WO2013103738A1 - Napthalene acetic acid derivatives against hiv infection - Google Patents

Napthalene acetic acid derivatives against hiv infection Download PDF

Info

Publication number
WO2013103738A1
WO2013103738A1 PCT/US2013/020172 US2013020172W WO2013103738A1 WO 2013103738 A1 WO2013103738 A1 WO 2013103738A1 US 2013020172 W US2013020172 W US 2013020172W WO 2013103738 A1 WO2013103738 A1 WO 2013103738A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
mmol
methylnaphthalen
dihydropyrano
acetate
Prior art date
Application number
PCT/US2013/020172
Other languages
French (fr)
Inventor
Kerim Babaoglu
Gediminas BRIZGYS
Hongyan Guo
Paul Hrvatin
Eric LANSDON
John O. Link
Hongtao Liu
Ryan Mcfadden
Michael L. Mitchell
Yingmei Qi
Paul A. Roethle
Randall W. Vivian
Lianhong Xu
Hong Yang
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to US14/370,466 priority Critical patent/US9284323B2/en
Publication of WO2013103738A1 publication Critical patent/WO2013103738A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • HIV-1 Human immunodeficiency virus
  • HIV-1 Human immunodeficiency virus type 1
  • reverse transcriptase enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860;
  • one embodiment provides a compound selected from:
  • Another embodiment provides a compound as described in any one of the Examples disclosed herein or a non-salt thereof or a salt thereof or an alternative salt thereof.
  • Another embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another embodiment provides a method for treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • Another embodiment provides a method for treating an HIV infection in a mammal (e.g., a human) comprising administering one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • Another embodiment provides a method for treating an HIV infection in a mammal (e.g., a human) comprising administering to the mammal 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 selected from the group consisting HIV protease inhibiting compounds, HIV non-nucleoside 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, and other drugs for treating HIV, and combinations thereof.
  • a mammal e.g., a human
  • additional therapeutic agents selected from the group consisting HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human)).
  • medical therapy e.g., for use in treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human)
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating e.g., preventing, mediating or inhibiting) an HIV infection in a mammal (e.g., a human)).
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment (e.g., prevention, mediation or inhibition) of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a mammal e.g., a human).
  • Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.
  • Another embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds disclosed herein or salts thereof.
  • ⁇ in the context of a chemical measurement (e.g., ⁇ 50 mg or pH ⁇ 7).
  • treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the compounds disclosed herein may have chiral centers, e.g., chiral carbon atoms. Such compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers.
  • the compounds disclosed herein include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
  • racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g.,, acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer can also be synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • a compound disclosed herein is greater than 50% a single enantiomer. In another embodiment, a compound disclosed herein is at least 80% a single enantiomer. In another embodiment, a compound disclosed herein is at least 90% a single enantiomer. In another embodiment, a compound disclosed herein is at least 98% a single enantiomer. In another embodiment, a compound disclosed herein is at least 99% a single enantiomer. In another embodiment, a compound disclosed herein is greater than 50% a single diastereomer. In another embodiment, a compound disclosed herein is at least 80% a single diastereomer. In another embodiment, a compound disclosed herein is at least 90% a single diastereomer. In another embodiment, a compound disclosed herein is at least 98% a single diastereomer. In another embodiment, a compound disclosed herein is at least 99% a single diastereomer.
  • Tautomers The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • Examples of pharmaceutically acceptable salts of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and N3 ⁇ 4 + (wherein X is Ci-C 4 alkyl).
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and N3 ⁇ 4 + (wherein X is Ci-C 4 alkyl).
  • Pharmaceutically acceptable salts of a nitrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • compositions of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX " (wherein X is independently selected from H or a C1-C4 alkyl group).
  • salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + ,
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with water as in hydrates.
  • this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
  • a -C3 ⁇ 4 group may be substituted with -CD 3 .
  • the invention provides for a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, 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 invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the therapeutic agent used in combination with the compound of the present invention can be any anti-HIV agent.
  • the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside 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, and other drugs for treating HIV, and combinations thereof, and a pharmaceutically acceptable carrier.
  • the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of:
  • HIV protease inhibiting compounds selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL- 100, DG35, and AG 1859;
  • HIV non-nucleoside inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, RDEA806 and KM023;
  • HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ⁇ -FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), ;
  • HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX- 157 (Chimerix)
  • HIV integrase inhibitors selected from the group consisting of 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, S- 1360, AR- 177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, GS-5696, elvitegravir and dolutegravir;
  • gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;
  • CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;
  • one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above..
  • the compounds disclosed herein are formulated with conventional carriers (e.g., inactive ingredient or excipient material) which will be selected in accord with ordinary practice.
  • Tablets will contain excipients including glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • One embodiment provides the formulation as a solid dosage form including a solid oral dosage form.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • compositions While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations (compositions).
  • compositions both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical excipients, etc.) which constitutes one or more accessory ingredients.
  • inactive ingredients e.g., a carrier, pharmaceutical excipients, etc.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions according to the present invention comprise one or more compounds disclosed herein together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • the amount of active ingredient that is combined with the inactive ingredients to produce a dosage form will vary depending upon the host treated and the particular mode of
  • a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (i.e., inactive ingredient or excipient material).
  • the carrier material varies from about 5 to about 95% of the total compositions (weighfcweight).
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
  • One or more compounds disclosed herein are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), 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 the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • the antiviral properties of a compound disclosed herein may be determined using Test A described below.
  • Test A Antiviral Assays in MT4 Cells
  • 189X test concentration 3 -fold serially diluted compound in DMSO was added to 40 ⁇ of cell growth medium (RPMI 1640, 10%FBS, 1 % penicillin/Streptomycin, 1 % L-Glutamine, 1 % HEPES) in each well of 384-well assay plates (10 concentrations) in quadruplicate.
  • cell growth medium RPMI 1640, 10%FBS, 1 % penicillin/Streptomycin, 1 % L-Glutamine, 1 % HEPES
  • MT4 °C with 25 ⁇ , (MT4) or of either cell growth medium (mock-infected) or a fresh 1 :250 dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for MT4 cells).
  • Infected and uninfected cells are diluted in cell growth medium and 35 ⁇ iL of 2000 (for MT4) cells is added to each well of the assay plates.
  • Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 ⁇ of 2X concentrated CellTiter-GloTM Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was carried out by incubating at room temperature for 2-3 min and then chemiluminescence was read using the Envision reader (PerkinElmer).
  • compositions of the present invention demonstrate antiviral activity in this assay (Test A) as depicted in Table I and Table II below.
  • the compounds demonstrate an EC50 of ⁇ 30 ⁇ . In certain embodiments, the compounds demonstrate an EC50 of ⁇ 10 ⁇ . In certain embodiments, the compounds demonstrate an EC50 of ⁇ 1 ⁇ . In certain embodiments, the compounds demonstrate an EC50 of ⁇ 0.5 ⁇ . In certain embodiments, the compounds demonstrate an EC50 of ⁇ 0.2 ⁇ . In certain embodiments, the compounds demonstrate an EC50 of ⁇ 0.1 ⁇ . It is to be understood that the compounds disclosed herein can be grouped according to the EC50 activities described above.
  • the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.
  • 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.
  • reaction mixture was cooled and poured into saturated ammonium chloride solution and diluted with water.
  • the product was extracted with ethyl acetate (2x) and the combined organic layer dried (MgS0 4 ), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate hexanes) to give the desired product.
  • the colorless oil was dissolved in dichloromethane (20 mL) and added to the reaction mixture over 10 minutes.
  • the reaction mixture was stirred at -40 °C for 1.5 hours, then warmed to -25 °C over 30 minutes.
  • the reaction mixture was quenched with acetic acid (5.8 mL).
  • Acetonitrile (30 mL) was added and the reaction mixture was stirred for 5 minutes.
  • the cold bath was removed and water (59 mL) was added and stirred for 15 minutes.
  • the mixture was diluted with water and brine and extracted with dichloromethane (3x).
  • reaction mixture was stirred for another 20 minutes and quenched with saturated sodium carbonate solution and ethyl acetate was added.
  • the mixture was stirred for 30 minutes, the aqueous layer removed and the organic layer washed with saturated sodium carbonate solution (3x), brine and dried (MgS0 4 ) and filtered.
  • reaction mixture was refluxed for 1 hour. Additional azabiisobutyronitrile (10 mg) was added and stirred for 1 hour. The reaction mixture was cooled to room temperature, adsorbed onto silica gel and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired product.
  • reaction mixture was concentrated and co- evaporated with dichloromethane and dried under house vacuum.
  • the resulting off-white residue was suspended in acetonitrile and cooled to -40 °C. l,8-Diazabicyclo[5.4.0]dunde-7-ene (7.19 mL, 48.09 mmol) was added over 5 minutes and the reaction mixture was warmed to room temperature overnight.
  • the reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute acetic acid solution, brine and dried (MgS0 4 ) and filtered. Concentration and purification by flash column chromatography (silica gel, 20-60% ethyl acetate/hexanes) gave an impure product.
  • reaction was stirred for another 30 minutes, and a solution of l-(3- chlorophenyl)propan-2-one (19.7 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0 °C during addition).
  • the reaction was allowed to warm to 23 °C overnight and quenched with saturated aqueous NH4CI (250 mL). After 2 h, the mixture was diluted with water (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2 x 150 mL).
  • reaction mixture was heated in microwave at 110 °C for 1 hour.
  • the reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine and dried (MgS0 4 ) and filtered. Concentration and purification by flash column
  • the other atropisomers were also prepared in a similar way.
  • the other atropisomers were also prepared in a similar way.
  • Example 7 (S)-2-tert-Butoxy-2-(6-cyano- 1 -((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-4-fluoro-3 -methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((R)- 2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid, (S)-2- tert-butoxy-2-(6-cyano-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3- methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((S)-2,3
  • the other atropisomers were also prepared in a similar way.
  • reaction mixture was stirred for 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at room temperature.
  • the aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4x), saturated ammonium chloride solution, dried, filtered, concentrated in vacuo and purified by flash column chromatography to give the desired product.
  • (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3- hydroxy-3-phenylbut-l-ynyl)naphthalen-2-yl)acetic acid (2S)-2-tert-butoxy-2-(l-(4- chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-l-ynyl)naphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate and l,l,l-trifluoro-2-phenylbut-3-yn-2-ol.
  • (2S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-3- yl)but- 1 -ynyl)-3 -methymaphthalen-2-yl)acetic acid (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7- (3-hydroxy-3-(pyridin-3-yl)but-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl
  • reaction mixture was absorbed directly onto silica gel and purified via Yamazen silica gel column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(4-fluoro-3,6-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate.
  • reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l-(methylsulfonyloxy)naphthalen-2-yl)acetate that was approximately an 85:15 mixture with an inseparable, uncharacterized side product.
  • reaction vessel was sealed and sparged with Ar for 30 minutes prior to heating in a microwave reactor at 125 °C for 90 minutes.
  • the reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2-yl)acetate and of (S)-ethyl 2- tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2- yl)acetate.
  • reaction mixture is sealed and sparged with Ar for 10 minutes prior to heating at 120 °C for 90 minutes.
  • the reaction mixture is allowed to cool to room temperature, loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3-methyl-l- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate.
  • the resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the suspension is filtered through a pad of Celite, and the filtrate is washed with batches of EtOAc until white in color. The collected mother liquor is further diluted with water and EtOAc. Following separation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. The residue is purified by Yamazen column chromatography (15-35%EtO Ac/hex) to afford the desired material.
  • reaction mixture was diluted with ethyl acetate and washed with brine.
  • the aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS0 4 ), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give the desired compound.
  • reaction mixture was diluted with ethyl acetate and washed with brine.
  • the aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS0 4 ), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give the desired compound.
  • Trifluoromethanesulfonic anhydride (0.1 mL, excess) was added dropwise over 20 minutes and stirred for 1 hour. Reaction was quenched with brine and stirred for 15 minutes at room temperature. The mixture was diluted with dichloromethane, washed with IN HC1 solution, saturated sodium bicarbonate solution/brine and dried (MgSC ⁇ ), filtered, concentrated to give the desired compound.
  • Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120°C for 40 minutes. Reaction mixture was diluted with ethyl acetate and washed with brine, dried
  • Reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS0 4 ), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give the desired compound.
  • reaction mixture was diluted with ethyl acetate and washed with brine.
  • the aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSC ⁇ ), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give the desired compound.
  • phenanthren-9-yl)acetate Preparation of ethyl 2-hydroxy-2-(10-hydroxyphenanthren-9-yl)acetate: Prepared by the similar method to make ethyl 2-(6-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2- hydroxyacetate in Example 20, using phenanthren-9-ol instead of 6-bromo-3-methylnaphthalen- l-ol.
  • reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgS0 4 ), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3 -methyl -2 -vinyl- naphthalene contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2x).
  • the vessel was evacuated under vacuum and backfilled with dry argon. Freshly distilled 1,2-dimethoxyethane (distilled from sodium/benzophenone, 20 mL) was introduced. With vigorous stirring, the flask was wrapped in foil and heated to 120 °C for 3 h. The reaction was cooled to 23 °C and added to brine (20 mL) and H 2 0 (20 mL). EtOAc (30 mL) was introduced, followed by hexane (10 mL). The slurry was filtered over a pad of Celite. The filtrate now separated into two layers. The organic phase was collected. The aq. layer was extracted with EtOAc (3x 30 mL).
  • alen-2-yl)acetate trifluoromethylsulfonyl DME
  • the first eluting mixture, mixture A was further purified via PRP HPLC (5 ⁇ Gemini C 18 column (100 x 30mm), (5 to 100% MeCN/H 2 0 + 0.05%TFA) and resulting in enriched (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid.
  • the system was extracted with two portions of diethyl ether (100 mL, then 50 mL). The combined extracts were washed with 1.0 M aq. CuS0 4 monohydrate (4x 50 mL), dried over MgS0 4 , and filtered. The filtrate was distilled at ambient pressure at a bath temperature of 80-100 °C to remove most of the diethyl ether. The resulting oil left in the pot was fractionally distilled through a Snyder column with 3 chambers under reduced pressure (6-8 mmHg). A small-volume forerun was collected and discarded (bp ⁇ 45 °C). The main fraction contained 2-methylhexan-2-yl acetate (bp 45-48 °C).
  • the reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgS0 4 ), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3 -methyl-2- vinyl- naphthalene contaminated by organotin.
  • the residue was dissolved in dichloromethane and stirred with 10% KF solution overnight.
  • the resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2x).
  • the organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1- chloro-3-methyl-2 -vinyl-naphthalene.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides compounds and salts thereof as d herein. The invention also provides pharmaceutical compositions comprising a compound disclosed herein, processes for preparing compounds disclosed herein, intermediates useful for preparing compounds disclosed herein and therapeutic methods for treating an HIV infection, treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds disclosed herein.

Description

NAPTHALENE ACETIC ACID DERIVATIVES AGAINST HIV INFECTION
Cross Reference to Related Application
This patent application claims the benefit of priority of U.S. Application Serial No. 61/583136, filed January 4, 2012. The content of this provisional application is hereby incorporated herein in its entirety.
Background of the Invention
Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860;
Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the inhibition of integrase.
Summary
Compounds and methods for the treatment of an HIV infection are disclosed.
Accordingly, one embodiment provides a compound selected from:
Figure imgf000003_0001
Figure imgf000003_0002
Figure imgf000003_0003
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
11 72
Figure imgf000013_0001
Figure imgf000014_0001

Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0004

Figure imgf000016_0001

Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003

Figure imgf000018_0001

Figure imgf000019_0001

Figure imgf000020_0001
Figure imgf000020_0002

Figure imgf000021_0001
Figure imgf000021_0002
20
Figure imgf000022_0001
Figure imgf000022_0002
21
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
22
Figure imgf000024_0001
and salts thereof.
Another embodiment provides a compound as described in any one of the Examples disclosed herein or a non-salt thereof or a salt thereof or an alternative salt thereof.
Another embodiment provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Another embodiment provides a method for treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the mammal.
Another embodiment provides a method for treating an HIV infection in a mammal (e.g., a human) comprising administering one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, to the mammal.
Another embodiment provides a method for treating an HIV infection in a mammal (e.g., a human) comprising administering to the mammal 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 selected from the group consisting HIV protease inhibiting compounds, HIV non-nucleoside 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, and other drugs for treating HIV, and combinations thereof.
Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human)). Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating e.g., preventing, mediating or inhibiting) an HIV infection in a mammal (e.g., a human)).
Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating (e.g., preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).
Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment (e.g., prevention, mediation or inhibition) of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.
Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a mammal e.g., a human).
Another embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.
Another embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds disclosed herein or salts thereof.
Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follows, and in part will be apparent from the description, or may be learned by practice, of the claimed invention. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the written description and claims hereof. The foregoing Summary has been made with the understanding that it is to be considered as a brief and general synopsis of some of the embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the appended claims are lawfully entitled.
Detailed Description
While the present invention is capable of being embodied in various forms, the description below of several embodiments 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 only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Definitions
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). The word "about" may also be represented
symbolically by "~" in the context of a chemical measurement (e.g., ~ 50 mg or pH ~ 7).
The term "treatment" or "treating," to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
Stereoisomers
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
The compounds disclosed herein may have chiral centers, e.g., chiral carbon atoms. Such compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds disclosed herein include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g.,, acids or bases followed by conversion back to the optically active substances. The desired optical isomer can also be synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
It is to be understood that for compounds disclosed herein when a bond is drawn in a non-stereochemical manner (e.g., flat) the atom to which the bond is attached includes all stereochemical possibilities. It is also to be understood that when a bond is drawn in a stereochemical manner (e.g., bold, bold- wedge, dashed or dashed- wedge) the atom to which the stereochemical bond is attached has the stereochemistry as shown unless otherwise noted.
Accordingly, in one embodiment, a compound disclosed herein is greater than 50% a single enantiomer. In another embodiment, a compound disclosed herein is at least 80% a single enantiomer. In another embodiment, a compound disclosed herein is at least 90% a single enantiomer. In another embodiment, a compound disclosed herein is at least 98% a single enantiomer. In another embodiment, a compound disclosed herein is at least 99% a single enantiomer. In another embodiment, a compound disclosed herein is greater than 50% a single diastereomer. In another embodiment, a compound disclosed herein is at least 80% a single diastereomer. In another embodiment, a compound disclosed herein is at least 90% a single diastereomer. In another embodiment, a compound disclosed herein is at least 98% a single diastereomer. In another embodiment, a compound disclosed herein is at least 99% a single diastereomer.
Tautomers The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
Salts and Hydrates
Examples of pharmaceutically acceptable salts of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and N¾+ (wherein X is Ci-C4 alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids.
Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX " (wherein X is independently selected from H or a C1-C4 alkyl group).
For therapeutic use, salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+,
Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HC1, HBr, H2S04, H3PO4 or organic sulfonic acids, to basic centers, typically amines. Finally, it is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with water as in hydrates. Isotopes
It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -C¾ group may be substituted with -CD3.
Compounds
In one embodiment compounds are selected from:
Figure imgf000029_0001
Figure imgf000030_0001

Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
30
Figure imgf000032_0001
Figure imgf000032_0002
In one embodiment compounds are selected from:
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000034_0002
33
Figure imgf000035_0001

Figure imgf000036_0001
Figure imgf000036_0002

Figure imgf000037_0001
and salts thereof.
In one embodiment compounds are selected from:
Figure imgf000037_0002
Figure imgf000038_0001

Figure imgf000039_0001
Figure imgf000039_0002

Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
Figure imgf000040_0004

Figure imgf000041_0001
Figure imgf000041_0002
40
Figure imgf000042_0001
Figure imgf000042_0002
41
Figure imgf000043_0001
42
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0003
Figure imgf000044_0004
43
Figure imgf000045_0001
Figure imgf000045_0002
44
Figure imgf000046_0001

Figure imgf000047_0001
Figure imgf000047_0002

Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0003

Figure imgf000049_0001

Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003

Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
50
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000053_0002
52
Figure imgf000054_0001
Figure imgf000054_0002
53
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
Figure imgf000055_0004
Figure imgf000055_0005
54
Figure imgf000056_0001
55
Figure imgf000057_0001
Figure imgf000057_0002

Figure imgf000058_0001

Figure imgf000059_0001

Figure imgf000060_0001
Figure imgf000060_0002
and salts thereof.
One embodiment provides compounds selected from:
Figure imgf000061_0001
60
Figure imgf000062_0001
61
Figure imgf000063_0001
Figure imgf000063_0002
62
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
and salts thereof.
One embodiment provides compounds selected from:
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000065_0003
Figure imgf000065_0004
64
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
65
Figure imgf000067_0001
and salts thereof.
One embodiment provides compounds selected from:
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003

Figure imgf000069_0001

Figure imgf000070_0001
Figure imgf000070_0002

Figure imgf000071_0001
Figure imgf000071_0002
One embodiment provides compounds selected from:
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000072_0003
Figure imgf000072_0004
71
Figure imgf000073_0001
Figure imgf000073_0002
72
Figure imgf000074_0001
73
Figure imgf000075_0001
Figure imgf000075_0002
74
Figure imgf000076_0001
75
Figure imgf000077_0001
76
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000080_0002

