HC1 (2N) was added until the pH was 2. The system was extracted with EtOAc (20 mL). The organic phase was washed with brine (200 mL), and concentrated under reduced pressure, giving Compound Q50 as a racemate.
Compound 051 and Compound 052
Figure imgf000139_0001
[0405] Compound Q51 and Compound Q52: A solution of Compound Q50 (2300 mg) was subjected to preparative chiral SFC: eluent was supercritical C02 and MeOH(doped with 0.1% ammonium hydroxide) on a DAICEL CHIRALPAK AD (250 mm x 50 mm; 10 pm) column with isocratic elution at 45% MeOH (doped with 0.1% ammonium hydroxide). Two peaks were obtained, corresponding to the two enantiomers of rac-(2R,3R)-2-methyl-3-(5-(p- tolylethynyl)benzofuran-2-yl)butanoic acid. Absolute stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed: eluent was supercritical CO2 and EtOH (doped with 0.05% isopropylamine) on a chiralcel AD-3 (3 pm, 0.46cm id x 15 cm length) column with gradient elution from 10 to 40% EtOH (doped with 0.05%
isopropylamine). This provided Compound Q51 (first to elute on analytical method): LCMS ESC calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.68 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.45 (s, 1H), 3.54-3.48 (m, 1H), 3.13-3.06 (m, 1H), 2.38 (s, 3H), 1.36 (d , J = 6.8 Hz, 3H), 1.15 (d, J= 7.2 Hz, 3H) and Compound Q52 (second to elute on analytical method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, CDCh) 5 7.68 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.45 (s, 1H), 3.55-3.48 (m, 1H), 3.13-3.06 (m, 1H), 2.38 (s, 3H), 1.35 (d, J= 6.8 Hz, 3H), 1.16 (d, J= 7.2 Hz, 3H).
Compound 053
Figure imgf000140_0001
[0406] Compound Q53A: (relative stereochemistry of this product is inferred based on the arbitrary E-olefin geometry of the starting material). A vessel was charged with Compound Q49 (11.0 g, 34.0 mmol, 1.00 eq) and PtCE (0.77 g, 3.40 mmol, 0.10 eq ) in EtOAc (77.0 mL). The system was sparged with Eh and placed under an atmosphere of Eh (50 psi) with stirring at 25°C for 24 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 1/0 to 0/1) giving Compound Q53A (9.10 g, 73.9% yield) as a racemate. LCMS ESI+ calc’d for CisHnBrCh : 325.0, 327.0 [M+H+] ; found 325.1, 327.1 [M+H+] ¾ NMR (400 MHz, CDCh) 5 7.61 (s, 1H), 7.58 (d, J= 2.8 Hz, 1H), 7.31-7.27 (m, 1H), 6.38 (s, 1H), 4.19-4.12 (m, 2H), 3.27-3.23 (m, 1H), 2.80-2.76 (m, 1H), 1.34-1.25 (m, 3H), 1.24-1.21 (m, 3H), 1.07-1.05 (m, 3H).
[0407] Compound Q53B: A vessel was charged with Compound Q53A (8.00 g, 24.6 mmol, 1.00 eq) in ACN (56.0 mL). l-ethynyl-4-m ethylbenzene (8.57 g, 73.8 mmol, 9.36 mL, 3.00 eq ), Pd-Sphos G2 (1.77 g, 2.46 mmol, 0.10 eq ), and CyiNMe (9.61 g, 49.2 mmol, 10.4 mL, 2.00 eq) were added. The mixture was purged with N2 (3x). The reaction was stirred at 80°C for
16 h. The reaction was filtered. The filtrate was poured into water (50 mL), and the system was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over NaiSCL, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/l), giving Compound Q53B as a racemate. 1H NMR (400 MHz, CDCb) d 7.67 (d, J= 1.6 Hz, 1H), 7.46-7.36 (m, 4H), 7.16 (d, J= 7.6 Hz, 1H), 6.43 (d, J= 4.8 Hz, 1H), 4.20-4.13 (m, 2H), 3.29- 3.25 (m, 1H), 2.83-2.77 (m, 1H), 2.38 (s, 3H), 1.37-1.34 (m, 3H), 1.27-1.23 (m, 3H), 1.11-1.09 (m, 3H).
[0408] Compound Q53: A vessel was charged with Compound Q53B (1.50 g, 4.16 mmol, 1.00 eq), THF (4.00 mL), MeOH (3.00 mL), and H20 (3.00 mL). NaOH (1.66 g, 41.6 mmol, 10.0 eq) was added. The reaction was stirred at 60°C for 2 h. The reaction was concentrated under reduced pressure. Aq HC1 (2N) was added until the pH was 2. The system was extracted with EtOAc (20 mL). The organic phase was washed with brine (200 mL), and concentrated under reduced pressure, giving Compound Q53 as a racemate.
Compound 054 and Compound 055
Figure imgf000141_0001
[0409] Compound Q54 and Compound Q55: A solution of Compound Q53 racemate
(1050 mg) was subjected to preparative chiral SFC: eluent was supercritical CO2 and IPA(doped with 0.1% ammonium hydroxide) on a DAICEL CHIRALPAK AD-H (250 mm x 30 mm; 5 pm) column with isocratic elution at 31% IPA(doped with 0.1% ammonium hydroxide). Two peaks were obtained, corresponding to the two enantiomers of rac-(2R,3S)-2-methyl-3-(5-(p- tolylethynyl)benzofuran-2-yl)butanoic acid. Absolute stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed: eluent was supercritical CO2 and IP A (doped with 0.05% isopropylamine) on a CHIRALPAK AD-3 (3 pm, 0.46cm id x 15 cm length) column with gradient elution from 10 to 40% IPA(doped with 0.05% isopropylamine). This provided Compound Q54 (first to elute on analytical method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.68 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.46 (s, 1H), 3.25-3.27 (m, 1H), 2.90-2.83 (m, 1H), 2.38 (s, 3H), 1.44 (d, J =
6.8 Hz, 3H), 1.15 (d, J= 12 Hz, 3H) and Compound Q55 (second to elute on analytical method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.68 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.46 (s, 1H), 3.34-3.33 (m, 1H), 2.90-2.83 (m, 1H), 2.38 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.15 (d, J= 7.2 Hz, 3H).
Compound 056
Figure imgf000142_0001
[0410] Compound Q56B: A mixture of Compound Q56A (61.2 g, 353.7 mmol) and
KOH (24.8 g, 442.0 mmol) in -PrOH/toluene/water (53 mL/85 mL/9 mL) was stirred at 85 °C for 40 minutes. A solution of hydroxylamine //-sulfonic acid (10.0 g, 88.4 mmol) in water (53 mL) was added dropwise into the stirred reaction mixture at 85 °C over 30 minutes via a dropping funnel. The reaction was then stirred for another 15 minutes at 85 °C and cooled to room temperature. Aq. NaOH (10 wt%, 400 mL) was added and the layers were separated. The aqueous layer was extracted with Et20 (3 X 150 mL) and the combined organic layers were washed with aq. NaOH (10 wt%, 200 mL), brine (100 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated to give Compound Q56B. LCMS ESI+ calc’d for CeHeBrNO : 188.0, 190.0 [M+H+] ; found 188.0, 190.0 [M+H+] ¾ NMR (400 MHz, DMSO- de) d 7.40 (dd, J= 6.8, 2.0 Hz, 2H), 7.04 (dd, J= 6.8, 2.4 Hz, 2H), 6.99 (s, 2H).
[0411] Compound Q56D: A solution of Compound Q56C (4.32 g, 25.4 mmol) and
Compound Q56B (4.77 g, 25.4 mmol) in EtOAc (20 mL) was concentrated at ca. 50 °C to dryness. The residue was further dissolved in EtOAc (20 mL) and concentrated at ca. 50 °C to dryness. The residue was further dissolved in EtOAc (80 mL) and concentrated at ca. 50 °C to dryness. The residue was further purified by silica gel chromatography eluted with Petroleum Ether/EtOAc (from 50/1 to 30/1) giving an E/Z mixture of Compound Q56D. LCMS ESI+ calc’d for CisHisBrNCh : 340.1, 342.0 [M+H+] ; found 340.0, 342.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.40-7.36 (m, 2H), 7.08-7.03 (m, 2H), 4.19-4.13 (m, 2H), 3.48-3.26 (m, 1H), 2.77-2.49 (m, 2H), 2.44-2.28 (m, 1H), 2.24-1.95 (m, 3H), 1.95-1.48 (m, 2H), 1.27 (dt, J= 7.2, 2.4 Hz, 3H).
[0412] Compound Q56E: To a stirred solution of Compound Q56D (3.46 g, 10.2 mmol) in AcOH (100 mL) under argon at room temperature was added HC1 in 1,4-dioxane (4 M, 15.5 mL, 62 mmol). The reaction was stirred under argon at 90 °C for 1 hour. The reaction mixture was diluted with ice water (1 L) and the residue was extracted with Et20 (3 X 500 mL). The combined organic extracts were neutralized with sat. aq. NaiCCh (ca. 1 L) and then washed with brine (500 mL), dried over anhydrous NaiSCh, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with Petroleum Ether/EtOAc (from 500/1 to 100/1) to give Compound Q56E. ¾ NMR (400 MHz, CDCh) d 7.52 (d, J= 1.6 Hz, 1H), 7.30 (dd, J= 8.6, 1.8 Hz, 1H), 7.27 (d, J= 8.4 Hz, 1H), 4.24-4.16 (m, 2H), 3.08-2.86 (m, 3H), 2.75-2.57 (m, 2H), 2.30-2.24 (m, 1H), 1.99-1.90 (m, 1H), 1.27 (t, J= 7.2 Hz, 3H). An isomeric product, ethyl 8-bromo-l,2,3,4-tetrahydrodibenzo[b,d]furan-4-carboxylate (643 mg) was also obtained after chromatography.
[0413] Compound Q56F: A vessel was charged with Compound Q56E (1.92 g, 5.94 mmol) in ACN (18 mL). The mixture was purged with Argon l-ethynyl-4-methylbenzene (2.07 g, 17.8 mmol, 11.7), Pd-Sphos G2 (428 mg, 0.595 mmol), and CyiNMe (3.48 g, 3.48 mmol) were added. The reaction was stirred at 80°C for 3 h. The reaction was poured into water (200 mL), and the system was extracted with EtOAc (3 x 100 mL). The organic phase was washed with brine (200 mL), dried over NaiSCL, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate= 500/1 to 100/1) and triturated with Petroleum Ether (40 mL). Filtration gave a cake, which was dried under reduced pressure, giving Compound Q56F. LCMS ESI+ calc’d for C24H22O3 : 359.2 [M+H+] ; found 359.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.59 (s, 1H), 7.43 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.4 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 8.0 Hz, 2H), 4.21 (q, J= 7.1 Hz, 2H), 3.09-2.87 (m, 3H), 2.78-2.60 (m, 2H), 2.37 (s, 3H), 2.35-2.26 (m, 1H), 1.98-1.91 (m, 1H), 1.30 (t, J= 7.0 Hz, 3H).
[0414] Compound Q56: A vessel was charged Compound Q56F (1.18 g, 3.29 mmol),
THF (14.0 mL) and H2O (4.00 mL). LiOH monohydrate (1.38 g, 32.9 mmol) was added. The reaction was stirred at 75°C for 3 h. The reaction was diluted with H2O (100 mL). Aq HC1 (2N, 20 mL) was added. The resulting mixture was filtered after 10 min. The cake was washed with water, and dried under reduced pressure, giving Compound Q56. ¾ NMR (400 MHz, CDCb) d 7.53 (s, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.33 (dd, J= 8.8, 1.6 Hz, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.09 (d, J= 8.0 Hz, 2H), 3.05-2.89 (m, 3H), 2.75-2.69 (m, 1H), 2.64-2.56 (m, 1H), 2.30 (s, 3H), 2.30-2.22 (m, 1H), 2.01-1.90 (m, 1H).
Compound 057 and Compound 058
Figure imgf000144_0001
[0415] Compound Q57 and Compound Q58: A solution of Compound Q56 (1150 mg) was subjected to preparative chiral SFC: eluent was supercritical CO2 and MeOH (doped with 0.1% TFA) on an AD (2.5 cm x 25 cm; 10 pm) column with isocratic elution at 40%
MeOH (doped with 0.1% TFA). Two peaks were obtained, corresponding to the two
enantiomers of Compound Q56. Stereochemistries of the products were arbitrarily assigned.
This provided Compound Q57 (first to elute on preparative method): LCMS ESI calc’d for C22H18O3 : 329.1 [M-H ] ; found 329.3 [M-H ]. ¾NMR (400 MHz, DMSO-de) d 12.50 (brs, 1H), 7.68 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (dd, J= 8.4, 1.6 Hz, 1H), 7.24 (d, J= 8.0 Hz, 2H), 2.94-2.90 (m, 3H), 2.71-2.59 (m, 2H), 2.34 (s, 3H), 2.18-2.14 (m, 1H), 1.91-1.87 (m, 1H) and Compound Q58 (second to elute on preparative method): LCMS EST calc’d for C22H18O3 : 329.1 [M-H ] ; found 329.3 [M-H ]. ¾ NMR (400 MHz, DMSO-de) d 12.49 (brs, 1H), 7.68 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (dd, J =
8.4, 1.6 Hz, 1H), 7.24 (d, J= 8.0 Hz, 2H), 2.95-2.90 (m, 3H), 2.71-2.59 (m, 2H), 2.34 (s, 3H), 2.18-2.12 (m, 1H), 1.91-1.85 (m, 1H).
Compound 059
Figure imgf000145_0001
[0416] Compound Q59B: A three-necked round-bottom flask was charged with
Compound Q59A (100.0 g, 465 mmol, 1.00 eq), ACN (600 mL), and DMF (100 mL). Ethyl bromoacetate (93.1 g, 558 mmol, 61.7 mL, 1.20 eq) and CS2CO3 (303.0 g, 930 mmol, 2.00 eq) were added at 15°C. The reaction was degassed with N2 (3x). The reaction was stirred at 100°C for 15 h. The reaction was poured into H2O (2.00 L) then stirred at 20°C for 40 min. The system was filtered, and the cake was treated with EtOAc. The system was dried over NaiSCE and filtered. The filtrate was concentrated under reduced pressure, giving Compound Q59B. LCMS ESI+ calc’d for CizHnBrOs : 283.0, 285.0 [M+H+] ; found 283.0, 285.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.74 (d, J= 2.0 Hz, 1H), 7.52 (dd, J= 1.6 Hz, J= 8.8 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 4.45 (q, J= 7.2 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J= 7.2 Hz, 3H).
[0417] Compound Q59C: A vessel was charged with LAH (5.36 g, 141 mmol, 0.80 eq) and THF (200 mL). The system was cooled to 0°C. A solution of Compound Q59B (50.0 g,
176 mmol, 1.00 eq) in THF (200 mL) was added to the reaction dropwise over a 2 h period. H20 (5.36 mL) was added. 15.0% aq. NaOH (5.36 mL) was added. Finally, H20 (16.1 mL) was added, completing the quench. The reaction was filtered. The filtrate was concentrated under reduced pressure. The resulting solid was triturated with Petroleum ether/Ethyl acetate = 5/1. Filtration gave a cake, which was dried under reduced pressure, providing Compound Q59C. ¾ NMR (400 MHz, CDCh) d 7.61 (d, J= 2.0 Hz, 1H), 7.39 (d, J= 8.8 Hz, 1H), 7.29 (d, J= 6.4 Hz, 1H), 4.43 - 4.48 (m, 2H), 2.21 (s, 3H), 1.98 - 2.01 (m, 1H).
[0418] Compound Q59D: A vessel was charged with Compound Q59C (26.0 g, 107 mmol, 1.00 eq) and ACN (180 mL). P3C (45.3 g, 161 mmol, 1.50 eq) was added. The reaction was stirred at 80°C for 2 h. Ethyl acetate (200 mL) was added to the mixture. The system was filtered and the cake was washed with EtOAc (3 x 50 mL). The combined filtrate was washed with sat. aq NaHCO, (200 mL), washed with brine (200 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving Compound Q59D. ¾ NMR (400 MHz, CDCh) d 10.03 (s, 1H), 7.81 (d, J= 2.0 Hz, 8.8 Hz, 1H), 7.59 (dd, J= 5.6 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 2.59 (s, 3H).
[0419] Compound Q59E: A three-necked round-bottom flask was charged with NaH
(2.51 g, 62.7 mmol, 60.0% purity, 1.50 eq) and THF (30.0 mL), then cooled to 0°C. A solution of tri ethyl 2-phosphonopropanoate (14.9 g, 62.7 mmol, 13.7 mL, 1.50 eq) in THF (30.0 mL) was added dropwise at 0°C. The reaction was then stirred at 20°C for 1 h. A solution of Compound Q59D (10.0 g, 41.8 mmol, 1.00 eq) in THF (30.0 mL) was added dropwise at 0°C. The reaction was then stirred at 20°C for 1 h. The reaction was quenched with sat. aq NH4CI (50.0 mL). The system was extracted with EtOAc (100 mL, 50 mL). Combined organic layers were dried (Na2S04), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 15/1 ~ 5/1) giving Compound Q59E. ¾ NMR (400 MHz, CDCh) d 7.65 (d, J= 1.6 Hz, 1H), 7.51 (d, J= 1.6 Hz, 1H), 7.41 (dd, J= 8.8 Hz, J= 1.6 Hz, 1H), 7.32 (d, J= 8.8 Hz, 1H), 4.30 (q, J= 6.8 Hz, 2H),
2.41 (s, 3H), 2.32 (s, 3H), 1.38 (t, J= 7.2 Hz, 3H). [0420] Compound Q59F: A vessel was charged wtih PtCh (1.60 g, 7.05 mmol, 0.19 eq) and EtOAc (30.0 mL). Compound Q59E (12.0 g, 37.1 mmol, 1.00 eq) was added. The reaction was stirred under ¾ at 15°C for 15 h. The reaction was filtered, and the filtrate was
concentrated under reduced pressure. The resulting residue was purified by column
chromatography (SiCh, Petroleum ether : Ethyl acetate = 30/1 to 5/1) giving Compound Q59F. LCMS ESI+ calc’d for CisHnBrCE : 325.0, 327.0 [M+H+] ; found 325.1, 327.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.55 (d, J= 2.0 Hz, 1H), 7.31 (dd, J= 2.0 Hz, J= 8.8 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 4.12 (q, J= 7.2 Hz, 2H), 3.09 - 3.12 (m, 1H), 2.80 - 2.83 (m, 1H), 2.14 (s, 3H), 1.19 - 1.22 (m, 6H).
[0421] Compound Q59G: A vessel was charged with Compound Q59F (7.60 g, 23.3 mmol, 1.00 eq) in ACN (50.0 mL). l-ethynyl-4-m ethylbenzene (8.14 g, 70.1 mmol, 8.89 mL, 3.00 eq ), Pd-Sphos G2 (1.68 g, 2.34 mmol, 0.10 eq ), and CyiNMe (9.13 g, 46.7 mmol, 9.91 mL, 2.00 eq) were added. The reaction was degassed and purged with N2 several times. The reaction was stirred at 80°C for 16 h. The reaction was poured into water (200 mL), and the system was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with sat. aq NH4CI (3 x 25.0 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, 100-200 mesh, Petroleum ether/ethyl acetate = 1/0 to 25/l)and triturated with Petroleum ether/Ethyl acetate (20: 1, v:v, 50 mL) at -70°C with stirring for 30 min. Filtration gave a cake, which was dried under reduced pressure, giving Compound Q59G. ¾ NMR (400 MHz, CDCh) d 7.62 (s, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (dd, 7= 1.6 Hz, 8.4 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 4.13 (q, J= 7.2 Hz, 2H), 3.13 (dd, J= 6.4 Hz, 14.4 Hz, 1H), 2.94 (m, 1H), 2.84 (dd, J= 7.6 Hz, 14.4 Hz, 1H), 2.38 (s, 3H), 2.17 (s, 3H), 1.19 - 1.23 (m, 6H).
[0422] Compound Q59: A vessel was charged with Compound Q59G (1.40 g, 3.88 mmol, 1.00 eq), THF (6.00 mL), MeOH (2.00 mL) and H20 (3.00 mL). NaOH (3.11 g, 77.6 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 2 h. The reaction was concentrated under reduced pressure. The system was diluted with H2O (20.0 mL). Aq HC1 (6N) was added until the pH was 3-4. The system was extracted with EtOAc (3 x 10 mL). Combined organic layers were washed with brine (10.0 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, 100-200 mesh, Petroleum ether/Ethyl acetate = 30/1 to 1/1), giving Compound Q59. Compound 060 and Compound 061
Figure imgf000148_0001
[0423] Compound Q60 and Compound Q61: A solution of Compound Q59 (900 mg) was subjected to preparative chiral SFC: eluent was supercritical CO2 and IPA (doped with 0.1% NH4OH) on a DAICEL CHIRALPCEL OJ (250 mm x 30 mm; 10 pm) column with isocratic elution at 40% IPA (doped with 0.1% NH4OH). Two peaks were obtained, corresponding to the two enantiomers of Compound Q59. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed: eluent was supercritical CO2 and IPA (doped with 0.05% isopropylamine) on a chiralcel OJ-3 (3 pm, 0.46cm id x 15 cm length) column with gradient elution from 10 to 40% IPA(doped with 0.05% isopropylamine). This provided
Compound Q60 (first to elute on preparative method): LCMS ESI+ calc’d for C22H20O3 : 333.1 [M+FC] ; found 333.1 [M+H+] 1H NMR (400 MHz, CDCh) d 12.31 (s, 1H), 7.71 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.23 (d, J= 8.0 Hz, 2H), 3.03-3.08 (m, 1H), 2.74-2.87 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.11 (d, C= 6.8 Hz, 2H) and Compound Q61 (second to elute on preparative method): LCMS ESC calc’d for C22H20O3 : 333.1 [M+H+] ; found 333.1 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 12. 30 (s, 1H), 7.71 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.39 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.23 (d, J= 8.0 Hz, 2H), 3.03-3.08 (m, 1H), 2.74-2.87 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.11 (d, J= 6.8 Hz, 2H). Compound 062
Figure imgf000149_0001
[0424] Compound Q62A: To a solution of Compound Q4 (3.20 g, 6.69 mmol) in THF
(22 mL) at -78 °C was added LiHMDS (1 M in THF, 10 mL, 10 mmol, 1.5 eq) dropwise (over 15 min). The reaction mixture was stirred at -78 °C for 1 h, then a solution of benzaldehyde (1.43 g, 13.4 mmol, 2.0 eq) in THF (12 mL) was added dropwise (over 15 min). The mixture was stirred at -78 °C for 3 h, quenched with saturated MLCl, extracted with EtOAc (3x), dried over Na2S04, and filtered. The filtrate was concentrated. Crude Compound Q62A was used for next step without further purification.
[0425] Compound Q62B: To a solution of crude Compound Q62A dissolved in DCM
(125 mL) at 0 °C was added triethylamine (4.65 mL, 5 eq). Then MsCl (1.04 mL, 2 eq) was added dropwise. The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was cooled again to 0 °C, DBU (5.0 mL, 5 eq) was added dropwise, and stirred at RT overnight. The reaction mixture was diluted with DCM, washed with saturated NH4CI (2x), dried over Na2SC>4, filtrated, and concentrated. Purification via chromotography (S1O2: 10%
EtO Ac/hexanes) afforded Compound Q62B.
[0426] Compound Q62: To a solution of Compound Q62B (3.2 g, 5.65 mmol) in DCM
(22 mL) was added formic acid (7 mL) and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with DCM, washed with saturated NaHCCL, brine, dried over Na2S04, filtrated, and concentrated. The residue was purified with flash column
chromatography (FCC) (30% EtOAc/hexanes) to provide Compound Q62. LCMS ESI+ calc’d for C20H20O4 : 325.1 [M+H+] ; found 325.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.56-7.25 (m, 11 H), 4.56 (s, 2H), 3.78 (dd, J= 28.8 and 11.7 Hz, 2H), 3.62 (dd, 7= 18.6 and 9.8 Hz), 3.13 (d, J= 1.8 Hz, 2H).
Compound 063
Figure imgf000150_0001
[0427] Compound Q63B: At -78 °C, to a THF solution (40 mL) of Compound Q63A
(4.08 g, 35.8 mmol) was added dropwise vinylmagnesium bromide (71.6 mL, 1 M in THF). The reaction mixture was allowed to reach RT and stirred for 1 hour. The reaction was quenched by the slow addition of MLCl aq (20 mL, sat’d). The resulting mixture was extracted with EtOAc (150 mL) and the combined organic layer was washed with water and brine, dried over NaiSCL and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtO Ac/Hexanes, 5-10% EtOAc). Compound Q63B was obtained. ¾ NMR (400 MHz, CDCh) 5 5.86 - 5.76 (m, 1H), 5.17 (dd, J= 17.4, 1.4 Hz, 1H), 5.09 - 5.05 (m, 1H), 1.52 - 1.39 (m, 4H), 1.35 - 1.23 (m, 4H), 0.89 (t, J= 7.3 Hz, 6H).
[0428] Compound Q63C: To a solution of PCC (19.0 g, 86.4 mmol) in DCM (40 mL, dried over 3 A MS) stirred at RT, was slowly added Compound Q63B (4.1 g, 28.8 mmol,
20 mL DCM solution). The reaction mixture was stirred at RT for overnight. The mixture was diluted with Et20 (200 mL) and stirred at RT for 1 hour. The reaction mixture was filtered over silica and celite and concentrated. The residue was suspended in Et20 (100 mL). The mixture was filtered on silica and Celite, and the filtrate was concentrated. Compound Q63C was carried crude to the next step without further purification. 'H NMR (400 MHz, CDCh) 5 9.94 (d, J= 8.2 Hz, 1H), 5.83 (d, J= 8.2 Hz, 1H), 2.59 - 2.38 (m, 2H), 2.21 - 1.94 (m, 2H), 1.73 - 1.38 (m, 4H), 0.97 - 0.77 (m, 6H).
[0429] Compound Q63: Crude Compound Q63C (3.1 g, 22.1 mmol) was dissolved in
DCM (20 mL) and to this solution was added Pd/C (300 mg, 10% on charcoal). The reaction was stirred under 1 atm of ¾ for 48 hours. The reaction was filtered and the filtrate was concentrated under vacuum to give Compound Q63 and used directly for next step without further purification. ¾ NMR (400 MHz, CDCh) 5 9.75 (t, J= 2.4 Hz, 1H), 2.31 (dd, J= 6.6, 2.4 Hz, 2H), 1.56 - 1.37 (m, 1H), 1.31 - 1.10 (m, 8H), 0.98 - 0.72 (m, 6H).
Compound 064
Figure imgf000151_0001
[0430] Compound Q64A: A stirred solution of Compound Q4 (809 mg, 1.69 mmol) in anhydrous THF (10 ml) was cooled to -78 °C under nitrogen and treated dropwise with
LiHMDS (2.54 mL, 1.0 M in THF). The mixture was stirred at -78 °C for 1 hour. A solution of the Compound Q63 (720 mg, 5.01 mmol) in anhydrous THF (3 ml) was added dropwise at the same temperature and stirring at -78 °C was continued for 2 hours. The reaction was quenched at -78 °C by the slow addition of a saturated aqueous solution of ammonium chloride (5 mL). The mixture as warmed to RT and the aqueous layer was extracted with Et20 (3x50 mL). The combined organic extracts were washed with water (3x20 mL), brine (20 mL), dried over MgSCri and filtered. The filtrate was concentrated under vacuum and purified by flash chromatography (5-10 % EtOAc in Hexane) to give Compound Q64A. LCMS ESI+ calc’d for C41H48O5 : 638.4 [M+ML+H+] ; found 638.6 [M+ML+H+].
[0431] Compound Q64B: Compound Q64A (861 mg, 1.39 mmol) was dissolved in toluene (21 mL) and to this solution were added DCC (434 mg, 2.08 mmol) and CuBr (102 mg, 0.69 mmol). Then the reaction mixture was heated at 110° C for 16 h. Then the reaction mixture was filtered and the filtrate was concentrated. The concentrate was purified by flash
chromatography (5% EtOAc in Hexane) to give Compound Q64B. LCMS ESI+ calc’d for C41H46O4 : 620.4 [M+ML+H+] ; found 620.6 [M+ML+H+]. [0432] Compound Q64: To a DCM (4 mL) solution of Compound Q64B (70 mg,
0.191 mmol) was added 4 (N) HC1 in dioxane (572 uL, 1 M in heptanes) dropwise and the reaction was stirred at room temperature for 4 hours. Then the reaction mixture was extracted with EtOAc (100 mL) and washed thoroughly with water (4x25 mL) and dried over NaiSCL. The organic extract was concentrated and purified by flash column chromatography (20% EtOAc in Hexane) to give Compound Q64. LCMS ESI+ calc’d for C22H32O4 : 361.2 [M+H+] ; found 361.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.39-7.26 (m, 5H), 6.77 (tt, J= 7.7, 2.9 Hz, 1H), 4.64- 4.49 (m, 1H), 3.77 (dd, J= 12.1, 7.1 Hz, 1H), 3.68 (dd, J= 12.1, 6.4 Hz, 1H), 3.61 (d, J= 9.9 Hz, 1H), 3.54 (d, J= 10.0 Hz, 1H), 2.83-2.63 (m, 2H), 2.23-2.06 (m,2H), 1.92 (m, 1H), 1.35-1.15 (m, 8H), 0.87 (m, 6H).
Compound 065
Figure imgf000152_0002
[0433] Compound Q65: A flask was charged with Compound Q65A (100 g, 587 mmol, 1.00 eq) and PhMe (1000 mL). NBS (104 g, 587 mmol, 1.00 eq) and p-TsOH
monohydrate (11.1 g, 58.7 mmol, 0.10 eq) were added to the mixture, which was stirred at 130°C for 2 h. The system was cooled to 23 °C and concentrated under reduced pressure. H2O (200.0 mL) was added to the solution. The system was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with sat. aq NaHC03 (300.0 mL) and brine (2 x 300.0 mL), dried over Na2S04, and filtered. Purification of the residue by column chromatography (S1O2, using Petroleum ether/Ethyl acetate = 50/1 to 2/1) gave Compound Q65. 'H NMR (400 MHz, CDCh) d 4.46-4.45 (m, 1H), 4.20-4.14 (m, 2H), 3.14-3.10 (m, 2H), 2.49-2.43 (m, 4H), 2.41-2.03 (m, 1H), 1.29-1.24 (m, 3H).
Compound 066
Figure imgf000152_0001
Q66A Q66
[0434] Compound Q66: A vessel was charged with Compound Q66A (65.0 g, 375 mmol, 1.00 eq) and MeOH (350 mL). NaOMe (67.6 g, 375 mmol, 1.00 eq) was added. The reaction was stirred at 85°C for 3 hrs. The reaction was concentrated under reduced pressure, giving Compound Q66. The material was used without further characterization to make
Compound Q67 immediately below.
Compound 067
Figure imgf000153_0001
[0435] Compound Q67A: A vessel was charged with Compound Q65 (90 g, 361 mmol, 1.00 eq) in PhMe (1260 mL). Compound Q66 (70.4 g, 361 mmol, 1.00 eq) was added to the mixture. The reaction was stirred for 10 h at 25°C. Aq NaOH (1 M, 200 mL) was added to the solution, followed by addition of water (200 mL), giving a final pH = 8. The system was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over NaiSCL, and filtered. The filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (S1O2, using Petroleum ether/Ethyl acetate = 100/1 to 10/1) gave Compound Q67A. LCMS ESI+ calc’d for C15H17B1O4 : 341.0 [M+H+] ; found 703.1 [2M+Na+]
[0436] Compound Q67B: A vessel containing Polyphosphoric Acid (100 mL) was charged with Compound Q67A (20.0 g, 58.6 mmol, 1.00 eq). The reaction was stirred for 0.15 h at 20°C. The reaction was quenched with ice water (200 mL). The system was extracted with EtOAc (2 x 200 mL). Combined organic layers were washed with brine (2 x 200 mL), dried over Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (SiCh, using Petroleum ether/Ethyl acetate = 100/1 to 10/1) gave Compound Q67B. ¾ NMR (400 MHz, CDCh) d 7.51 (s, 1H), 7.31-7.24 (m, 2H), 4.22- 4.16 (m, 2H), 3.03-2.99 (m, 3H), 2.90-2.68 (m, 2H), 2.29-2.24 (m, 1H), 1.95-1.93 (m, 1H), 1.30-
1.27 (m, 3H).
[0437] Compound Q67C: A solution of Compound Q67B (7.50 g, 23.2 mmol, 1.00 eq) in THF (56.0 mL) was cooled to -65°C. LDA (2 M, 23.2 mL, 2.00 eq) was added in dropwise manner at -65°C, and the reaction was stirred at -65°C for 1 h. Iodomethane (6.59 g, 46.4 mmol, 2.00 eq) was added in dropwise manner to the reaction at -65°C. The reaction was then stirred at 23°C for 2 h. The reaction was quenched with ice water (50.0 mL). The system was extracted with EtOAc (2 x 50 mL). Combined organic layers were washed with brine (2 x 100 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. After purification of the resulting residue by column chromatography (SiCh, using Petroleum ether/Ethyl acetate = 100/1 to 10/1), product-containing fractions were combined and
concentrated, giving a residue. Further purification of this new residue via preparative HPLC (Nano-micro Kromasil C18 100*40mm 10um;mobile phase: [water(0.1%TFA)-ACN];B%: 70%-88%,10min) gave Compound Q67C. LCMS ESI+ calc’d for CieHnBrCh : 337.1 [M+H+] ; found 337.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.43 (s, 1H), 7.23-7.17(m, 3H), 4.09-4.03 (m, 2H), 3.24 (d, J= 16.0 Hz, 1H), 2.56-2.53 (m, 3H), 2.16-2.13 (m, 1H), 1.78-1.75 (m, 1H),
1.28 (s, 3H), 1.17-1.13 (m, 3H).
[0438] Compound Q67D: A vessel was charged with Pd-Xphos G2 (0.186 g, 0.237 mol, 0.10 eq) and CS2CO3 (2.32 g, 7.12 mmol, 3.00 eq) in PhMe (48.0 mL) . The system was degassed with N2 several times. Compound Q67C (0.800 g, 2.37 mmol, 1.00 eq) and 1- ethynyl-4-methylbenzene (0.551 mg, 4.74 mmol, 2.00 eq) were added to the mixture. The system was degassed with N2 several times. The reaction was stirred at 100°C for 16 hrs. Water (150.0 mL) was added, and the resulting system was filtered. The filtrate was extracted with EtOAc (3 x 80 mL). Combined organic layers were washed with brine (2 x 80 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. After purification of the resulting residue by column chromatography (S1O2, using Petroleum ether/Ethyl acetate = 100/1 to 10/1), product-containing fractions were combined and concentrated, giving a residue. Further purification of this new residue via preparative HPLC (column: Nano-Micro UniSil 5- 100 C18 ULTRA 100*250mm 5um;mobile phase: [water(0.1%TFA)-ACN];B%: 90%- 95%,10min) gave Compound Q67D. LCMS ESC calc’d for C25H24O3 : 373.2 [M+H+] ; found 373.1 [M+H+] ¾ NMR (400 MHz, CDCh) 5 7.59 (s, 1H), 7.45-7.35(m, 4H), 7.17-7.15 (m,
2H), 4.18-4.12 (m, 2H), 3.33 (d, = 16.0 Hz, 1H), 2.68-2.61 (m, 3H), 2.38 (s, 3H), 2.25-2.22 (m, 1H), 1.88-1.84 (m, 1H), 1.37 (s, 3H), 1.25-1.22 (m, 3H).
[0439] Compound Q67: A vessel was charged with Compound Q67D (.80 g, 4.83 mmol, 1.00 eq) in THF (36.0 mL), H20 (9.00 mL) and MeOH (18.0 mL). LiOH-H20 (2.03 g, 48.3 mmol, 10.00 eq) was added to the solution. Reaction was stirred for 3 h at 75 °C. Water (50.0 mL) was added. Aq HC1 (2.0 M, 80.0 mL) was added to the system, giving a pH = 3. The reaction was filtered, and the filtrate was concentrated, giving Compound Q67, which was immediately subjected to chiral separation (immediately below) without further characterization.
Figure imgf000155_0001
[0440] Compound Q68 and Compound Q69: A solution of Compound Q67 (900 mg) was subjected to chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALCEL OD-H column (250mm x 30mm x 5 pm) with isocratic elution at 50% MeOH in 50% CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q67. Stereochemistries of the products were arbitrarily assigned. This provided Compound Q68
(first to elute): LCMS ESC calc’d for C23H20O3 : 345.1 [M+H+] ; found 345.1 [M+H+] Ή NMR (400 MHz, CDCb) d 7.57 (s, 1H), 7.44-7.35 (m, 4H), 7.16 (d, J= 8.0 Hz, 2H), 3.32 (d, J= 20.0 Hz, 1H), 2.74-2.63 (m, 3H), 2.37 (s, 3H), 2.27-2.23 (m, 1H), 1.90-1.86 (m, 1H), 1.42 (s, 3H) and Compound Q69 (second to elute): LCMS ESC calc’d for C23H20O3 : 345.1 [M+H+] ; found 345.1 [M+H+] ¾ NMR (400 MHz, CDCh) 5 7.59 (s, 1H), 7.44-7.34 (m, 4H), 7.15 (d, 7= 8.0 Hz, 2H), 3.31 (d, J = 16.0 Hz, 1H), 2.71-2.62 (m, 3H), 2.37 (s, 3H), 2.24-2.21 (m, 1H), 1.88- 1.84 (m, 1H), 1.44 (s, 3H).
Compound 070
Figure imgf000156_0001
[0441] Compound Q70: A 3-necked flask was charged with THF (700 mL) and degassed with N2 (3x). LDA (2 M, 538 mL, 1.10 eq) was added, and the system was cooled to - 70°C. Compound Q70A (100.0 g, 979 mmol, 112 mL, 1.00 eq) was added to the mixture dropwise at -70°C. Propargyl bromide (160 g, 1.08 mol, 116 mL, 1.10 eq) was added to the mixture dropwise at -70°C. The reaction was stirred at -70°C for 1 h, then warmed to 15°C with stirring for 12 h. The reaction was quenched by pouring the reaction into water (1000 mL) at 0- 10°C. n-Pentane (100 mL) was added. The organic layer was washed with brine (2 x 500 mL), dried over Na2S04, and filtered. The filtrate was concentrated at 25°C and the resulting residue was purified by silica gel column twice (100 ~ 200 mesh, petroleum ether isocratic elution) giving Compound Q70. ¾ NMR (400 MHz, CDCh) d 4.19-4.14 (m, 2H), 2.66-2.53 (m, 1H), 2.52 (m, 1H), 2.40 (m, 1H), 2.00-1.99 (m, 1H), 1.30-1.25 (m, 9H).
Compound 071
Figure imgf000156_0002
Q71C Q71
[0442] Compound Q71B: A vessel was charged with Compound Q70 (1.55 g, 11.04 mmol, 1.10 eq) in DMF (21 mL). The mixture was purged with N2 for 5 min. Cul (95.5 mg, 501 umol, 0.05 eq), Pd(PPh3)2Ch (352.2 mg, 501 umol, 0.05 eq), and TEA (3.05 g, 30.1 mmol, 3.00 eq) were added to the mixture. Compound Q71A (3 g, 10.04 mmol, 1.00 eq) was added. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 16 h. The mixture was poured onto H2O (50 mL) and EtOAc (25 mL) and stirred for 5 min at 23°C. The organic layer was dried over INfeSCE, and filtered. The filtrate was concentrated, and the residue was purified by column (S1O2, Petroleum ether/Ethyl acetate=50/l), giving Compound Q71B. The material was immediately used in the next reaction below without further characterization.
[0443] Compound Q71C: A vessel was charged with Compound Q71B (2.00 g, 6.43 mmol, 1.00 eq ) in DMF (14 mL). The mixture was purged with N2 for 30 min. l-ethynyl-4- methylbenzene (2.24 g, 19.2 mmol, 2.45 mL, 3.00 eq ), and K2CO3 (2.66 g, 19.2 mmol, 3.00 eq) were added. The mixture was purged with N2 (3x). XPhos (245.1 mg, 514 umol, 0.08 eq) and Pd2(dba)3 (235.4 mg, 257 umol, 0.04 eq) were added to the mixture. The mixture was purged again with N2 (3x). The reaction was stirred at 80°C for 16 h. The reaction was poured into water (30 mL) and EtOAc (15 mL), and the system was stirred for 5 min. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=2/l), giving Compound Q71C, which was immediately used in the next reaction without further characterization.
[0444] Compound Q71: A vessel was charged with Compound Q71C (2.00 g, 5.77 mmol, 1.00 eq), THF (8.0 mL), MeOH (2.6 mL), and H20 (4.0 mL). NaOH (4.62 g, 115 mmol, 20.0 eq) was added. The reaction was stirred at 25°C for 30 min. Aq HC1 (IN) was added until the pH was 4. The system was extracted with EtOAc. The organic phase was dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=2/l). This gave
Compound Q71 which was immediately purified via chiral chromatography as detailed below.
Compound 072 and Compound 073
Figure imgf000158_0001
[0445] Compound Q72 and Compound Q73: A solution of Compound Q71 (1000 mg) was subjected to preparative chiral SFC using supercritical CO2 and MeOH as a mobile phase on a DAICEL CHIRALPAK AD column (250mm x 30mm x 10 pm) with isocratic elution at 78% IPA in 22% CO2 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q71. Stereochemistries of the products were arbitrarily assigned. This provided Compound Q72 (first to elute): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+EE]; found 319.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.52 (d, J= 7.6Hz, 2H), 7.46 (s, d, J = 7.6Hz, 1H), 7.39 (s, d, J= 7.6Hz, 1H), 7.20-7.17 (m, 3H), 6.49 (s, 1H), 3.31-3.26 (m, 1H), 3.07- 3.05 (m, 1H), 2.94-2.89 (m, 1H), 2.39 (s, 3H), 1.31 (d, J= 6.8Hz, 3H) and Compound Q73 (second to elute): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 319.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.52 (d, J= 7.6Hz, 2H), 7.46 (s, d, J= 7.6Hz, 1H), 7.39 (s, d, J = 7.6Hz, 1H), 7.20-7.15 (m, 3H), 6.49 (s, 1H), 3.31-3.26 (m, 1H), 3.07-3.05 (m, 1H), 2.94-2.89 (m, 1H), 2.39 (s, 3H), 1.31 (d, J= 6.8Hz, 3H).
Compound 074
Figure imgf000159_0001
[0446] Compound Q74B: A vessel was charged with Compound Q70 (7.03 g, 50.1 mmol, 1.50 eq) in DMF (70.0 mL). The mixture was purged with N2 for 5 min. Cul (318 mg, 1.67 mmol, 0.05 eq), Pd(PPh3)2Ch (1.17 g, 1.67 mmol, 0.05 eq), and TEA (10.1 g, 100 mmol, 13.9 mL, 3.00 eq) were added to the mixture. Compound Q74A (10.0 g, 33.4 mmol, 1.00 eq) was added. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The mixture was poured onto H2O (100 mL) and EtOAc (100 mL) and stirred for 5 min at 23°C. The organic layer was washed with brine (100 mL), dried over INfeSCri, and filtered. The filtrate was concentrated, and the residue was purified by column (S1O2, Petroleum ether/Ethyl acetate=10/l to 0/1), giving Compound Q74B. The material was immediately used in the next reaction below without further characterization.
[0447] Compound Q74C: A vessel was charged with Compound Q74B (1.10 g, 3.54 mmol, 1.00 eq) in DMF (11.0 mL). l-ethynyl-4-methylbenzene (615 mg, 5.30 mmol, 672 uL, 1.50 eq), and K2CO3 (1.47 g, 10.6 mmol, 3.00 eq) were added. XPhos (134 mg, 282 umol, 0.08 eq) and Pd2(dba)3 (129 mg, 141 umol, 0.04 eq) were added to the mixture at 15 °C. The reaction was stirred 80°C for 12 h. The reaction was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine (40 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=50/l to 0/1), giving Compound Q74C, which was immediately used in the next reaction without further
characterization. [0448] Compound Q74: A vessel was charged with Compound Q74C (3.00 g, 8.66 mmol, 1.00 eq ), THF (10.0 mL), MeOH (5.00 mL), and H20 (5.00 mL). NaOH (6.93 g, 173 mmol, 20.0 eq) was added. The reaction was stirred at 60°C for 5 h. Aq HC1 (1.0 M, 5 mL) was added until the pH was 1. The system was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, giving a residue, which was purified by column chromatography (Si02, Diehl oromethane/Methanol = 50/1-5/1). This gave Compound Q74 which was immediately purified via chiral chromatography as detailed below.
Compound 075 and Compound 076
Figure imgf000160_0001
[0449] Compound Q75 and Compound Q76: A solution of Compound Q74 (950 mg) was subjected to preparative chiral SFC using supercritical C02 and EtOH (doped with 0.1% NH4OH) as a mobile phase on a Chiralpak OJ column (250mm x 30mm x 10 pm) with isocratic elution at 45% EtOH (doped with 0.1% NH4OH) in 55% C02. Two peaks were obtained, corresponding to the two enantiomers of Compound Q74. Stereochemistries of the products were arbitrarily assigned. Combined fractions of the individual peaks were separately processed by concentrating to a residue that was treated with aq HC1 (1 M, 5 mL). The resulting systems were separately extacted with EtOAc (3 x 5 mL). Combined organic extracts were washed with brine (2 x 10 mL), dried over Na2S04, and filtered. The filtrate was concentrated. This provided Compound Q75 (first to elute): LCMS ESI+ calc’d for C HisCh : 319.1 [M+H+] ; found 637.3 [2M+H+] ¾ NMR (400 MHz, CDCh) d 7.57 (s, 1H), 7.45-7.43 (d, J= 8.0 Hz, 3H), 7.38-7.35 (d, J= 9.2 Hz, 1H), 7.17-7.15 (d, J= 8.0 Hz, 2H), 6.48 (s, 1H), 3.27-3.21 (m, 1H), 3.04-3.02 (m, 1H), 2.93-2.87 (m, 1H), 2.38 (s, 3H), 1.31-1.29 (d, J= 7.2 Hz, 3H) and Compound Q76
(second to elute): LCMS ESI+ calc’d for C HisCh : 319.1 [M+H+] ; found 637.3 [2M+H+] ¾ NMR (400 MHz, CDCh) d 7.57 (s, 1H), 7.45-7.43 (d, J= 8 Hz, 3H), 7.38-7.35 (d, J= 9.2 Hz , 1H), 7.17-7.15 (d, J= 8 Hz, 2H), 6.48 (s, 1H), 3.27-3.21 (m, 1H), 3.04-3.02 (m, 1H), 2.93- 2.87 (m, 1H), 2.38 (s, 3H), 1.31-1.29(d, J= 7.2 Hz, 3H).
Compound 077
Figure imgf000161_0001
[0450] Compound Q77B: A vessel was charged with Compound Q77A (7.00 g, 23.4 mmol, 1.00 eq), piperidine (2.39 g, 28.1 mmol, 2.78 mL, 1.2 eq), and DMF (21.0 mL). The mixture was purged with N2 for 30 min. Compound Q70 (4.92 g, 35.1 mmol, 1.50 eq) was introduced. Pd(PPh3)2(OAc)2 (263 mg, 351 umol, 0.015 eq) and Cul (178 mg, 936 umol, 0.04 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred at 60°C for 15.5 h. The mixture was poured onto H2O (300 mL) and EtOAc (500 mL). The organic layer was washed with brine (3x 200 mL), dried over INfeSCL, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/0 to 0/1), giving Compound Q77B. LCMS ESI+ calc’d for CwHisBrCL : 311.0 [M+EC] ; found 311.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.35 (dd, J= 8.4, 3.2 Hz, 2H), 7.10 (t, J= 8.0 Hz, 1H), 6.49 (s, 1H), 4.19-4.13 (m, 2H), 3.22-3.17 (m, 1H), 2.96-2.85 (m, 2H), 1.27-1.22 (m, 6H).
[0451] Compound Q77C: A vessel was charged with Compound Q77B (2.50 g, 8.03 mmol, 1.00 eq ) in DMF (17.5 mL). l-ethynyl-4-methylbenzene (2.80 g, 24.1 mmol, 3.06 mL, 3.00 eq), and K2CO3 (3.33 g, 24.1 mmol, 3.00 eq) were added. The mixture was purged with N2 (3x). XPhos (306 mg, 642 umol, 0.08 eq) and Pd2(dba)3 (294 mg, 321 umol, 0.04 eq) were added to the mixture. The mixture was purged with N2 (3x). The reaction was stirred 80°C for 16 h. The reaction was poured into water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine (150 mL), dried over Na2SC>4, and filtered.
The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/0 to 0/1), giving Compound Q77C, which was immediately used in the next reaction without further characterization.