Figure imgf000081_0001
80
Figure imgf000082_0001
81
Figure imgf000083_0001
82
Figure imgf000084_0001
and salts thereof. Combination Therapy
In one embodiment, the invention provides for a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, 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.
In one embodiment, the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. For example, the therapeutic agent used in combination with the compound of the present invention can be any anti-HIV agent.
In one embodiment, the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside 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, and other drugs for treating HIV, and combinations thereof, and a pharmaceutically acceptable carrier. In another embodiment, the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of:
(1) HIV protease inhibiting compounds selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL- 100, DG35, and AG 1859;
(2) HIV non-nucleoside inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, RDEA806 and KM023;
(3) HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), ;
(4) HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX- 157 (Chimerix)
(5) HIV integrase inhibitors selected from the group consisting of 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, S- 1360, AR- 177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, GS-5696, elvitegravir and dolutegravir;
(6) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;
(7) the CXCR4 inhibitor AMD-070;
(8) the entry inhibitor SP01 A;
(9) the gpl20 inhibitor BMS-488043;
(10) the G6PD and NADH-oxidase inhibitor immunitin; (1 1) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;
(12) other drugs for treating HIV selected from the group consisting of B AS- 100, SPI- 452, REP 9, SP-01 A, TNX-355, DES6, ODN-93, ODN-1 12, VGV-1 , PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007 A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040).
In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
In some embodiments, one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents. Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
In yet another embodiment, the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above..
Pharmaceutical Formulations
The compounds disclosed herein are formulated with conventional carriers (e.g., inactive ingredient or excipient material) which will be selected in accord with ordinary practice. Tablets will contain excipients including glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. One embodiment provides the formulation as a solid dosage form including a solid oral dosage form. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations (compositions). The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical excipients, etc.) which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
Pharmaceutical formulations according to the present invention comprise one or more compounds disclosed herein together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
The amount of active ingredient that is combined with the inactive ingredients to produce a dosage form will vary depending upon the host treated and the particular mode of
administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (i.e., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weighfcweight).
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
Routes of Administration
One or more compounds disclosed herein (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), 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 the compounds of this invention is that they are orally bioavailable and can be dosed orally.
The antiviral properties of a compound disclosed herein may be determined using Test A described below.
Test A: Antiviral Assays in MT4 Cells
For the antiviral assay utilizing MT-4 cells, 0.4 of 189X test concentration of 3 -fold serially diluted compound in DMSO was added to 40 μΙ of cell growth medium (RPMI 1640, 10%FBS, 1 % penicillin/Streptomycin, 1 % L-Glutamine, 1 % HEPES) in each well of 384-well assay plates (10 concentrations) in quadruplicate.
1 mL aliquots of 2x10e6 MT-4 cells are pre-infected for 1 and 3 hrs respectively, @ 37
°C with 25 μΐ, (MT4) or of either cell growth medium (mock-infected) or a fresh 1 :250 dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cells are diluted in cell growth medium and 35 \iL of 2000 (for MT4) cells is added to each well of the assay plates.
Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 μΐ of 2X concentrated CellTiter-Glo™ Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was carried out by incubating at room temperature for 2-3 min and then chemiluminescence was read using the Envision reader (PerkinElmer).
Compounds of the present invention demonstrate antiviral activity in this assay (Test A) as depicted in Table I and Table II below.
Table I
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
acid
Figure imgf000093_0001
Figure imgf000094_0001
yl)acetic acid
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
yl)acetic acid
Table II
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
101
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
111
Figure imgf000113_0001
In
Figure imgf000114_0001
In certain embodiments, the compounds demonstrate an EC50 of < 30 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 10 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 1 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 0.5 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 0.2 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 0.1 μΜ. It is to be understood that the compounds disclosed herein can be grouped according to the EC50 activities described above.
The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention. 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.
Example 1. (S)-2-tert-Butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,4- dimethylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-(l-((S)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetic acid
Figure imgf000116_0001
flJoSzene 2.3*™thylfuran
3,4-dimethylnaphthalen-1 -ol
[4,3,2- ronic
Figure imgf000116_0002
(S)-ethyl 2-(3,4-dimethyl-1- (trifluoromethylsulfonyloxy) (S)-ethyl 2-ferf-butoxy-2-(3,4-dimethyl-1 - naphthalen-2-yl)-2- (trifluoromethylsulfonyloxy)naphthalen-2- hydroxyacetate yl)acetate
Figure imgf000116_0003
(S)-2-ferf-butoxy-2-(1-((R)-2,3-
(S)-ethyl 2-ferf-butoxy-2-(1-((R)- dihydropyrano[4,3,2-de]quinolin- 2,3-dihydropyrano[4,3,2- 7-yl)-3,4-dimethylnaphthalen-2- de]quinolin-7-yl)-3,4- yl)acetic acid
dimethylnaphthaleri-2-yl)acetate
Preparation of 3,4-dimethylnaphthalen-l-ol: To a solution of 2,3-dimethylfuran (1.06 mL, 10 mmol) in anhydrous THF (10 mL) was added magnesium powder (0.292 g, 12 mmol). The reaction mixture was heated to reflux for 5 minutes. The reaction flask was placed in a room temperature oil bath and a solution of l-bromo-2-fluorobenzene (1.08 mL, 10 mmol) in anhydrous THF (10 mL) was added. The reaction mixture was heated to 35 °C for 1 hour, heated to reflux over 1 hour, and stirred at reflux for 1 hour. The reaction mixture was cooled and poured into saturated ammonium chloride solution and diluted with water. The product was extracted with ethyl acetate (2x) and the combined organic layer dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate hexanes) to give the desired product.
To as solution of the above residue (1.088 g, 6.32 mmol) in dichloromethane (30 mL) was added p-toluenesulfonic acid (0.24 g, 1.26 mmol) and the reaction mixture was heated to 75 °C. After 5 hours, the reaction was cooled to room temperature and concentrated to ~5 mL, filtered and purified by flash column chromatography (silica gel, 0 to 20% ethyl
acetate/hexanes) to give 3,4-dimethylnaphthalen-l -ol. LCMS-EST (m/z) [M-H]" calcd for C12HnO: 171.2; Found: 171.0.
Preparation of ethyl 2-hydroxy-2-(l-hydroxy-3,4-dimethylnaphthalen-2-yl)acetate: To a solution of 3,4-dimethylnaphthalen-l-ol (3.18 g, 18.46 mmol) in dichloromethane (180 mL) at - 40 °C was added a 1M solution of titanium tetrachloride in dichloromethane (18.46 mL, 18.46 mmol) over 10 minutes. In a separate flask, ethyl glyoxalate (2.26 g, 22.16 mmol) was heated at 100 °C for 45 minutes. The colorless oil was dissolved in dichloromethane (20 mL) and added to the reaction mixture over 10 minutes. The reaction mixture was stirred at -40 °C for 1.5 hours, then warmed to -25 °C over 30 minutes. The reaction mixture was quenched with acetic acid (5.8 mL). Acetonitrile (30 mL) was added and the reaction mixture was stirred for 5 minutes. The cold bath was removed and water (59 mL) was added and stirred for 15 minutes. The mixture was diluted with water and brine and extracted with dichloromethane (3x). The combined organic layer was dried (MgS04), filtered, concentrated and purified twice by flash column chromatography (silica gel, 0 to 25% ethyl acetate/hexanes) to give ethyl 2-hydroxy-2- (l-hydroxy-3,4-dimethylnaphthalen-2-yl)acetate. LCMS-EST (m/z): [M-H]" calcd for C16H]704: 273.31 ; Found: 272.8.
Preparation of ethyl 2-(3,4-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- oxoacetate: To a solution of ethyl 2-hydroxy-2-(l-hydroxy-3,4-dimethylnaphthalen-2-yl)acetate (3.69 g, 13.45 mmol) in dichloromethane (100 mL) at 0 °C was added imidazole (1.19 g, 17.49 mmol), followed by chlorotriethylsilane (2.48 mL, 14.80 mmol). The reaction mixture was stirred for 1.5 hours at 0 °C, quenched with water, and stirred for 5 minutes. The mixture was diluted with dichloromethane, washed with water, IN HCl/brine, dried (MgS04), filtered and concentrated to give the desired product that was used in the next step without further purification.
The above residue was dissolved in dichloromethane (100 mL) and cooled to -78 °C. Triethylamine (2.25 mL, 16.14 mmol) was added, followed by dropwise addition of
trifluoromethanesulfonic anhydride (2.49 mL, 14.80 mmol) over 10 minutes. The resulting yellow solution was stirred for 1 hour at -78 °C, quenched with brine and stirred for 10 minutes at room temperature. The mixture was washed with IN HC1, saturated sodium bicarbonate solution/brine, dried (MgS04), filtered, concentrated and dried under vacuum to give the product that was used in the next step without further purification.
To a solution of the above residue in tetrahydrofuran (100 mL) at 0 °C was added 48% aqueous hydrofluoric acid. The reaction mixture was warmed room temperature overnight. The reaction was incomplete, so the reaction was warmed to 45 °C. After 1.5 hours, the reaction was complete and neutralized with the slow addition of solid sodium bicarbonate. Water was added and mixture was extracted with ethyl acetate (2x) and the combined organic layer was washed with saturated sodium bicarbonate solution/brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+Na]+ calcd for C17H17F3Na06S: 429.37; Found: 428.8.
The above foam was dissolved in dichloromethane (100 mL), and cooled to 0 °C. Dess- Martin periodinane (5.45 g, 12.85 mmol) was added in two portions over 5 minutes. The reaction mixture was stirred for 2 hours at 0 °C, then quenched with sodium thiosulfate solution. The mixture was stirred for 10 minutes, diluted with dichloromethane and washed with sodium thiosulfate solution, water, saturated sodium bicarbonate solution, brine, dried (MgSC«4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give ethyl 2-(3,4-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)- 2-oxoacetate. !H NMR (400 MHz, CDC13) δ 8.1 1 (d, J= 8.8 Hz, 2H), 7.73 - 7.59 (m, 2H), 4.39 (q, J= 7.1 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 1.37 (t, J= 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-(3,4-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)- 2-hydroxyacetate: To a solution of ethyl 2-(3,4-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (3.93 g, 9.72 mmol) and (R)-2- methyl-CBS-oxazaoborolidine (0.539 g, 1.94 mmol) in anhydrous toluene (30 mL) at -40 °C was added dropwise a solution of catecholborane (1.40 mL, 13.22 mmol) in toluene (5 mL) over 20 minutes to give a pale yellow reaction mixture. The reaction mixture was stirred for another 20 minutes and quenched with saturated sodium carbonate solution and ethyl acetate was added. The mixture was stirred for 30 minutes, the aqueous layer removed and the organic layer washed with saturated sodium carbonate solution (3x), brine and dried (MgS04) and filtered.
Concentration and purification by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) gave the desired product. LCMS-ESI* (m/z): [M+Na]+ calcd for
C17H17F3Na06S: 429.37; Found: 428.8.
Preparation of (S)-ethyl 2-tert-butoxy-2-(3,4-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-(3,4- dimethyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (3.80 g, 9.35 mmol) in tert-butyl acetate (94 mL) was added 70% perchloric acid (0.160 mL, 1.37 mmol). The reaction mixture was stirred for 5h and quenched with solid sodium bicarbonate. The mixture was stirred for 5 minutes and saturated sodium bicarbonate solution was carefully added until pH 7, then diluted with water and extracted with ethyl acetate (2x). The combined organic layer was washed with saturated sodium bicarbonate solution and dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 25% ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDC13) δ 8.08 (dd, J= 8.7, 8.7 Hz, 2H), 7.63 - 7.55 (m, 2H), 5.75 (s, 1H), 4.3 - 4.1 (m, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 1.20 (s, 3H), 1.17 (t, J= 7.4 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3,4-dimethylnaphthalen-2-yl)acetate: Three separate Smith process vials were each charged with (S)-ethyl 2-tert-butoxy-2-(3 ,4-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2- yl)acetate (0.500 g, 1.08 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (0.326 g, 1.30 mmol) (prepared by the methods described in WO 2009/062289), SPhos
Palladacycle (Strem, 0.109 g, 0.162 mmol) and cesium fluoride (0.722 g, 4.75 mmol) in distilled DME (10 mL) and was sparged with nitrogen for 5 minutes. The reaction mixture was heated in microwave at 120 °C for 1.5 hours. The three reaction mixtures were combined, diluted with ethyl acetate and washed with water brine, dried (MgS04), filtered, and concentrated.
Purification by flash column chromatography (silica gel, 0 to 35% ethyl acetate/hexanes) gave the desired atropisomer, (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3,4-dimethylnaphthalen-2-yl)acetate. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H34N04: 484.2; Found: 484.1. The other atropisomer, (S)-ethyl 2-tert-butoxy-2-(l -((S)-2,3-dihy dropyrano [4,3,2- de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetate was also isolated. LCMS-ESI+ (m/z): [M+H]+calcd for C31H34N04: 484.2; Found: 484.1. Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-
3,4-dimethylnaphthalen-2-yl)acetic acid: To a mixture of (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetate (0.329 g, 0.680 mmol), 5M LiOH (2.72 mL, 13.61 mmol) in methanol (3.0 mL) and THF (10 mL) was added water and MeOH to give a clear yellow solution. The reaction mixture was heated at 45 °C for 36 hours, then at 55 °C for 24 hours. LC/MS indicated reaction was complete. The reaction mixture was concentrated to ~6 mL, acetic acid (0.82 mL, 14.3 mmol) was added, diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered and concentrated. The residue was dissolved in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the title compound as a TFA salt. 1H-NMR: 400 MHz,
(CD3OD) δ 8.64 (d, J= 5.6 Hz, 1H), 8.26 (d, J= 8.6 Hz, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.59 - 7.42 (m, 2H), 7.25 (dd, J= 7.6, 7.6 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 5.22 (s, 1H), 4.78 - 4.67 (m, 2H), 3.66 (t, J= 5.9 Hz, 2H), 2.79 (s, 3H), 2.71 (s, 3H), 0.97 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30NO4: 456.2; Found: 456.1.
The other atropisomer, (S)-2-tert-butoxy-2-(l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-3,4-dimethylnaphthalen-2-yl)acetic acid was prepared in a similar manner. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H3oN04: 456.2; Found: 456.1.
Example 2. (S)-2-tert-Butoxy-2-(5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-l,3- dihydronaphtho[l,2-c]fiiran-4-yl)acetic acid
Figure imgf000121_0001
(S)-2-terf-butoxy-2-(1 -(( ?)- (S)-methyl 2-terf-butoxy-2-(1- 2,3-dihydropyrano[4,3,2- (( ?)-2,3-dihydropyrano[4,3,2- cie]quinolin-7-yl)-3,4- cfe]quinolin-7-yl)-3,4- dimethylnaphthalen-2- dimethylnaphthalen-2- yl)acetic acid yl)acetate
Figure imgf000121_0002
(S)-methyl 2-(3,4- (S)-2-terf-butoxy-2-(5-((R)- bis(bromomethyl)-1 -((R)-2,3- 2,3-dihydropyrano[4,3,2- dihydropyrano[4,3,2- de]quinolin-7-yl)-1 ,3- de]quinolin-7-yl)naphthalen-2- dihydronaphtho[1 ,2- yl)-2-ieri-butoxy acetate c]furan-4-yl)acetic acid
Preparation of (S)-methyl 2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3,4-dimethylnaphthalen-2-yl)acetate: To a solution of (S)-2-tert-butoxy-2-(l-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetic acid (250 mg, 0.439 mmol) in MeOH (0.40 mL) and DMF (4.0 mL) was added a 2.0M solution of
(trimethylsilyl)diazomethane in hexanes (0.48 mL, 0.966 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then more 2.0M solution of
(trimethylsilyl)diazomethane in hexanes (0.24 mL) was added and reaction mixture was stirred for 1 hour. A third portion of 2.0M solution of (trimethylsilyl)diazomethane in hexanes (0.24 mL) was added and reaction was complete after 1 hour. The reaction was quenched with acetic acid, diluted with ethyl acetate and washed with 5% lithium chloride solution/saturated sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgS04) and filtered. The residue was concentrated and purified by flash column chromatography (silica gel, 15 to 50% ethyl acetate/hexanes) to give the desired product. LCMS-ESI* (m/z): [M+H]+ calcd for
C3oH32N04: 470.2; Found: 470.1.
Preparation of (S)-methyl 2-(3,4-bis(bromomethyl)-l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)naphthalen-2-yl)-2-tert-butoxyacetate: A mixture of (S)-methyl 2-tert-butoxy- 2-(l -((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetate (105.3 mg, 0.224 mmol) and N-bromosuccinimide (80 g, 0.448 mmol) in carbon tetrachloride (2.5 mL) was heated to reflux. Azabiisobutyronitrile (5.5 mg, 0.0336 mmol) was added and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was diluted with dichloromethane, adsorbed onto silica gel and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give the desired product. LCMS-ESI* (m z): [M+H]+ calcd for
C30H30Br2NO4: 628.4; Found: 626.0, 627.9, 629.9.
Preparation of (S)-2-tert-butoxy-2-(5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- l,3-dihydronaphtho[l,2-c]furan-4-yl)acetic acid: A solution of (S)-rnethyl 2-(3,4- bis(bromornethyl)-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)-2-tert- butoxyacetate (64 mg, 0.102 mmol) and 5M sodium hydroxide (0.816 mL, 4.08 mmol) in dioxane (5.0 mL) was stirred at 80 °C overnight. Acetic acid (0.234 mL, 4.08 mmol) was added and the mixture concentrated to ~1 mL, then diluted with DMF and acetic acid (0.2 mL). The crude solution was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the title compound as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.65 (d, J= 5.7 Hz, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.37 (ddd, J= 8.1, 6.9, 1.1 Hz, 1H), 7.07 (d, J= 8.6 Hz, 1H), 5.67 - 5.47 (m, 4H), 4.92 (s, 1H), 4.75 (t, J= 6.1 Hz, 2H), 3.68 (t, J= 6.0 Hz, 2H), 1.09 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH28N05: 470.2; Found: 470.1.
Example 3. (S)-2-tert-Butoxy-2-(5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methyl- 2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetic acid and (S)-2-tert-butoxy-2-(5-((S)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methyl-2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetic acid (S
Figure imgf000123_0001
)-ethyl 2-ierf-butoxy-2-
(3,4-dimethyl-1- (S)-ethyl 2-(3,4-bis(bromomethyl)-1 - (trifluoromethylsulfonyloxy (trifluoromethylsulfonyloxy)naphthal
)naphthalen-2-yl)acetate en-2-yl)-2-terf-butoxyacetate
Figure imgf000123_0002
(S)-ethyl 2-terf-butoxy-2-(2-methyl- (2S)-ethyl 2-ferf-butoxy-2-(5- 5-(trifluoromethylsulfonyloxy)-2,3- (2,3-dihydropyrano[4,3,2- dihydro-1 H-benzo[e]isoindol-4- cfe]quinolin-7-yl)-2-methyl-2,3- yl)acetate dihydro-1 /- -benzo[e]isoindol-4- yl)acetate
Figure imgf000123_0003
(S)-2-ferf-butoxy-2-(5-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-
7-y l)-2-methy l-2,3-dihydro-1 H- benzo[e]isoindol-4-yl)acetic acid
Preparation of (S)-ethyl 2-(3,4-bis(bromomethyl)-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate: To a solution of (S)-ethyl 2- tert-butoxy-2-(3,4-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.5145 g, 1.112 mmol) in carbon tetrachloride (4.0 mL) was added N-bromosuccinimide (0.435 g, 2.447 mmol), followed by azabiisobutyronitrile (10 mg, 0.061 mmol). The reaction mixture was refluxed for 1 hour. Additional azabiisobutyronitrile (10 mg) was added and stirred for 1 hour. The reaction mixture was cooled to room temperature, adsorbed onto silica gel and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDC13) δ 8.22 (d, J= 8.6 Hz, 1H), 8.15 (d, J= 8.2 Hz, 1H), 7.79 - 7.68 (m, 2H), 5.81 (s, 1H), 5.32 - 5.13 (m, 3H), 4.86 (d, J= 15.0 Hz, 1H), 4.34 - 4.22 (m, 1H), 4.19 - 4.08 (m, 1H), 1.24 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(2-methyl-5-(trifluoromethylsulfonyloxy)-2,3- dihydro-lH-benzo[e]isoindol-4-yl)acetate: To a solution of (S)-ethyl 2-(3,4-bis(bromomethyl)-
1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.1356 g, 0.219 mmol) and triethylamine (61 pL, 0.438 mmol) in anhydrous THF (10 mL) at 0 °C was added a 2M solution of methylamine in THF (109 iL, 0.219 mmol). The reaction mixture was stirred for 1 hour, then stirred overnight at room temperature. LC/MS shows some desired product.
Reaction mixture was heated at 45 °C for 1.5 hours, then additional 2M solution of methylamine in THF (109 μί, 0.219 mmol) was added. After 1 hour, 2M solution of methylamine in THF (0.9 mL) was added and stirred for 45 minutes. LC/MS showed no starting material. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 30 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H27F3N06S: 490.2; Found: 490.1. Preparation of (2S)-ethyl 2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-
2- methyl-2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetate: A mixture of (S)-ethyl 2-tert-butoxy-2- (2-methyl-5-(trifluoromethylsulfonyloxy)-2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetate (72.8 mg, 0.149 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl salt (45 mg, 0.178 mmol), SPhos Palladacycle (Strem, 15 mg g, 0.022 mmol) and cesium fluoride (100 mg, 0.656 mmol) in distilled DME (1.0 mL) and was sparged with nitrogen for 10 minutes. The reaction mixture was heated in a microwave at 120 °C for 1.5 hours. The reaction mixture was diluted with water/brine, extracted with ethyl acetate (2x), dried (MgS04), filtered, and concentrated. Purification by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) and lyophilization gave the title compound as a 1 :1 mixture of atropisomers. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35N204: 51 1.6; Found: 511.2.
Preparation of (S)-2-tert-butoxy-2-(5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2- methyl-2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetic acid: A solution of (2S)-ethyl 2-tert- butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methyl-2,3-dihydro-lH- benzo[e]isoindol-4-yl)acetate (14.9 mg, 0.021 mmol), 5M NaOH solution (83 μί, 0.415 mmol) in methanol (0.1 mL) and THF (1.0 mL) was stirred at 45 °C for 24 hours, then stored in freezer for 2 days. Acetic acid (25 \L, 21 eq) was added and mixture was concentrated to give a yellow paste that was dissolved in DMF/water, filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the title compound as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J= 4.7 Hz, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.83 (d, J- 8.1 Hz, 1H), 7.71 - 7.56 (m, 2H), 7.53 - 7.40 (m, 2H), 7.17 (d, J= 8.5 Hz, 1H), 5.61 - 5.30 (m, 2H), 5.10 - 4.91 (m, 1H), 4.90 (s, 1H), 4.69 (t, J= 5.8 Hz, 2H), 3.59 (d, J= 5.5 Hz, 2H), 3.30 (s, 3H), 1.11 (s, 9H). LCMS-ESI+ (m/z) [M+H]+ calcd for C30H31N2O4: 483.2; Found: 483.2.
The other atropisomer, (S)-2-tert-butoxy-2-(5-((S)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-2-methyl-2,3-dihydro-lH-benzo[e]isoindol-4-yl)acetic acid was also isolated. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH3iN204: 483.2; Found: 483.2. Example 4. (S)-2-tert-Butoxy-2-(l -((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6- (methylsulfonyl)naphthalen-2-yl)acetic acid and ((S)-2-tert-butoxy-2-(l-((S)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(methylsulfonyl)naphthalen-2-yl)acetic acid
yl)- -
Figure imgf000126_0001
(S)-2-ferf-butoxy-2-(1 -((f?)- 2,3-dihydropyrano[4,3,2- cfe]quinolin-7-yl)-3-methyl-6- (methylsulfonyl)naphthalen-2- yl)acetic acid
Preparation of 3-methyl-6-(methylsulfonyl)-3,4-dihydronaphthalen-l(2H)-one: A mixture of 6-bromo-3-methyl-3,4-dihydronaphthalen-l(2H)-one (10 g, 41.8 mmol)
methanesulfinic acid, sodium salt (16.7 g, 163.1 mmol), copper(I) iodide (3.18 g, 16.7 mmol), cesium carbonate (6.81 g, 20.9 mmol) and L-proline (3.85 g, 33.4 mmol) in DMSO (200 mL) was heated at 100 °C, protected from light. After 3.5 hours, copper(I) iodide (1.59 g) and L- proline (1.9 g) were added and the reaction continued for 5 hours, and then stirred overnight at room temperature. The mixture was diluted with ice/water (200 mL) and extracted with ethyl ether (3x), ethyl acetate (3x). The combined organic layer was washed with brine, dried
(MgS04), filtered, and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDC13) δ 8.20 (d, J= 8.1 Hz, 1H), 7.87 (s, 1H), 7.86 (d, J= 7.7 Hz, 1H), 3.10 - 3.00 (m, 1H), 3.08 (s, 3H), 2.86 - 2.71 (m, 2H), 2.48 - 2.31 (m, 2H), 1.19 (d, J = 6.0 Hz, 3H). Preparation of 2-bromo-3-methyl-6-(methylsulfonyl)naphthalen-l-ol: To a solution of 3- methyl-6-(methylsulfonyl)-3,4-dihydronaphthalen-l(2H)-one (7.64 g, 32.06 mmol) in dichloromethane (200 mL) at room temperature was added a solution of bromine (3.38 mL, 65.72 mmol) in dichloromethane (5 mL) over 30 minutes to give an orange mixture. The reaction mixture was stirred at room temperature for 2 hours, then more bromine (0.3 mL) was added and stirring continued for 1 hour. The reaction mixture was concentrated and co- evaporated with dichloromethane and dried under house vacuum. The resulting off-white residue was suspended in acetonitrile and cooled to -40 °C. l,8-Diazabicyclo[5.4.0]dunde-7-ene (7.19 mL, 48.09 mmol) was added over 5 minutes and the reaction mixture was warmed to room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute acetic acid solution, brine and dried (MgS04) and filtered. Concentration and purification by flash column chromatography (silica gel, 20-60% ethyl acetate/hexanes) gave an impure product. Repurification by flash column chromatography (silica gel, 40% ethyl acetate/hexanes) gave the desired product. LCMS-ESI+ (m/z): [M-H]"calcd for C12H!oBr03S: 314.2; Found: 313.2, 315.1
Preparation of 3-methyl-6-(methylsulfonyl)naphthalen-l-ol: A mixture of 2-bromo-3- methyl-6-(methylsulfonyl)naphthalen-l-ol (0.500 g, 1.59 mmol), 10% palladium on carbon (0.050 g) and triethylamine (0.331 mL, 2.38 mmol) in ethanol was stirred under a hydrogen atmosphere for 1.5 hours. Celite was added and the mixture was stirred for 10 minutes, filtered through a pad of Celite and the filtrate concentrated. The residue was dissolved in ethyl acetate, washed with dilute HCl/brine, dried (MgS04), filtered, concentrated, and purified by flash column chromatography (silica gel, 20 to 50% ethyl acetate/hexanes) to give the desired product. LCMS-ESf (m/z): [M-H]"calcd for C12Hu03S: 235.3; Found: 235.2.
Preparation of (S)-2-tert-butoxy-2-(l -((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methyl-6-(methylsulfonyl)naphthalen-2-yl)acetic acid: (S)-2-tert-butoxy-2-(l-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(methylsulfonyl)naphthalen-2-yl)acetic acid was prepared in a similar way as (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano [4,3,2- de]quinolin-7-yl)-3,4-dimethylnaphthalen-2-yl)acetic acid in Example 1 expect using 3-methyl- 6-(methylsulfonyl)naphthalen-l-ol instead of 3,4-dimethylnaphthalen-l-ol. 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J= 5.6 Hz, 1H), 8.61 (s, 1H), 8.20 (s, 1H), 7.82 (t, J= 8.1 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.47 (d, J= 8.1 Hz, 1H), 7.20 (d, J= 9.1 Hz, 1H), 5.27 (s, 1H), 4.73 (dd, J= 11.1, 5.9 Hz, 2H), 3.67 (t, J= 6.0 Hz, 2H), 3.15 (s, 3H), 2.83 (s, 3H), 0.93 (s, 9H). LCMS-ESI+ (m/z) [M+H]+ calcd for C29H30NO6S: 520.2; Found: 520.1.
The other atropisomer, ((S)-2-tert-butoxy-2-(l-((S)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methyl-6-(methylsulfonyl)naphthalen-2-yl)acetic acid was also prepared in a similar way. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30NO6S: 520.2; Found: 520.1.
Example 5. (S)-2-tert-Butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid, 6-((S)-tert- butoxy(carboxy)methyl)-5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2- naphthoic acid, (S)-2-tert-butoxy-2-(6-cyano-l -((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3-methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((S)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid and 6-((S)-tert- butoxy(carboxy)methyl)-5-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2- naphthoic acid
ethyl 2-
Figure imgf000129_0001
(diethoxyphosp
1 -(3 horyl)acetate
-chlorophenyl)propan- ethyl 4-(3-chlorophenyl)-3- 2-one methylbut-2-enoate
Figure imgf000129_0002
6-chloro-3- (S)-ethyl 2-ierf-butoxy-2-(6- methylnaphthalen-1 -ol chloro-3-methyl-1- (trifluoromethylsulfonyloxy)n
Figure imgf000129_0003
(S)-ethyl 2-ierf-butoxy-2-(6- (S)-ethyl 2-ferf-butoxy-2-(6-cyano- cyano-3-methyl-1- 1 -((f?)-2,3-dihydropyrano[4,3,2- (trifluoromethylsulfonyloxy)n
de]quinolin-7-yl)-3- aphthalen-2-yl)acetate
methylnaphthalen-2-yl)acetate
Figure imgf000129_0004
(S)-2-ter f-butoxy-2-(6-cyano-1 - (S)-2-ieri-butoxy-2-(6-carbamoyl- 6-((S)-tert- ((R)-2,3-dihydropyrano[4,3,2- 1 -((R)-2,3-dihydropyrano[4,3^2- butoxy(carboxy)methyl)-5-((R)-2,3- de]quinolin-7-yl)-3- de]quinolin-7-yl)-3- dihydropyrano[4,3,2-de]quinolin-7- methylnaphthalen-2-yl)acetic acid methylnaphthalen-2-yl)acetic acid yl)-7-methyl-2-naphthoic acid
Preparation of ethyl 4-(3-chlorophenyl)-3-methylbut-2-enoate: At 0 °C, a suspension of 60% w/w NaH/mineral oil (7.13 g, 0.176 mol) in THF (250 mL) was treated dropwise with a solution of ethyl 2-(diethoxyphosphoryl)acetate (39.5 g, 0.176 mol) in THF (72 mL) over a 30 min period. The reaction was stirred for another 30 minutes, and a solution of l-(3- chlorophenyl)propan-2-one (19.7 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0 °C during addition). The reaction was allowed to warm to 23 °C overnight and quenched with saturated aqueous NH4CI (250 mL). After 2 h, the mixture was diluted with water (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2 x 150 mL). Combined organic phases were dried (MgS04), filtered, and concentrated, giving crude ethyl 4-(3-chlorophenyl)-3-methylbut-2- enoate as a mixture of E and Z isomers. The residue was carried onward without further purification. (-25 grams). The 1H NMR reported below is from a crude mixture containing both the E and Z isomer. 1H NMR (400 MHz, CDC13) δ 7.24-7.22 (m, 2H), 7.16 (s, 1H), 7.06-7.04 (m, 1H); 5.67 (s, 1H); 4.18-4.13 (dd, 2H); 3.40 (s, 2H), 2.11 (s, 3 H), 1.30-1.26 (t, 3H).
Preparation of 6-chloro-3-methylnaphthalen-l-ol: A flask containing the crude ethyl 4- (3-chlorophenyl)-3-methylbut-2-enoate (-25 grams) was treated with concentrated H2S04 (120 mL) and warmed to 50 °C for 2.5 h. The reaction was poured onto -500 mL of crushed ice. Once the ice had melted, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated aq. NaHC03, dried (MgS04), filtered, and concentrated to -55 mL. The residue was treated with DCM and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate hexanes) giving the desired product. lH NMR (400 MHz, CDC13) δ 8.07-8.05 (d, J= 8.8 Hz, 1H), 7.69-7.68 (d, J - 2.0 Hz, 1H), 7.35-7.32 (dd, J= 2.0, 8.8 Hz, 1H); 7.12 (s, 1H); 6.65 (s, 1H); 5.21(bs, 1H); 4.21-4.17 (dd, 2H); 2.41 (s, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(6-chloro-3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(3 ,4-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 1 except using 6-chloro-3-methylnaphthalen-l-ol instead of 3,4-dimefhylnaphthalen- l-ol. 1H NMR (400 MHz, CDC13) δ 7.98 (d, J= 9.1 Hz, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (dd, J= 9.0, 1.8 Hz, 1H), 5.70 (s, 1H), 4.17 (dqd, J= 14.2, 7.1, 3.2 Hz, 2H), 2.55 (s, 3H), 1.20 (s, J= 6.5 Hz, 9H), 1.17 (t, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A mixture of (S)-ethyl 2-tert-butoxy-2-(6- chloro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.546 g, 1.13 mmol), zinc(II) cyanide (0.080 g, 0.678 mmol), XPhos Palladacycle (Strem, 0.083 g, 0.113 mmol) and sodium bicarbonate (0.009 g, 0.113 mmol) in DMF (3.0 mL) was sparged with nitrogen for 5 minutes. The reaction mixture was heated in microwave at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine and dried (MgS04) and filtered. Concentration and purification by flash column
chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) gave the title compound. 1H NMR (400 MHz, CDC13) δ 8.19 (s, H), 8.13 (d, J= 8.8 Hz, H), 7.74 (s, H), 7.71 (d, J= 8.8 Hz, H), 5.73 (s, H), 4.27 - 4.09 (m, 2H), 2.59 (s, 3H), 1.21 (s, 9H), 1.17 (t, J = 7.1 Hz, 2H). Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(6-cyano- 1 -((R)- 2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,4- dimethylnaphthalen-2-yl)acetate in Example 1 except (S)-ethyl 2-tert-butoxy-2-(6-cyano-3- methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2- tert-butoxy-2-(3 ,4-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. LCMS-ESI+ (m/z) [M+H]+ calcd for C31H31N204: 495.2; Found: 495.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-(6-cyano-l-((S)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate was also isolated.
LCMS-ESI+ (m/z) [M+H]+ calcd for C31H31N204: 495.2; Found: 495.1.
Preparation of (S)-2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2-(6-cyano-l- ((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (113 mg, 0.228 mmol), 5M NaOH solution (0.91 mL, 5.57 mmol) in methanol (0.91 mL) and THF (3.0 mL) was stirred at 55 °C for 40 hours. Acetic acid (21 eq) was added and the mixture was concentrated to ~1 mL, diluted with DMF, filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product was lyophilized to give the title compound as a TFA salt. Ή NMR (400 MHz, CD3OD) 5 8.70 (d, J= 5.7 Hz, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7.89 - 7.78 (m, 2H), 7.46 (dd, J= 8.4, 5.2 Hz, 2H), 7.12 (d, J= 8.8 Hz, 1H), 5.26 (s, 1H), 4.77 - 4.68 (m, 2H), 3.67 (t, J= 5.9 Hz, 2H), 2.81 (s, 3H), 0.93 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H27N204: 467.2; Found: 467.1.
(S)-2-tert-butoxy-2-(6-carbamoyl-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid was also isolated (30.8 mg, %). 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J= 5.7 Hz, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.89 - 7.78 (m, 2H), 7.71 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 8.1 Hz, 1H), 7.02 (d, J= 8.8 Hz, 1H), 5.26 (s, 1H), 4.79 - 4.68 (m, 2H), 3.67 (t, J= 5.9 Hz, 2H), 2.81 (s, 3H), 0.93 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C29H29N205: 485.5; Found: 485.1.
6-((S)-tert-butoxy(carboxy)methyl)-5-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7- methyl-2-naphthoic acid was also isolated (5.7 mg, %). 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J= 5.9 Hz, 1H), 8.66 (s, 1H), 8.12 (s, 1H), 7.85 7.75 (m, 2H), 7.46 (d, J= 8.1 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 5.26 (s, 1H), 4.75 - 4.68 (m, 2H), 3.67 (t, J= 5.9 Hz, 2H), 2.81 (s, 3H), 0.93 (s, 9H). LCMS-ESf (m/z) [M+H]+ calcd for C29H28N206: 486.2; Found: 486.1.
The other atropisomers were also prepared in a similar way.
(S)-2-tert-butoxy-2-(6-cyano-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid: LCMS-ESf (m/z): [M+H]+calcd for C29H27N204: 467.2; Found: 467.1.
(S)-2-tert-butoxy-2-(6-carbamoyl-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid: LCMS-ESf (m/z): [M+H]+calcd for C29H29N205: 485.5; Found: 485.1.
6-((S)-tert-butoxy(carboxy)methyl)-5-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7- methyl-2-naphthoic acid: LCMS-ESf (m/z): [M+H]+ calcd for C29H28N206: 486.2; Found:
486.1.
Example 6. (S)-2-(6-Cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid, (S)-2-(6-carbamoyl- 1 -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid, (S)-2-(6-cyano-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2- (tert-pentyloxy)acetic acid, (S)-2-(6-carbamoyl-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3 -methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid
Figure imgf000133_0001
(S)-2-(6-cyano-1 -((R)-2,3- dihydropyrano[4,3,2-cfe]quinolin-7- yl)-3-methylnaphthalen-2-yl)-2- (ierf-pentyloxy)acetic acid
(S)-ethyl 2-(6-cyano-3- methyl-1- (trifluoromethylsulfonyloxy)n
aphthalen-2-yl)-2-(ferf- pentyloxy)acetate
Figure imgf000133_0002
(S)-2-(6-carbamoyl-1 -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)-2- (ferf-pentyloxy)acetic acid
Preparation of (S)-ethyl 2-(6-cyano-3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen- 2-yl)-2-(tert-pentyloxy)acetate: (S)-ethyl 2-(6-cyano-3-methyl-l (trifluoromethylsulfonyloxy)- naphthalen-2-yl)-2-(tert-pentyloxy)acetate was prepared in a similar way to (S)-ethyl 2-tert- butoxy-2-(6-cyano-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 5 except ter/-amyl acetate was used instead of tert-butyl acetate. 1H NMR (400 MHz, CDC13) δ 8.18 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.71 (d, J= 8.9 Hz, 1H), 5.73 (s, 1H), 4.27 - 4.08 (m, 2H), 2.59 (s, 3H), 1.62 - 1.43 (m, 2H), 1.20 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H), 1.08 (s, 3H), 0.77 (t, J = 7.4 Hz, 3H).
Preparation of (S)-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid: (S)-2-(6-cyano-l -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid was prepared in a similar way to (S)-2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid in Example 5 except (S)-ethyl 2-(6- cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert- pentyloxy)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-cyano-l-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J= 5.5 Hz, 2H), 8.44 (s, 1H), 8.09 (s, 1H), 7.84 (d, J= 7.4 Hz, 1H), 7.79 (d, J= 5.4 Hz, 1H), 7.47 (d, J= 9.3 Hz, 1H), 7.43 (s, 1H), 7.11 (d, J= 8.7 Hz, 1H), 5.20 (s, 1H), 4.78 - 4.63 (m, 2H), 3.66 (t, J= 5.9 Hz, 2H), 2.81 (s, 3H), 1.31 - 1.02 (m, 2H), 0.92 (s, 6H), 0.62 (t, J= 7.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H29N2O4: 480.2; Found: 480.0.
(S)-2-(6-carbamoyl- 1 -((R)-2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 - methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid was also isolated. 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J= 5.6 Hz, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 7.86 (d, J= 8.6 Hz, 1H), 7.80 (d, J= 5.7 Hz, 1H), 7.70 (d, J= 9.0 Hz, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.01 (d, J= 8.7 Hz, 1H), 5.21 (s, 1H), 4.80 - 4.62 (m, 2H), 3.67 (t, J= 5.9 Hz, 2H), 2.80 (s, 3H), 1.31 - 1.04 (m, 2H), 0.92 (d, J= 6.0 Hz, 6H), 0.62 (t, J= 7.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH31N205: 499.2; Found: 499.1.
The other atropisomers were also prepared in a similar way.