[0452] Compound Q77: A vessel was charged with Compound Q77C (3.00 g, 8.66 mmol, 1 eq ), THF (11.1 mL), MeOH (3.90 mL), and H20 (6.00 mL). NaOH (6.93 g, 173 mmol, 20.0 eq ) was added. The reaction was stirred at 25°C for 16 h. The reaction was washed with petroleum ether; the remaining aq layer was treated with aq HC1 (5.0 M) until the pH was 1. The system was treated with more H2O (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2S04, and filtered.
The filtrate was concentrated under reduced pressure, giving Compound Q77, which was immediately purified via chiral chromatography as detailed below.
Compound 078 and Compound 079
Figure imgf000162_0001
[0453] Compound Q78 and Compound Q79: A solution of Compound Q77 (900 mg) was subjected to preparative chiral SFC using supercritical CO2 and IPA (doped with 0.1%
NH4OH) as a mobile phase on a DAICEL CHIRALPAK AD-H column (250mm x 30mm x 5 pm) with isocratic elution at 35% IPA (doped with 0.1% NH4OH) in 65% CO2. Two peaks were obtained, corresponding to the two enantiomers of Compound Q77. Combined fractions of the individual peaks were separately processed by concentrating to a residue that was treated with aq HC1 (1 M, 15 mL). The resulting systems were separately extacted with DCM (2 x 20 mL). Combined organic extracts were separately concentrated to provide the individual separated enantiomers. Stereochemistries of the products were arbitrarily assigned. This provided
Compound Q78 (first to elute): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+EC] ; found 319.1 [M+EE] ¾ NMR (400 MHz, CDCh) d 12.35 (s, 1H) , 7.57-7.5 l(m, 3H), 7.38 (d, =8.8 Hz, 1H), 7.28-7.24 (m, 2H), 6.82 (s, 1H), 3.31-3.10 (m, 1H), 2.93-2.86 (m, 2H), 2.33(s, 3H), 1.60 (d, .7=6.4 Hz, 3H) and Compound Q79 (second to elute): LCMS ESI+ calc’d for C21H18O3 : 319.1 [M+H+] ; found 637.3 [2M+H+] ¾ NMR (400 MHz, CDCb) d 12.35 (s, 1H) , 7.57-7.5 l(m, 3H), 7.38 (d, 7=8.8 Hz, 1H), 7.28-7.24 (m, 2H), 6.82 (s, 1H), 3.31-3.10 (m, 1H), 2.93-2.86 (m, 2H), 2.33(s, 3H), 1.60 (d, 7=6.4 Hz, 3H).
Compound 080
Figure imgf000163_0001
[0454] Compound Q80B: A vessel was charged with triethyl-(2-phosphono)- propanoate (17.1 g, 71.8 mmol, 15.7 mL, 1.05 eq) and THF (60.0 mL). The system was degassed and sparged with N2 (3x) then cooled to 0°C. NaOH (3.01 g, 75.2 mmol, 1.10 eq) was added. Reaction was stirred at 0°C for 0.5 hrs. Compound Q80A (10.0 g, 68.4 mmol, 1.00 eq) was added at 0 to 10°C. Reaction was stirred at 15°C for 1 hr. The mixture was treated with sat. aq NaHCCb (200.0 mL). The system was extracted with EtOAc (2x 200.0 mL). The combined organic layers were dried over INfeSCb and filtered. The filtrate was concentrated, giving
Compound Q80B. LCMS ESI+ calc’d for C14H14O3 : 231.1 [M+H+] ; found 231.0 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.63 (d, 7= 7.6 Hz, 1H), 7.58 (s, 1H), 7.53 (d, 7= 8.4 Hz, 1H), 7.37 (t, 7= 5.6 Hz, 1H), 7.29 (d, 7= 4.2 Hz, 1H), 6.96 (s, 1H), 4.35-4.30 (m, 2H), 2.41 (s, 3H), 1.40 (t, 7= 6.8 Hz, 3H).
[0455] Compound Q80C: A vessel was charged with Compound Q80B (3.00 g, 13.0 mmol, 1.00 eq) and THF (30.0 mL). 10% Pd/C (w/w) (0.30 g) was added. The mixture was sparged with ¾ three times. The reaction was stirred at 15°C for 3 h. The reaction was filtered. Concentration of the filtrate under reduced pressure provided Compound Q80C. LCMS ESI+ calc’d for C14H16O3 : 233.1 [M+H+] ; found 233.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.50 (d, 7= 8.4 Hz, 1H), 7.42 (d, 7= 7.6 Hz, 1H), 7.25-7.19 (m, 1H), 6.45 (s, 1H), 4.18-4.13 (m, 2H), 3.23-3.17 (m, 1H), 2.97-2.85 (m, 2H), 1.27-1.22 (m, 6H). [0456] Compound Q80: A vessel was charged with Compound Q80C (2.00 g, 8.61 mmol, 1.00 eq) in THF (40.0 mL), MeOH (20.0 mL), and H20 (20.0 mL). NaOH (6.89 g, 172 mmol, 20.0 eq) was added. The reaction was stirred at 70 °C for 1 h. Aq HC1 (1 M, 50 mL) was added, giving a pH of 3 to 4. The system was extracted with EtOAc (2x 200 mL). Combined organic layers were dried over Na2SC>4 and filtered. The filtrated was concentrated under reduced pressure, giving Compound Q80. ¾ NMR (400 MHz, CDCh) d 7.50 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.22-7.19 (m, 2H), 6.48 (s, 1H), 3.26-3.21 (m, 1H), 3.03-3.01 (m, 1H), 2.92-2.86 (m, 2H), 1.29 (d, J= 7.6 Hz, 3H).
Compound 081 and Compound 082
Figure imgf000164_0001
[0457] Compound Q81 and Compound Q82: A solution of Compound Q80 (850 mg) was subjected to chiral SFC using supercritical C02 and MeOH as a mobile phase on a DAICEL CHIRALPAK AY-3 column (150mm x 46mm x 3 pm) with gradient elution from 10 to 40% MeOH (doped with 0.05% isopropylamine) in C02 . Two peaks were obtained, corresponding to the two enantiomers of Compound Q80. Stereochemistries of the products were arbitrarily assigned. An analytical chiral SFC method was developed (differing from the preparative method): eluent was supercritical C02 and MeOH (doped with 0.05% isopropylamine) on a chiralcel AD-3 (5 pm, 0.46cm id x 5 cm length) column with gradient elution from 10-40% MeOH (doped with 0.05% isopropylamine). This provided Compound Q81 (first to elute): LCMS ESI+ calc’d for CI2HI203 : 205.1 [M+H+] ; found 205.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.50 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.22-7.19 (m, 2H), 6.48 (s, 1H), 3.26-3.21 (m, 1H), 3.03-3.01 (m, 1H), 2.92-2.86 (m, 2H), 1.29 (d, J= 7.6 Hz, 3H) and
Compound Q82 (second to elute): LCMS ESI+ calc’d for CI2HI203 : 205.1 [M+H+] ; found 205.1 [M+H+] 1H NMR (400 MHz, CDCh) d 7.50 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.22-7.19 (m, 2H), 6.48 (s, 1H), 3.26-3.21 (m, 1H), 3.03-3.01 (m, 1H), 2.92-2.86 (m, 2H), 1.29 (d, J= 7.6 Hz, 3H). Compound 083
Figure imgf000165_0001
Q83B Q83
[0458] Compound Q83A: A vessel was charged with triethyl-(2-phosphono)- propanoate (11.1 g, 46.7 mmol, 10.2 mL, 1.05 eq) and THF (40.0 mL). The system was degassed and sparged with N2 (3x) then cooled to 0°C. NaOH (1.96 g, 48.8 mmol, 1.10 eq) was added. Reaction was stirred at 0°C for 0.5 hrs. Compound Q21A (10 g, 44.4 mmol, 1.0 eq) was added as a solution in THF (40.0 mL) in a dropwise manner. Reaction was stirred at 20°C for 1 h. The mixture was treated with sat. aq NaHC03 (50.0 mL). The system was extracted with EtOAc (50 mL then 30 mL). The combined organic layers were dried over Na2S04 and filtered. The filtrate was concentrated, giving a residue. The residue was purified via column
chromatography (S1O2, Petroleum ether/Ethyl acetate = 20/1 to 10/1), giving Compound Q83A. LCMS ESI+ calc’d for C^HisBrOs : 309.0 [M+H+] ; found 309.2 [M+H+]
[0459] Compound Q83B: A vessel was charged with Compound Q83A (8.00 g, 25.8 mmol, 1.00 eq) and l-ethynyl-4-m ethylbenzene (6.01 g, 51.7 mmol, 2.00 eq). K2CO3 (10.7 g, 77.6 mmol, 3.00 eq) was added along with DMF (56.0 mL). The mixture was purged with N2 (3x). XPhos (986 mg, 2.07 mmol, 0.08 eq) and Pd2(dba)3 (947 mg, 1.04 mmol, 0.04 eq) were added to the mixture. The reaction was stirred at 80°C for 15.0 h. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/0 to 20/1), giving Compound Q83B. LCMS ESC calc’d for C23H20O3 : 345.1 [M+H+] ; found 345.1 [M+H+]
[0460] Compound Q83: A vessel was charged with Compound Q83B (1.50 g, 4.36 mmol, 1.00 eq) in THF (100 mL). NaOH (696 mg, 17.4 mmol, 4.0 eq) was added. The mixture was purged with N2 (3x). H2O (20.0 mL) and MeOH (20.0 mL) were added, and the reaction was stirred at 20°C for 1.0 h. The reaction was concentrated under reduced pressure. The resulting residue was triturated with water (20.0 mL) at 20°C for 30 min, and filtered, giving a cake, which upon drying under reduced pressure gave Compound Q83. LCMS ESI+ calc’d for C21H16O3 : 317.1 [M+LL] ; found 317.0 [M+H+] ¾ NMR (400 MHz, DMSO-de) d 7.78 (s, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.46-7.41 (m, 3H), 7.25-7.21 (m, 3H), 6.89 (s, 1H), 2.34 (s, 3H), 2.18 (s, 3H).
Example B1
Figure imgf000166_0001
[0461] Compound E1A: Oxalyl Chloride (51 pL, 2.0 mmol) was added dropwise to an ice-cooled solution of Compound Q3 (46 mg, 0.15 mmol), pyridine (1 drop) and
dichloromethane (0.50 mL). The reaction mixture was allowed to warm to room temperature, and was stirred for 30 mins. The reaction was condensed in vacuo to afford Compound E1A. This material was used without further purification. LCMS ESI+ calc’d for C20H17O2CI: 321.1 in MeOH [M+CH3OH-HCl+H+] ; found Found: 320.9 [M+CH3OH-HCl+H+].
[0462] Example Bl: To a stirred solution of Compound Q2 (15.0 mg, 0.08 mmol) and pyridine (20 pL, 0.24 mmol) in dry DCM (1.00 mL) at 0 °C was added dropwise a solution of Compound E1A (39 mg, 0.12 mmol) in 0.60 mL of DCM. The reaction mixture was stirred at room temperature for an additional 20 mins. The reaction was condensed and purified by column chromatography (10-60% EtOAc in hexanes, 12 g column) giving crude Example Bl. The crude Example B1 was purified a second time using 0-40% EtOAc in DCM giving
Example Bl. LCMS ESI+ calc’d for Ci-TEoOe: 475.2 [M+H+] Found: 475.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.38 (d, J= 8.0 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.13 (d, J= 8.0 Hz, 2H),
6.69 (d, J= 8.2 Hz, 1H), 4.88 - 4.77 (m, 1H), 4.33 - 4.22 (m, 1H), 4.18 (t, J= 11.8 Hz, 1H),
3.74 - 3.58 (m, 2H), 3.32 (dd, J= 13.6, 9.1 Hz, 1H), 2.89 - 2.76 (m, 2H), 2.71 - 2.61 (m, 1H), 2.57 (td, J= 7.3, 3.4 Hz, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.12 - 1.99 (m, 3H), 1.86 (d, J= 2.8 Hz, 3H).
Example B2 and Example B3
Figure imgf000167_0001
[0463] Compound E2A: To a solution of Compound Q6 (30 mg, 0.08 mmol) in dichloromethane (1.60 mL) was added Compound Q9 (27 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and the mixture was extracted 3 times with DCM (3 x 3 mL). The combined organic phases were dried (NaiSCE), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E2A. LCMS ESI+ calc’d for C47H58O6 : 719.4 [M+H+] ; found 719.4 [M+H+]
[0464] Example B2: To a solution of Compound E2A (46 mg, 0.06 mmol) in anhydrous toluene (1.30 mL) at -78 °C was added dropwise a solution of BCL, (0.18 mL, 1.0 M in dichloromethane, 0.18 mmol). The reaction mixture was stirred for 10 minutes and quenched at -78 °C with a saturated solution of NaHCCb (5 mL). The resulting solution was warmed to room temperature and stirred for 30 minutes. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers were dried overNaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example B2. LCMS ESI+ calc’d for C40H52O6 : 629.4 [M+H+] ; found 629.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.42 (d, J= 8.5 Hz, 2H), 7.37 - 7.27 (m, 4H), 6.84 - 6.77 (m, 1H), 6.69 (d, J= 8.2 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.34 (d, J= 11.9 Hz, 1H), 4.17 (d, J= 11.9 Hz, 1H), 3.77 - 3.63 (m, 2H), 3.33 (dd, 7= 15.7, 9.1 Hz, 1H), 2.90 - 2.76 (m, 2H), 2.69 - 2.53 (m, 3H), 2.15 - 1.99 (m, 5H), 1.76 - 1.67 (m, 1H), 1.66 - 1.57 (m, 2H), 1.32 (s, 9H), 1.16 - 1.02 (m, 4H), 0.86 (d, J= 6.5 Hz, 12H).
Figure imgf000168_0001
Example B3 [0465] Compound E3A: To a solution of Compound Q6 (30 mg, 0.08 mmol) in dichloromethane (1.60 mL) was added Compound Q10 (27 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and the mixture was extracted 3 times with DCM (3 x 3 mL). The combined organic phases were dried (NaiSCL), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E3A. LCMS ESI+ calc’d for C47H58O6 : 719.4 [M+H+] ; found 737.7 [M+H20+H+]
[0466] Example B3: To a solution of Compound E3A (47 mg, 0.07 mmol) in anhydrous toluene (1.30 mL) at -78 °C was added dropwise a solution of BCE (0.21 mL, 1.0 M in dichloromethane, 0.21 mmol). The reaction mixture was stirred for 10 minutes and quenched at -78 °C with a saturated solution of NaElCCh (5 mL). The resulting solution was warmed to room temperature and stirred for 30 minutes. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers were dried over Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example B3. LCMS ESI+ calc’d for C40H52O6 : 629.4 [M+H+] ; found 629.4 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.43 (d, J= 8.4 Hz, 2H), 7.37 - 7.28 (m, 4H), 6.85 - 6.77 (m, 1H), 6.70 (d, J= 8.1 Hz, 1H), 4.91 - 4.77 (m, 1H), 4.30 (d, J= 10.0 Hz, 1H), 4.21 (d, = 11.8 Hz, 1H), 3.73 (dd, = 12.2, 7.1 Hz, 1H), 3.65 (dd, 7= 12.0, 6.3 Hz, 1H), 3.32 (dd, J= 15.7, 9.2 Hz, 1H), 2.92 - 2.77 (m, 2H), 2.65 (d, J= 17.0 Hz, 1H), 2.57 (td, J= 7.3, 2.4 Hz, 2H), 2.12 (t, J= 6.9 Hz, 2H), 2.05 (dd, J= 14.5, 7.2 Hz, 3H), 1.76 - 1.67 (m, 1H), 1.67 - 1.58 (m, 2H), 1.32 (s, 9H), 1.16 - 1.02 (m, 4H), 0.86 (d, J= 6.5 Hz, 12H).
Example B4 and Example B5
Figure imgf000170_0001
Example B4
[0467] Compound E4A: To a solution of Compound Q6 (30 mg, 0.09 mmol) in dichloromethane (1.60 mL) was added Compound Qll (24 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and the mixture was extracted 3 times with DCM (3X 3 mL). The combined organic phases were dried (NaiSCL), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E4A. LCMS ESI+ calc’d for C44H52O6 : 677.4 [M+H+] ; found 677.2 [M+H+]
[0468] Example B4: To a solution of Compound E4A (29 mg, 0.04 mmol) in anhydrous DCM (0.90 mL) at -78 °C was added dropwise a solution of BCE (0.12 mL, 1.0 M in heptane, 0.12 mmol). The reaction mixture was stirred for 30 minutes and quenched at -78 °C with a saturated solution of NaElCCh (3 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried overNaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-50% EtOAc in Hexanes, 12 g column) giving Example B4. LCMS ESI+ calc’d for C37H46O6 : 587.3 [M+H+] ; found 587.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.38 (d, 7 = 8.0 Hz, 2H),
7.33 - 7.27 (m, 2H), 7.13 (d, 7 = 7.9 Hz, 2H), 6.84 - 6.76 (m, 1H), 6.69 (d, 7 = 8.2 Hz, 1H), 4.90 - 4.77 (m, 1H), 4.34 (d, 7 = 11.9 Hz, 1H), 4.17 (d, 7= 11.9 Hz, 1H), 3.69 (q, 7= 12.1 Hz, 2H),
3.33 (dd, 7 = 15.7, 9.1 Hz, 1H), 2.90 - 2.76 (m, 2H), 2.68 - 2.53 (m, 3H), 2.35 (s, 3H), 2.11 (t, 7 = 6.7 Hz, 2H), 2.08 - 1.99 (m, 7 = 13.9, 7.1 Hz, 3H), 1.76 - 1.57 (m, 3H), 1.16 - 1.00 (m, 4H), 0.86 (d, 7= 6.5 Hz, 12H).
Figure imgf000171_0001
Example B5
[0469] Compound E5A: To a solution of Compound Q6 (25 mg, 0.06 mmol) in dichloromethane (1.30 mL) was added Compound Q12 (20 mg, 0.06 mmol) followed by DMAP (20 mg, 0.16 mmol) and BOPC1 (41 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and the mixture was extracted 3 times with DCM (3X 3 mL). The combined organic phases were dried (NaiSCE), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E5A. LCMS ESI+ calc’d for C44H52O6 : 677.4 [M+H+] ; found 677.2 [M+H20+H+]
[0470] Example B5: To a solution of Compound E5A (30 mg, 0.04 mmol) in anhydrous DCM (0.90 mL) at -78 °C was added dropwise a solution of BCE (0.12 mL, 1.0 M in heptane, 0.12 mmol). The reaction mixture was stirred for 30 minutes and quenched at -78 °C with a saturated solution of NaHCCh (3 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried overNaiSCE, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-50% EtOAc in Hexanes, 12 g column) giving Example B5. LCMS ESI+ calc’d for C37H46O6 : 587.3 [M+H+] ; found 587.1 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.38 (d, J= 8.1 Hz, 2H), 7.30 (dd, J= 12.8, 3.7 Hz, 2H), 7.14 (d, J= 7.9 Hz, 2H), 6.85 - 6.77 (m, 1H), 6.70 (d, J= 8.1 Hz, 1H), 4.88 - 4.77 (m, 1H), 4.31 (d, 7= 11.9 Hz, 1H), 4.24 - 4.14 (m, 1H), 3.76 - 3.69 (m, 1H), 3.68 - 3.61 (m, 1H), 3.32 (dd, 7= 15.7, 9.0 Hz, 1H), 2.84 (dd, 7= 27.2, 11.8 Hz, 2H), 2.70 - 2.61 (m, 1H), 2.61 - 2.54 (m, 2H), 2.36 (s, 3H), 2.12 (t, 7 = 6.6 Hz, 2H), 2.10 - 1.97 (m, 7 = 13.8, 7.2 Hz, 3H), 1.76 - 1.58 (m, 3H), 1.17 - 1.01 (m, 4H), 0.86 (d, 7 = 6.5 Hz, 12H).
Example B6 and Example B7
Figure imgf000172_0001
Example B6
[0471] Compound E6A: To a solution of Compound Q5 (0.052 g, 0.188 mmol) in anhydrous dichloromethane (3.76 mL) was added Compound Qll (0.058 g, 0.188 mmol), followed by 4-(dimethylamino)pyridine (0.057 g, 0.470 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 0.120 g, 0.470 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E6A. LCMS ESI+ calc’d for CsefLeOe: 565.3 [M+H+] Found: 565.3 [M+H+]
[0472] Example B6: To a solution of Compound E6A (0.071 g, 0.126 mmol) in toluene
(5.0 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.377 mL, 0.377 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (6 mL) and the mixture was stirred at rt for 20 min. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal -phase chromatography (10 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B6. LCMS ESI+ calc’d for C29H30O6 : 475.2 [M+EL] ; found 475.0 [M+EL] ¾ NMR (400 MHz, CDCh) d 7.39 (d, J= 8.1 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.70 (d, J= 8.2 Hz, 1H), 4.89 - 4.78 (m, 1H), 4.30 (d, J= 1 1.8 Hz, 1H), 4.18 (d, 7= 11.8 Hz, 1H), 3.67 (qd, J = 12.1, 6.9 Hz, 2H), 3.33 (dd, J = 15.7, 9.2 Hz, 1H), 2.90 - 2.77 (m, 2H), 2.71 - 2.61 (m, 1H), 2.61 - 2.53 (m, 2H), 2.36 (s, 3H), 2.26 (t, J = 2.0 Hz, 3H), 2.11— 2.00 (m, 3H), 1.87 (s, 3H).
Figure imgf000173_0001
Example B7
[0473] Compound E7A: To a solution of Compound Q5 (0.035 g, 0.127 mmol) in anhydrous dichloromethane (2.53 mL) was added Compound Q12 (0.039 g, 0.127 mmol), followed by 4-(dimethylamino)pyridine (0.039 g, 0.317 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 0.081 g, 0.317 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give Compound E7A which was used in the next step without further purification. LCMS ESI+ calc’d for C36H36O6: 565.3 [M+H+] Found: 565.3 [M+H+]
[0474] Example B7: To a solution of Compound E7A (0.063 g, 0.112 mmol) in toluene
(4.5 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.355 mL, 0.355 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (6 mL) and the mixture was stirred at rt for 20 min. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal -phase chromatography (10 - 50 % ethyl acetate in hexanes) to give, after lyophilization, Example B7. LCMS ESI+ calc’d for C29H30O6 : 475.2 [M+H+] ; found 475.0 [M+LL] ¾ NMR (400 MHz, CDCb) d 7.39 (d, J= 8.1 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.70 (d, J= 8.2 Hz, 1H), 4.88 - 4.78 (m, 1H), 4.24 (dd, J= 27.0, 11.8 Hz, 2H), 3.66 (dd, J= 27.3, 11.4 Hz, 2H), 3.32 (dd, J= 15.7, 9.1 Hz, 1H), 2.91 - 2.77 (m, 2H), 2.66 (dd, J= 16.5, 1.7 Hz, 1H), 2.58 (td, J= 7.3, 2.6 Hz, 2H), 2.36 (s, 3H), 2.26 (t, J= 2.0 Hz, 3H), 2.15 - 1.99 (m, 3H), 1.87 (s, 3H).
Example B8
Figure imgf000174_0001
E8A Example B8
[0475] Compound E8A: To a solution of Compound Q5 (25 mg, 0.09 mmol) in anhydrous dichloromethane (1.81 mL) was added Compound Q13 (28 mg, 0.09 mmol), followed by 4-(dimethylamino)pyridine (28 mg, 0.23 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 58 mg, 0.23 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 50% ethyl acetate in hexanes) to give Compound E8A. LCMS ESI+ calc’d for C36H34O6 : 563.2 [M+H+]+] ; found 563.4 [M+H+]
[0476] Example B8: To a solution of Compound E8A (45 mg, 0.08 mmol) in toluene
(1.6 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.240 mL, 0.240 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (6 mL) and the mixture was stirred at rt for 20 min. The layers were separated and the aqueous phase was extracted 3 times with EtOAc The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B8. LCMS ESI+ calc’d for C29H28O6 : 473.2 [M+EC] ; found 472.9 [M+EC] ¾ NMR (400 MHz, CDCb) d 7.66 (s, 1H), 7.43 (d, 7 = 8.0 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.16 (d, 7 = 7.9 Hz, 2H), 6.43 (s, 1H), 4.29 (d, 7 = 11.8 Hz, 1H), 4.20 (d, 7= 11.8 Hz, 1H), 3.65 (d, 7 = 11.7 Hz, 1H), 3.58 (d, 7 = 12.1 Hz, 1H), 3.11 (t, 7= 7.4 Hz, 2H), 2.82 (t, 7= 7.4 Hz, 2H), 2.75 (d, 7= 16.6 Hz, 1H), 2.58 (d, 7= 16.7 Hz, 1H), 2.37 (s, 3H), 2.25 (s, 3H), 2.01 (s, 1H), 1.82 (s, 3H).