(S)-2-(6-cyano-l -((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(tert-pentyloxy)acetic acid: LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH29N204: 480.2; Found: 480.0.
(S)-2-(6-carbamoyl-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid: LCMS-ESI+ (m/z): [M+H]+calcd for C30H3iN2O5: 499.2; Found: 499.1.
Example 7. (S)-2-tert-Butoxy-2-(6-cyano- 1 -((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-4-fluoro-3 -methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((R)- 2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid, (S)-2- tert-butoxy-2-(6-cyano-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3- methylnaphthalen-2-yl)acetic acid, (S)-2-tert-butoxy-2-(6-carbamoyl- 1 -((S)-2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid
Figure imgf000135_0001
(S)-ethyl 2-ferf-butoxy-2-(6-chloro- 4-fluoro-1 -hydroxy-3- methylnapht alen-2-yl)acetate
Figure imgf000135_0002
(S)-ethyl 2-feri-butoxy-2-(6- (S)-2-ferf-butoxy-2-(6-cyano-1 - (S)-2-ieri-butoxy-2-(6-carbamoyl- cyano-4-fluoro-3-methyl-1 - ((R)-2,3-dihydropyrano[4,3,2- 1 -((R)-2,3-dihydropyrano[4,3,2- (trifluoromethylsulfonyloxy)n cfe]quinolin-7-yl)-4-fluoro-3- c e]quinolin-7-yl)-4-fluoro-3- aphthalen-2-yl)acetate methylnaphthalen-2-yl)acetic acid methylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-hydroxy-3-methylnaphthalen-2- yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.521 g, 3.15 mmol) in anhydrous THF (30 mL) at 0 °C was added a 1M solution of tetrabutylammonium fluoride in THF (6.30 mL. 6.30 mmol) to give a bright yellow solution. The reaction mixture was stirred for 45 minutes and quenched with saturated ammonium chloride solution and stirred for 5 minutes. The product was extracted with ethyl acetate/hexane (1 :1, 2x). The combined organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H24C104: 349.1; Found: 349.1.
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-l-hydroxy-3- methylnaphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-hydroxy- 3-methylnaphthalen-2-yl)acetate (0.9705 g, 2.77 mmol) in anhydrous acetonitrile (20 mL) at 0 °C was added SelectFluor (1.078 g, 3.04 mmol) in one portion. The reaction mixture was stirred for 4 hours at 0 °C, then 1 hour at room temperature. The reaction mixture was quenched with saturated Na2HP04 solution and stirred for 20 minutes. The mixture was extracted with ethyl acetate (2x), dried (MgS04), filtered, concentrated and stored overnight in a freezer. The residue was purified by flash column chromatography (silica gel, 0 to 15% ethyl acetate/hexanes) to give the desired product. LCMS-ES (m/z): [M+H]+ calcd for C19H21C1F04: 367.8; Found: 366.9, 368.9.
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-4-fluoro-l-hydroxy-3- methylnaphthalen-2-yl)acetate: A mixture of (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-l- hydroxy-3-methylnaphthalen-2-yl)acetate (0.2186 g, 0.593 mmol), zinc(II) cyanide (0.0695 g, 0.593 mmol), XPhos Palladacycle (0.044 g, 0.0593 mmol) and sodium bicarbonate (0.005 g, 0.0593 mmol) in anhydrous DMF (3.0 mL) was heated in a microwave at 100 °C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (2x). The
Combined organic layer was washed with 5% lithium chloride solution, brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 15% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+calcd for C2oH21FN04: 358.2; Found: 357.9. Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-4-fluoro-3 -methyl- 1 -
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2- (6-cyano-4-fluoro-l-hydroxy-3-methylnaphthalen-2-yl)acetate (42.5 mg, 0.118 mmol) in anhydrous THF (1.2 mL) at 0 °C was added N-phenyltrifluoromethylsulfonimide (84.5 mg, 0.237 mmol), followed by cesium carbonate (77.2 mg, 0.237 mmol) to give a yellow mixture that was warmed to room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2x). The combined organic layer was washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDCl3) 5 8.47 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.77 (d, J= 8.9 Hz, 1H), 5.71 (s, 1H), 4.29 - 4.05 (m, 2H), 2.48 (d, J= 2.8 Hz, 3H), 1.20 (s, 9H), 1.18 (t, J= 7.2 Hz, 3H).
Preparation of (S)-2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid: (S)-2-tert-butoxy-2-(6-cyano-l -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid was prepared in a similar way as (S)-2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid in Example 5 except (S)-ethyl 2-tert- butoxy-2-(6-cyano-4-fluoro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-cyano-l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate. 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J= 5.6 Hz, 1H), 8.65 (s, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.80 (d, J= 5.7 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.18 (d, J= 8.8 Hz, 1H), 5.20 (s, 1H), 4.79 - 4.67 (m, 2H), 3.66 (t, J= 5.9 Hz, 2H), 2.70 (d, J= 2.6 Hz, 3H), 0.96 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H26FN204: 485.2; Found: 485.1.
(S)-2-tert-butoxy-2-(6-carbamoyl-l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4- fluoro-3-methylnaphthalen-2-yl)acetic acid was also isolated. 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.68 (d, J= 5.7 Hz, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.79 (d, J= 7.0 Hz, 1H), 7.47 (d, J= 8.5 Hz, 1H), 7.08 (d, J- 8.9 Hz, 1H), 5.20 (s, 1H), 4.78 - 4.67 (m, 25H), 3.66 (t, J= 5.6 Hz, 2H), 2.69 (d, J= 2.2 Hz, 3H), 0.96 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C29H28FN205: 503.2; Found: 503.1.
The other atropisomers were also prepared in a similar way.
(S)-2-tert-butoxy-2-(6-cyano-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro- 3-methylnaphthalen-2-yl)acetic acid: LCMS-ESf (m/z): [M+H]+ calcd for C29H26FN204: 485.2; Found: 485.1.
(S)-2-tert-butoxy-2-(6-carbamoyl-l-((S)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4- fluoro-3-methylnaphthalen-2-yl)acetic acid: LCMS-ESf (m/z): [M+H]+ calcd for C29H28FN205: 503.2; Found: 503.1. Example 8. (2S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -(4-fluorophenyl)-3 -hydroxybut- 1 - ynyl)-3 -methylnaphthalen-2-yl)acetic acid
Figure imgf000138_0001
7-bromo-3-methyl
ethyl 2-(7-bromo-3-methyl-1- naphthalen-1-ol
(trifluoromethylsulfonyloxy) na hthalen-2-yl)-2-hydroxyacetate
Dess-Martin (R)-Me-CBS
catecholborane
Figure imgf000138_0002
ethyl 2-(7-bromo-3-methyl-1- (trifluoromethylsulfonyloxy) ethyl 2-(7-bromo-1-(4- naphthalen-2-yl)-2-oxoacetate chlorophenyl)-3-methyl
naphthalen-2-yl)-2-oxoacetate
Figure imgf000138_0003
(2S)-ethyl 2-ferf-butoxy-2-(1 -(4-chlorophenyl)- (2S)-2-ferf-butoxy-2-(1-(4-chlorophenyl)- 7-(3-(4-fluorophenyl)-3-hydroxybut-1-ynyl)-3- 7-(3-(4-fluorophenyl)-3-hydroxybut-1-ynyl)-3- methylnaphthalen-2-yl)acetate methylnaphthalen-2-yl)acetic acid
Preparation of ethyl 2-(7-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate: 7-Bromo-3-methylnaphthalen-l-ol was prepared in a similar manner as 6-chloro-3- methylnaphthalen-l-ol in Example 5 except using l-(4-bromophenyl)propan-2-one instead of 1- (3-chlorophenyl)propan-2-one. To a solution of 7-bromo-3-methylnaphthalen-l-ol (11.5 g, 48.5 mmol) in dichloromethane (145 mL) at 0 °C was added a 1 M titanium(IV) chloride solution in dichloromethane (48.5 mL, 48.5 mmol) and stirred for 20 min. Ethyl glyoxylate (50% solution in PhCH3, 10.6 mL, 53.3 mmol) was added over 15 minutes and stirred for 1 hour at 0 °C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room
temperature for 14 hours. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (EtOAc/Hexanes) to provide the desired product. 1H-NMR: 400 MHz, (CDCI3) δ : 8.52 (s, 1H), 8.34 (s, 1H), 7.49 (m, 2H), 7.13 (s, 1H), 5.67 (s, 1H), 4.24 (m, 1H), 4.16 (m, 1H), 2.29 (s, 3H), 1.23 (m, 3H).
Preparation of ethyl 2-(7-bromo-3-methyl-l-(trifluoromethylsulfonyloxy)-naphthalen-2- yl)-2-hydroxyacetate: To a solution of ethyl 2-(7-bromo-l-hydroxy-3-methylnaphthalen-2-yl)- 2-hydroxyacetate (7.67 g, 22.6 mmol) in CH2CI2 (50 mL) was added imidazole (3.08 g, 45.2 mmol) and chlorotriethylsilane (4.55 mL, 27.1 mmol). After 16 h, a saturated solution of NH4CI was added. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, concentrated to -50 mL of solution. The solution was cooled to -78 °C, and triethylamine (1.7 eq) and trifluoromethanesulfonic anhydride (1.5 eq) were added. After 30 min, a saturated solution of NH4CI was added. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, concentrated. THF was added (100 mL) followed by 48% aqueous HF solution (10 mL). The reaction was stirred in a plastic vessel overnight at rt. Solid NaHC03 was added in small portions then H20 was added to reach pH of -7-8. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered, concentrated in vacuo. The product was used without further purification. 'H-NMR: 400 MHz, (CDCI3) δ: 8.20 (s, 1H), 7.65 (m, 3H), 5.79 (s, 1H), 4.24 (m, 2H), 3.46 (br s, 1H), 2.48 (s, 3H), 1.20 (m, 3H).
Preparation of ethyl 2-(7-bromo-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2- yl)-2-oxoacetate: To a solution of ethyl 2-(7-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (-8.7 mmol) in CH2C12 (40 mL) was added Dess-Martin periodinane (4.07 g, 9.6 mmol). After 1.5 h, a saturated solution of Na2S204 (20 mL) and water (20 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 3 the titled compound. 1H-NMR: 400 MHz, (CDC13) δ: 8.22 (s, 1H), 7.70 (m, 3H), 4.41 (q, J = 7 Hz, 2H),
2.47 (s, 3H), 1.39 (t, J - 7 Hz, 3H). 19F-NMR: 377 MHz, (CDCI3) δ: -73.2.
Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate: To a solution of ethyl 2-(7-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (235 mg, 0.50 mmol) in PhCH3 (1.2 mL), EtOH (0.6 mL), H20 (0.6 mL) was added 4-chlorophenylboronic acid (86 mg, 0.55 mmol), K2C03 (207 mg, 1.5 mmol), and PdCl2dppf (11 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 2 h and was then diluted with H20 and EtOAc. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound and 37 mg of the bis-coupled product (ethyl 2-(l,7-bis(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-oxoacetate). 1H-NMR: 400 MHz, (CDC13) δ: 7.60-7.72 (m, 4H), 7.45 (m, 2H), 7.23 (m, 2H), 3.93 (q, J = 7 Hz, 2H), 2.48 (s, 3H), 1.13 (t, J = 7 Hz, 3H). Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- hydroxyacetate: To a solution of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-oxoacetate (1.6 g, 2.78 mmol) and (R)-2-methyl-CBS-oxazaborolidine (116 mg, 0.42 mmol) in anhydrous toluene at -40 °C was added a solution of catecholborane (355 μί, 3.34 mmol) in toluene (1.6 mL) over 15 minutes. The reaction mixture was stirred for 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at room temperature. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4x), saturated ammonium chloride solution, dried, filtered, concentrated in vacuo and purified by flash column chromatography to give the desired product.
1H-NMR: 400 MHz, (CDC13) δ: 7.64(m, 2H), 7.45 (m, 3H), 7.39 (s, 1H), 7.28 (m, 2H), 5.18 (s, 1H), 4.17 (m, 2H), 2.48 (s, 3H), 1.20 (t, J = 7 Hz, 3H).
Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate: To a solution of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-hydroxyacetate (-2.78 mmol) in t-BuOAc (14 mL) was added 70% perchloric acid (HC104) (334 μL, 5.56 mmol). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound. Ή-NMR: 400 MHz, (CDC13) δ: 7.62 (m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59 (s, 3H), 1.19 (t, J = 7 Hz, 3H), 1.00 (s, 9H).
Preparation of (2S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-(4-fluorophenyl)-3- hydroxybut-l-ynyl)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (70 mg, 0.14 mmol) in THF (2 mL) was added 2-(4-fluorophenyl)but-3-yn-2-ol (46 mg, 0.28 mmol), Cul (5 mg, 0.028 mmol), Pd(PPh3)4 (17 mg, 0.014 mmol), and Et3N (80 μΐ, 0.57 mmol). The reaction mixture was stirred at 70 °C for 1 h. A saturated solution of NH4C1 was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound. 1H-NMR: 400 MHz, (CDC13) δ: 7.56-7.66 (m, 4H), 7.29 (m, 6H), 6.97 (m, 2H), 5.02 (s, 1H), 4.06 (q, J = 7 Hz, 2H). 2.54 (s, 3H), 1.76 (s, 3H), 1.10 (s, 9H), 0.80 (t, J = 7 Hz, 3H). Preparation of (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -(4-fluorophenyl)-3 - hydroxybut- l-ynyl)-3-methylnaphthalen-2-yl)acetic acid: To a solution of (2S)-ethyl 2-tert- butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -(4-fluorophenyl)-3 -hydroxybut- 1 -ynyl)-3 -methylnaphthalen- 2-yl)acetate (22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H20 (1 mL total) was added a NaOH solution (4 M, 0.2 mL). The reaction mixture was stirred at 60 °C for 2 h. The mixture was partially concentrated and diluted with MeCN and H20 and purified by reverse phase HPLC (MeCN/H20) to give the titled compound. 'H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J = 8 Hz, 1H), 7.67 (m, 4H), 7.56 (m, 2H), 7.43 (m, 1H), 7.35 (s, 1H), 7.31 (d, J = 8 Hz, 1H), 7.05 (m, 2H), 5.12 (s, 1H), 2.62 (s, 3H), 1.74 (s, 1H), 0.96 (s, 9H). LCMS-ESI+ (m/z): [M-OH]+calcd for C33H29C1F03: 527.2; Found: 527.2.
Example 9. (2S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3- phenylbut-1 -ynyl)naphthalen-2-yl)acetic acid
Figure imgf000141_0001
(2S)-2-terf-butoxy-2-(1-(4-chloropheriyl)- 3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3- phenylbut-1 -ynyl)naphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3- hydroxy-3-phenylbut-l-ynyl)naphthalen-2-yl)acetic acid: (2S)-2-tert-butoxy-2-(l-(4- chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-l-ynyl)naphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate and l,l,l-trifluoro-2-phenylbut-3-yn-2-ol. 1H- NMR: 400 MHz, (CD3OD) δ: 7.74 (m, 3H), 7.67 (s, 1H), 7.55 (m, 4H), 7.46 (m, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 5.07 (s, 1H), 2.66 (s, 3H), 0.94 (s, 9H). LCMS-ESf (m/z): [M-OH]+ calcd for C31H32C1F303: 563.2; found: 563.1.
Example 10. (2SV2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -(pyridin-2-yl)but- 1 - ynyl)-3 -methylnaphthalen-2-yl)acetic acid
Figure imgf000142_0001
(2S)-2-feri-butoxy-2-(1 -(4-chlorophenyl)-7- (3-hydroxy-3-(pyridin-2-yl)but-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3 -hydroxy-3 -(pyridin-2- yl)but-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid: (2S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-
7-(3-hydroxy-3-(pyridin-2-yl)but-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-
2-tert-butoxyacetate and 2-(pyridin-2-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 8.61
(d, J = 6 Hz, 1H), 8.22 (t, J = 8 Hz, 1H), 8.05 (d, J = 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.66 (m, 2H), 7.57 (m, 3H), 7.47 (d, J = 8Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8 Hz, 1H), 5.16 (s, 1H), 2.61
(s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C32H3oClN04: 528.2; found: 528.1.
Example 11. (2S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -(pyridin-3-yl)but- 1 - ynyl)-3-methylnaphthalen-2-yl)acetic acid
Figure imgf000142_0002
(2S)-2-feri-butoxy-2-(1-(4-chlorophenyl)- 7-(3-hydroxy-3-(pyridin-3-yl)but-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid Preparation of (2S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-3- yl)but- 1 -ynyl)-3 -methymaphthalen-2-yl)acetic acid: (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7- (3-hydroxy-3-(pyridin-3-yl)but-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-tert-butoxyacetate and 2-(pyridin-3-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 9.05 (s, 1H), 8.86 (d, J = 8 Hz, 1H), 8.80 (s, 1H), 8.08 (m, 1H), 7.80 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.49 (d, J = 8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2;
found: 528.1.
Example 12. (2S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -(pyridin-4-yl)but- 1 - ynyl)-3 -methylnaphthalen-2-yl)acetic acid
Figure imgf000143_0001
(2S)-2-ferf-butoxy-2-(1-(4-chlorophenyl)-7- (3-hydroxy-3-(pyridin-4-yl)but-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-4- yl)but- 1 -ynyl)-3 -methylnaphthalen-2-yl)acetic acid: (2S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-
7-(3-hydroxy-3-(pyridin-4-yl)but-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- tert-butoxyacetate and 2-(pyridin-4-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) 5: 8.80 (d, J
= 5Hz, 2H), 8.27 (d, J = 5H, 2H), 7.80 (d, J = 8 Hz, 1H), 7.71 (s, 1H), 7.56 (m, 3H), 7.48 (d, J = 8 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J = 8Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.83 (s, 3H), 0.98 (s,
9H). LCMS-ESf (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2; found: 528.1.
Example 13. (2S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3-(2,4-dimethylthiazol-5-yl)-3- hydroxybut-1 -ynyl)-3-methylnaphthalen-2-yl)acetic acid
Figure imgf000144_0001
(2S)-2-ferf-butoxy-2-(1-(4-chlorophenyl)-7- (3-(2,4-dimethylthiazol-5-yl)-3-hydroxybut-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-(2,4-dimethylthiazol-5-yl)-
3-hydroxybut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid: (2S)-2-tert-butoxy-2-(l-(4- cUorophenyl)-7-(3-(2,4-dimethyltWazol-5-yl)-3-hydroxybut-l-ynyl)-3-methylnaphthalen-2- yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(2,4-dimethylthiazol-5- yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J = 8 Hz, 1H), 7.70 (s, 1H), 7.58 (m,
3H), 7.43 (d, J = 8 Hz, 1H), 7.32 (m, 2H), 5.18 (s, 1H), 2.64 (s, 3H), 2.61 (s, 3H), 2.47 (s, 3H),
1.82 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32C1NS04: 562.2; found: 562.1.
Example 14. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-((R)-3 -hydroxy-3 -phenylbut- 1 -ynyl)-3 - methylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-7-((S)-3- hydroxy-3 -phenylbut- 1 -ynyl)-3 -methylnaphthalen-2-yl)acetic acid
Figure imgf000144_0002
(S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-((R)-3 -hydroxy-3 -phenylbut- 1 -ynyl)-3 - methylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-7-((S)-3- hydroxy-3-phenylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid were prepared by the method Example 8 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate and 2-phenylbut-3-yn-2-ol. The diastereomers were separated as their ethyl esters using Chiralcel OJ-H with heptane/ethanol (80:20), and then they were saponified
independently. Their 1H-NMR spectra were identical. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J = 8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J = 8 Hz, 1H), 7.33 (m, 5H), 5.18 (s, 1H), 2.61 (s, 3H), 1.75 (s, 3H), 0.98 (s, 9H). LCMS-ESf (m/z): [M-OH]+calcd for C33H31C104: 509.1; found: 508.8.
Example 15. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,7- dimethylnaphthalen-2-yl)acetic acid
Figure imgf000146_0001
me y na a en- -y - - er - u oxyace a e
Figure imgf000146_0002
(S)-2-(7-bromo-1 -hydroxy-3- (S)-2-(7-bromo-3-methyl-1 - methylnaphthalen-2-yl)-2-feri- (trifluoromethylsulfonyloxy)naphthalen-2-yl)- butoxyethyl pivalate 2-ferf-butoxyethyl pivalate
Figure imgf000146_0003
(S)-2-ieri-butoxy-2-(3,7-dimethyl- (S)-2-ie/-f-butoxy-2-((R)-1-(2,3-dihydropyrano 1-(trifluoromethylsulfonyloxy)naphthalen-2-yl) [4,3,2-de]quinolin-7-yl)-3,7-dimethylnaphthalen- ethyl pivalate -yl)ethyl pivalate
Figure imgf000146_0004
(S)-2-ferf-butoxy-2-((R)-1-(2,3- (S)-2-ierf-butoxy-2-((R)-1- dihydropyrano[4,3,2-afe]quinolin-7-yl)-3,7- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- dimethylnaphthalen-2-yl)ethanol 3,7-dimethylnaphthalen-2-yl)acetic acid
Preparation of (S)-((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-l-hydroxy- 3-methylnaphthalen-2-yl)-2-hydroxyacetate: To a solution of 7-bromo-3 -methylnaphthalen- l-ol (11.8 g, 50.0 mmol) in dichloromethane (25 mL) at -40 °C was added a 1 M titanium(iV) chloride solution in dichloromethane (50.0 mL, 50.0 mmol) and stirred for 20 min. (lR)-(-)- Menthyl glyoxylate hydrate (12.1 g, 52.5 mmol) was added over 15 minutes in small portions as a solid and stirred for 1 hour at 40 °C. Then acetic acid (20 mL) and acetonitrile (60 mL) were added while cold. Water (200 mL) was added and the resulting solution was stirred at room temperature for 30 min. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layer was dried, filtered, concentrated. The crude material, which was about 8:1 d.r., was taken on without further purification.