Figure imgf000176_0001
[0477] Compound E9A: To a solution of Compound Q6 (95 mg, 0.24 mmol) in anhydrous dichloromethane (4.89 mL) was added Compound Q13 (74 mg, 0.24 mmol), followed by 4-(dimethylamino)pyridine (75 mg, 0.61 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 156 mg, 0.61 mmol) at it. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E9A. LCMS ESI+ calc’d for C44H50O6 : 675.4 [M+H+]+] ; found 675.3 [M+H+]
[0478] Example B9: To a solution of Compound E9A (123 mg, 0.18 mmol) in toluene
(3.6 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.540 mL, 0.540 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (6 mL) and the mixture was stirred at rt for 20 min. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B9. LCMS ESI+ calc’d for C35H44O5 : 545.3 [M+H+] ; found 545.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.42 (dd, J= 14.2, 8.0 Hz, 4H), 7.19 - 7.12 (m, 4H), 6.82 - 6.75 (m, 1H), 4.29 (d, J= 11.9 Hz, 1H), 4.15 (d, J= 11.9 Hz, 1H), 3.60 (dd, 7= 31.9,
11.6 Hz, 2H), 2.95 (t, J= 7.6 Hz, 2H), 2.79 - 2.64 (m, 3H), 2.54 (d, 7= 18.2 Hz, 1H), 2.36 (s, 3H), 2.11 (t, J = 6.6 Hz, 2H), 1.99 (s, 1H), 1.75 - 1.66 (m, 1H), 1.64 - 1.58 (m, 2H), 1.15 - 0.99 (m, 4H), 0.85 (d, J= 6.4 Hz, 12H).
Example B10
Figure imgf000177_0001
[0479] Compound E10A: To a solution of Compound Q6 (30 mg, 0.08 mmol) in anhydrous dichloromethane (1.54 mL) was added Compound Q14 (26 mg, 0.08 mmol), followed by 4-(dimethylamino)pyridine (47 mg, 0.39 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 49 mg, 0.19 mmol) at rt. The solution became was stirred for about 40 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with di chi or om ethane (3 x 2 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal -phase chromatography (0 - 30% ethyl acetate in hexanes) to give
Compound E10A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+]+] ; found 703.5 [M+H+]
[0480] Example B10: To a solution of Compound E10A (35 mg, 0.05 mmol) in toluene
(1.05 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.15 mL, 0.15 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and the mixture was stirred at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 2 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after
lyophilisation, Example B10. LCMS ESI+ calc’d for C39H48O6 : 613.4 [M+H+] ; found 613.3 [M+LL] ¾ NMR (400 MHz, CDCh) d 7.66 (s, 1H), 7.44 - 7.39 (m, 2H), 7.38 (d, J= 1.5 Hz, 1H), 7.33 (d, J= 8.5 Hz, 1H), 7.15 (d, J= 7.9 Hz, 2H), 6.81 - 6.74 (m, 1H), 6.42 (s, 1H), 4.33 (d, J= 11.9 Hz, 1H), 4.18 (d, J= 11.8 Hz, 1H), 3.67 (qd, = 12.1, 6.8 Hz, 2H), 3.08 - 2.92 (m, 2H), 2.75 (d, J= 17.0 Hz, 1H), 2.58 (d, J= 16.0 Hz, 1H), 2.36 (s, 3H), 2.09 (t, J= 6.8 Hz, 1H), 2.00 (t, J= 6.8 Hz, 2H), 1.71 - 1.52 (m, 3H), 1.26 (d, J= 7.5 Hz, 6H), 1.14 - 0.96 (m, 4H), 0.84 (d, J= 6.5 Hz, 12H).
Example Bll
Figure imgf000179_0001
[0481] Compound E11A: To a solution of Compound Q6 (30 mg, 0.08 mmol) in anhydrous dichloromethane (1.54 mL) was added Compound Q15 (23 mg, 0.08 mmol), followed by 4-(dimethylamino)pyridine (24 mg, 0.19 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 49 mg, 0.19 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E11A. LCMS ESI+ calc’d for C44H51NO5 : 674.4 [M+H+] ; found 674.4 [M+H+]
[0482] Example Bll: To a solution of Compound E11A (39 mg, 0.06 mmol) in toluene
(1.15 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.18 mL, 0.18 mmol) dropwise. After stirring for 15 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and the mixture was stirred at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 2 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by normal -phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after
lyophilisation, Example Bll. LCMS ESI+ calc’d for C37H45NO5 : 584.3 [M+H+] ; found 584.4 [M+H+] ¾ NMR (400 MHz, CDCh) d 8.55 (s, 1H), 7.72 (s, 1H), 7.42 (d, J= 8.1 Hz, 2H), 7.30 (d, J= 0.9 Hz, 2H), 7.14 (d, J= 7.9 Hz, 2H), 6.83 - 6.74 (m, 1H), 6.23 (s, 1H), 4.33 (d, J= 11.8 Hz, 1H), 4.23 (d, 7= 11.8 Hz, 1H), 3.69 - 3.55 (m, 2H), 3.07 (t, J= 6.6 Hz, 2H), 2.81 - 2.69 (m, 3H), 2.57 (d, 7= 17.1 Hz, 1H), 2.36 (s, 3H), 2.07 (t, J= 6.5 Hz, 2H), 1.74 - 1.47 (m, 4H), 1.17 - 0.98 (m, 4H), 0.85 (d, J= 6.5 Hz, 12H).
Example B12
Figure imgf000180_0001
[0483] Compound E12A: To a solution of Compound Q6 (35 mg, 0.09 mmol) in anhydrous dichloromethane (1.80 mL) was added Compound Q16 (25 mg, 0.09 mmol), followed by 4-(dimethylamino)pyridine (28 mg, 0.23 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 57 mg, 0.23 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E12A. LCMS ESI+ calc’d for C42H5606 : 647.3 [M+H+] ; found 647.4 [M+H+]
[0484] Example B12: To a solution of Compound E12A (35 mg, 0.05 mmol) in toluene
(1.08 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.15 mL, 0.15 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and the mixture was stirred at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 2 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after
lyophilisation, Example B12. LCMS ESI+ calc’d for C35H40O6 : 557.3 [M+H+] ; found 557.2 [M+LL] ¾ NMR (400 MHz, CDCh) d 7.85 (s, 1H), 7.62 (dd, J= 8.7, 1.6 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.17 (d, J= 7.9 Hz, 2H), 6.89 - 6.80 (m, 1H), 4.62 - 4.48 (m, 2H), 3.80 (qd, 7 = 12.1, 6.5 Hz, 2H), 2.97 - 2.81 (m, 1H), 2.75 (d, J = 17.0 Hz, 1H), 2.38 (s, 3H), 2.20 - 2.07 (m, 3H), 1.71 (dd, 7= 12.9, 6.5 Hz, 1H), 1.64 - 1.50 (m, 2H), 1.16 - 1.00 (m, 4H), 0.90 - 0.77 (m, 12H).
Example B13
Figure imgf000182_0001
[0485] Compound E13A: To a solution of CDI (93 mg, 0.56 mmol, 1.0 eq.) in dry
DCM (2.4 mL) under a nitrogen atmosphere was added a solution of Compound Q6 (219 mg, 0.56 mmol, 1.0 eq.) and iPri Et (0.2 mL, 1.13 mmol, 2.0 eq.) in dry DCM (1.8 mL). The resulting mixture was stirred at room temperature for lh and a solution of Compound Q17 (147 mg, 0.56 mmol, 1.0 eq.) and DMAP (18 mg, 0.14 mmol, 0.25 eq.) in dry DCM (1.3 mL) was added. The solution was stirred for another 24h and some DMAP (18 mg, 0.14 mmol, 0.25 eq.) was added. Stirring was pursued for 12h and a solution of IN HC1 (2 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. Purification by silica gel
chromatography (3 to 25% Acetone/nHex) afforded Compound E13A. LCMS ESI+ calc’d for C43H49NO6 : 676.4 [M+EL] ; found 677.1 [M+H+]
[0486] Example B13: To a solution of Compound E13A (164 mg, 0.24 mmol, 1.0 eq.) in dry toluene (9.7 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.73 mL, 0.73 mmol) dropwise. After stirring for 30h at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at room temperature for 10 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. Purification by silica gel chromatography (10% to 40% Acetone/nHex) afforded Example B13. LCMS ESI+ calc’d for CsefLsNOe : 586.3 [M+H+] ; found 587.0
[MALL] ¾ NMR (400 MHz, CDCh) d 7.69 (s, 1H), 7.41 (dd, J= 16.4, 8.1 Hz, 4H), 7.15 (d, J = 7.8 Hz, 2H), 6.78 (t, J= 7.3 Hz, 1H), 6.59 (s, 1H), 5.44 (t, J= 5.4 Hz, 1H), 4.49 (d, J= 5.7 Hz, 2H), 4.39 (d, J= 12.0 Hz, 1H), 4.16 (d, J= 12.0 Hz, 1H), 3.65 (s, 2H), 2.83 (d, J= 17.1 Hz, 2H), 2.59 (d, J= 17.5 Hz, 1H), 2.37 (s, 3H), 2.11 (t, J= 6.2 Hz, 2H), 1.74 - 1.52 (m, 4H), 1.07 (tt, J = 14.2, 7.1 Hz, 4H), 0.85 (d, J= 6.4 Hz, 12H).
Example B14
Figure imgf000183_0001
[0487] Compound E14A: To a solution of CDI (36 mg, 0.22 mmol, 1.0 eq.) in dry
DCM (1.0 mL) under a nitrogen atmosphere was added a solution of Compound Q6 (85 mg, 0.22 mmol, 1.0 eq.) and iPriNEt (77 pL, 0.44 mmol, 2.0 eq.) in dry DCM (0.7 mL). The resulting mixture was stirred at room temperature for lh and a solution of Compound Q18 (60 mg, 0.22 mmol, 1.0 eq.) and DMAP (27 mg, 0.22 mmol, 1.0 eq.) in dry DCM (0.5 mL) was added. The solution was stirred for another 72h and a solution of IN HC1 (2 mL) was added.
The mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. Purification by silica gel chromatography (0 to 20% Acetone/nHex) afforded Compound E14A. LCMS ESI+ calc’d for C44H51NO6 : 690.9 [M+EL] ; found 690.3 [M+H+]
[0488] Example B14: To a solution of Compound E14A (56 mg, 0.081 mmol, 1.0 eq.) in dry toluene (3.25 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.24 mL, 0.24 mmol, 3.0 eq.)) dropwise. After stirring for 30h at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at room temperature for 10 min. The mixture was diluted and extracted with
dichloromethane (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. Purification by silica gel chromatography (3 to 25% Acetone/nHex) afforded Example B14 (mixture of rotamers). LCMS ESI+ calc’d for C37H45NO6 : 600.8 [M+H+] ; found 600.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.70 (s, 1H), 7.47 - 7.38 (m, 3H), 7.25 (m (mixed with chloroform), 1H), 7.16 (m, 2H), 6.76 (m, 1H), 6.60 (m, 1H), 4.55 (s, broad, 1H), 4.52 (s, broad, 1H), 4.46 (s, broad, 0.5H), 4.43 (s, broad, 0.5H), 4.18 (m, 1H),
3.81 - 3.56 (m, 3H), 3.04 (s, broad, 1.5H), 2.98 (s, broad, 1.5H), 2.92 - 2.54 (m, 4H), 2.36 (m, 3H), 2.05 (m, 2H), 1.58 (s, broad, 3H), 1.07 (s, broad, 4H), 0.84 (s, 12H).
Example B15
Figure imgf000185_0001
[0489] Compound E15A: To a solution of Compound Q6 (61 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.14 mL) under nitrogen atmosphere at room temperature was added Compound Q19 (50.0 mg, 0.16 mmol, 1.0 eq.), followed by DMAP (39 mg, 0.32 mmol, 2.0 eq.) and BOPC1 (80 mg, 0.32 mmol). The resulting mixture was stirred at room temperature overnight and a solution of sat. aq. NLLCl (5 mL) was then added. The mixture was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 0 to 20% EtOAc///-Hex) afforded Compound E15A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EL] ; found 689.5 [M+H+]
[0490] Example B15: To a solution of Compound E15A (84 mg, 0.12 mmol) in toluene
(4.9 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.37 mL, 0.37 mmol) dropwise. After stirring for 2h at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at rt for 45 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by reverse-phase chromatography (15-80% iPrOH/FbO + 10 mM Ammonium formate) and by normal-phase chromatography (0 - 60% EtOAc///-Hex) to give, after lyophilisation, Example B15. LCMS ESI+ calc’d for CssfEeOe : 599.3 [M+H+] ; found 599.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.62 (dd, 7 = 1.6, 0.6 Hz, 1H), 7.51 - 7.37 (m, 3H), 7.32 (dd, 7 = 8.4, 0.6 Hz, 1H), 7.17 (dd, 7 = 8.4, 0.6 Hz, 2H), 6.79 (tt, 7 = 7.5, 2.8 Hz, 1H), 4.32 (d, 7= 11.8 Hz, 1H), 4.20 (d, 7 = 11.8 Hz, 1H), 3.68 (d, 7 = 12.1 Hz, 1H), 3.61 (d, 7 = 12.1 Hz, 1H), 3.07 (t, 7= 7.4 Hz, 2H), 2.85 - 2.69 (m, 3H), 2.68 - 2.51 (m, 1H), 2.38 (s, 3H), 2.19 (s, 3H), 2.08 (dt, 7 = 14.9, 7.5 Hz, 2H), 1.70 (dt, 7 = 13.3, 6.6 Hz, 1H), 1.67 - 1.53 (m, 2H), 1.17 - 1.00 (m, 4H), 0.86 (dt, 7 = 6.5, 1.6 Hz, 12H).
Example B16
Figure imgf000186_0001
[0491] Compound E16A: To a solution of Compound Q6 (63 mg, 0.16 mmol, 1.0 eq.) and Compound Q20 (50 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.24 mL) under nitrogen atmosphere were added successively DMAP (101 mg, 0.81 mmol, 5.0 eq.) and BOPC1 (103 mg, 0.41 mmol, 2.5 eq.), and the resulting solution was stirred at room temperature for 3h. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 0 to 20% Acetone///-Hex) afforded Compound E16A. LCMS ESI+ calc’d for C43H50O7 : 679.4 [M+H+] ; found 680.1 [M+H+]
[0492] Example B16: To a solution of Compound E16A (86 mg, 0.13 mmol, 1.0 eq.) in dry toluene (5.1 mL) under a nitrogen atmosphere at -78°C was added BCb (1M in DCM, 0.38 mL, 0.38 mmol, 3.0 eq.) dropwise. The reaction was stirred at -78°C for 30 min and a solution of sat. aq. NaHCCh (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. The residue was purified by silica gel chromatography chromatography (0 to 25%
Acetone/nHex), affording, after lyophilisation, Example B16. LCMS ESI+ calc’d for C36H44O7 : 599.3 [M+EC] ; found 599.9 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.40 (d, J= 7.9 Hz, 2H), 7.15 (d, J= 7.9 Hz, 2H), 7.04 (d, J= 8.0 Hz, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.74 (d, J= 8.0 Hz, 1H), 6.24 (d, J= 4.2 Hz, 1H), 4.27 (dd, J= 47.0, 11.8 Hz, 2H), 3.70 (dd, J= 27.2, 12.0 Hz, 2H), 2.81 (d, J= 17.1 Hz, 1H), 2.61 (m, 3H), 2.37 (s, 3H), 2.29 (dd, J= 21.3, 13.9 Hz, 4H), 2.13 (t, J = 6.6 Hz, 2H), 1.77 - 1.56 (m, 3H), 1.17 - 1.02 (m, 4H), 0.87 (d, = 6.5 Hz, 12H).
Example B17 and Example B18
Figure imgf000188_0001
[0493] Compound E17A: To a solution of Compound Q6 (61 mg, 0.16 mmol, 1.0 eq.) and Compound Q22 (50 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.14 mL) under nitrogen atmosphere were added successively DMAP (98 mg, 0.79 mmol, 5.0 eq.) and BOPC1 (100 mg, 0.39 mmol, 2.5 eq.), and the resulting solution was stirred at rt for 3h. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 0 to 20% EtOAc/«-Hex) afforded Compound E17A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EL] ; found 690.1 [M+H+]
[0494] Example B17: To a solution of Compound E17A (86 mg, 0.13 mmol, 1.0 eq.) in dry toluene (4.99 mL) under a nitrogen atmosphere at -78°C was added BCE (1M in DCM, 0.39 mL, 0.39 mmol, 3.0 eq.) dropwise. The reaction was stirred at -78°C for 30 min and a solution of sat. aq. NaElCCh (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. The residue was purified by silica gel chromatography chromatography (20 to 60%
EtOAc/nHex), affording, after lyophilisation, Example B17. LCMS ESI+ calc’d for C38H46O6 : 599.3 [M+EC] ; found 600.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.67 (s, 1H), 7.45 - 7.34 (m, 4H), 7.15 (d, J= 7.8 Hz, 2H), 6.78 (t, J= 7.5 Hz, 1H), 6.41 (s, 1H), 4.29 (d, J= 11.9 Hz, 1H), 4.18 (d, J = 11.8 Hz, 1H), 3.61 (ddd, J= 29.7, 11.9, 5.7 Hz, 2H), 3.47 (dd, J= 13.9, 7.0 Hz, 1H), 2.88 (dd, J= 15.7, 7.0 Hz, 1H), 2.63 (ddd, J= 34.0, 30.9, 17.1 Hz, 3H), 2.37 (s, 3H), 2.07 (t, J= 6.3 Hz, 2H), 1.77 - 1.55 (m, 4H), 1.41 (d, J= 6.9 Hz, 3H), 1.08 (m, 3H), 0.86 (d, J= 6.5 Hz, 12H).
Figure imgf000189_0001
[0495] Compound E18A: To a solution of Compound Q6 (61 mg, 0.16 mmol, 1.0 eq.) and Compound Q21 (50 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.14 mL) under nitrogen atmosphere were added successively DMAP (98 mg, 0.79 mmol, 5.0 eq.) and BOPC1 (100 mg, 0.39 mmol, 2.5 eq.), and the resulting solution was stirred at rt for 3h. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCE, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 0 to 20% EtOAC/«-Hex) afforded Compound E18A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EC] ; found 690.1 [M+H20+H+]
[0496] Example B18: To a solution of Compound E18A (81 mg, 0.12 mmol, 1.0 eq.) in dry toluene (4.7 mL) under a nitrogen atmosphere at -78°C was added BCb (1M in DCM, 0.35 mL, 0.35 mmol, 3.0 eq.) dropwise. The reaction was stirred at -78°C for 30 min and a solution of sat. aq. NaHCCh (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCE, filtered and concentrated. The residue was purified by silica gel chromatography chromatography (20 to 60%
EtOAc/nHex), affording, after lyophilisation, Example B18. LCMS ESI+ calc’d for CssEL^CE : 599.3 [M+EC] ; found 600.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.67 (s, 1H), 7.46 - 7.35 (m, 4H), 7.16 (d, J= 7.9 Hz, 2H), 6.79 (t, J= 7.5 Hz, 1H), 6.44 (s, 1H), 4.25 (dd, J= 48.4, 11.8 Hz, 2H), 3.62 (dd, J= 30.2, 12.0 Hz, 2H), 3.15 (dd, J= 14.8, 7.3 Hz, 1H), 3.08 - 2.97 (m, 1H), 2.91 (dd, J= 14.9, 6.6 Hz, 1H), 2.74 (dd, J= 17.4, 0.8 Hz, 1H), 2.55 (dd, J= 16.5, 1.3 Hz, 1H), 2.38 (s, 3H), 2.07 (t, J= 6.7 Hz, 5H), 1.70 (dt, J= 15.7, 7.9 Hz, 1H), 1.60 (td, J= 13.3, 6.7 Hz, 3H), 1.27 - 1.24 (d, J = 4.6 Hz, 3H), 1.17 - 1.01 (m, 4H), 0.86 (d, 7= 6.5 Hz, 12H).
Example B19 and Example B20
Figure imgf000191_0001
[0497] Compound E19A: To a solution of Compound Q6 (61 mg, 0.16 mmol, 1.0 eq.) and Compound Q23 (50 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.14 mL) under nitrogen atmosphere were added successively DMAP (98 mg, 0.79 mmol, 5.0 eq.) and BOPC1 (100 mg, 0.39 mmol, 2.5 eq.), and the resulting solution was stirred at rt for 3h. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 3 to 15% Acetone/«-Hex) afforded Compound E19A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+H+] ; found 690.1 [M+H+]
[0498] Example B19: To a solution of Compound E19A (38 mg, 0.055 mmol, 1.0 eq.) in dry toluene (2.2 mL) under a nitrogen atmosphere at -78°C was added BCh (1M in DCM,
0.17 mL, 0.17 mmol, 3.0 eq.) dropwise. The reaction was stirred at -78°C for 30 min and a solution of sat. aq. NaHCCL (3 mL) was added. The mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. The residue was purified by silica gel chromatography (3 to 20% Acetone/nHex), affording, after lyophilisation, Example B19. LCMS ESI+ calc’d for C38H46O6 : 599.3 [M+H+] ; found 600.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.68 (s, 1H), 7.46 - 7.35 (m, 4H), 7.16 (d, J = 7.8 Hz, 2H), 6.79 (s, 1H), 6.42 (s, 1H), 4.32 (d, 7= 12.0 Hz, 1H), 4.18 (d, 7= 11.8 Hz, 1H), 3.73 - 3.54 (m, 2H), 3.49 (dd, J= 14.0, 6.8 Hz, 1H), 2.87 (dd, J= 15.9, 6.9 Hz, 1H), 2.81 - 2.50 (m, 4H), 2.38 (s, 3H), 2.06 (dd, J= 13.7, 7.0 Hz, 2H), 1.76 - 1.54 (m, 4H), 1.42 (d, J= 7.0 Hz, 3H), 1.07 (m, 4H), 0.86 (d, J= 6.5 Hz, 12H).
Figure imgf000192_0001
[0499] Compound E20A: To a solution of Compound Q6 (61 mg, 0.16 mmol, 1.0 eq.) and Compound Q24 (50 mg, 0.16 mmol, 1.0 eq.) in dry DCM (3.14 mL) under nitrogen atmosphere were added successively DMAP (98 mg, 0.79 mmol, 5.0 eq.) and BOPC1 (100 mg, 0.39 mmol, 2.5 eq.), and the resulting solution was stirred at rt for 3h. A solution of sat. aq. NH4CI (5 mL) was then added, and the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient from 3 to 15% Acetone/«-Hex) afforded Compound E20A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+H+] ; found 690.1 [M+H+]
[0500] Example B20: To a solution of Compound E20A (70 mg, 0.102 mmol, 1.0 eq.) in dry toluene (4.06 mL) under a nitrogen atmosphere at -78°C was added BCb (1M in DCM, 0.31 mL, 0.31 mmol, 3.0 eq.) dropwise. The reaction was stirred at -78°C for 30 min and solution of sat. aq. NaHCCL (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated. The residue was purified by silica gel chromatography (3 to 20% Acetone/nHex), affording, after lyophilisation, Example B20 after lyophilization. LCMS ESI+ calc’d for C38H4606 : 599.3 [M+H+] ; found 600.0 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.68 (s, 1H), 7.46 - 7.35 (m, 4H), 7.16 (d, J= 7.8 Hz, 2H), 6.79 (s, 1H), 6.42 (s, 1H), 4.32 (d, J= 12.0 Hz, 1H), 4.18 (d, J = 11.8 Hz, 1H), 3.73 - 3.54 (m, 2H), 3.49 (dd, J= 14.0, 6.8 Hz, 1H), 2.87 (dd, J = 15.9, 6.9 Hz, 1H), 2.81 - 2.50 (m, 4H), 2.38 (s, 3H), 2.06 (dd, J= 13.7, 7.0 Hz, 2H), 1.76 - 1.54 (m, 4H), 1.42 (d, J= 7.0 Hz, 3H), 1.07 (m, 4H), 0.86 (d, J= 6.5 Hz, 12H).