Preparation of (S)-((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-l-hydroxy- 3-methylnaphthalen-2-yl)-2-tert-butoxyacetate: To a solution of (S)-((lR,2S,5R)-2-isopropyl-5- methylcyclohexyl) 2-(7-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate in t- BuOAc (150 mL) was added 70% perchloric acid (HC104) (3.0 mL). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes). Upon sitting, crystals formed in the resulting oil that were the desired diastereomer. 1H-NMR: 400 MHz, (CDC13) δ: 9.11 (s, 1H), 8.39 (s, 1H), 7.48 (m, 2H), 7.10 (s, 1H), 5.46 (s, 1H), 4.66 (m, 2H), 2.53 (s, 3H), 1.71 (m, 2H), 1.62 (m, 2H), 1.36 (m, 2H), 1.32 (s, 9H), 0.80 (m, 7H), 0.60 (d, J = 6 Hz, 3H).
Preparation of (S)-7-bromo-2-( 1 -tert-butoxy-2-hydroxyethyl)-3 -methylnaphthalen- 1 -ol : To a solution of (S)-((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-l-hydroxy-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate (4.56 g, 9.02 mmol) in THF (45 mL) was added lithium triethylborohydride solution (Super Hydride, 1.0 M in THF, 36 mL, 36 mmol). The reaction was stirred at 55 °C for 2.5 h. A saturated solution of NH4CI was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 2.84 g. 1H-NMR: 400 MHz, (CDCI3) δ: 9.77 (s, 1H), 8.37 (s, 1H), 7.50 (m, 2H), 7.10 (s, 1H), 5.26 (dd, J = 9, 4 Hz, 1H), 4.20 (m, 2H), 2.48 (s, 3H), 1.25 (s, 9H) 1.21 (s, 9H).
Preparation of (S)-2-(7-bromo- 1 -hydroxy-3 -methylnaphthalen-2-yl)-2-tert-butoxyethyl pivalate: To a solution of (S)-7-bromo-2-(l-tert-butoxy-2-hydroxyethyl)-3 -methylnaphthalen- 1- ol (1.84 g, 5.20 mmol) in CH2C12 (15 mL) added imidazole (426 mg, 6.25 mmol) and pivalyl chloride (705 μί, 5.7 mmol). The reaction was stirred at room temperature for 36 h. A saturated solution of NH4CI was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the product. 1H-NMR: 400 MHz, (CDC13) δ: 8.21 (s, 1H), 7.63 (m, 2H), 7.26 (s, 1H), 5.47 (dd, J = 10, 3 Hz, 1H), 4.62 (dd, J = 12, 10 Hz, 1H), 4.14 (dd, J = 12, 3 Hz, 1H), 2.75 (s, 3H), 1.22 (s, 9H) 1.11 (s, 9H).
Preparation of (S)-2-(7-bromo-3-methyl-l -(trifluoromethylsulfonyloxy)naphthalen-2-yl)- 2-tert-butoxyethyl pivalate: To a solution of (S)-2-(7-bromo-l-hydroxy-3-methylnaphthalen-2- yl)-2-tert-butoxyethyl pivalate (1.70 g, 3.89 mmol) in CH2C12 (20 mL) at -78 °C was added z'Pr2NEt (7.8 mmol) and trifluoromethanesulfonic anhydride (5 mmol). After 30 min, a saturated solution of NH4CI was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the desired product. 1H-NMR: 400 MHz, (CDC13) δ: 8.21 (s, 1H), 7.63 (m, 2H), 7.26 (s, 1H), 5.47 (dd, J = 10, 3 Hz, 1H), 4.62 (dd, J = 12, 10 Hz, 1H), 4.14 (dd, J = 12, 3 Hz, 1H), 2.75 (s, 3H), 1.22 (s, 9H) 1.11 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-(3,7-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-(7-bromo-3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyethyl pivalate (825 mg, 1.45 mmol) in 1,4-dioxane (7 mL) was added potassium carbonate (601 mg, 4.35 mmol), trimethylboroxine (220 mg, 1.74 mmol), and PdXPhos catalyst (107 mg, 0.145 mmol). The mixture was heated in a sealed vial in the microwave at 125 °C for 1 h. The mixture was filtered and concentrated in vacuo. The crude material was purified by column chromatography
(EtOAc/hexanes) to give the desired product. 1H-NMR: 400 MHz, (CDC13) δ: 7.84 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 7.62 (s, 1H), 7.36 (d, J = 8 Hz, 1H), 5.48 (dd, J = 9, 3 Hz, 1H), 4.65 (dd, J = 12, 9 Hz, 1H), 4.16 (dd, J = 12, 3 Hz, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 1.23 (s, 9H) 1.12 (s, 9H). Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-
3,7-dimethylnaphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-tert-butoxy-2-(3,7-dimethyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)ethyl pivalate (610 mg, 1.2 mmol) in distilled dimethoxyethane (12 mL) was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (HC1 salt, 456 mg (1.8 mmol) and cesium fluoride (881 mg, 5.8 mmol). The mixture was stirred in a sealed tube at 115 °C for 4 h. The mixture was diluted with H20 and EtOAc. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc with 5% MeOH/hexanes) to give the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.46 (d, J = 4 Hz, 1H), 7.68 (m, 2H), 7.58 (d, J = 8 Hz, 1H), 7.21 (m, 3H), 6.82 (s, 1H), 4.58 (m, 3H), 4.24 (dd, J = 12, 9 Hz, 1H), 4.11 (m, 1H), 3.34 (m, 2H), 2.77 (s, 3H), 2.19 (s, 3H), 0.99 (s, 9H), 0.87 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,7-dimethylnaphthalen-2-yl)ethanol: To a solution of (S)-2-tert-butoxy-2-((R)-l -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,7-dimethylnaphthalen-2-yl)ethyl pivalate (352 mg) in THF/MeOH (1:1, 5 mL) was added 2 M NaOH (200 μί). The reaction mixture was stirred at 50 °C for 16 h. A saturated solution of NH4CI was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the desired product. 1H-NMR: 400 MHz,
(CD3OD) δ: 8.50 (d, J = 4 Hz, 1H), 7.66 (m, 2H), 7.58 (d, J = 8 Hz, 1H), 7.25 (d, J = 4 Hz, 1H), 7.20 (m, 2H), 6.83 (s, 1H), 4.56 (m, 3H), 3.69 (dd, J = 12, 10 Hz, 1H), 3.43 (dd, J = 12, 4 Ηζ,ΙΗ), 3.36 (m, 2H), 2.78 (s, 3H), 2.15 (s, 3H), 1.04 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,7-dimethylnaphthalen-2-yl)acetic acid: A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H20) to a volume of 114 mL. To a solution of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,7- dimethylnaphthalen-2-yl)ethanol (211 mg) in MeCN (3 mL) was added the above stock solution (200 μί). After 2 h, the mixture was filtered and purified by reverse phase HPLC (MeCN w/ 0.1% TFA/H20) to give the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.55 (d, J = 5 Hz, 1H), 7.69 (m, 2H), 7.53 (d, J = 8 Hz, 1H), 7.35 (d, J = 5 Hz, 1H), 7.24 (d, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 6.63 (s, 1H), 5.18 (s, 1H), 4.58 (m, 2H), 3.42 (m, 2H), 2.66 (s, 3H), 2.17 (s, 3H), 0.90 (s, 9H). LCMS-ESI+ (m/z): [M+H]+calcd for C29H29N04: 456.2; Found: 456.1.
Example 16. (5 -2-tert-Butoxy-2-((5)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid
Figure imgf000150_0001
1 -m-tolylpropan-2-one ethyl 3-methyl-4-m- ethyl 3-methyl-4- tolylbut-2-enoate m-tol lbutanoate
Figure imgf000150_0002
3-methyl-4-m- 3,6-dimethyl-3,4- 2,2-dibromo^,6-dimethyl-3,4- tolylbutanoic acid dihydronaphthalen-1 (2H)-one dihydronaphthalen-1 (2H)-one
Figure imgf000150_0003
2-bromo-3,6- 3,6-dimethylnaphthalen-1 -ol ethyl 2-hydroxy-2-(1-hydroxy- dimethylnaphthalen-1 -ol 3,6-dimethylnaphthalen-2-yl)
acetate
Figure imgf000150_0004
ethyl 2-triethylsilyloxy-2-(1- hydroxy-3,6- dimethylnaphthalen-2-yl)
acetate
Figure imgf000150_0005
ethyl 2-(3,6-dimethyl-1- (S)-ethyl 2-(3,6-dimethyl-1- (S)-ethyl 2-/erf-butoxy-2-(3,6-dimethyl- (trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy) 1 -(trifluoromethylsulf onyloxy) naphthalen-2-yl)-2-oxoacetate naphthalen-2-yl)-2- naphthalen-2-yl)acetate
hydroxyacetate
Figure imgf000150_0006
(S)-ethyl 2-ieri-butoxy-2-((S)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- (S)-2-ferf-butoxy-2-((S)-1 -(2,3- 3,6-dimethylnaphthalen-2-yl)acetate dihydropyrano[4,3,2-Gfe]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid
Preparation of ethyl 3-methyl-4-wi-tolylbut-2-enoate. A three neck flask was charged with NaHMDS (1M in THF, 59 mL, 59 mmol) under an atmosphere of Ar and cooled to an internal temperature of 0 °C. Triethyl phosphonoacetate (10.1 mL, 50.6 mmol) was diluted in THF (41 mL) and added via additional funnel at a rate to maintain a temperature < 5 °C. The resulting yellow-orange solution was allowed to stir for 15 minutes at 0 °C following completion of addition. Following addition of l-m-tolylpropan-2-one (5 g, 33.7 mmol, diluted in 50 mL THF) via addition funnel, the resulting mixture was allowed to stir at 0 °C for 60 minutes before removing cooling and allowing the reaction to warm to room temperature over 1.5 hours. The reaction was slowly quenched with water, and the resulting aqueous phase extracted thoroughly with EtOAc. The combined organics were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. The resulting oil was eluted on Yamazen silica gel chromatography (0-15% EtO Ac/hex) to afford 3-methyl-4-#2-tolylbut-2-enoate as an approximately 85:15 E:Z mixture. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H1902: 219.3; found: 219.3.
Preparation of ethyl 3-methyl-4-Aw-tolylbutanoate. Ethyl 3-methyl-4- W-tolylbutanoate (50 g, 229 mmol) was taken up in EtO Ac (1 L) and treated with Rh (5% on alumina, 24 g catalyst). The atmosphere was replaced with H2 and the reaction left under balloon pressure of H2 overnight with vigorous stirring. The next morning, the H2 atmosphere was replaced with air and Celite (25 g) was added with stirring. After 10 min, the reaction slurry was filtered through a pad of Celite and the filtrate concentrated to produce the desired product that was used in the next step without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H2102: 221.3; found: 221.2.
Preparation of 3-methyl-4-m-tolylbutanoic acid. The material from the previous preparation was taken up in a 1/1 mixture of THF/EtOH (250 mL each), treated with a solution of LiOH«H20 (46.5 g, 1.1 mol) in water (250 mL) and heated to 50 °C. After 2.5 hours, the solution was cooled to 0 °C, diluted with EtO Ac (300 mL) and treated with 2M HC1 (300 mL). The solution was further adjusted to pH ~ 3 using aliquots of concentrated HC1. The resulting aqueous layer was extracted with EtO Ac. The combined organics were washed with brine and allowed to stand over anhydrous Na2S04 for 72 hours. The EtO Ac was removed in vacuo and the resulting oil taken up in hexanes and allowed to stand over anhydrous Na2S04 overnight. Following concentration, the material was taken up in CHC13 and concentrated again to afford 3- methyl-4-w-tolylbutanoic acid. 1H-NMR: 400 MHz, (CDC13) δ: 7.18 (t, J = 8 Hz, 1H); 7.02 (d, J = 8 Hz, 1H); 6.99 (s, 1H); 6.97 (d, J = 8 Hz, 1H); 2.61 (dd, J = 13.6, 6.8 Hz, 1H); 2.50 (dd, J = 14, 7 Hz, 1H); 2.40 (dd, J = 14.8, 5.6 Hz, (1H); 2.34 (s, 3H); 2.28 (m, 1H); 2.18 (dd, J = 16, 8 Hz, 1H); 0.99 (d, J = 6.4 Hz, 3H). Preparation of 3,6-dimethyl-3,4-dihydronaphthalen-l(2H)-one. 3-Methyl-4-m- tolylbutanoic acid (20.6 g, 107 mmol, dissolved in 125 mL DCM) was added slowly to triflic acid (250 g, 1.7 mol) that was pre-cooled to 0 °C under an Ar atmosphere. After 30 minutes, the volume of the reaction is doubled with DCM and poured slowly onto 1.5 L crushed ice. The resulting icy slurry is allowed to stir and come to room temperature over 1 hour. The resulting aqueous layer was extracted with DCM and the combined organics dried over anhydrous MgS04 and concentrated in vacuo. The procedure was repeated once and the two lots of crude product were combined and purified via elution on Isco silica gel column chromatography (0-15% EtOAc/hex) to afford 3,6-dimethyl-3,4-dihydronaphthalen-l(2H)-one. LCMS-ESI+ (m/z):
[M+H]+calcd for C12H150: 175.3; found: 175.4.
Preparation of 2,2-dibromo-3 ,6-dimethyl-3 ,4-dihydronaphthalen- 1 (2H)-one. 3 ,6- Dimethyl-3,4-dihydronaphthalen-l(2H)-one (32.4 g, 186 mmol) was taken up in DCM (1.5 L and treated with a solution of Br2 (19.1 mL, 372 mmol) in DCM (300 mL) that was added via an addition funnel at room temperature over 2 hours. An additional 1.5 mL of Br2 was added and the reaction allowed to age another 1.5 hours. The reaction was concentrated in vacuo to produce 2,2-dibromo-3,6-dimethyl-3 ,4-dihydronaphthalen- l(2H)-one that was used directly in the next procedure without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for
C12H13Br20: 333.1; found: 333.2.
Preparation of 2-bromo-3 ,6-dimethylnaphthalen- 1 -ol. A solution of 2,2-dibromo-3 ,6- dimethyl-3 ,4-dihydronaphthalen- l(2H)-one (61.2 g, 184 mmol) in MeCN (1.5 L) was cooled to -40 °C internal temperature using a dry ice/acetone bath. l,8-Diazabicycloundec-7-ene (41.6 mL, 279 mmol) was added as a solution in MeCN (150 mL) and the reaction was allowed to warm to room temperature overnight. The majority of the reaction solvent was removed in vacuo and the residue taken up in EtOAc (1 L) and washed with 0.5 M HC1 (1 L). The resulting aqueous layer was extracted with several portions of EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgS04 and concentration in vacuo, the resulting residue was absorbed directly onto 200 g silica gel and eluted on Isco silica gel column chromatography (0-20% EtOAc/hex) to afford 2-bromo-3,6-dimethylnaphthalen-l-ol. LCMS- ESI+ (m/z): [M]+ calcd for C12HnBrO: 251.1; found: 251.4. Preparation of 3,6-dimethylnaphthalen-l-ol. A solution of 2-bromo-3,6- dimethylnaphthalen-l-ol (31.9 g, 127 mmol) in EtOH (1.3 L) was treated with Et3N (26.6 mL, 191 mmol) at room temperature. Pd/C (13.5 g, 12.7 mmol, 10% wt on C) was added in one portion and the atmosphere replaced with ¾. The reaction was left under balloon pressure of H2 for 6 hours. After replacing the atmosphere with air, Celite (20 g) was added and the slurry stirred for 15 minutes before filtering the solution through a pad of Celite. The volatiles were removed in vacuo, and the residue was taken up in EtO Ac/water (250 mL each). The organics were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The resulting residue was purified on Isco silica gel column chromatography (0-35% EtO Ac/hex) to afford 3,6-dimethylnaphthalen-l-ol. LCMS-ESI+ (m/z): [M+H]+calcd for C12H130: 173.1; found: 173.4.
Preparation of ethyl 2-hydroxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. A solution of 3,6-dimethylnaphthalen-l-ol (4.76 g, 27.6 mmol) in DCM (345 mL) was cooled to 0 °C internal temperature. TiCl4 (1M in DCM, 36 mL, 36 mmol) was added at a rate to maintain the internal temperature at 0 °C to produce a dark purple solution that was allowed to stir at 0 °C for 20 min. Freshly distilled ethyl glyoxylate (3.66 g, 35.9 mmol) was gently warmed with a heat gun for 3 minutes prior to dilution in DCM (250 mL). The reagent solution was then added via addition funnel slowly. After 90 minutes, the reaction was poured onto 800 mL ice/500 mL saturated Rochelle's salt solution. The opaque orange slurry was allowed to come to room temperature over 2.5 hours and filtered through a Celite pad. The aqueous phase was extracted with DCM and the combined organics were washed with water, brine, and dried over anhydrous MgS04, and filtered. Following concentration in vacuo, the resulting residue was purified via Yamazen silica gel column chromatography (3-35% EtOAc/hex) to provide 2-hydroxy-2-(l- hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. LCMS-ESI+ (m/z): [M-OH]+ calcd for C16H1703: 257.3; found: 257.5.
Preparation of ethyl 2-triethylsilyloxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. A solution of 2-hydroxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate (4.55 g, 16.6 mmol) in DCM (165 mL) at 0 °C was subsequently treated with imidazole (1.53 g, 22.4 mmol) and triethylsilyl chloride (3.2 mL, 19.1 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 1.5 hours. Water was added, and the resulting aqueous layer was extracted with DCM. The combined organics were washed with 1M HC1 and brine. Following drying over anhydrous MgS04, concentration in vacuo afforded the desired product that was used without further purification.
Preparation of ethyl 2-triethylsilyloxy-2-(l-trifluoromethylsulfonyloxy-3,6- dimethylnaphthalen-2-yl) acetate. A solution of ethyl 2-triethylsilyloxy-2-(l-hydroxy-3,6- dimethylnaphthalen-2-yl) acetate (5.62 g of crude product from above, 14.5 mmol) in THF (58 mL) was treated with phenyl triflimide (7.75 g, 21.7 mmol) and Cs2C03 (11.8 g, 36.3 mmol) at room temperature. After 3 hours, the reaction was diluted with EtOAc and water. The resulting organics were washed with 1M NaOH and brine. Following drying over MgS04 and concentration in vacuo, the resulting residue was purified via Yamazen silica gel column chromatography (0-10% EtO Ac/hex) to afford ethyl 2-triethylsilyloxy-2-(l- trifluoromethylsulfonyloxy-3,6-dimethylnaphthalen-2-yl) acetate. LCMS-ESI* (m/z): [M+Na]+ calcd for C23H31F306SSiNa: 543.6; found: 543.0. Preparation of ethyl 2-(3 ,6-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- hydroxyacetate. A solution of ethyl 2-triethylsilyloxy-2-(l-trifluoromethylsulfonyl-oxy-3,6- dimethylnaphthalen-2-yl) acetate (~ 29 g) in THF (375 mL) was treated with 48% HF (71 mL, 1.96 mol) at room temperature and allowed to stir overnight. Solid NaHC03 was added in small portions until pH ~ 8 by test strip. Water and EtOAc were added, and the layers separated. The aqueous layer was slurried with Celite, filtered through a Celite pad and further extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The resulting ethyl 2-(3,6-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate was used without further purification. LCMS-ESI+ (m/z): [M-OH]+ calcd for C17H16F305S: 389.4; found: 389.4.
Preparation of ethyl 2-(3,6-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- oxoacetate. A solution of ethyl 2-(3,6-dimethyl-l-(trifluoromethylsulfonyloxy) naphthalen-2- yl)-2-hydroxyacetate (~ 22.8 g, 56 mmol) in DCM (560 mL) was treated with solid Dess-Martin periodinane (35.7 g, 84.2 mmol) at room temperature. After 60 minutes, isopropyl alcohol (25 mL) was added and allowed to stir for 30 minutes. A mixture of saturated NaHC03 and saturated Na2S203 (100 mL each, diluted to 400 mL with water) was added and the resulting aqueous layer extracted with DCM. The combined organics were washed with water, brine and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, the residue was purified via Isco silica gel column chromatography (0-35% EtOAc/hex) to afford ethyl 2-(3,6- dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. Ή-NMR: 400 MHz, (CDC13) δ: 7.98 (d, J = 8.4 Hz, 1H); 7.66 (s, 1H); 7.61 (s, 1H); 7.47 (d, J = 8.4 Hz, 1H); 4.41 (q, J = 7.2 Hz, 2H); 2.55 (s, 3H); 2.49 (s, 3H); 1.40 (t, J = 8.4 Hz, 3H).
Preparation of (S)-ethyl 2-(3,6-dimethyl-l-(trifluoromethylsulfonyloxy) naphthalen-2- yl)-2-hydroxyacetate. A solution of ethyl 2-(3,6-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (16.3 g, 40 mmol) in toluene (250 mL) cooled to an internal temperature of -40 °C was treated with (i?)-(+)-2-methyl-CBS- oxazaborolidine (5.6 g, 20.1 mmol). Freshly distilled catecholborane (4.7 mL, 44.2 mmol) was diluted with toluene (20 mL) and the solution added dropwise to the reaction over 30 minutes to produce a clear yellow solution. After an additional 15 minutes, saturated Na2C03 (300 mL) was added and the reaction allowed to warm to room temperature over 2.5 hours. The aqueous layer is extracted with EtOAc and the combined organics are washed with saturated Na2C03 (3 X 300 mL), saturated NH4CI (300 mL) and brine. Following drying over anhydrous MgS04 and concentration in vacuo, the residue was purified using Isco silica gel column chromatography (10-75% EtOAc/hex) to produce 15.1 g of (S)-ethyl 2-(3,6-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate that was determined to be 66% enantiomeric excess by HPLC analysis on a Chiralpak AS-H column with a 80:20 heptane/EtOH isocratic method. LCMS-ESI+ (m/z): [M+Na]+ calcd for C17H17F306SNa: 429.3; found: 429.3.
Preparation of (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-l-(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-(3,6-dimethyl-l-(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (7.5 g, 18.5 mmol) in tBuOAc (100 mL) at room temperature was treated with perchloric acid (70%, 0.16 mL, 1.8 mmol) and allowed to stir at room temperature overnight. The reaction was slowly poured into ice-cold saturated NaHC03 (150 mL). The aqueous layer was extracted with EtOAc and the combined organics washed with brine and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, purification of the residue by Yamazen silica gel column chromatography (2-20-50%