Example B21
Figure imgf000194_0001
[0501] Compound E21A: To a solution of Compound Q25 (60 mg, 0.15 mmol, 1.0 eq.) in anhydrous dichloromethane (3.0 mL) was added Compound Q14 (50 mg, 0.15 mmol,
1.0 eq.), followed by 4-(dimethylamino)pyridine (96 mg, 0.75 mmol, 5.0 eq.) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 94 mg, 0.38 mmol, 2.5 eq.) at it. The solution was stirred for about 3 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 12% Acetone/nHex) to give Compound E21A. LCMS ESI+ calc’d for C47H50O6 : 710.9 [M+H+] ; found 711.6 [M+H+]
[0502] Example B21: To a solution of Compound E21A (54 mg, 0.076 mmol, 1.0 eq.) in dry toluene (3mL) cooled to -78 °C was added boron trichloride (1 M solution in
dichloromethane, 0.23 mL, 0.23 mmol, 3.0 eq.) dropwise. After stirring for 30 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and the mixture was stirred at rt for 10 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by normal-phase chromatography (0 - 20 % Acetone/nHex) to give, after lyophilisation, Example B21. LCMS ESI+ calc’d for C40H44O6 : 621.8 [M+H+] ; found 622.0 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.67 (s, 1H), 7.47 - 7.32 (m, 4H), 7.15 (d, J= 7.9 Hz, 2H), 6.86 (t, 7= 8.1 Hz, 1H), 6.43 (s, 1H), 4.33 (d, J= 11.8 Hz, 1H), 4.18 (d, J= 11.9 Hz, 1H), 3.67 (q, J= 12.2 Hz, 2H), 3.01 (q, J= 14.7 Hz, 2H), 2.75 (d, J= 17.4 Hz, 1H), 2.59 (d, J = 16.8 Hz, 1H), 2.37 (s, 3H), 2.17 (s, 1H), 1.94 (s, 3H), 1.83 (d, J= 8.2 Hz, 2H), 1.64 (dd, J = 37.7, 12.1 Hz, 6H), 1.49 (s, 6H), 1.27 (d, 7= 9.1 Hz, 6H).
Example B22
Figure imgf000195_0001
Example B22
[0503] Compound E22A: To a solution of Compound Q27 (63 mg, 0.15 mmol. 1.0 eq.) and Compound Q14 (50 mg, 0.15 mmol, 1.0 eq.) in anhydrous dichloromethane (3.0 mL) under a nitrogen atmosphere at room temperature was added DMAP (94 mg, 0.75 mmol, 5.0 eq.), followed by BOPC1 (96 mg, 0.38 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature for 2h and a sat. aq. solution of NaHCCh (5 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSCri, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (3 to 20% Acetone/nHexane) afforded
Compound E22A. LCMS ESI+ calc’d for C48H5806 : 732.0 [M+H+] ; found 731.4 [M+H+]
[0504] Example B22: To a solution of Compound E22A (80 mg, 0.11 mmol, 1.0 eq.) in dry toluene (4.6 mL) cooled to -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in dichloromethane, 0.34 mL, 0.34 mmol, 3.0 eq.) dropwise. After stirring for 30 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at rt for 10 min. The mixture was diluted and extracted with DCM (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgSCri, filtered and concentrated. Purification by silica gel chromatography (0 to 20% Acetone/nHexane) afforded Example B22 after lyophilisation. LCMS ESI+ calc’d for C41H52O6 : 641.9 [M+H+] ; found 641.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.67 (d, = 1.0 Hz, 1H), 7.39 (m, 4H), 7.15 (d, J= 7.9 Hz, 2H), 6.90 - 6.74 (m, 1H), 6.43 (s, 1H), 4.26 (dd, J= 59.8, 11.8 Hz, 2H), 3.67 (dd, J= 25.6, 12.1 Hz, 2H), 3.01 (m, 2H), 2.85 - 2.51 (m, 2H), 2.37 (s, 3H), 2.10 (dd, J= 7.2,
5.7 Hz, 2H), 1.80 - 1.63 (m, 1H), 1.37 - 1.06 (m, 10H), 0.89 (s, 18H).
Example B23
Figure imgf000197_0001
Example B23
[0505] Compound E23A: To a solution of Compound Q6 (59.8 mg, 0.154 mmol, 1.00 equiv) in anhydrous CH2CI2 (3.06 mL) was added Compound Q29 (55.5 mg, 0.154 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (96.0 mg, 0.770 mmol, 5.00 equiv) and bis(2- oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 98.0 mg, 0.385 mmol, 2.5 equiv) at rt. The solution was stirred for about 72 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over INfeSCL and concentrated under reduced pressure. Purification by silica gel chromatography (24.0 g, hexanes/EtOAc, 0 - 30%) gave Compound E23A. LCMS ESI+ calc’d for C48H5806 : 732.4 [M+H+] ; found 731.6 [M+H+]
[0506] Example B23: Boron trichloride (0.164 mL, 0.164 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E23A (40.0 mg, 0.0547 mmol, 1.00 equiv) in dry toluene (2.19 mL) at -78 °C. After stirring for 2 hours at -78 °C, saturated aqueous NaHCCb (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24.0 g, hexane s/EtO Ac, 0-60%) followed by reverse phase chromatography (C18-24.0 g, water/ ACN, 30-100%) gave Example B23. LCMS ESI+ calc’d for C41H52O6 : 641.4 [MATE] ; found 641.4 [M+H+] 1H NMR (400 MHz, CDCh) d 7.66 (dd, J= 1.6, 0.6 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.39 (dd, J= 8.5, 1.6 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.15 (dd, J= 8.5, 0.6 Hz, 2H), 6.78 (tt, J= 7.5, 2.8 Hz, 1H), 6.42 (d, J= 0.6 Hz, 1H), 4.35 (d, J= 11.9 Hz, 1H), 4.19 (d, 7= 11.9 Hz, 1H), 3.70 (m, 2H), 3.05 (s, 2H), 2.81 - 2.72 (m, 1H), 2.65 - 2.56 (m, 1H), 2.37 (s, 3H), 2.13 (br s, 1H), 2.02 (dd, J= 7.5, 5.9 Hz, 2H), 1.73 - 1.52 (m, 7H + HOH), 1.13 - 0.98 (m, 4H), 0.89 (t, J= 7.5 Hz, 6H), 0.84 (dt, J= 6.5, 1.6 Hz, 12H).
Example B24
Figure imgf000198_0001
[0507] Compound E24A: To a solution of Compound Q6 (56 mg, 0.145 mmol, 1.0 eq.) in anhydrous dichloromethane (2.9 mL) was added Compound Q31 (50 mg, 0.145 mmol, 1.0 eq.), followed by 4-(dimethylamino)pyridine (89 mg, 0.73 mmol, 5.0 eq.) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 92 mg, 0.36 mmol, 2.5 eq.) at it. The solution was stirred for about 3 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with di chi or om ethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal -phase chromatography (3 - 15% Acetone/nHeptane) to give Compound E24A. LCMS ESI+ calc’d for C47H54O6 : 715.9 [M+H+] ; found 715.5 [M+H+]
[0508] Example B24: To a solution of Compound E24A (57 mg, 0.08 mmol, 1.0 eq.) in dry toluene (3.2 mL) cooled to -78 °C was added boron trichloride (1 M solution in
dichloromethane, 0.24 mL, 0.24 mmol, 3.0 eq.) dropwise. After stirring for 30 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and the mixture was stirred at rt for 10 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified twice by normal-phase chromatography (0 - 20 % Acetone///-Heptane) to give, after lyophilisation, Example B24. LCMS ESI+ calc’d for C39H48O6 : 625.8 [M+H+] ; found 625.1 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (s, 1H), 7.46 - 7.31 (m, 4H), 7.15 (d, J = 8.0 Hz, 2H), 6.77 (m, 1H), 6.40 (s, 1H), 4.34 (d, J= 11.8 Hz, 1H), 4.18 (d, J= 11.9 Hz, 1H), 3.62 (qd, J= 12.1, 6.8 Hz, 2H), 3.26 (s, 2H), 2.69 (d, J= 17.1 Hz, 1H), 2.52 (m, 3H), 2.37 (s, 3H), 2.14 (m, 2H), 2.00 (m, 5H), 1.72 - 1.51 (m, 4H), 1.12 - 0.97 (m, 4H), 0.85 (d, J= 6.5 Hz, 12H).
Example B25
Figure imgf000200_0001
[0509] Compound E25A: To a solution of Compound Q6 (59.8 mg, 0.154 mmol, 1.00 equiv) in anhydrous CH2CI2 (3.06 mL) was added Compound Q33 (51.2 mg, 0.154 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (96.0 mg, 0.770 mmol, 5.00 equiv) and bis(2- oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 98.0 mg, 0.385 mmol, 2.5 equiv) at rt. The solution was stirred for about 3 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (24.0 g, hexanes/EtOAc, 0 - 30%) gave Compound E25A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 703.6 [M+H+]
[0510] Example B25: Boron trichloride (0.351 mL, 0.351 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E25A (82.2 mg, 0.117 mmol, 1.00 equiv) in dry toluene (4.68 mL) at -78 °C. After stirring for 2 hours at -78 °C, saturated aqueous NaHCCh (10.0 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (24.0 g, hexane s/EtO Ac, 0-60%) followed by reverse phase chromatography (C18-24.0 g, water/ ACN, 30-100%) gave Example B25. LCMS ESI+ calc’d for Cs-TLsOe :
613.4 [MATE] ; found 613.4 [M+H+] 1H NMR (400 MHz, CDCh) d 7.67 (dd, J = 1.5, 0.8 Hz, 1H), 7.45 - 7.37 (m, 4H), 7.17 - 7.13 (m, 2H), 6.78 - 6.70 (m, 1H), 6.41 (d, J = 0.6 Hz, 1H),
4.13 - 4.06 (m, 2H), 3.49 (d, J = 12.1 Hz, 1H), 3.42 (d, J = 12.1 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.50 (dd, J = 17.1, 2.7 Hz, 1H), 2.37 (s, 3H), 2.35 - 2.30 (m, 1H), 2.02 (t, J = 6.6 Hz, 2H), 1.93 (br s, 1H), 1.69 (td, J = 13.3, 6.8 Hz, 1H), 1.64 - 1.52 (m, 2H), 1.49 (s, 6H), 1.14 - 1.00 (m, 4H), 0.88 - 0.82 (m, 12H).
Example B26
Figure imgf000201_0001
[0511] Compound E26A: To a solution of Compound Q6 (59 mg, 0.15 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q35 (50 mg, 0.15 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (92 mg, 0.76 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 96.0 mg, 0.38 mmol, 2.5 equiv) at rt. The solution was stirred for about 3 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over INfeSCL and concentrated under reduced pressure. Purification by silica gel chromatography (3 to 20% Acetone in Hexanes) afforded Compound E26A. LCMS ESI+ calc’d for C46H52O6 : 701.4 [M+H+] ; found 701.3 [M+H+]
[0512] Example B26: Boron trichloride (0.27 mL, 0.27 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E26A (63 mg, 0.09 mmol, 1.00 equiv) in dry toluene (3.6 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over
Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (5 to 40% Acetone in Hexanes) afforded Example B26. LCMS ESI+ calc’d for Cs-TLeOe : 611.1 [M+H+]; found 611.2 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.68 - 7.65 (m, 1H), 7.42 (d, 7 = 8.1 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.15 (d, 7 = 7.9 Hz, 2H), 6.77 - 6.71 (m, 1H), 6.47 (s, 1H), 4.26 (d, 7 = 11.8 Hz, 1H), 4.15 (d, 7 = 11.8 Hz, 1H), 3.59 (qd, 7 = 12.1, 6.9 Hz,
2H), 3.08 (dd, 7 = 36.7, 16.3 Hz, 2H), 2.54 (ddd, 7 = 65.1, 17.2, 2.6 Hz, 2H), 2.37 (s, 3H), 2.04 (t, 7= 6.8 Hz, 1H), 1.96 (dd, 7= 7.5, 6.0 Hz, 2H), 1.72 - 1.52 (m, 5H), 1.38 (dd, 7= 5.0, 2.3 Hz, 2H), 1.13 - 0.97 (m, 6H), 0.85 (d, 7= 6.6 Hz, 12H).
Example B27
Figure imgf000203_0001
[0513] Compound E27A: To a solution of Compound Q6 (78.1 mg, 0.201 mmol, 1.00 equiv) in anhydrous CH2CI2 (4.0 mL) at room temperature was added Compound Q37 (72.0 mg, 0.201 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (125 mg, 1.01 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 128 mg, 0.503 mmol, 2.5 equiv). The mixture was stirred for 24 hours at r.t. Saturated aqueous NH4CI (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 40%) gave Compound E27A. LCMS ESI+ calc’d for C48H5606 : 729.4 [M+H+] ; found 729.6 [M+H+]
[0514] Example B27: Boron trichloride (0.334 mL, 0.334 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E27A (81.1 mg, 0.111 mmol, 1.00 equiv) in dry toluene (4.5 mL) at -78 °C. After stirring for 40 mins at -78 °C, the mixture was warmed to 0°C and saturated aqueous NaHCCh (10 mL) was added. The mixture was stirred at r.t. for 15 mins. The mixture was diluted with water (10 mL) and CH2CI2 (15 mL). The layers were separated and the aqueous layer was extracted twice with CH2CI2 (2 x 15 mL). The combined organic layers were dried over INfeSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0-40%) followed by a reverse phase chromatography (Cl 8-24.0 g, lOmM ammonium formate in water/ ACN, 10- 100%) gave Example B27. LCMS ESI+ calc’d for C4iH5o06 : 639.4 [M+H+] ; found 639.5
[M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (dd, J = 1.6, 0.6 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.39 (dd, J = 8.5, 1.6 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.19 - 7.12 (m, 2H), 6.81 - 6.72 (m, 1H), 6.41 (d, J = 0.7 Hz, 1H), 4.25 (dd, J = 62.9, 11.9 Hz, 2H), 3.64 (q, J = 12.1 Hz, 2H), 3.09 (d, J = 3.9 Hz, 2H), 2.77 - 2.51 (m, 2H), 2.37 (s, 3H), 2.05 (ddd, J = 13.4, 10.1, 6.2 Hz, 5H), 1.77 - 1.49 (m,
8H + water), 1.13 - 0.98 (m, 4H), 0.84 (dd, J = 6.5, 2.1 Hz, 12H).
Example B28
Figure imgf000204_0001
[0515] Compound E28A: To a solution of Compound Q6 (75.5 mg, 0.194 mmol, 1.00 equiv) in anhydrous CH2CI2 (3.9 mL) at room temperature was added Compound Q39 (72.4 mg, 0.194 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (121 mg, 0.972 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 124 mg, 0.486 mmol,
2.5 equiv). The mixture was stirred for 3 hours at r.t. Saturated aqueous NH4CI (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over INfeSCL and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 40%) gave Compound E28A. LCMS ESI+ calc’d for C49H58O6 : 743.4 [M+H+] ; found 743.7 [M+H+]
[0516] Example B28: Boron trichloride (0.389 mL, 0.389 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E28A (96.3 mg, 0.130 mmol, 1.00 equiv) in dry toluene (5.2 mL) at -78 °C. After stirring for 40 mins at -78 °C, the mixture was warmed to 0°C and saturated aqueous NaHCCh (10 mL) was added. The mixture was stirred at r.t. for 45 mins. The mixture was diluted with water (10 mL) and CH2CI2 (15 mL). The layers were separated and the aqueous layer was extracted twice with CH2CI2 (2 x 15 mL). The combined organic layers were dried over INfeSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0-60%) followed by two reverse phase chromatographies (C18-24.0 g, lOmM ammonium formate in water/ ACN, 30- 100%) gave Example B28. LCMS ESI+ calc’d for C42H52O6 : 653.4 [M+H+] ; found 653.6
[M+EL] ¾ NMR (400 MHz, CDCh) d 7.66 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 8.5, 1.6 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.75 (dd, J = 8.8, 6.1 Hz, 1H), 6.40 (s, 1H), 4.21 (dd, J = 78.1, 11.9 Hz, 2H), 3.62 (qd, J = 12.2, 6.9 Hz, 2H), 2.97 (q, J = 14.7 Hz, 2H), 2.54 (dd, J = 86.4, 16.1 Hz, 2H), 2.37 (s, 3H), 2.18 - 2.00 (m, 2H), 1.96 (dd, J = 15.9, 7.0 Hz, 3H), 1.72 - 1.47 (m, 4H + water), 1.46 - 1.16 (m, 6H), 1.17 - 0.94 (m, 4H), 0.85 (d, J = 6.5 Hz, 12H).
Example B29 and Example B30
Figure imgf000206_0001
Example B29
[0517] Compound E29A: To a solution of Compound Q6 (50 mg, 0.13 mmol, 1.0 eq.) and Compound Q42 (43 mg, 0.13 mmol, 1.0 eq.) in dry dichloromethane (2.57 mL) at room temperature under a nitrogen atmosphere was added DMAP (80 mg, 0.64 mmol, 5.0 eq.), followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 82 mg, 0.32 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature for 3h and a solution of sat. aq. NH4CI (3 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 - 40%
EtO Ac/Hex) afforded Compound E29A. LCMS ESI+ calc’d for C46H54O6 : 703.4 [M+EC] ; found 703.7 [M+H+]
[0518] Example B29: To a solution of Compound E29A (80 mg, 0.11 mmol, 1.0 eq.) in dry toluene (2.3 mL) at -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in heptane, 0.34 mL, 0.34 mmol, 3.0 eq.) dropwise. The resulting mixture was stirred at -78 °C for 10 min and a sat. aq. solution of NaHCCL (4 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 4 mL). The combined organic layers were dried over Na2S04, concentrated under reduced pressure and purified by column chromatography (0 to 60% EtOAc in hexanes) to afford Example B29 after lyophilisation. LCMS ESC calc’d for CsgHwOe : 613.4 [M+H+] ; found 613.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (dd, J= 1.6, 0.6 Hz, 1H), 7.44 - 7.33 (m, 4H), 7.15 (dd, J= 8.5, 0.6 Hz, 2H), 6.80 - 6.73 (m, 1H), 6.42 (d, 7= 0.7 Hz, 1H), 4.32 (d, 7= 11.9 Hz, 1H), 4.13 (d, 7= 11.9 Hz, 1H), 3.59 (qd, 7 = 12.1, 6.9 Hz, 2H), 3.10 (dd, 7 = 15.2, 8.7 Hz, 1H), 2.94 (dd, 7 = 15.2, 5.8 Hz, 1H), 2.85 (tt, 7 = 8.6, 5.8 Hz, 1H), 2.66 (dd, 7 = 17.1, 2.8 Hz, 1H), 2.51 (dd, 7 = 17.1, 2.7 Hz, 1H), 2.37 (s, 3H), 2.08 - 1.97 (m, 3H), 1.79 - 1.56 (m, 5H), 1.14 - 0.99 (m, 4H), 0.96 (t, 7 = 7.4 Hz, 3H), 0.85 (dd, 7 = 6.6, 1.8 Hz, 12H).
Figure imgf000207_0001
Example B30
[0519] Compound E30A: To a solution of Compound Q6 (50 mg, 0.13 mmol, 1.0 eq.) and Compound Q43 (43 mg, 0.13 mmol, 1.0 eq.) in dry dichloromethane (2.57 mL) at room temperature under a nitrogen atmosphere was added DMAP (80 mg, 0.64 mmol, 5.0 eq.), followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 82 mg, 0.32 mmol, 2.5 eq.). The resultaing mixture was stirred at room temperature for 3h and a solution of sat. aq. NH4CI (3 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 - 40%
EtO Ac/Hex) afforded Compound E30A. LCMS ESI+ calc’d for C46H54O6 : 703.4 [M+EC] ; found 703.7 [M+H+]
[0520] Example B30: To a solution of Compound E30A (60 mg, 0.09 mmol, 1.0 eq.) in dry toluene (1.7 mL) at -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in heptane, 0.26 mL, 0.26 mmol, 3.0 eq.) dropwise. The resulting mixture was stirred at -78 °C for 10 min and a sat. aq. solution of NaElCCL (4 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 4 mL). The combined organic layers were dried over NaiSCL, concentrated under reduced pressure and purified by column chromatography (0 to 60% EtO Ac in hexanes) to afford Example B30 after lyophilisation. LCMS ESC calc’d for Cs-TCsOe : 613.4 [M+H+] ; found 613.7 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.68 - 7.63 (m, 1H), 7.44 - 7.33 (m, 4H), 7.15 (d, J = 8.3 Hz, 2H), 6.78 (td, J = 7.5,
3.7 Hz, 1H), 6.42 (s, 1H), 4.30 (d, J = 11.8 Hz, 1H), 4.21 - 4.09 (m, 1H), 3.60 (dd, J = 12.0, 7.2 Hz, 1H), 3.52 (dd, J = 12.1, 6.4 Hz, 1H), 3.09 (dd, J = 15.1, 8.6 Hz, 1H), 2.99 - 2.82 (m, 2H), 2.75 - 2.62 (m, 1H), 2.57 - 2.44 (m, 1H), 2.37 (s, 3H), 2.07 - 1.99 (m, 2H), 1.94 (t, J = 6.8 Hz, 1H), 1.79 - 1.56 (m, 5H), 1.13 - 0.99 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.85 (dd, J = 6.5, 2.2 Hz, 12H).
Example B31 and Example B32
Figure imgf000209_0001
[0521] Compound E31A: To a solution of Compound Q6 (100 mg, 0.257 mmol, 1.00 equiv) in anhydrous CH2CI2 (5.2 mL) at room temperature was added Compound Q46 (89.2 mg, 0.257 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (157 mg, 1.29 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (164 mg, 0.643 mmol, 2.50 equiv). After 6 hours, an additional portion of 4-(dimethylamino)pyridine (16 mg, 0.13 mmol, 0.50 equiv) was added, and the mixture was stirred for 14 hours at r.t. A saturated aqueous NH4CI solution (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 30%) gave Compound E31A. LCMS ESI+ calc’d for C47H56O6 : 717.4 [M+H+] ; found 717.7
[M+LL]
[0522] Example B31: Boron trichloride (0.57 mL, 0.57 mmol, 1.0 M solution in
CH2CI2, 3.0 equiv.) was added dropwise to a solution of Compound E31A (136 mg, 0.190 mmol, 1.00 equiv) in dry toluene (7.5 mL) at -78 °C. After stirring for 1.5 hours at -78 °C, a saturated aqueous NaHCCL solution (5.0 mL) was added to the mixture and the mixture was warmed to room temperature. The mixture was diluted with water (10.0 mL) and CLLCh (15.0 mL). The aqueous layer was extracted with CLLCh (3 x 10.0 mL). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24 g, hexanes/EtOAc, 0-40%) gave Example B31 after lyophilisation. LCMS ESI+ calc’d for C4oH5o06 : 626.8 [M+H+] ; found 627.4 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (s, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H),
7.16 (d, J = 8.0 Hz, 2H), 6.81 - 6.74 (m, 1H), 6.43 (s, 1H), 4.33 (d, J = 11.9 Hz, 1H), 4.18 (d, J = 11.9 Hz, 1H), 3.68 (q, J = 12.1 Hz, 2H), 3.15 (d, J = 14.8 Hz, 1H), 2.88 (d, J = 14.7 Hz, 1H),
2.74 (dd, J = 17.2, 1.8 Hz, 1H), 2.56 (dd, J = 16.9, 1.8 Hz, 1H), 2.37 (s, 3H), 2.03 (br s, 1H),
1.99 (t, J = 6.7 Hz, 2H), 1.83 - 1.73 (m, 1H), 1.70 - 1.61 (m, 2H), 1.62 - 1.51 (m, 2H+H20),
1.17 (s, 3H), 1.11 - 0.98 (m, 4H), 0.91 (t, J = 7.5 Hz, 3H), 0.85 (d, J = 6.6 Hz, 12H).
Figure imgf000210_0001
Example B32
[0523] Compound E32A: To a solution of Compound Q6 (100 mg, 0.257 mmol, 1.00 equiv) in anhydrous CH2CI2 (5.2 mL) at room temperature was added Compound Q47 (89.2 mg, 0.257 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (157 mg, 1.29 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (164 mg, 0.643 mmol, 2.50 equiv). After 6 hours, an additional portion of 4-(dimethylamino)pyridine (16 mg, 0.13 mmol, 0.5 equiv) was added, and the mixture was stirred for 14 hours at r.t. A saturated aqueous NH4CI solution (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over NaiSCL and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 30%) gave
Compound E32A. LCMS ESI+ calc’d for C47H56O6 : 717.4 [M+H+] ; found 717.7 [M+H+]
[0524] Example B32: Boron trichloride (0.52 mL, 0.52 mmol, 1.0 M solution in
CH2CI2, 3.0 equiv.) was added dropwise to a solution of Compound E32A (124 mg, 0.172 mmol, 1.00 equiv) in dry toluene (6.8 mL) at -78 °C. After stirring for 1.5 hours at -78 °C, a saturated aqueous NaHCCh solution (5.0 mL) was added to the mixture and the mixture was warmed to room temperature. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over INfeSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24 g, hexanes/EtOAc, 0-30%) gave Example B32 after lyophilisation. LCMS ESC calc’d for C4oH5o06 : 627.8 [M+H+] ; found 627.6 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.66 (s, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.82 - 6.75 (m, 1H), 6.42 (s, 1H), 4.34 (d, J = 11.8 Hz, 1H), 4.19 (d, J = 11.8 Hz, 1H), 3.68 (ddd, J = 15.7, 12.3, 5.1 Hz, 2H), 3.11 (d, J = 14.9 Hz, 1H), 2.90 (d, J = 14.7 Hz, 1H), 2.77 (dd, J = 17.1, 1.6 Hz, 1H), 2.63 (dd, J = 17.0, 1.3 Hz, 1H), 2.37 (s, 3H), 2.07 (br s, 1H), 2.01 (t, J = 6.7 Hz, 2H), 1.82 - 1.71 (m, 1H), 1.71 - 1.61 (m, 2H), 1.62 - 1.50 (m,
2H+H2O), 1.20 (s, 3H), 1.12 - 0.99 (m, 4H), 0.91 (t, J = 7.3 Hz, 3H), 0.84 (dd, J = 6.4, 2.5 Hz, 12H).