EtOAc/hex) afforded (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. LCMS-ESI+ (m/z): [M+Na]+ calcd for C21H25F306SNa: 485.5; found: 485.8. Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3,6-dimethylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate. A solution of (S)- ethyl 2-tert-butoxy-2-(3 ,6-dimethyl- 1 -(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetate (-0.5 g, 1.1 mmol) in 10.8 mL DME (freshly distilled from Na/benzophenone) was treated with 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (0.33 g, 1.3 mmol), SPhos precatalyst (Strem, 0.073 g, 0.11 mmol), and CsF (0.722 g, 4.8 mmol). The reaction tube was sealed and the reaction mixture sparged with Ar for 30 minutes prior to heating at 120 °C for 90 minutes in a microwave reactor. The reaction mixture was absorbed directly onto silica gel and purified via Yamazen silica gel column chromatography (3-50% EtO Ac/hex) to afford (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2- yl)acetate (1H-NMR: 400 MHz, (CDC13) δ: 8.68 (br s, 1H); 7.64 (s, 1H); 7.54 (s, 1H); 7.49 (d, J = 8 Hz, 1H); 7.11 (d, J = 8 Hz, 1H); 7.08 (br s, 1H); 6.99-6.84 (m, 2H); 5.08 (s, 1H); 4.58 (t, J - 6 Hz, 2H); 3.98 (m, 1H); 3.82 (m, 1H); 3.34 (m, 2H); 2.78 (s, 3H); 2.42 (s, 3H); 0.97 (s, 9H); 0.97 (obscured t, 3H)) and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate (1H-NMR: 400 MHz, (CDC13) δ: 8.64 (d, J = 4 Hz, 1H); 7.73 (d, J = 8 Hz, 1H); 7.60 (s, 1H); 7.53 (s, 1H); 7.11 (d, J - 8 Hz, 1H); 7.04 (d, J = 4 Hz, 1H); 6.93 (dd, J = 8, 1.2 Hz, 1H); 6.82 (d, J = 8 Hz, 1H); 5.12 (s, lH); 4.57 (t, J = 5.6 Hz, 2H); 4.20-4.04 (m, 2H); 3.33 (m, 2H); 2.65 (s, 3H); 2.42 (s, 3H); 1.22 (t, J - 7.2 Hz, 3 H); 0.76 (s, 9H)).
Preparation of (S)-2-tert-butoxy-2-((S)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,6-dimethylnaphthalen-2-yl)acetic acid. A solution of (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate (1.06 g, 2.2 mmol) in THF (32 mL)/MeOH ( 16 mL)/water ( 18 mL) was treated with LiOH«H20 (0.92 g, 22 mmol) and heated to 60 °C for 24 hours. The reaction mixture was filtered through glass wool, concentrated in vacuo and purified via preparatory HPLC to produce (S)-2-tert-butoxy-2-((S)-l- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (TFA salt). LCMS-ESf (m/z): [M+H]+ calcd for C29H30NO4: 456.5; found: 456.8.
Example 17. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro- 3,6-dimethylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6-dimethyl-naphthalen-2-yl)acetic acid.
Figure imgf000157_0001
(S)-ethyl 2-feri-butoxy-2-(3,6-dimethyl- (S)-ethyl 2-ier/-butoxy-2-(1-hydroxy- 1 -(trif luoromethylsulfonyloxy) 3,6-dimethylnaphthalen-2-yl)acetate na hthalen-2-yl)acetate
fl
Figure imgf000157_0002
(S)-ethyl 2-terf-butoxy-2-((S)-1-(2,3- (S)-2-ferf-butoxy-2-((S)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)-4- 4-fluoro-3,6-dimethylnaphthalen-2- fluoro-3,6-dimethylnaphthalen-2- yl)acetate yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2- yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(3,6-dirnethyl-l-(trifluoromethyl- sulfonyloxy) naphthalen-2-yl)acetate (1.8 g, 3.9 mmol) in THF (18.2 mL) pre-cooled to -10 °C was treated dropwise with tetrabutylammonium fluoride (1M in THF, 7.8 mL, 7.8 mmol). After 1 hour, saturated NaHC03 was added and the mixture stirred for 20 minutes. Following extraction of the aqueous layer with EtOAc, the combined organics were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification via Yamazen silica gel column chromatography afforded (S)-ethyl 2-tert-butoxy-2-(l-hydroxy-3,6- dimethylnaphthalen-2-yl)acetate. LCMS-ESI" (m/z): [M-H]" calcd for C20H25O4: 329.4; found: 329.1.
Preparation of (S)-ethyl 2-tert-butoxy-2-(4-fluoro-l-hydroxy-3,6-dimethylnaphthalen-2- yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2- yl)acetate (0.62 g, 1.9 mmol) in MeCN (14 mL) cooled to 0 °C was treated with SelectFluor® fluorinating reagent (0.66 g, 1.9 mmol). The cold bath was removed and after 90 minutes the reaction was quenched with pH 7 buffer solution. The aqueous layer was extracted with EtOAc and the combined organics washed with brine and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, the desired product was obtained via silica gel
chromatography followed by preparatory HPLC to afford (S)-ethyl 2-tert-butoxy-2-(4-fluoro-l- hydroxy-3,6-dimethylnaphthalen-2-yl)acetate. LCMS-EST (m/z): [M-H]" calcd for C20H24O4F: 347.4; found: 347.2.
Preparation of (S)-ethyl 2-tert-butoxy-2-(4-fluoro-3,6-dimethyl-l-(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(4-fluoro-l- hydroxy-3,6-dimethylnaphthalen-2-yl)acetate (0.225 g, 0.65 g) in THF (5 mL) was treated with phenyl triflimide (0.26 g, 0.72 mmol) and allowed to stir at room temperature overnight. The reaction mixture was absorbed directly onto silica gel and purified via Yamazen silica gel column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(4-fluoro-3,6-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDC13) δ: 7.93 (d, J = 8.4 Hz, 1H); 7.86 (s, 1H); 7.47 (d, J = 8.4 Hz, 1H); 5.70 (s, 1H); 4.28-4.09 (m, 2H); 2.56 (s, 3H); 2.44 (d, JHF = 2.8 Hz, 3H); 1.21 (s, 9 H); 1.19 (t, J = 6.8 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-4-fluoro-3,6-dimethylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6-dimethylnaphthalen-2-yl)acetate. (S)-ethyl 2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6- dimethylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((S)-l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-4-fluoro-3,6-dimethylnaphthalen-2-yl)acetate were prepared in a similar fashion to (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate beginning with (S)-ethyl 2-tert-butoxy-2- (4-fluoro-3 ,6-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. Purification via Yamazen silica gel column chromatography afforded (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6-dimethylnaphthalen-2-yl)acetate. (LCMS- ESI+ (m/z): [M+H]+ calcd for C31H33FN04: 502.6; found: 502.6) and (S)-ethyl 2-tert-butoxy-2- ((S)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6-dimethylnaphthalen-2- yl)acetate. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33FN04: 502.6; found: 502.6.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4- fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid. A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l- (2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 ,6-dimethylnaphthalen-2-yl)acetate in THF/MeOH/water (1 mL each) was treated with ΠΟΗ·Η20 (0.055 g, 1.3 mmol), sealed and heated to 60 °C overnight for 2 days. The reaction is purified by preparatory HPLC to afford (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3,6- dimethylnaphthalen-2-yl)acetic acid (TFA salt). LCMS-ESI+ (m/z): [M+H]+ calcd for
C29H29FN04: 474.5; found: 474.5. 1H-NMR: 400 MHz, (CD3OD) δ: 8.65 (d, J = 5.6 Hz, 1H); 7.95 (s, 1H); 7.81 (d, J = 8.4 Hz, 1H); 7.73 (d, J = 5.2 Hz, 1H); 7.42 (d, J = 8.4 Hz, 1H); 7.19 (dd, J = 8.8, 1.2 Hz, 1H); 6.85 (br d, J = 8.8 Hz, 1H); 5.17 (s, 1H); 4.70-4.65 (m, 2H); 3.63 (t, J - 6 Hz, 2H); 2.64 (d, JHF = 2.8 Hz, 3H); 2.50 (s, 3H); 0.96 (9H).
Preparation of (S)-2-tert-butoxy-2-((S)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4- fluoro-3 ,6-dimethylnaphthalen-2-yl)acetic acid. (S)-2-tert-Butoxy-2-((S)- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid was prepared in a similar fashion to (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-4-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid beginning with (S)-ethyl 2- tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3,6- dimethylnaphthalen-2-yl)acetate to afford (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-4-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid. LCMS-ESI ^ (m/z): [M+H]+ calcd for C29H29FN04: 474.5; found: 474.5.
Example 18. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5- dimethylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,5-dimethylnaphthalen-2-yl)acetic acid.
Figure imgf000160_0001
(S)-ethyl 2-ferf-butoxy-2-(1- (S)-ethyl 2-feri-butoxy-2-(3,5-dimethyl-1- hydroxy-3,5-dimethylnaphthalen- (trifluoromethylsulfonyloxy)naphthalen-2- 2-yl)acetate yl)acetate
Figure imgf000161_0001
(S)-ethyl 2-ferf-butoxy-2-((S)-1-(2,3- (S)-2-ierf-butoxy-2-((S)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7- dihydropyrano[4,3,2-de]quinolin-7-yl)- yl)-3,5-dimethylnaphthalen-2- 3,5-dimethylnaphthalen-2-yl)acetic acid
yl)acetate
Preparation of (S)-ethyl 2-(5-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate. A solution of (S)-ethyl 2-(5-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.90 g, 1.7 mmol; prepared in a similar fashion to (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate beginning with l-(2-bromophenyl)propan- 2-one) in THF (7 mL) cooled to 0 °C was treated with tetrabutylammonium fluoride (1M in THF, 1.7 mL, 1.7 mmol) dropwise. After 1 hour, saturated NaHC03 and EtOAc were added and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. Purification via Yamazen column chromatography (0-15% EtO Ac/hex) afforded (S)-ethyl 2-(5-bromo-l-hydroxy-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate. LCMS-ESI" (m/z): [M-H]" calcd for C19H2204Br: 395.07; found: 395.04.
Preparation of (S)-ethyl 2-(5-bromo-3-methyl-l-(methylsulfonyloxy)naphthalen-2-yl)-2- tert-butoxyacetate. A solution of (S)-ethyl 2-(5-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2- tert-butoxyacetate (0.215 g, 0.54 mmol) in DCM (5 mL) cooled to 0 °C was treated with methanesulfonic anhydride (0.142 g, 0.82 mmol) and diisopropylethylamine (0.28 mL, 1.6 mmol). After 1 hour, the reaction mixture was loaded directly onto silica gel and eluted via Yamazen column chromatography (0-40% EtOAc/hex) to afford (S)-ethyl 2-(5-bromo-3-methyl- l-(methylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate. 1H-NMR: 400 MHz, (CDC13) δ: 8.25 (br d, J = 8 Hz, 1H); 8.04 (s, 1H); 7.81 (d, J = 7.2 Hz, 1H); 7.38 (dd, J = 8, 7.2 Hz, 1H); 5.72 (s, 1H); 4.28-4.10 (m, 2H); 3.49 (s, 3H); 2.67 (s, 3H); 1.24 (s, 9H); 1.19 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l-(methylsulfonyloxy)
naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-(5-bromo-3-methyl-l- (methylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.47 g, 0.99 mmol) in toluene/EtOH (6 mL/2.5 mL) was treated with trimethylboroxine (0.42 mL, 3 mmol), PdCl2dppf (0.036 g, 0.05 mmol) and K2C03 (2M, 1.5 mL, 3 mmol). The vessel was sealed and sparged with Ar for 20 minutes prior to heating in a microwave reactor at 125 °C for 90 minutes. The reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l-(methylsulfonyloxy)naphthalen-2-yl)acetate that was approximately an 85:15 mixture with an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDC13) δ: 8.09 (br d, J = 8.4 Hz, 1H); 7.77 (s, 1H); 7.44 (dd, J = 8.4, 7.2 Hz, 1H); 7.35 (d, J = 7.2 Hz, 1H); 5.77 (s, 1H); 4.27-4.09 (m, 2H); 3.43 (s, 3H); 2.68 (s, 3H); 2.63 (s, 3H); 1.24 (s, 9H); 1.20 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(l -hydroxy-3,5-dimethylnaphthalen-2- yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l-
(methylsulfonyloxy)naphthalen-2-yl)acetate (0.19 g, 0.48 mmol) in THF (3 mL) cooled to 0 °C was treated with tetrabutylammonium fluoride ( 1M in THF, 1.4 mL, 1.4 mmol). After 1 hour, saturated NaHC03 was added and the aqueous layer extracted with EtOAc. The combined organics are washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. Purification via Yamazen column chromatography afforded (S)-ethyl 2-tert-butoxy-2-(l- hydroxy-3,5-dimethylnaphthalen-2-yl)acetate that is contaminated with a small percentage of an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDC13) δ: 8.96 (s, 1H); 8.13 (obs m, 1H); 7.30 (obs m, 2H); 5.51 (s, 1H); 4.23-4.05 (m, 2H); 2.62 (br s, 6H); 1.31 (s, 9H); 1.19 (t, J = 7.2 Hz, 3H). Preparation of (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(l- hydroxy-3,5-dimethylnaphthalen-2-yl)acetate (0.103 g, 0.312 mmol) in DCM (3 mL) cooled to 0 °C was treated with diisopropylethylamine (0.16 mL, 0.94 mmol) and trifluoromethanesulfonic anhydride (0.08 mL, 0.47 mmol) to produce a dark red-orange solution. After 1 hour, the reaction mixture is loaded directly onto silica gel and purified via Yamazen column
chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate that is contaminated with a small amount of an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDC13) δ: 7.94 (d, J = 8.8 Hz, 1H); 7.84 (s, 1H); 7.47 (dd, J = 8.8, 7.2 Hz, 1H); 7.39 (d, J = 7.2 Hz, 1H); 5.75 (s, 1H); 4.26- 4.08 (m, 2H); 2.70 (s, 3H); 2.60 (s, 3H); 1.22 (s, 9H); 1.18 (t, J = 7.2 Hz, 3H).
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,5-dimethylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2-yl)acetic acid. A solution of (S)-ethyl 2-tert-butoxy-2-(3 ,5-dimethyl- 1 -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (0.035 g, 0.076 mmol) in DME (1 mL, freshly distilled from Na/benzophenone) was treated with 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (0.025 g, 0.098 mmol), SPhos precatalyst (0.009 g, 0.01 1 mmol) and CsF (0.051 g, 0.334 mmol). The reaction vessel was sealed and sparged with Ar for 30 minutes prior to heating in a microwave reactor at 125 °C for 90 minutes. The reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2-yl)acetate and of (S)-ethyl 2- tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2- yl)acetate. Both compounds were taken up separately in THF/MeOH/water (0.30 mL each) and treated with LiOH»H20 (0.003 g, 0.072 mmol). The reaction vessels were sealed and heated to 65 °C in a microwave reactor for 2 hours. Each sample was purified separately via preparatory HPLC to produce (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5- dimethylnaphthalen-2-yl)acetic acid (TFA salt, LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30NO4: 456.6; found: 456.3. 1H-NMR: 400 MHz, (CD3CN) δ: 8.56 (d, J = 5.2 Hz, 1H); 8.07 (s, 1H); 7.68 (d, J - 8 Hz, 1H); 7.51 (d, J = 5.2, 1H); 7.32 (d, J = 6.8 Hz, 1H); 7.28 (d, J = 8 Hz, 1H); 7.11 (dd, J = 8, 6.8 Hz, 1H); 6.71 (d, J = 8 Hz, 1H); 5.18 (s, 1H); 4.65-4.58 (m, 2H); 3.28 (t, J = 5.6 Hz, 2H); 2.73 (s, 3H); 2.71 (s, 3H); 0.92 (s, 9H)) and (S)-2-tert-butoxy-2-((S)-l -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethylnaphthalen-2-yl)acetic acid (TFA salt, LCMS-ESf (m/z): [M+H]+ calcd for C29H30NO4: 456.6; found: 456.3).
Example 19. (S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-6-
(difluoromeuiyl)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid.
Figure imgf000165_0001
(S)-ethyl 2-ferf-butoxy-2-(3-methyl- 1 -(trifluoromethylsulfonyloxy)-6- vinylnaphthalen-2-yl)acetate
(S)-ethyl 2-ferf-butoxy-2-(6- (dif luoromethyl)-3-methyl-1 - (trifluoromethylsulfonyloxy)
naphthalen-2-yl)acetate
(S)-2-ferf-butoxy-2-((R)-6-(difluoromethyl)-1- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid
Figure imgf000165_0002
(S)-ethyl 2-ferf-butoxy-2-((S)- (S)-2-ferf-butoxy-2-((S)-6-(difluoromethyl)- 6-(difluoromethyl)-1 -(2,3- 1-(2,3-dihydropyrano[4,3,2-de]quinolin-7- dihydropyrano[4,3,2- yl)-3-methylnaphthalen-2-yl)acetic acid
de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetate
Preparation of (S)-ethyl 2-tert-butoxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy)-6- vinylnaphthalen-2-yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.0 g, 2.1 mmol) in DMF (10 mL) at room temperature is treated with BrettPhos precatalyst (Strem, 0.23 g, 0.31 mmol), vinyl tributyltin (0.68 mL, 2.3 mmol) and solid NaHC03 (0.026 g, 0.31 mmol). The reaction mixture is sealed and sparged with Ar for 10 minutes prior to heating at 120 °C for 90 minutes. The reaction mixture is allowed to cool to room temperature, loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3-methyl-l- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDC13) δ: 8.00 (d, J = 8.8 Hz, 1H); 7.72 (d, J = 8.8 Hz, 1H); 7.70 (s, 1H); 7.64 (s, 1H); 6.87 (dd, J = 17.2, 11.2 Hz, lH); 5.92 (d, J = 17.2 Hz, 1H); 5.41 (d, J = 11.2 Hz, 1H); 4.27-4.08 (m, 2H); 2.55 (s, 3H); 1.22 (s, 9H); 1.18 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-formyl-3 -methyl- 1 -(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-(3 -methyl- 1- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (0.60 g, 1.3 mmol) in THF (7 mL) at room temperaturewas treated with a previously prepared mixture of K20s04*2H20 (0.023 g, 0.063 mmol) and NaI04 (0.81 g, 3.8 mmol) in water (5 mL). The resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the suspension is filtered through a pad of Celite, and the filtrate is washed with batches of EtOAc until white in color. The collected mother liquor is further diluted with water and EtOAc. Following separation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue is purified by Yamazen column chromatography (15-35%EtO Ac/hex) to afford the desired material. 'H-NMR: 400 MHz, (CDC13) δ: 10.19 (s, 1H); 8.31 (br s, 1H); 8.16 (d, J = 8.8 Hz, 1H); 8.05 (dd, J = 8.8, 1.6 Hz, 1H); 7.85 (s, 1H); 5.76 (s, 1H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s, 9H); 1.18 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-(difluoromethyl)-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-tert-butoxy-2-(6- formyl-3 -methyl- l-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)acetate (0.100 g, 0.21 mmol) in DCM (1 mL) cooled to 0 °C was treated with Deoxo-Fluor® (0.097 mL, 0.53 mmol) and allowed to stir. A second lot was prepared identically beginning with 0.225 g of the starting material. After 3 hours, the reactions were combined and loaded directly onto silica gel (exothermic!) and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert- butoxy-2-(6-(difluoromethyl)-3-methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDC13) 8: 8.14 (d, J = 8.8 Hz, 1H); 7.95 (s, 1H); 7.75 (s, 1H); 7.69 (d, J = 8.8 Hz, 1H); 6.81 (t, JHF = 56.4 Hz, 1H); 5.75 (s, 1H); 4.28-4.10 (m, 2H); 2.58 (s, 3H); 1.22 (s, 9H); 1.18 (t, J = 7.2 Hz, 3H). Preparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-6- (difluoromemyl)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaph1halen-2-yl)acetic acid. (S)-ethyl 2-tert-butoxy-2-(6-(difluoromethyl)-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was converted to (S)-2-tert-butoxy-2-((R)- 6-(difluoromethyl)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)acetic acid (TFA salt, LCMS-ESI+ (m/z): [M+H]+ calcd for C29H28F2N04: 492.2; found: 492.1. 1H-NMR: 400 MHz, (CD3OD) δ: 8.67 (d, J = 4.4 Hz, 1H); 8.13 (s, 1H); 8.08 (s, 1H); 7.85-7.99 (m, 2H); 7.46 (d, J = 8.8 Hz, 1H); 7.40 (d, J = 8.8 Hz, 1H); 7.07 (d, 8.8 Hz, lH); 6.90 (t, JHF = 56 Hz, 1H); 5.26 (s, 1H); 4.77-4.69 (m, 2H); 3.67 (t, J = 6 Hz, 2H); 2.80 (s, 3H); 0.93 (s, 9H)) and (S)-2-tert-butoxy-2-((S)-6-(difluoromethyl)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (TFA salt, LCMS-ESI+ (m/z): [M+H]+ calcd for C29H28F2N04: 492.2) via a sequence of steps similar to those described in Example 16 for the conversion of (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl- 1 -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate to (S)-2-tert-butoxy-2-((S)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3,6-dimethylnaphthalen-2-yl)acetic acid.
Example 20. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl- 6-(prop- 1 -ynyl)naphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)- 1 -(2,3 - dihydropyrano [4,3 ,2-de] quinolin-7-yl)-3 -methyl-6-(prop- 1 -ynyl)naphthalen-2-yl)acetic acid
Figure imgf000168_0001
hydroxyacetate
Figure imgf000168_0002
(S)-ethyl 2-(6-bromo-3- methyl-1 - 2,3-dihydropyrano[4,3,2- (trifluoromethylsulfonyloxy) (S)-ethyl 2-ierf-butoxy-2-(3- de]quinolin-7-ylboronic naphthalen-2-yl)-2-ferf- methyl-6-(prop-1-ynyl)-1- acid, HCI salt