Example B33, Example B34, Example B35, and Example B36
Figure imgf000212_0001
Example B33
[0525] Compound E33A: To a solution of Compound Q6 (50 mg, 0.13 mmol, 1.0 eq.) and Compound Q51 (43 mg, 0.13 mmol, 1.0 eq.) in dry dichloromethane (2.57 mL) at room temperature under a nitrogen atmosphere was added DMAP (80 mg, 0.64 mmol, 5.0 eq.), followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 82 mg, 0.32 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature for 3h and a solution of sat. aq. NH4CI (3 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 - 40%
EtO Ac/Hex) afforded Compound E33A. LCMS ESI+ calc’d for C46H54O6 : 703.9 [M+EC] ; found 703.7 [M+H+]
[0526] Example B33: To a solution of Compound E33A (57 mg, 0.08 mmol, 1.0 eq.) in dry toluene (1.7 mL) at -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in heptane, 0.24 mL, 0.24 mmol, 3.0 eq.) dropwise. The resulting mixture was stirred at -78 °C for 10 min and a sat. aq. solution of NaHCCL (4 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 4 mL). The combined organic layers were dried over NaiSCL, concentrated under reduced pressure and purified by column chromatography (0 to 60% EtOAc in hexanes) to afford Example B33 after lyophilisation. LCMS ESI+ calc’d for CsgHwOe : 613.4 [M+H+] ; found 613.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (d, J = 0.7 Hz, 1H), 7.46 - 7.32 (m, 4H), 7.14 (d, J = 7.9 Hz, 2H), 6.81 - 6.72 (m, 1H), 6.41 (s, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 11.4 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H), 3.41 - 3.29 (m, 1H), 3.08 - 2.95 (m, 1H), 2.68 (d, J = 17.2 Hz, 1H), 2.49 (d, J = 17.1 Hz, 1H), 2.36 (s, 3H), 2.12 - 2.00 (m, 2H), 1.94 - 1.81 (m, 1H), 1.74 - 1.56 (m, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H), 1.12 - 0.99 (m, 4H), 0.84 (d, J = 6.4 Hz, 12H).
Figure imgf000213_0001
[0527] Compound E34A: To a solution of Compound Q6 (50 mg, 0.129 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q52 (42.8 mg, 0.129 mmol), followed by 4-dimethylaminopyridine (80.2 mg, 0.643 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (84.4 mg, 0.322 mmol) at it. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and the mixture was extracted with dichloromethane (3 x 10 mL). The organic layers were combined and dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 50% ethyl acetate in hexanes) to give Compound E34A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 703.7 [M+H+]
[0528] Example B34: To a solution of Compound E34A (50 mg, 0.071 mmol) in toluene (1.4 mL) cooled to -78 °C was added boron trichloride (1M in dichloromethane, 0.213 mL, 0.213 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was allowed to stir at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B34. LCMS ESI+ calc’d for C39H48O6 : 613.8 [M+H+] ; found 613.6 [M+LL] ¾ NMR (400 MHz, CDCh) d 7.66 (s, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.82 - 6.75 (m, 1H), 6.42 (s, 1H), 4.34 (d, J = 11.8 Hz, 1H), 4.19 (d, J = 11.8 Hz, 1H), 3.68 (ddd, J = 15.7, 12.3, 5.1 Hz, 2H), 3.11 (d, J = 14.9 Hz, 1H), 2.90 (d, J = 14.7 Hz, 1H), 2.77 (dd, J = 17.1, 1.6 Hz, 1H), 2.63 (dd, J = 17.0, 1.3 Hz, 1H), 2.37 (s, 3H), 2.07 (br s, 1H), 2.01 (t, J = 6.7 Hz, 2H), 1.82 - 1.71 (m, 1H), 1.71 - 1.61 (m, 2H), 1.62 - 1.50 (m, 2H+H20), 1.20 (s, 3H), 1.12 - 0.99 (m, 4H), 0.91 (t, J = 7.3 Hz, 3H), 0.84 (dd, J = 6.4, 2.5 Hz, 12H).
Figure imgf000215_0001
[0529] Compound E35A: To a solution of Compound Q6 (58 mg, 0.149 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q54 (50 mg, 0.149 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (91 mg, 0.746 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 95 mg, 0.373 mmol, 2.5 equiv) at rt. The solution was stirred for about 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over INfeSCL and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E35A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 702.9 [M+H+]
[0530] Example B35: Boron trichloride (0.31 mL, 0.306 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E35A (72 mg, 0.137 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (20% EtOAc in Hexanes) afforded Example B35. LCMS ESI+ calc’d for C39H48O6 : 613.8 [M+H+] ; found 613.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.64 (d, J= 1.0 Hz, 1H), 7.43 - 7.29 (m, 4H), 7.12 (d, J= 7.9 Hz, 2H), 6.80 - 6.70 (m, 1H), 6.40 (s, 1H), 4.30 (d, = 11.8 Hz, 1H), 4.15 (d, = 11.9 Hz, 1H), 3.61 (qd, = 12.1, 6.0 Hz, 2H), 3.27 (p, J= 7.0 Hz, 1H), 2.86 (p, J= 7.0 Hz, 1H), 2.69 (dd, J= 17.1, 2.8 Hz, 1H), 2.54 - 2.47 (m, 1H), 2.34 (s, 3H), 2.02 (dd, J= 7.5, 5.9 Hz, 3H), 1.71 - 1.61 (m, 3H), 1.60 - 1.49 (m, 7H), 1.33 (d, J= 7.0 Hz, 3H), 1.09 - 0.98 (m, 7H), 0.82 (d, J= 6.6, 3.0 Hz, 12H).
Figure imgf000216_0001
[0531] Compound E36A: To a solution of Compound Q6 (61 mg, 0.157 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q55 (52 mg, 0.157 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (96 mg, 0.785 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 100 mg, 0.393 mmol, 2.5 equiv) at rt. The solution was stirred for about 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E36A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 702.9 [M+H+]
[0532] Example B36: Boron trichloride (0.34 mL, 0.339 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E36A (80 mg, 0.113 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over
Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (20% EtOAc in Hexanes) afforded Example B36. LCMS ESI+ calc’d for C39H4806 : 613.8 [M+H+] ; found 613.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (d, J= 1.0 Hz, 1H), 7.47 - 7.23 (m, 6H), 7.15 (t, J= 12.8 Hz, 2H), 6.80 - 6.63 (m, 1H), 6.41 (s, 1H), 4.50 - 4.08 (m, 2H), 3.78 - 3.38 (m, 2H), 3.25 (p, J= 7.0 Hz, 1H), 2.96 - 2.74 (m, 1H), 2.70 (d, J =
17.1 Hz, 1H), 2.57 (d, J= 17.2 Hz, 1H), 2.34 (s, 3H), 2.03 (dd, J= 7.4, 6.0 Hz, 3H), 1.64 (ddd, J = 15.2, 9.5, 5.0 Hz, 2H), 1.31 (dd, = 20.3, 7.0 Hz, 4H), 1.13 - 0.95 (m, 9H), 0.84 (dd, = 12.8, 6.5 Hz, 16H).
Example B37 and Example B38
Figure imgf000218_0001
[0533] Compound E37A: To a solution of Compound Q6 (50 mg, 0.129 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q57 (42.5 mg, 0.129 mmol), followed by 4-dimethylaminopyridine (40.1 mg, 0.322 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (84.4 mg, 0.322 mmol) at it. The solution became cloudy after stirring for 5 min and the mixture was stirred for an additional 25 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and the mixture was extracted with dichloromethane (3 x 10 mL). The organic layers were combined and dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 50% ethyl acetate in hexanes) to give Compound E37A. LCMS ESI+ calc’d for C46H5206 : 701.4 [M+H+] ; found 701.7 [M+H+]
[0534] Example B37: To a solution of Compound E37A (48 mg, 0.069 mmol) in toluene (1.4 mL) cooled to -78 °C was added boron trichloride (1M in dichloromethane, 0.205 mL, 0.205 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was allowed to stir at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B37. LCMS ESI+ calc’d for C49H46O6 : 611.3 [M+H+] ; found 611.6 [M+LL] ¾ NMR (400 MHz, CDCh) d 7.59 (dd, J= 1.5, 0.5 Hz, 1H), 7.46 - 7.33 (m, 4H), 7.16 (dd, J= 8.5, 0.6 Hz, 2H), 6.82 (tt, J= 7.6, 2.8 Hz, 1H), 4.40 (d, J= 11.9 Hz, 1H), 4.23 (d, J = 11.9 Hz, 1H), 3.69 (ddd, J= 29.3, 12.1, 6.8 Hz, 2H), 3.06 - 2.92 (m, 3H), 2.85 - 2.60 (m, 4H), 2.37 (s, 3H), 2.31 - 2.21 (m, 1H), 2.13 (t, J= 6.7 Hz, 2H), 2.08 (t, J= 6.8 Hz, 1H), 2.05 - 1.92 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.57 (m, 2H), 1.16 - 1.02 (m, 4H), 0.90 - 0.82 (m, 12H).
Figure imgf000219_0001
Example B38
[0535] Compound E38A: To a solution of Compound Q6 (50 mg, 0.129 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q58 (42.5 mg, 0.129 mmol), followed by 4-dimethylaminopyridine (40.1 mg, 0.322 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (84.4 mg, 0.322 mmol) at it. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and the mixture was extracted with dichloromethane (3 x 10 mL). The organic layers were combined and dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 50% ethyl acetate in hexanes) to give Compound E38A. LCMS ESI+ calc’d for C46H5206 : 701.4 [M+H+] ; found 701.7 [M+H+]
[0536] Example B38: To a solution of Compound E38A (40 mg, 0.057 mmol) in toluene (1.2 mL) cooled to -78 °C was added boron trichloride (1M in dichloromethane, 0.171 mL, 0.171 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was allowed to stir at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilization, Example B38. LCMS ESI+ calc’d for C49H46O6 : 611.3 [M+H+] ; found 611.6 [M+LL] ¾ NMR (400 MHz, CDCh) d 7.59 (d, J= 1.3 Hz, 1H), 7.45 - 7.34 (m, 4H), 7.16 (d, J = 8.3 Hz, 2H), 6.81 (tt, J= 7.6, 2.8 Hz, 1H), 4.37 (d, J= 11.8 Hz, 1H), 4.24 (d, J= 11.8 Hz, 1H), 3.70 (ddd, J= 18.4, 12.2, 6.7 Hz, 2H), 3.06 - 2.93 (m, 3H), 2.83 - 2.57 (m, 4H), 2.37 (s, 3H), 2.29 - 2.20 (m, 1H), 2.14 - 2.07 (m, 2H), 2.04 - 1.93 (m, 2H), 1.75 - 1.66 (m, 1H), 1.66 - 1.57 (m, 2H), 1.17 - 1.00 (m, 4H), 0.86 (dd, J= 6.5, 1.5 Hz, 12H).
Example B39 and Example B40
Figure imgf000221_0001
[0537] Compound E39A: To a solution of Compound Q6 (100 mg, 0.257 mmol, 1.00 equiv) in anhydrous CH2CI2 (5.2 mL) at room temperature was added Compound Q60 (85.5 mg, 0.257 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (157 mg, 1.29 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (164 mg, 0.643 mmol, 2.50 equiv). The reaction mixture was stirred for 14 hours at r.t. A saturated aqueous NH4CI solution (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 30%) gave Compound E39A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 703.7 [M+H+]
[0538] Example B39: Boron trichloride (0.47 mL, 0.47 mmol, 1.0 M solution in hexanes, 3.0 equiv.) was added dropwise to a solution of Compound E39A (110 mg, 0.156 mmol, 1.00 equiv) in dry toluene (6.2 mL) at -78 °C. After stirring for 1.5 hours at -78 °C, saturated aqueous NaHCCh solution (5.0 mL) was added to the mixture and the mixture was warmed to room temperature. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24 g, hexanes/EtOAc, 0-30%) gave Example B39 after lyophilisation. LCMS ESI+ calc’d for CsgHwOe : 613.8 [M+H+] ; found 613.7 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.62 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.40 (dd, J = 8.5, 1.5 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.16 (d, J = 7.4 Hz, 2H), 6.82 - 6.74 (m, 1H), 4.31 (d, J = 11.9 Hz, 1H), 4.15 (d, J = 11.8 Hz, 1H), 3.60 (dd, J = 21.2, 12.2 Hz, 2H), 3.10 (dd, J = 14.4, 6.8 Hz, 1H), 2.99 (dd, J = 13.9, 6.5 Hz, 1H), 2.85 (dd, J = 14.4, 7.4 Hz, 1H), 2.70 (d, J = 16.6 Hz, 1H), 2.56 (d, J = 16.9 Hz, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 2.07 - 2.02 (m, 2H), 2.02 (br s, 1H), 1.72 - 1.64 (m, 1H), 1.64 - 1.57 (m, 2H+H20), 1.22 (d, J = 6.9 Hz, 3H), 1.10 - 1.00 (m, 4H), 0.85 (d, J =
6.4 Hz, 12H).
Figure imgf000222_0001
[0539] Compound E40A: To a solution of Compound Q6 (100 mg, 0.257 mmol, 1.00 equiv) in anhydrous CH2CI2 (5.2 mL) at room temperature was added Compound Q61 (85.5 mg, 0.257 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (157 mg, 1.29 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (164 mg, 0.643 mmol, 2.50 equiv). The reaction mixture was stirred for 14 hours at r.t. A saturated aqueous NH4CI solution (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 30%) gave Compound E40A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 703.7 [M+H+]
[0540] Example B40: Boron trichloride (0.45 mL, 0.45 mmol, 1.0 M solution in hexanes, 3.0 equiv.) was added dropwise to a solution of Compound E40A (105 mg, 0.149 mmol, 1.00 equiv) in dry toluene (5.9 mL) at -78 °C. After stirring for 1.5 hours at -78 °C, saturated aqueous NaHCCh solution (5.0 mL) was added to the mixture and the mixture was warmed to room temperature. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (24 g, hexanes/EtOAc, 0-30%) gave Example B40 after lyophilisation. LCMS ESC calc’d for Cs-TLsOe : 613.8 [M+H+] ; found 613.6 [M+H+] 1H NMR (400 MHz, CDCb) d 7.61 (d, 7 = 1.4 Hz, 1H), 7.43 (d, 7 = 8.1 Hz, 2H), 7.40 (dd, 7 = 8.5, 1.6 Hz, 1H), 7.32 (d, 7 = 8.4 Hz, 1H), 7.16 (d, 7 = 7.9 Hz, 2H), 6.81 - 6.74 (m, 1H), 4.29 (d, 7= 11.9 Hz, 1H),
4.17 (d, 7= 11.8 Hz, 1H), 3.58 (dd, 7= 30.0, 12.1 Hz, 2H), 3.10 (dd, 7= 14.2, 7.1 Hz, 1H), 3.01 (dd, 7= 13.9, 6.9 Hz, 1H), 2.86 (dd, 7= 14.2, 6.9 Hz, 1H), 2.72 (dd, 7= 17.3, 2.2 Hz, 1H), 2.52 (dd, 7= 16.9, 2.2 Hz, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 2.06 (t, 7= 6.6 Hz, 2H), 1.95 (br s, 1H),
1.73 - 1.64 (m, 1H), 1.63 - 1.57 (m, 2H+H20), 1.21 (d, 7= 6.9 Hz, 3H), 1.13 - 1.00 (m, 4H), 0.85 (dd, 7= 6.5, 2.9 Hz, 12H).
Example B41
Figure imgf000224_0001
Example B41
[0541] Compound E41A: To a solution of Compound Q27 (58.6, 0.14 mmol, 1.00 equiv) in anhydrous CH2CI2 (10.0 mL) was added Compound Q13 (42.8 mg, 0.14 mmol, 1.00 equiv), followed by 4-(dimethylamino) pyridine (86.0 mg, 0.70 mmol, 5.00 equiv) and bis(2- oxo-3 -oxazolidinyl) phosphinic chloride (BOPC1, 89.5 mg, 0.35 mmol, 2.5 equiv) at rt. The solution was stirred for about 8 hours at rt. Saturated aqueous NH4CI (lO.OmL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 20% Ethyl acetate in Hexanes) afforded
Compound E41A. LCMS ESI+ calc’d for C46H5406 : 703.4 [M+H+] ; found 703.6 [M+H+]
[0542] Example B41: Boron trichloride (0.30 mL, 0.30 mmol, 3.00 equiv, 1.0 M solution in Heptane) was added dropwise to a solution of Compound E41A (72.0 mg, 0.10 mmol, 1.00 equiv) in dry toluene (5.0 mL) at -78 °C. After stirring for 1.5 hours at -78 °C, saturated aqueous NaHCCb (5.0 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (30.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (5 to 50% Acetone in Hexanes) afforded Example B41 after lyophilisation. LCMS ESI+ calc’d for CsgHwOe : 613.4 [M+H+] ; found 613.7 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.66 (m, 1H), 7.45-7.33 (m, 4H), 7.15 (dd, J = 7.9, 0.5 Hz, 2H), 6.81 (m, 1H), 6.42 (s, 1H), 4.33 (d, J = 12.1 Hz, 1H), 4.19 (d, J = 12.1 Hz, 1H), 3.66 (d, J = 12.1 Hz, 1H), 3.61 (d, J = 12.1 Hz, 1H), 3.10 (t, J = 7.4 Hz, 2H), 2.81-2.71 (m, 3H), 2.58 (dd, J = 17.4, 2.3 Hz, 1H), 2.36 (s, 3H), 2.24-2.11 (m, 2H), 1.73 (td, J = 10.7, 5.6 Hz, 1H), 1.28-1.20 (m, 5H), 1.18 (m, 2H), 0.90(s, 9H), 0.88 (s, 9H).
Example B42
Figure imgf000225_0001
[0543] Compound E42A: To a solution of Compound Q25 (47 mg, 0.12 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q13 (36 mg, 0.12 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (72 mg, 0.60 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 75.0 mg, 0.30 mmol, 2.5 equiv) at rt. The solution was stirred for about 3 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (5% Ethylacetate in Hexanes) afforded Compound E42A. LCMS ESI+ calc’d for C45H46O6 : 683.3 [M+H+] ; found 683.4 [M+H+]
[0544] Example B42: Boron trichloride (0.18 mL, 0.18 mmol, 3.00 equiv, 1.00 M solution in Heptane) was added dropwise to a solution of Compound B42 (42 mg, 0.06 mmol, 1.00 equiv) in dry toluene (3.6 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (20% EtOAc in Hexanes) afforded Example B42 after lyophilization. LCMS ESC calc’d for C38H4o06 : 593.3 [M+H+] ; found 593.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (d, J= 0.9 Hz, 1H), 7.45 - 7.33 (m, 4H), 7.15 (d, 7= 7.9 Hz, 2H), 6.91 - 6.83 (m, 1H), 6.42 (d, 7= 0.8 Hz, 1H), 4.32 (d, 7 = 11.9 Hz, 1H), 4.21 (d, 7 = 11.8 Hz, 1H), 3.65 (m, 2H), 3.10 (t, 7 = 7.3 Hz, 2H), 2.85-2.71 (m, 3H), 2.60 (d, 7 = 19.9 Hz, 1H), 2.37 (s, 3H), 1.96 (d, 7 = 6.9 Hz, 4H), 1.90 (d, 7= 8.1 Hz, 2H), 1.75 - 1.55 (m, 6H), 1.51 (d, 7 = 2.4 Hz, 5H).
Example B43
Figure imgf000227_0001
[0545] Compound E43A: To a solution of Compound Q25 (58 mg, 0.15 mmol. 1.0 eq.) and Compound Q31 (48 mg, 0.14 mmol, 1.0 eq.) in anhydrous dichloromethane (3.0 mL) under a nitrogen atmosphere at room temperature was added DMAP (101 mg, 0.83 mmol, 6.0 eq.), followed by BOPC1 (100 mg, 0.39 mmol, 2.8 eq.). The resulting mixture was stirred at room temperature for 2 h and a sat. aq. solution of NaHCCb (5 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (10 mL), brine (2 x 10 mL), dried over anhydrous MgSCri, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 80% EtOAc/nHexane) afforded Compound E43A. LCMS ESI+ calc’d for C48H50O6 : 723.4 [M+EL] ; found 723.1 [M+H+]
[0546] Example B43: To a solution of Compound E43A (58 mg, 0.08 mmol, 1.0 eq.) in dry toluene (3.0 mL) cooled to -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in dichloromethane, 0.24 mL, 0.24 mmol, 3.0 eq.) dropwise. After stirring for 30 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at rt for 1 h. The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with water (10 mL), brine (2 x 10 mL), dried over anhydrous MgS04, filtered and concentrated. Purification by silica gel chromatography (0 to 40% EtOAc/nHexane, gold column) afforded Example B43 after lyophilisation. LCMS ESI+ calc’d for C4IH4406 : 633.3 [M+H+] ; found 633.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.74 (d, 7= 1.4 Hz, 1H), 7.53 (d, 7= 8.5 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 (dd, J= 8.5, 1.7 Hz, 1H), 7.24 (d, J= 7.9 Hz, 2H), 6.58 (s, 1H), 6.57 - 6.49 (m, 1H), 5.28 (t, J= 5.8 Hz, 1H), 4.21 (dd, J = 27.8, 11.8 Hz, 2H), 3.58 - 3.46 (m, 2H), 2.73 - 2.64 (m, 1H), 2.40 - 2.26 (m, 6H), 2.09 - 1.72 (m, 10H), 1.58 (dd, J= 32.8, 11.4 Hz, 7H), 1.46 - 1.39 (m, 6H).
Example B44
Figure imgf000228_0001
Example B44
[0547] Compound E44A: To a solution of Compound Q25 (79 mg, 0.20 mmol. 1.1 eq.) and Compound Q29 (67 mg, 0.19 mmol, 1.0 eq.) in anhydrous dichloromethane (3.0 mL) under a nitrogen atmosphere at room temperature was added DMAP (118 mg, 0.96 mmol, 5.0 eq.), followed by BOPC1 (115 mg, 0.45 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature for 2 h. DCM (15 mL) was added, the organic layer was washed with a sat. aq. solution of NaHCCb (5 mL), water (5 mL), brine (2 x 5 mL), dried over anhydrous MgSCL, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 70% EtOAc/nHexane) afforded Compound E44A. LCMS ESI+ calc’d for C49H54O6 : 739.4 [MALE] ; found 739.2 [M+H+]
[0548] Example B44: To a solution of Compound E44A (19 mg, 0.03 mmol, 1.0 eq.) in dry toluene (1.5 mL) cooled to -78 °C under a nitrogen atmosphere was added boron trichloride (1 M solution in dichloromethane, 80 pL, 0.08 mmol, 3.0 eq.) dropwise. After stirring for 1 h at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with water (10 mL), brine (2 x 10 mL), dried over anhydrous MgSCL, filtered and concentrated. Purification by silica gel chromatography (0 to 40% EtOAc/nHexane, gold column) afforded Example B44 after lyophilisation. LCMS ESI+ calc’d for C42H4806 : 649.4 [M+H+] ; found 649.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.74 (d, J= 1.6 Hz, 1H), 7.54 (d, J= 8.5 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.40 (dd, J= 8.6, 1.7 Hz, 1H), 7.24 (d, J= 8.0 Hz, 2H), 6.66 (s, 1H), 6.61 - 6.49 (m, 1H), 5.30 (t, J= 5.6 Hz, 1H), 4.22 (dd, J = 29.7, 11.7 Hz, 2H), 3.61 - 3.49 (m, 2H), 2.76 - 2.54 (m, 3H), 2.37 - 2.30 (m, 3H), 1.85 (br s, 3H), 1.77 (dd, J= 14.2, 6.6 Hz, 2H), 1.66 - 1.37 (m, 17H), 0.86 - 0.74 (m, 6H).
Example B45
Figure imgf000230_0001
Example B45
[0549] Compound E45A: To a solution of Compound Q62 (70.0 mg, 0.216 mmol,
1.00 equiv) in anhydrous CH2CI2 (4.3 mL) at room temperature was added Compound Q13 (65.7 mg, 0.216 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (135 mg, 1.08 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 137 mg, 0.539 mmol, 2.5 equiv). The mixture was stirred for 18.5 hours at r.t. Saturated aqueous NH4CI (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 60%) gave Compound E45A. LCMS ESI+ calc’d for C40H34O6 : 611.2 [M+H+] ; found 611.5 [M+H+]
[0550] Example B45: Boron trichloride (0.418 mL, 0.418 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E45A (85.1 mg, 0.139 mmol, 1.00 equiv) in dry toluene (5.5 mL) at -78 °C. After stirring for 30 mins at -78 °C, the mixture was warmed to 0°C and saturated aqueous NaHCCh (10 mL) was slowly added. The mixture was stirred at r.t. for 30 mins. The mixture was diluted with water (10 mL) and CH2CI2 (15 mL). The layers were separated and the aqueous layer was extracted twice with CH2CI2 (2 x 15 mL). The combined organic layers were dried overNa2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 20-80%) followed by two reverse phase chromatographies (C18-30g, Amm. Form./ACN, 20-100%) gave Example B45. LCMS ESI+ calc’d for C33H28O6 : 521.2 [M+H+] ; found 521.4 [M+H+] ¾
NMR (400 MHz, CDCb) d 7.61 (d, J = 1.4 Hz, 1H), 7.58 (t, J = 2.9 Hz, 1H), 7.49 - 7.40 (m,
7H), 7.37 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.37 (d, J = 0.7 Hz, 1H), 4.37 (d, J = 11.9 Hz, 1H), 4.28 (d, J = 11.9 Hz, 1H), 3.72 (ddd, J = 28.0, 12.1, 6.7 Hz, 2H), 3.19 (dd, J = 17.7, 2.9 Hz, 1H), 3.08 (t, J = 7.4 Hz, 2H), 3.00 (dd, J = 17.7, 2.8 Hz, 1H), 2.85 - 2.74 (m, 2H), 2.37 (s, 3H), 2.02 (t, J = 6.8 Hz, 1H).
Example B46
Figure imgf000231_0001
Example B46
[0551] Compound E46A: To a solution of Compound Q62 (60.0 mg, 0.185 mmol,
1.00 equiv) in anhydrous CH2CI2 (3.7 mL) at room temperature was added Compound Q14 (61.5 mg, 0.185 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (115 mg, 0.925 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 118 mg, 0.462 mmol, 2.5 equiv). The mixture was stirred for 18.5 hours at r.t. Saturated aqueous NH4CI (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 0 - 60%) gave Compound E46A. LCMS ESI+ calc’d for C42H38O6 : 639.3 [M+H+] ; found 639.6 [M+H+]
[0552] Example B46: Boron trichloride (0.555 mL, 0.555 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E46A (118 mg, 0.185 mmol, 1.00 equiv) in dry toluene (7.4 mL) at -78 °C. After stirring for 30 mins at -78 °C, the mixture was warmed to 0°C and saturated aqueous NaHCCh (10 mL) was added. The mixture was stirred at r.t. for 30 mins. The mixture was diluted with water (10 mL) and CH2CI2 (15 mL) The layers were separated and the aqueous layer was extracted twice with CH2CI2 (2 x 15 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (12 g, heptanes/EtOAc, 20-60%) followed by one reverse phase chromatography (C18-24.0 g, water/ ACN, 30-100%) gave Example B46. LCMS ESC calc’d for C35H32O6 : 549.2 [M+H+] ; found 549.5 [M+H+] 1H NMR (400 MHz, CDCb) d 7.61 (dd, J = 1.6, 0.6 Hz, 1H), 7.58 (t, J = 2.9 Hz, 1H), 7.46 - 7.33 (m, 8H), 7.30 (d, J = 4.6 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.35 (s, 1H), 5.30 (trace DCM), 4.31 (dd, J = 54.5, 11.9 Hz, 2H), 3.75 (q, J = 13.0 Hz, 2H), 3.20 (dd, J = 17.6, 3.0 Hz, 1H), 3.00 (dd, J = 17.7, 2.7 Hz, 1H), 2.96 (s, 2H), 2.37 (s, 3H), 2.11 (s, 1H), 1.56 (H20), 1.23 (d, J = 4.0 Hz, 6H).
Example B47
Figure imgf000232_0001
Example B47
[0553] Compound E47A: To a solution of Compound Q62 (67 mg, 0.20 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q31 (69 mg, 0.20 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (128 mg, 1.03 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 131 mg, 0.51 mmol, 2.5 equiv) at rt. The solution was stirred for about 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E47A. LCMS ESI+ calc’d for C43H38O6 : 651.3 [M+H+] ; found 651.6 [M+H+]
[0554] Example B47: Boron trichloride (0.41 mL, 0.41 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E47A (89 mg, 0.137 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over
Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (20% EiOAc in Hexanes) afforded Example B47. LCMS ESI+ calc’d for C36H32O6 : 561.2 [M+H+] ; found 561.4 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.57 (dd, J = 1.6, 0.6 Hz, 1H), 7.55 (t, J= 2.9 Hz, 1H), 7.45 - 7.32 (m, 8H), 7.27 (d, J= 0.7 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.31 (d, 7= 0.8 Hz, 1H), 4.37 (d, 7= 13.8 Hz, 1H), 4.24 (d, 7= 11.9 Hz, 1H), 3.69 (q, 7 = 12.1 Hz, 2H), 3.21 (s, 2H), 3.15 (dd, 7 = 17.7, 3.0 Hz, 1H), 2.95 (m, 1H), 2.57 - 2.40 (m, 2H), 2.37 (s, 2H), 2.17 - 2.01 (m, 2H), 1.99 - 1.84 (m, 2H).
Example B48
Figure imgf000233_0001
Example B48
[0555] Compound E48A: To a solution of Compound Q62 (70.0 mg, 0.216 mmol,
1.00 equiv) in anhydrous CH2CI2 (4.3 mL) at room temperature was added Compound Q29 (77.8 mg, 0.216 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (135 mg, 1.08 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 137 mg, 0.539 mmol, 2.5 equiv). The mixture was stirred for 18.5 hours at r.t. 1.25 equiv. of 4- Dimethylaminopyridine (33.0 mg, 0.270 mmol) and 0.625 equiv. of Bis(2-oxo-3- oxazolidinyl)phosphinic chloride (35.4 mg, 0.135 mmol) were added to the reaction, which was stirred at r.t. for 3 hours. Saturated aqueous NH4CI (6 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel
chromatography (25 g, heptanes/EtOAc, 0 - 40%) gave Compound E48A. LCMS ESI+ calc’d for C44H42O6 : 667.3 [M+H+] ; found 667.6 [M+H+]
[0556] Example B48: Boron trichloride (0.449 mL, 0.449 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E48A (99.9 mg, 0.150 mmol, 1.00 equiv) in dry toluene (5.5 mL) at -78 °C. After stirring for 30 mins at -78 °C, the mixture was warmed to 0°C and saturated aqueous NaHCCh (10 mL) was added. The bi-phasic mixture was stirred at r.t. for 30 mins. The mixture was diluted with water (10 mL) and CH2CI2 (15 mL). The layers were separated and the aqueous layer was extracted twice with CH2CI2 (2 x 15 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (25 g, heptanes/EtOAc, 20-60%) followed by two reverse phase chromatographies (C18-24.0 g, water/ ACN, 30-100%) gave Example B48. LCMS ESI+ calc’d for CsvfLeOe : 577.3 [M+H+] ; found 577.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.61 (d, J = 1.4 Hz, 1H), 7.58 (t, J = 2.8 Hz, 1H), 7.47 - 7.35 (m, 8H), 7.30 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.34 (s, 1H), 4.38 (d, J = 11.9 Hz, 1H), 4.26 (d, J = 11.9 Hz, 1H), 3.78 (ddd, J = 27.1, 12.2, 6.8 Hz, 2H), 3.21 (dd, J = 17.6, 3.1 Hz, 1H), 3.03 (dd, J = 12.8, 2.5 Hz, 1H), 3.00 (s, 2H), 2.37 (s, 3H), 2.08 (dd, J = 8.4, 5.0 Hz, 1H), 1.67 - 1.57 (m, 6H+water), 0.82 (q, J = 7.5 Hz, 4H).
Example B49
Figure imgf000235_0001
[0557] Compound E49A: To a solution of Compound Q64 (51.4 mg, 0.169 mmol,
1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q13 (61.0 mg, 0.169 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (103 mg, 0.845 mmol, 5.00 equiv) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 111 mg, 0.422 mmol, 2.5 equiv) at rt. The solution was stirred for about 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded
Compound E49A. LCMS ESI+ calc’d for C42H4606 : 647.3 [M+H+] ; found 647.6 [M+H+]
[0558] Example B49: Boron trichloride (0.35 mL, 0.351 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E49A (76 mg, 0.117 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCb (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (25% EtOAc in Hexanes) afforded Example B49. LCMS ESI+ calc’d for C35H40O6 : 557.2 [M+H+] ; found 557.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (dd, J =
I.5, 0.6 Hz, 1H), 7.46 - 7.32 (m, 5H), 7.15 (d, J= 7.9 Hz, 2H), 6.79 (tt, J= 7.7, 2.9 Hz, 1H), 6.42 (d, 7= 0.8 Hz, 1H), 4.33 (d, 7 = 11.9 Hz, 1H), 4.21 (d, 7 = 11.8 Hz, 1H), 3.65 (dd, 7= 29.3,
I I.6 Hz, 2H), 3.11 (t, 7= 7.4 Hz, 2H), 2.90 - 2.67 (m, 4H), 2.66 - 2.46 (m, 1H), 2.37 (s, 4H), 2.06 (dt, 7 = 23.2, 10.6 Hz, 3H), 1.36 - 1.13 (m, 8H), 0.97 - 0.73 (m, 6H).
Example B50
Figure imgf000236_0001
[0559] Compound E50A: To a solution of Compound Q64 (66.0 mg, 0.20 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q14 (72.0 mg, 0.20 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (122 mg, 1.0 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 131 mg, 0.5 mmol, 2.5 equiv) at it. The solution was stirred for about 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E50A. LCMS ESI+ calc’d for C44H5o06 : 675.4 [M+H+] ; found 675.7 [M+H+]
[0560] Example B50: Boron trichloride (0.34 mL, 0.339 mmol, 3.00 equiv, 1.00 M solution in CH2CI2) was added dropwise to a solution of Compound E50A (76 mg, 0.113 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over
Na2S04, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (30% EtOAc in Hexanes) afforded Example B50. LCMS ESI+ calc’d for C37H44O6 : 585.3 [M+H+] ; found 585.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (d, J= 1.5 Hz, 1H), 7.44 - 7.30 (m, 4H), 7.15 (d, J= 8.3 Hz, 2H), 6.78 (tt, J= 7.6, 2.9 Hz, 1H), 6.42 (s,
1H), 4.33 (d, J= 11.9 Hz, 1H), 4.18 (d, J= 11.8 Hz, 1H), 3.66 (dd, = 25.4, 12.1 Hz, 2H), 3.06 - 2.93 (m, 2H), 2.79 - 2.70 (m, 1H), 2.58 (dd, J= 17.1, 2.7 Hz, 1H), 2.36 (s, 3H), 2.01 (dd, 7 = 7.6, 6.3 Hz, 2H), 1.65 - 1.48 (m, 3H), 1.31 - 1.15 (m, 16H), 0.90 - 0.80 (m, 6H).
Example B51 and Example B52
Figure imgf000238_0001
E51A Example B51
[0561] Compound E51A: To a solution of Compound Q6 (65.7 mg, 0.169 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q68 (58.0 mg, 0.169 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (103 mg, 0.845 mmol, 5.00 equiv) and bis(2- oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 111 mg, 0.422 mmol, 2.5 equiv) at it. The solution was stirred for 5 min and the mixture was stirred for 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 10.0 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E51A. LCMS ESI+ calc’d for C47H54O6 : 714.4 [M+H+] ; found 732.5 [M+NH4 +]
[0562] Example B51: Boron trichloride (0.26 mL, 0.253 mmol, 3.00 equiv, 1.00 M solution in Heptane) was added dropwise to a solution of Compound E51A (60.5 mg, 0.084 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 15.0 mL). The combined organic layers were dried over
Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel
chromatography (25% EtOAc in Hexanes) gave Example B51. LCMS ESI+ calc’d for C40H48O6 : 624.4 [M+H+] ; found 642.6 [M+NH4 +] ¾ NMR (400 MHz, CDCh) d 7.57 (d, J= 1.3 Hz, 1H), 7.47 - 7.29 (m, 4H), 7.14 (d, J= 7.9 Hz, 2H), 6.84 - 6.72 (m, 1H), 4.40 - 4.06 (m, 2H), 3.58 (dd, J= 26.3, 12.2 Hz, 2H), 3.42 - 3.14 (m, 1H), 2.85 - 2.48 (m, 4H), 2.36 (s, 3H), 2.28 - 2.15 (m, 1H), 2.12 - 1.96 (m, 2H), 1.96 - 1.76 (m, 1H), 1.75 - 1.48 (m, 4H), 1.38 (s, 3H), 1.17 - 0.97 (m, 4 H), 0.91 - 0.80 (m, 12H).
Figure imgf000239_0001
E52A Example B52
[0563] Compound E52A: To a solution of Compound Q6 (90.1 mg, 0.232 mmol, 1.00 equiv) in anhydrous CH2CI2 (3 mL) was added Compound Q69 (80.0 mg, 0.232 mmol, 1.00 equiv), followed by 4-(dimethylamino)pyridine (141 mg, 1.16 mmol, 5.00 equiv) and bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOPC1, 152 mg, 0.580 mmol, 2.5 equiv) at rt. The solution was stirred for 5 min and the mixture was stirred for 16 hours at rt. Saturated aqueous NH4CI (5.00 mL) was added to the mixture. The aqueous layer was extracted with CH2CI2 (3 x 25 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in Hexanes) afforded Compound E52A. LCMS ESI+ calc’d for C47H54O6 : 714.4 [M+H+] ; found 732.5 [M+NH4 +]
[0564] Example B52: Boron trichloride (0.26 mL, 0.253 mmol, 3.00 equiv, 1.00 M solution in Heptane) was added dropwise to a solution of Compound E52A (63.0mg, 0.088 mmol, 1.00 equiv) in dry toluene (5 mL) at -78 °C. After stirring for 1 hour at -78 °C, saturated aqueous NaHCCh (5.00 mL) was added to the mixture and the mixture was stirred at rt for 45 min. The mixture was diluted with water (10.0 mL) and CH2CI2 (15.0 mL). The aqueous layer was extracted with CH2CI2 (3 x 25.0 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (25% EtOAc in Hexanes) gave Example B52. LCMS ESI+ calc’d for C40H48O6 : 624.4 [M+H+] ; found 642.6 [M+NH4 +] ¾ NMR (400 MHz, CDCh) d 7.59 - 7.53 (m, 1H), 7.44 - 7.31 (m, 4 H), 7.18 - 7.11 (m, 1H), 6.81 - 6.69 (m, 1H), 4.37 - 4.04 (m, 2H), 3.71 - 3.49 (m, 2H), 3.27 (d, J = 13.9 Hz, 1H), 2.70 - 2.55 (m, 4H), 2.49 - 2.38 (m, 1H), 2.36 (s, 3H), 2.29 - 2.17 (m, 1H), 1.98 (dd, J = 7.5, 5.9 Hz, 2H), 1.89 - 1.76 (m, 1H), 1.73 - 1.53 (m, 4H), 1.37 (s, 3H), 1.05 (m, 4H), 0.90 - 0.78 (m, 12H).
Example B53 and Example B54
Figure imgf000240_0001
[0565] Compound E53A: Compound Q6 (52.0 mg, 134 pmol) and Compound Q72
(46.0 mg, 134 pmol) were dissolved in CH2CI2 (3.0 mL). DMAP (86.0 mg, 670 pmol) and BOP-C1 (106.0 mg, 335 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with saturated aq NH4CI (10.0 mL) and extracted with CH2CI2 (2 x15.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over Na2SC>4.
The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E53A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+H+] ; found 706.7 [M+NH4 +]
[0566] Example B53: Compound E53A (81.0 mg, 118.0 pmol) was dissolved in toluene (3.0 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (354 pL, 354 pmol) was added drop-wise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCb (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-30% EtOAc in Hexanes gave Example B53. LCMS ESI+ calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.7 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.52 - 7.48 (m, 2H), 7.47 - 7.42 (m, 1H), 7.38 (dd, J= 7.6, 1.2 Hz, 1H), 7.19-7.15 (m, 3H), 6.70 (tt, J= 7.5, 2.7 Hz, 1H), 6.46 (s, 1H), 4.31- 4.18 (m, 2H), 3.55-3.42 (m, 2H), 3.20 - 3.09 (m, 1H), 3.07 - 2.94 (m, 2H), 2.66 - 2.40 (m, 2H), 2.37 (s, 3H), 1.92 (ddd, J= 7.3, 6.0, 1.4 Hz, 2H), 1.66 - 1.46 (m, 3H), 1.23 (dd, J= 7.4, 3.8 Hz, 3H), 1.08 - 0.93 (m, 4H), 0.82 (dd, J= 6.5, 1.8 Hz, 12H).
Figure imgf000241_0001
[0567] Compound E54A: Compound Q6 (45.0 mg, 116 pmol) and Compound Q73
(55.4 mg, 174 pmol) were dissolved in CH2CI2 (2.32 mL). DMAP (73.2 mg, 580 pmol) and BOP-C1 (76.1 mg, 290 pmol) were added sequentially. The reaction mixture was stirred for 18 h and quenched with saturated aq NH4CI (10.0 mL) and extracted with CH2CI2 (2 x15.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over Na2SC>4.
The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E54A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+H+] ; found 706.7 [M+NH4 +]
[0568] Example B54: Compound E54A (78.5 mg, 114 pmol) was dissolved in toluene
(2.28 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (342 pL, 342 pmol) was added drop-wise. The reaction mixture was stirred for 1 h and quenched with satd. NaHCCb (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-30% EtOAc in Hexanes gave Example B54. LCMS ESI+ calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.4 [M+H+] ¾ NMR (400 MHz, CDCb) d 7.51 (d, J= 8.0 Hz, 2H), 7.46 (d, J= 7.7 Hz, 1H), 7.39 (d, J= 7.3 Hz, 1H), 7.20-7.16 (m, 3H), 6.74 - 6.66 (m, 1H), 6.47 (s, 1H), 4.31-4.19 (m, 2H), 3.55-3.42 (m, 2H), 3.16 (dd, J= 16.7, 9.6 Hz, 1H), 3.05 - 2.95 (m, 2H), 2.56-2.52 (m, 2H), 2.39 (s, 3H), 1.92 - 1.86 (m, 2H), 1.72-1.52 (m, 3H), 1.26 (d, J= 6.6 Hz, 3H), 1.09 - 0.92 (m, 4H), 0.85 - 0.79 (m, 12H).
Example B55 and Example B56
Figure imgf000242_0001
[0569] Compound E55A: Compound Q6 (62.0 mg, 160 pmol) and Compound Q75
(55.0 mg, 160 pmol) were dissolved in CH2CI2 (3.0 mL). DMAP (98.0 mg, 800 pmol) and
BOP-C1 (126.0 mg, 800 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over Na2SC>4. The organic layer was concentrated and purified by flash chromatography eluting with 0-15%
EtOAc-Hexanes to afford Compound E55A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+H+] ; found 720.6 [M+Na+]
[0570] Example B55: Compound E55A (78.0 mg, 113 mihoΐ) was dissolved in toluene
(3.0 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (339 pL, 339 pmol) was added drop-wise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCL (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with LLO (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-30% EtOAc in Hexanes gave Example B55. LCMS ESI+ calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.54 (s, 1H), 7.43-7.41 (m, J= 8.0 Hz, 3H), 7.37 - 7.32 (m, 1H), 7.18 - 7.12 (m, 2H), 6.82 - 6.73 (m, 1H), 6.43 (s, 1H), 4.38 - 4.14 (m, 2H), 3.76 - 3.48 (m, 2H), 3.14 (dd, J= 14.8, 7.2 Hz, 1H), 3.06 - 2.95 (m, 1H), 2.95 - 2.82 (m, 1H), 2.73-2.53 (m, 2H), 2.36 (s, 3H), 2.10 - 2.00 (m, 3H), 1.74 - 1.51 (m, 3H), 1.28 - 1.19 (m, 3H), 1.14 - 0.97 (m, 3H), 0.84 (dd, J= 6.6, 1.6 Hz, 12H).
Figure imgf000243_0001
[0571] Compound E56A: Compound Q6 (62.0 mg, 160 pmol) and Compound Q76
(55.0 mg, 160 pmol) were dissolved in CH2CI2 (3.0 mL). DMAP (98.0 mg, 800 pmol) and
BOP-C1 (126.0 mg, 800 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over Na2SC>4. The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E56A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EC] ; found 706.6 [M+NH4 +]
[0572] Example B56: Compound E56A (72.0 mg, 113 pmol) was dissolved in toluene
(3.0 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (339 pL, 339 pmol) was added drop-wise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCL (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-30% EtOAc in Hexanes gave Example B56. LCMS ESC calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.54 (dd, J= 1.6, 1.0 Hz, 1H), 7.43-7.41 (m, 3H), 7.37- 7.33 (m, 1H), 7.17-7.13 (m, 2H), 6.81 - 6.72 (m, 1H), 6.43 (d, C= 0.8 Hz, 1H), 4.36 - 4.11 (m, 2H), 3.62 (q, J= 12.1 Hz, 2H), 3.19 - 3.09 (m, 1H), 2.99 (h, J= 6.9 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.75 - 2.49 (m, 2H), 2.36 (s, 3H), 2.08 - 1.96 (m, 3H), 1.76 - 1.49 (m, 3H), 1.29 - 1.18 (m, 3H), 1.13 - 0.97 (m, 3H), 0.90 - 0.77 (m, 12H).
Figure imgf000244_0001
[0573] Compound E57A: Compound Q6 (57.1 mg, 147 pmol) and Compound Q78
(70.2 mg, 220 pmol) were dissolved in CH2CI2 (2.94 mL). DMAP (91.6 mg, 735 pmol) and
BOP-C1 (135.0 mg, 515 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E57A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EC] ; found 689.6 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.46 (d, 7 = 8.1 Hz, 2H), 7.35 (d, 7 = 7.7 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.25 (m, 3H), 7.19 - 7.13 (m, 3H), 6.79 - 6.70 (m, 1H), 6.66 (s, 1H), 4.47 (s, 2H), 4.25 (s, 2H), 3.48 (dd, 7 = 20.9, 10.0 Hz, 2H), 3.15 (dd, 7 = 14.8, 6.7 Hz, 1H), 3.00 (dd, 7 = 13.9, 7.0 Hz, 1H), 2.88 (dd, 7 = 14.8, 7.2 Hz, 1H), 2.75 (dd, 7 = 17.2, 2.3 Hz, 1H), 2.55 (dd, 7 = 17.2, 2.2 Hz, 1H), 2.37 (s, 3H), 2.02 (t, 7 = 6.7 Hz, 2H), 1.66 (dt, 7 = 13.5, 6.6 Hz, 1H), 1.60 - 1.51 (m, 2H), 1.21 (d, 7= 7.0 Hz, 3H), 1.10 - 0.97 (m, 4H), 0.83 (d, 7= 6.6 Hz, 12H).
[0574] Example B57: Compound E57A (82.7 mg, 120 pmol) was dissolved in toluene
(2.4 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (360 pL, 360 pmol) was added drop-wise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCL (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-30% EtOAc in Hexanes gave Example B57. LCMS ESC calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.5 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.49 - 7.44 (m, 2H), 7.40 - 7.34 (m, 2H), 7.22 - 7.16 (m, 3H), 6.77 (tt, 7 = 7.5, 2.8 Hz, 1H), 6.67 (d, 7 = 0.8 Hz, 1H), 4.31 (dd, 7= 11.8 Hz, 1H), 4.18 (dd, 7 = 11.8 Hz, 1H), 3.64 (dd, 7 = 12.1 Hz, 1H), 3.56 (dd, 7 = 12.1 Hz, 1H), 3.18 (ddd, 7 =
14.7, 7.1, 0.6 Hz, 1H), 3.05 (h, 7= 6.9 Hz, 1H), 2.94 (ddd, 7= 14.7, 6.8, 0.6 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.56 - 2.49 (m, 1H), 2.38 (s, 3H), 2.08 - 2.01 (m, 2H), 2.00 (br s, 1H), 1.73 - 1.53 (m, 4H + H20), 1.26 (d, 7= 7.0 Hz, 3H), 1.11 - 0.98 (m, 4H), 0.84 (dd, 7= 6.6, 1.3 Hz, 12H).
Figure imgf000246_0001
E58A Example B58
[0575] Compound E58A: Compound Q6 (48.2 mg, 124 mihoΐ) and Compound Q79
(59.2 mg, 186 pmol) were dissolved in CH2CI2 (2.48 mL). DMAP (77.3 mg, 620 pmol) and BOP-C1 (81.4 mg, 310 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E58A. LCMS ESI+ calc’d for C45H52O6 : 689.4 [M+EC] ; found 689.5 [M+H+]
[0576] Example B58: Compound E58A (72.3 mg, 105 pmol) was dissolved in toluene
(2.1 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (315 pL, 315 pmol) was added drop-wise. The reaction mixture was stirred for 2 h and quenched with satd. NaElCCh (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 0-70% EtOAc in Hexanes gave Example B58. LCMS ESC calc’d for C45H52O6 : 599.3 [M+H+] ; found 599.4 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.56 - 7.42 (m, 2H), 7.42 - 7.31 (m, 2H), 7.25 - 7.12 (m, 3H), 6.84 - 6.71 (m, 1H), 6.67 (s, 1H), 4.33 (d, = 11.9 Hz, 1H), 4.17 (d, = 11.9 Hz, 1H), 3.74 - 3.54 (m, 2H), 3.19 (dd, J= 14.6, 6.8 Hz, 1H), 3.01 (h, J= 6.9 Hz, 1H), 2.92 (dd, J= 14.7, 7.0 Hz, 1H), 2.69 (dd, J= 17.0, 2.7 Hz, 1H), 2.55 (dd, J= 17.2, 2.4 Hz, 1H), 2.38 (s, 3H), 2.08 - 1.99 (m, 3H), 1.73 - 1.62 (m, 1H), 1.63 - 1.57 (m, 1H), 1.26 (d, C= 7.0 Hz, 3H), 1.11 - 0.97 (m, 4H), 0.84 (d, J= 6.6 Hz, 12H). Example B59 and Example B60
Figure imgf000247_0001
[0577] Compound E59A: To a solution of Compound Q6 (50 mg, 0.129 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q81 (26.3 mg, 0.129 mmol), followed by 4-(dimethylamino)pyridine (40.1 mg, 0.322 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 84.4 mg, 0.322 mmol) at rt. The solution was stirred for 5 min and the mixture was stirred an additional 50 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with
dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 40% ethyl acetate in hexanes) to give Compound E59A. LCMS ESI+ calc’d for C36H46O6 : 575.3 [M+LL] ; found 575.3 [M+H+]
[0578] Example B59: To a solution of Compound E59A (27.0 mg, 0.047 mmol) in dichloromethane (0.94 mL) cooled to -78 °C was added boron trichloride (1 M solution in heptane, 141 pL, 0.141 mmol) dropwise. After stirring for 20 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at rt for
20 min. The mixture was diluted and extracted with dichloromethane (2 x 10 mL) and the organic layers were combined, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 50 % ethyl acetate in hexanes) to give, after lyophilisation, Example B59. LCMS ESI+ calc’d for C29EL0O6 : 485.3
[M+LL] ; found 485.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.51 - 7.46 (m, 1H), 7.42 - 7.38
(m, 1H), 7.25 - 7.16 (m, 2H), 6.78 (tt, J= 7.6, 2.8 Hz, 1H), 6.44 (d, J= 0.8 Hz, 1H), 4.29 (d, J =
11.9 Hz, 1H), 4.17 (d, J= 11.8 Hz, 1H), 3.61 (d, J = 12.1 Hz, 1H), 3.54 (d, J= 12.0 Hz, 1H), 3.14 (dd, J= 15.0, 6.9 Hz, 1H), 3.08 - 2.97 (m, 1H), 2.91 (dd, = 14.6, 6.6 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.57 - 2.49 (m, 1H), 2.09 - 2.02 (m, 2H), 1.73 - 1.65 (m, 1H), 1.64 - 1.49 (m, 3H), 1.25 (d, J= 6.9 Hz, 3H), 1.12 - 1.01 (m, 4H), 0.85 (dd, J= 6.5, 1.2 Hz, 12H).
Figure imgf000248_0001
[0579] Compound E60A: To a solution of Compound Q6 (60 mg, 0.154 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q82 (47.3 mg, 0.232 mmol), followed by 4-(dimethylamino)pyridine (96.3 mg, 0.722 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 142 mg, 0.540 mmol) at it. The solution was stirred for 5 min and the mixture was stirred an additional 50 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with
dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 40% ethyl acetate in hexanes) to give Compound E60A. LCMS ESI+ calc’d for C36H46O6 : 575.3 [M+LL] ; found 575.3 [M+H+]
[0580] Example B60: To a solution of Compound E60A (38.0 mg, 0.066 mmol) in dichloromethane (1.32 mL) cooled to -78 °C was added boron trichloride (1 M solution in heptane, 198 pL, 0.198 mmol) dropwise. After stirring for 20 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and the mixture was stirred at rt for
20 min. The mixture was diluted and extracted with dichloromethane (2 x 10 mL) and the organic layers were combined, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 50 % ethyl acetate in hexanes) to give, after lyophilisation, Example B60. LCMS ESI+ calc’d for C29EL0O6 : 485.3
[M+LL] ; found 485.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.51 - 7.46 (m, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.81 - 6.73 (m, 1H), 6.45 (s, 1H), 4.32 (d, 7= 11.8 Hz, 1H), 4.16 (d, 7= 11.8 Hz, 1H), 3.64 (d, 7= 12.2 Hz, 1H), 3.57 (d, 7= 12.2 Hz, 1H), 3.15 (dd, 7 = 14.6, 7.2 Hz, 1H), 3.04 - 2.94 (m, 1H), 2.89 (dd, 7= 14.8, 6.4 Hz, 1H), 2.70 (d, 7= 17.5 Hz, 1H), 2.56 (d, 7= 17.5 Hz, 1H), 2.03 (dd, 7= 7.5, 6.2 Hz, 2H), 1.71 - 1.56 (m, 3H), 1.25 (d, 7 = 7.0 Hz, 3H), 1.13 - 1.00 (m, 4H), 0.85 (d, 7= 6.6 Hz, 12H).
Example B61
Figure imgf000249_0001
[0581] Compound E61A: Compound Q6 (60 mg, 154 pmol)) and Compound Q83
(52.2 mg, 154 pmol) was dissolved in CH2CI2 (6 mL) and BOP-C1 (101 mg, 386 pmol) and DMAP (94.3 mg, 772 pmol) were added sequentially. The reaction mixture was stirred for 16 h and quenched with satd. NH4CI (5 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL) and brine (10 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 10- 60% EtOAc-Hexanes to afford Compound E61A. LCMS ESI+ calc’d for C45H50O6 : 687.4 [M+H+] ; found 687.5 [M+H+]
[0582] Example B61: Compound E61A (104 mg, 151 pmol) was dissolved in Toluene
(6 mL) and the reaction was cooled to -78 °C. Then a 1M Heptane solution of Boron trichloride (454 pL, 454 pmol) was added dropwise. The reaction mixture was stirred for 1 h and quenched with satd. NaHCCL (5 mL) solution. Organic material was extracted with EtOAc (30 mL), washed with H2O (15 mL) and dried over Na2S04. Flash chromatography eluting with 15-70% EtOAc in Hexanes gave Example B61. LCMS ESC calc’d for C38H44O6 : 597.4 [M+H+] ; found 597.3 [M+H+] ¾ NMR (400 MHz, CDCC) d 7.76 (d, J= 0.7 Hz, 1H), 7.53 - 7.40 (m, 5H),
7.16 (d, J= 8.3 Hz, 2H), 6.93 (s, 1H), 6.87 - 6.80 (m, 1H), 4.38 (dd, J= 42.4, 11.9 Hz, 2H),
3.75 (dd, J= 28.2, 12.3 Hz, 2H), 2.78 (dd, J= 68.6, 17.9 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H),
2.13 (t, 7= 6.6 Hz, 2H), 1.70 (dt, 7 = 12.8, 6.5 Hz, 1H), 1.65 - 1.57 (m, 2H), 1.14 - 1.01 (m,
4H), 0.83 (dd, 7 = 6.1, 3.2 Hz, 12H).
Example B62 and Example B63
Figure imgf000250_0001
Compound E62A Example B62
[0583] Compound E62A: Compound Q64 (50.0 mg, 139 pmol) and Compound Q21
(44.2 mg, 139 mihoΐ) were dissolved in CH2CI2 (3 mL). DMAP (84.7 mg, 693 pmol) and BOP- C1 (91 mg, 307 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E62A. LCMS ESI+ calc’d for C45H52O6 : 661.4 [M+EC] ; found 661.3 [M+H+]
[0584] Example B62: Compound E62A (26 mg, 39.3 pmol) was dissolved in toluene
(3 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (118 pL, 118 pmol) was added dropwise. The reaction mixture was stirred for 2 h and quenched with satd. NaElCCL (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 15-70% EtOAc in Hexanes gave Example B62. LCMS ESC calc’d for C36H42O6 : 571.3 [M+H+] ; found 571.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.66 (s, 1H), 7.38 (dt, J= 17.7, 8.3 Hz, 4H), 7.14 (d, J = 7.8 Hz, 2H), 6.77 (td, J= 7.5, 3.7 Hz, 1H), 6.42 (s, 1H), 4.23 (dd, J= 50.2, 11.8 Hz, 2H), 3.69 - 3.48 (m, 2H), 3.13 (dd, J= 14.7, 7.2 Hz, 1H), 3.09 - 2.96 (m, 1H), 2.89 (dd, J= 14.9, 6.6 Hz, 1H), 2.62 (dd, J= 74.4, 16.9 Hz, 2H), 2.36 (s, 3H), 2.05 (t, J= 7.0 Hz, 2H), 2.00 - 1.89 (m, J = 16.7 Hz, 1H), 1.36 - 1.13 (m, 12H), 0.86 (t, J= 6.8 Hz, 6H).
Figure imgf000251_0001
Compound E63A Example B63
[0585] Compound E63A: Compound Q64 (59.0 mg, 164 pmol) and Compound Q22
(52.1 mg, 164 mihoΐ) were dissolved in CH2CI2 (3 mL). DMAP (100 mg, 818 pmol) and BOP-C1 (107 mg, 409 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 0-15% EtOAc-Hexanes to afford Compound E63A. LCMS ESI+ calc’d for C45H52O6 : 661.4 [M+EC] ; found 661.5 [M+H+]
[0586] Example B63: Compound E63A (49.8 mg, 75.4 pmol) was dissolved in toluene (3 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (226 pL, 226 pmol) was added dropwise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCb (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 15-70% EtOAc in Hexanes gave Example B63. LCMS ESI+ calc’d for C36H42O6 : 571.3 [M+H+] ; found
571.3 [M+H+] ¾ NMR (400 MHz, CDCh) d 7.65 (s, 1H), 7.46 - 7.30 (m, 4H), 7.14 (d, J= 7.8 Hz, 2H), 6.81 - 6.73 (m, 1H), 6.42 (s, 1H), 4.23 (dd, J= 67.4, 11.9 Hz, 2H), 3.62 (dt, J= 23.1,
7.3 Hz, 2H), 3.14 (dd, J= 14.9, 7.2 Hz, 1H), 2.97 (dt, J= 14.1, 6.9 Hz, 1H), 2.87 (dd, J= 15.0, 6.6 Hz, 1H), 2.75 - 2.47 (m, 2H), 2.36 (s, 3H), 2.04 (t, J= 6.8 Hz, 3H), 1.34 - 1.11 (m, 12H), 0.86 (t, 7= 6.8 Hz, 3H).
Example B64 and Example B65
Figure imgf000252_0001
[0587] Compound E64A: Compound Q27 (60.0 mg, 144 pmol) and Compound Q21
(45.9 mg, 144 pmol) were dissolved in CH2CI2 (3 mL). DMAP (88.3 mg, 723 pmol) and BOP- C1 (94.1 mg, 359 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 10-60% EtOAc-Hexanes to afford Compound E64A. LCMS ESI+ calc’d for C47H56O6 : 717.4 [M+H+] ; found 717.6 [M+H+]
[0588] Example B64: Compound E64A (22 mg, 30.7 pmol) was dissolved in toluene
(3 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (92.1 pL, 92.1 pmol) was added dropwise. The reaction mixture was stirred for 2 h and quenched with satd. NaElCCL (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with H2O (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 15-70% EtOAc in Hexanes gave Example B64. LCMS ESC calc’d for C40H50O6 : 627.4 [M+H+] ; found 627.6 [M+H+] ¾ NMR (400 MHz, CD3OD) d 7.67 (d, J= 1.0 Hz, 1H), 7.46 - 7.33 (m, 4H), 7.19 (d, J= 7.9 Hz, 2H), 6.70 - 6.60 (m, 1H), 6.54 (s, 1H), 4.26 (dd, J= 38.2, 11.8 Hz, 2H), 3.63 (dd, J = 34.0, 12.1 Hz, 2H), 3.12 (ddd, J= 17.1, 7.7, 3.6 Hz, 1H), 3.04 - 2.92 (m, 2H), 2.78 - 2.56 (m, 2H), 2.36 (s, 3H), 2.16 - 2.04 (m, 2H), 1.78 - 1.68 (m, 1H), 1.28 - 1.14 (m, 7H), 0.90 (d, J= 2.2 Hz, 18H).
Figure imgf000253_0001
[0589] Compound E65A: Compound Q27 (60.0 mg, 144 mihoΐ) and Compound Q22
(45.9 mg, 144 pmol) were dissolved in CH2CI2 (3 mL). DMAP (88.3 mg, 723 pmol) and BOP- C1 (94.1 mg, 359 pmol) were added sequentially. The reaction mixture was stirred for 8 h and quenched with satd. NH4CI (10.0 mL) and extracted with CH2CI2 (2 xl5.0 mL). The organic layer was washed with water (10.0 mL) and brine (10.0 mL) and dried over INfeSCL. The organic layer was concentrated and purified by flash chromatography eluting with 10-60% EtOAc-Hexanes to afford Compound E65A. LCMS ESI+ calc’d for C47H56O6 : 717.4 [M+EC] ; found 717.6 [M+H+]
[0590] Example B65: Compound E65A (25 mg, 34.9 pmol) was dissolved in toluene
(3 mL) and was cooled to -78 °C. 1M solution of Boron trichloride in heptane (105 pL, 105 mihoΐ) was added dropwise. The reaction mixture was stirred for 2 h and quenched with satd. NaHCCb (5.00 mL) solution. Organic material was extracted with EtOAc (3 x 30.0 mL), washed with ThO (15.0 mL) and dried over Na2S04. Flash chromatography eluting with 15-70% EtOAc in Hexanes gave Example B65. LCMS ESI+ calc’d for C40H50O6 : 627.4 [M+H+] ; found 627.6 [M+H+] ¾ NMR (400 MHz, CD3OD) d 7.64 (d, J = 0.9 Hz, 1H), 7.41 - 7.32 (m, 4H), 7.16 (d, J = 7.8 Hz, 2H), 6.67 - 6.58 (m, 1H), 6.52 (s, 1H), 4.23 (dd, J = 38.0, 11.9 Hz, 2H), 3.60 (dd, J = 27.9, 11.9 Hz, 2H), 3.12 - 3.02 (m, 1H), 2.92 (dt, J = 10.8, 5.8 Hz, 2H), 2.62 (dd, J = 50.9, 17.4 Hz, 2H), 2.34 (s, 3H), 2.03 (dd, J = 9.3, 3.4 Hz, 2H), 1.76 - 1.64 (m, 1H), 1.26 - 1.09 (m, 7H), 0.87 (d, J = 1.2 Hz, 18H).
PKC Isoform Translocation Assays
[0591] The specificity of PKC isoform activation was determined in eight A549 cell lines, each stably expressing a single PKC isoform fused to tGFP. Cells were plated in clear bottom 384-well plates in 80 mΐ at 100K cells/mL in RPMI with 10% FBS one day before adding compounds in 10-point dose responses. Cells were incubated with compound for 60 min at 37°C. Within the last 15 minutes of this incubation, Hoechst was added to stain nuclei. Plates were then washed with cold DPBS (IX, 20 mM Hepes) to remove all compounds and fixed with 2% paraformaldehyde for 30 minutes at 4°C. Cells were stained with membrane dye WGA-647 for 10 minutes at 4°C and then washed vigorously with cold DPBS (IX, 20 mM Hepes) to remove excess dye. Cells were quickly imaged using a Cellomics Array Scan (Thermo Fisher) with 20x objective at room temperature (22°C). The images were analyzed using a Cellomics automated image analysis algorithm to quantify cytoplasm and plasma membrane localization. This algorithm quantified the mean percentage of GFP that co-localized with the plasma membrane dye relative to the total GFP. The values are plotted against concentrations of the compound to determine EC50 values.
Induced HIV-1 Expression in CD4 T cell Cultures from HIV-1 Infected Subjects on cART Treated with PKC Agonists
[0592] To assess the ability to activate HIV-1 expression in CD4 T cells, leukapheresis samples were obtained from HIV-1 infected human subjects on cART and virally suppressed with plasma HIV RNA < 50 copies/mL for at least 1 year. The leukapheresis product was diluted 1 : 1 with PBS and layered over Ficoll for isolation of PBMCs. PBMCs were treated with red blood cell lysis buffer and rested overnight (10 million cells/ml) in tissue culture medium (RPMI 1640 supplemented with 10% FBS and Pen/Strep). Total CD4 T cells were isolated using bead-based purification methods. Purified CD4 T cells were cultured and treated with 10 mM of each compound or with dimethyl sulfoxide (DMSO, vehicle control) for 3 days, using 4 replicates per condition. The cultures were maintained in the presence of antivirals (100 nM elvitegravir, 100 nM efavirenz) to prevent viral spread and amplification. At the end of the incubation period, cell-free culture supernatants were harvested and HIV-1 RNA levels were quantified by the COBAS® AmpliPrep/COBAS® TaqMan HIV-1 Test, v2.0 (Sizmann et al., J Clin. Virology, 2010, Vol. 49, pp. 41-46). Geometric mean of the 4 replicates was calculated for each donor. HIV-1 RNA was normalized to 5 mM Prostratin (% prostratin) and separately, to the DMSO vehicle control (fold increase). The number of donors tested for each is also shown (N).
Induced CD69 activation in CD4 T cell Cultures from Subjects Treated with PKC Agonists
[0593] To assess the ability to activate CD69 on CD4 T cells, leukapheresis samples were obtained from healthy (HIV-1 uninfected) human subjects. PBMCs were isolated by Ficoll method and CD4 T cells were isolated from PBMCs. Purified CD4 T cells were cultured in 96- well tissue culture plates and treated with PKC modulating compounds ranging from 1 to 25000 nM or with dimethyl sulfoxide (DMSO, vehicle control) for 24 hrs. At the end of the incubation, cells were stained with live dead dye and antibodies specific for CD4 and CD69. The percent CD69+ CD4 T cells were measured by flow cytometry using the BD Fortessa instrument, analyzed using FlowJo software and plotted against compound concentration to determine EC o values.
[0594] Analytical data for Examples B1 to B50 are set forth in Table 1. Analytical data for reference compounds are set forth in Table 2.
Table 1.
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Table 2.
Figure imgf000282_0001
Figure imgf000283_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I,
Figure imgf000284_0001
Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
each R1 is C1-3 alkyl;
each R2 is Ci-6 alkyl;
one of R3 and R4 is H, Ci-15 alkyl, or C6-10 aryl, and the other of R3 and R4 is Ci-15 alkyl or C6-10 aryl, wherein each Ci-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;
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 R5;
each R5 is independently C 1-3 alkyl, or
two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;
A is a 6-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
heteroatoms independently selected from N, O, and S, or
A is a 6-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, 2, or 3; and
m is 0, 1, 2, or 3.
2. A compound of Formula I,
Figure imgf000284_0002
Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
each R1 is C1-3 alkyl;
each R2 is Ci-6 alkyl;
one of R3 and R4 is H or C 1-3 alkyl, and the other of R3 and R4 is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl;
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 R5;
each R5 is independently C 1-3 alkyl, or
two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;
A is a 9-10 membered monocyclic or fused bicyclic heteroarylene having 1-3
heteroatoms independently selected from N, O, and S, or
A is a 9-14 membered monocyclic, fused bicyclic, or fused tricyclic heterocyclylene having 1-3 heteroatoms independently selected from N, O, and S; n is 0, 1, or 2; and
m is 1 or 2.
3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein m is 1.
4. The compound of any one of claims 1-3, wherein the compound is of Formula II:
Figure imgf000285_0001
Formula II,
or a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1-4, wherein the compound is of Formula Ila,
Figure imgf000285_0002
Formula Ila,
or a pharmaceutically acceptable salt thereof.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein one of R3 and R4 is H or methyl and the other of R3 and R4 is phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein one of R3 and R4 is H or methyl and the other of R3 and R4 is phenyl,
Figure imgf000286_0001
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein one of R3 and R4 is H and the other of R3 and R4 is
Figure imgf000286_0002
9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl and R4 is phenyl or Ci-12 alkyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L is a Ci-6 alkylene optionally substituted with 2 R5, wherein the two R5 are attached to the same carbon and the two R5, together with the carbon to which they are attached, form a C3-6 cycloalkyl.
12. The compound of any one of claims 1-9 and 11, or a pharmaceutically acceptable salt thereof, wherein -A-L- is -A-methylene-, -A-ethylene-, -A-CH(CH3)CH2-, -A-CH2CH(CH3)-, -A-CH2CH(CH2CH3)-, -A-CH2C(CH )2-, -A-C(CH )2CH2-, -A-CH(CH3)CH(CH )-,
-A-CH2C(CH2CH3)(CH3)-, -A-CH2C(CH2CH3)2-, -A-propylene-, -A-butylene-,
Figure imgf000287_0001
13. The compound of any one of claims 1-9 and 11-12, or a pharmaceutically acceptable salt thereof, wherein -A-L- is
Figure imgf000287_0002
14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L is a C1-3 heteroalkylene optionally substituted with methyl.
15. The compound of any one of claims 1-9 and 14, or a pharmaceutically acceptable salt thereof, wherein L is -CH2NH- or -CThNlOTb)-.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is a 9 membered fused bicyclic heteroarylene containing 1 heteroatom selected from N and O, or a 9-13 membered fused bicyclic or fused tricyclic heterocyclylene containing 1 or 2 oxygen atoms, each of which is optionally substituted with one R1.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein A is a benzofuranylene, dihydrobenzofuranylene, or indolylene, each of which is optionally substituted with one R1.
19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein -A-L- is:
Figure imgf000288_0001
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.
21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein -A-L- is
Figure imgf000288_0002
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R2 is Ci-4 alkyl.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl or tert-butyl.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
25. A compound selected from the group consisting of:
Figure imgf000288_0003
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
or a pharmaceutically acceptable salt thereof.
26. A compound selected from the group consisting of:
Figure imgf000294_0001
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
28. The pharmaceutical composition of claim 27, further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.
29. The pharmaceutical composition of claim 28, wherein 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, tenofovir alafenamide hemifumarate, emtricitabine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
30. A method of activating protein kinase C in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-29.
31. A method of treating a disease or disorder associated with decreased protein kinase C activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-28.
32. 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 the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-28.
33. A method of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-28.
34. A method of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-28.
35. A method of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-28.
36. The method of any one of claims 32-35, further comprising administering a
therapeutically effective amount of one or more additional therapeutic agents, or a
pharmaceutically acceptable salt thereof.
37. The method of claim 36, wherein 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 inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
38. The method of any one of claims 36-37, wherein 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.
39. The method of any one of claims 36-38, wherein 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 pharmaceutically acceptable salt of any of the foregoing, or any
combinations thereof.
40. The method of any one of claims 36-39, wherein 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 or tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any
combinations thereof.
41. The method of any one of claims 36-40, wherein 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, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.
42. The method of any one of claims 36-41, further comprising administering a
therapeutically effective amount of an additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.
43. The method of any one of claims 36-41, further comprising administering a
therapeutically effective amount of emtricitabine or a pharmaceutically acceptable salt thereof.
44. A method of activating T cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 27-29.
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