butoxyacetate (trifluoromethylsulfonyloxy)naph
thalen-2-yl)acetate
Figure imgf000168_0003
(S)-ethyl 2-feri-butoxy-2-((S)-1 -(2,3- (S)-ethyl 2-ierf-butoxy-2-((R)-1 -(2,3- dihydropyrano^^^-deJquinolin-T-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)- (S)-2-ierf-butoxy-2-((R)-1-(2,3- 3-methyl-6-(prop-1-ynyl)naphthalen-2- 3-methyl-6-(prop-1-ynyl)naphthalen-2- dihydropyrano[4,3,2-de]quinolin-7- yl)acetate yl)acetate yl)-3-methyl-6-(prop-1 - ynyl)naphthalen-2-yl)acetic acid
Figure imgf000168_0004
Preparation of ethyl 4-(3-bromophenyl)-3-methylbut-2-enoate: To a solution of tnethylphosphonoacetate (28.18 mL, 140.79 mmol) in anhydrous tetrahydrofuran (300 mL) at 0°C was added 60% sodium hydride (5.63 g, 140.79 mmol) and the resulting mixture stirred for 30 minutes. l-(3-Bromophenyl)propan-2-one (20 g, 93.86 mmol) in tetrahydrofuran (10 mL) was added and reaction mixture was stirred for 2 hours and quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give mixture of E/Z isomers. 1H NMR (400 MHz, CDC13): δ 7.38 (m, 1H), 7.32 (m, 1H), 7.18 (m, 1H), 7.06 (m, 1H), 5.79, 5.64 (s,s, 1H), 4.13 (m, 2H), 3.36 (s, 2H), 2.03 (s, 3H), 1.26 (m, 3H).
Preparation of 6-bromo-3-methylnaphthalen-l-ol: A solution of ethyl 4-(3- bromophenyl)-3-methylbut-2-enoate (8.07 g, 28.5 mmol) in concentrated sulfuric acid (20 mL) was stirred at 60°C for 90 minutes. The reaction mixture was poured onto ice and diluted with water and extracted with ethyl acetate. The organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired compound. Ή- NMR: 400 MHz, (CDC13) δ: 7.98 (d, J = 10.4 Hz, 1H), 7.83 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.08 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H). LCMS-EST ( /z): [M-H]" calcd for CnH9BrO: 236.09; Found: 236.9.
Preparation of ethyl 2-(6-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate: To a mixture of 6-bromo-3-methylnaphthalen-l-ol (3.79 g, 15.98 mmol) in anhydrous dichloromethane (150 mL) at -40°C was added a 1M titanium(iV) chloride solution in dichloromethane (20.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxalate (2.45 g, 23.97 mmol) dissolved in dichloromethane (10 mL) was added over 15 minutes and stirred for 1 hour at -40°C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2x). The combined organic layer was dried
(MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give the desired compound. LCMS-EST (m/z): [M-H]" calcd for C15H15Br04: 338.18; Found: 338.8.
Preparation of ethyl 2-(6-bromo-3-methyl-l-(trifluoromethylsulfonyloxy)-naphthalen-2- yl)-2-hydroxyacetate: To a solution of ethyl 2-(6-bromo-l-hydroxy-3-methylnaphthalen-2-yl)- 2-hydroxyacetate (2.03 g, 6 mmol) in anhydrous dichloromethane (120 mL) at 0 °C was added imidazole (531 mg, 7.8 mmol), followed by chlorotriethylsilane (1.21 mL, 7.2 mmol). The cloudy reaction mixture was stirred for 1 hour, quenched with water and diluted with dichloromethane. The mixture was washed with IN HC1 solution/brine and organic layer dried (MgS04), filtered, concentrated and used in next step without further purification.
The above residue was dissolved in anhydrous dichloromethane (130 mL) containing triethylamine (1 mL, 7.2 mmol) and cooled in a dry ice/acetone bath. Trifluoromethanesulfonic anhydride (1.1 1 mL, 6.6 mmol) was added dropwise over 20 minutes and stirred for 1 hour. The reaction was quenched with brine and stirred for 15 minutes at room temperature. The mixture was diluted with dichloromethane, washed with IN HC1 solution, saturated sodium bicarbonate solution brine and dried (MgS04), filtered, concentrated to give an orange oil that used in next step without further purification.
The above residue was dissolved in tetrahydrofuran (100 mL) and 48% hydrofluoric acid
(4.31 mL, 120 mmol) was added. The reaction mixture was stirred overnight at room
temperature and quenched with solid sodium bicarbonate and stirred for 30 minutes. Water and then saturated sodium bicarbonate solution were added and the mixture was extracted with ethyl acetate (2x). The combined organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to the desired compound. LCMS-EST (m/z): [M-H]" calcd for C16H14BrF304S: 470.24; Found: 470.14.
Preparation of ethyl 2-(6-bromo-3 -methyl- l-(trifluoromethylsulfonyloxy)-naphthalen-2- yl)-2-oxoacetate: To a solution of ethyl 2-(6-bromo-3 -methyl- 1 - (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (2.19 g, 4.65 mmol) in anhydrous dichloromethane (50 mL) at 0°C was added Dess-Martin Periodinane (2.76 g, 6.51 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0°C for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3x), brine and dried (MgS04), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired compound. Preparation of (S)-ethyl 2-(6-bromo-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-
2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(6-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (2 g, 4.26 mmol) and (R)-2-methyl- CBS-oxazaborolidine (0.236 g, 0.85 mmol) in anhydrous toluene at -40°C was added a solution of catecholborane (0.615 mL, 5.79 mmol) in toluene (10 mL) over 40 minutes. The reaction mixture was stirred for 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at -20°C, then at room temperature for 45 minutes. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4x), saturated ammonium chloride solution, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired compound.
Preparation of (S)-ethyl 2-(6-bromo-3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen- 2-yl)-2-tert-butoxyacetate: To a solution of (S)-ethyl 2-(6-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (2 g, 4.26 mmol) in tert- butylacetate (30 mL) was added 70% perchloric acid (1.10 mL, 4.69 mmol). The reaction mixture was stirred for 2.5 hours and quenched with solid sodium bicarbonate and stirred for 45 minutes. Water and solid sodium bicarbonate were carefully added and stirred for another 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated bicarbonate solution (2x), brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired compound. 1H NMR (400 MHz, CDC13) δ: 7.96 (s, 1H), 7.90 (d, J = 10.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 5.90 (s, 1H), 4.26 - 4.08 (m, 2H), 2.53 (s, 3H), 1.20 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(3-methyl-6-(prop-l-ynyl)-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A Smith process vial was charged (S)- ethyl 2-(6-bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (55 mg, 0.104 mmol), (l-Propynyl)tributylstannane (35 \i , 0.115 mmol), Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l ,1 '-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(II) (8 mg, 0.01 mmol), NaHC03 (4 mg, 0.05 mmol),
triethylamine (44 μί, 0.3 mmol) and flushed with nitrogen. DMF (2.0 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120°C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(3-methyl-6-(prop-l-ynyl)-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H NMR (400 MHz, CDC13): δ 7.94 (d, J = 4.4 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.50 (d, J = 4.6 Hz, 1H), 5.63 (s, 1H), 4.08 (m, 2H), 2.52 (s, 3H), 2.08 (s, 3H), 1.21(s, 9H), 1.18 (t, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(3 -methyl-6-(prop- 1 -ynyl)- 1 -(trifluoromethylsulfonyloxy)naphthalen- 2-yl)acetate (66 mg, 0.136 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (41 mg, 0.163 mmol), Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l '-biphenyl)[2- (2-aminoethylphenyl)]palladium(II) - methyl-t-butyl ether adduct (9.4 mg, 0.014 mmol), cesium fluoride (91 mg, 0.60 mmol) and flushed with nitrogen. Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120°C for 40 minutes. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert- butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(prop- 1 - ynyl)naphthalen-2-yl)acetate. LCMS-ESf (m/z): [M+H]+ calcd for C33H34N04: 508.62; Found: 508.20.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetate, was also isolated. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34N0 : 508.62; Found: 508.20.
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2- ((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2- yl)acetate (14 mg, 0.0275 mmol) and 1M sodium hydroxide (1 mL) in tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 50°C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound. 1H-NMR: 400 MHz, (CD3OD) δ: 8.67 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 12.9 Hz, 2H), 7.81 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 5.21 (s, 1H), 4.71 (m, 2H), 3.66 (t, J = 6.2 Hz, 2H), 2.76 (s, 3H), 2.04 (s, 3 H), 0.92 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C31H30NO4: 480.57; Found: 480.16. Preparation of (S)-2-tert-butoxy-2-((S)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2-((S)- l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetate (14 mg, 0.0275 mmol) and 1M sodium hydroxide (1 mL) in tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 50°C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound. 1H-NMR: 400 MHz, (CD3OD) δ: 8.58 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 8.21 Hz, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.68 (d, J = 5.48 Hz, 1H), 7.48 (d, J = 8.21 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 5.20 (s, 1H), 4.68 (m, 2H), 3.66 (t, J = 6.2 Hz, 2H), 2.71 (s, 3H), 2.04 (s, 3 H), 0.87 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C31H30NO4: 480.57; Found: 480.16.
Example 21. (S)-2-tert-Butoxy-2-((R)-6-(cyclopropylethynyl)- 1 -(2,3 -dihydropyri
de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid
Figure imgf000174_0001
(S)-ethyl 2-(6-bromo-3- (S)-ethyl 2-(6-bromo-3-
(S)-ethyl 2-(6-bromo-1- methyl-1- hydroxy-3-methylnaphthalen- methyl-1- (trifluoromethylsulfonyloxy) (triethylsilyloxy)naphthalen
2-yl)-2-ferf-butoxyacetate
naphthalen-2-yl)-2-feri- -2-yl)-2-ferf-butoxyacetate
butox acetate
Figure imgf000174_0002
(S)-ethyl 2-ferf-butoxy-2-(6- (S)-ethyl 2-ferf-butoxy-2-(6- 2, 3-dihydropyrano[4, 3, 2- (cyclopropylethynyl)-1-hydroxy-3- (cyclopropylethynyl)-3-methyl-1 - de]quinolin-7-ylboronic
methylnaphthalen-2-yl)acetate (trifluoromethylsulfonyloxy)naphthalen-2- acid, HCI salt
tate
Figure imgf000174_0003
ac
Preparation of (S)-ethyl 2-(6-bromo-l -hydroxy-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate: To a solution of (S)-ethyl 2-(6-bromo-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (260 mg, 0.5 mmol) in anhydrous THF (4 mL) at 0°C was added a IN tetrabutylammonium fluoride in THF (0.6 mL, 0.6 mmol) and stirred for 1 hour. The reaction was quenched by the addition saturated NaHC03 solution and extracted using EtOAc. The organic layer was dried (MgS04), filtered,
concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give the desired compound. LCMS-ESI" (m/z): [M-H]" calcd for
C19H22Br04: 394.29; Found: 394.0.
Preparation of (S)-ethyl 2-(6-bromo-3 -methyl- l-(triethylsilyloxy)naphthalen-2-yl)-2-tert- butoxyacetate: To a solution of (S)-ethyl 2-(6-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2- tert-butoxyacetate (238 mg, 0.6 mmol) in anhydrous DCM (20 mL) at 0°C was added diisopropylethylamine (0.21 mL, 1.2 mmol), followed by chlorotriethylsilane (0.12 mL, 0.72 mmol) and the resulting mixture stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with DCM and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired compound. 1H NMR (400 MHz, CDC13): δ 7.82 (m, 2H), 7.42 (m, 1H), 7.08 (s, 1H), 5.98 (,s, 1H), 4.19 (m, 2H), 2.43 (s, 3H), 1.21 (s, 9 H), 0.98(t, 9H), 0.83 (m, 6H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-(cyclopropylemynyl)-l -hydroxy-3 - methylnaphthalen-2-yl)acetate: A Smith process vial was charged (S)-ethyl 2-(6-bromo-3- methyl-l-(triethylsilyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (151 mg, 0.287 mmol), (cyclopropylethynyl)trimethylsilane (195 mg, 0.316 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), Cul (55 mg, 0.28 mmol), triethylamine (0.12 mL, 0.86 mmol), cesium fluoride (144 mg, 0.95 mmol) and flushed with nitrogen. THF (3 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110°C for 1 hour. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert- butoxy-2-(6-(cyclopropylethynyl)- 1 -hydroxy-3 -methylnaphthalen-2-yl)acetate. LCMS-ESI" (m/z): [M-H]" calcd for C24H2704: 379.48; Found: 379.20.
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-(cyclopropylethynyl)-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(6- (cyclopropylethynyl)-l -hydroxy-3 -methylnaphthalen-2-yl)acetate( 36 mg) was dissolved in anhydrous dichloromethane (2 mL) containing triethylamine (0.1 mL, excess) and cooled in a dry ice/acetone bath. Trifluoromethanesulfonic anhydride (0.1 mL, excess) was added dropwise over 20 minutes and stirred for 1 hour. Reaction was quenched with brine and stirred for 15 minutes at room temperature. The mixture was diluted with dichloromethane, washed with IN HC1 solution, saturated sodium bicarbonate solution/brine and dried (MgSC^), filtered, concentrated to give the desired compound. 1H-NMR: 400 MHz, (CDC13) δ: 8.18 (d, J = 5.4 Hz, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 5.95 (s, 1H), 4.40 (m, 2H), 3.73 (s, 3H), 1.78(m, 1 H), 1.42 (s, 9H), 1.40 (m, 3 H), 1.14 (m, 4H). 19F-NMR: 377 MHz, (CDC13) 6: -73.39.
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-(cyclopropylethynyl)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2 -tert-butoxy-2-(6-(cyclopropylethynyl)-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (45 mg, 0.088 mmol), 2,3- dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (27 mg, 0.11 mmol), Chloro(2- dicyclohexylphospWno-2^6'-dimemoxy-l, -biphenyl)[2-(2-aminoethylphenyl)]palladium(II) - methyl-i-butyl ether adduct (7 mg, 0.009 mmol), cesium fluoride (59 mg, 0.39 mmol) and flushed with nitrogen. Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120°C for 40 minutes. Reaction mixture was diluted with ethyl acetate and washed with brine, dried
(MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-6-(cyclopropylethynyl)-l- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate. LCMS-ESI (m/z): [M+H]+ calcd for C35H36N04: 534.66; Found: 534.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-(cyclopropylethynyl)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate, was also isolated. LCMS-ESf (m/z): [M+H]+ calcd for C35H36N04: 534.66; Found: 534.1.
Preparation of (S)-2-tert-butoxy-2-((R)-6-(cyclopropylethynyl)-l -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid: A solution of (S)- ethyl 2-tert-butoxy-2-((R)-6-(cyclopropylethynyl)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetate (5 mg) and 1M sodium hydroxide (1 mL) in
tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 50°C overnight. Reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound.
1H-NMR: 400 MHz, (CD3OD) δ: 8.57 (d, J = 5.8 Hz, 1H), 7.81 (d, J = 9.78 Hz, 2H), 7.68 (m, 2H), 7.34 (d, J = 8.21 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 5.11 (s, 1H), 4.61 (m, 2H), 3.56 (t, J = 5.86 Hz, 2H), 2.65 (s, 3H), 1.38 (m, 1 H), 0.82 (s +m, 11 H), 0.64 (m, 2H). LCMS-ESf (m/z): [M+H]+ calcd for C33H32N04: 506.6; Found: 506.25. Example 22. (S)-2-tert-Butoxy-2-((R)-6-cyano- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5- ethoxy-3 -methylnaphthalen-2-y l)acetic acid
Figure imgf000177_0001
1-(3-chloro-2- (S)-ethyl 2-ferf-butoxy-2-(6- 2-ierf-butoxy-2-((R)-6- fluorophenyl)prop chloro-5-fluoro-3-methyl-1- chloro-1-(2,3-dihydropyrano[4,3,2- an-2-one (trifluoromethylsulfonyloxy)napht /e]quinolin-7-yl)-5-fluoro-3- halen-2-yl)acetate methylnaphthalen-2-yl)acetate
Figure imgf000177_0002
de]quinolin-7-yl)-5-fluoro-3- methylnaphthalen-2-yl)acetate (S)-2-ierf-butoxy-2-((R)-6-cyano-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5- ethoxy-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-((R)-6- cUoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetate in Example 20, except used l-(3-chloro-2-fluorophenyl)propan-2-one instead of l-(3-bromophenyl)propan-2-one. LCMS- ESI+ (m/z): [M+H]+ calcd for C30H30ClFNO4: 522.01; Found: 522.08. Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyano-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5- fluoro-3-methylnaphthalen-2-yl)acetate (21 mg, 0.04 mmol), Zn(CN)2 (5 mg, 0.04 mmol), NaHC03 (5mg, 0.04 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, - biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (7 mg, 0.009 mmol). Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 130°C for one hour. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2- tert-butoxy-2-((R)-6-cyano-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3- -methylnaphthalen-2-yl)acetate. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H30FN2O4: 513.57; Found: 513.1.
Preparation of (S)-2-tert-butoxy-2-((R)-6-cyano-l -(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-5-ethoxy-3-methylnaphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2- ((R)-6-cyano-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2- yl)acetate (12 mg) and 5M lithium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 50°C overnight. Reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound. 1H-NMR: 400 MHz, (CD3OD) δ: 8.69 (d, J = 5.47 Hz, 1H), 8.33 (s, 1H), 7.81 (m, 2H), 7.44 (d, J = 7.82 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.23 (s, 1H), 4.69 (m, 2H), 4.54 (m, 2H), 3.64 (t, J = 5.86 Hz, 2H), 2.81 (s, 3H), 1.61 (t, J = 7.03 Hz, 3H), 0.92 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H31N205: 51 1.58; Found: 51 1.1.
Example 23. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl- 6-(prop-l -ynyl)naphthalen-2-yl)acetic acid and (S)-2-tert-butoxy-2-((S)-l -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-4,5,7-trifluoro-3-methylnaphthalen-2-yl)acetic acid
di
Figure imgf000179_0001
(S)-ethyl 2-ferf-butoxy-2- (4,5,7-trifluoro-3-methyl-1- (trifluoromethylsulfonyloxy)na
phthalen-2-yl)acetate
Figure imgf000179_0002
(S)-ethyl 2-ierf-butoxy-2-((S)-1- (S)-ethyl 2-ferf-butoxy-2-((R)-1-
(2,3-dihydropyrano[4,3,2- (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-4,5,7-trifluoro-3- de]quinolin-7-yl)-4,5,7-trifluoro-3- methylnaphthalen-2-yl)acetate methylnaphthalen-2-yl)acetate
Figure imgf000179_0003
-y ace c ac
Preparation of (S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3- methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar was as (S)-ethyl 2-(6-bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert- butoxyacetate in Example 20, except using l-(2,4-difluorophenyl)propan-2-one instead of l-(3- bromophenyl)propan-2-one. 1H-NMR: 400 MHz, (CDC13) δ: 7.82(s, 1H), 7.39 (d, J = 5.47 Hz, 1H), 6.99 (m, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 2.49 (s, 3H), l.l l(s+t, 12H). 19F-NMR: 377 MHz, (CDC13) 5: -73.27 (s, 3F), -109.1(m, IF), -117.5(m, IF).
Preparation of (S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-l-hydroxy-3-methylnaphthalen-
2- yl)acetate: (S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro- 1 -hydroxy-3-methylnaphthalen-2- yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-l- hydroxy-3-methylnaphthalen-2-yl)acetate in Example 7 except (S)-ethyl 2-tert-butoxy-2-(5,7- difluoro-3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro- 1 -hydroxy-3 -methylnaphthalen-2-yl)acetate.
Preparation of (S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-
3- memyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar manner as (S)-ethyl 2-tert-butoxy-2-(6-cyano-4-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 7.
1H-NMR: 400 MHz, (CDC13) δ: 7.44 (d, J = 5.47 Hz, 1H), 7.08 (m, 1H), 5.63 (s, 1H), 4.20 (m, 2H), 2.41 (s, 3H), 1.22(s+t, 12H). 19F-NMR: 377 MHz, (CDC13) δ: -73.19 (s, 3F), -107.6(m, IF), -110.07(m, IF), -114.72(d, IF).
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-4,5,7-trifluoro-3-methylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)- ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-3-methyl-l -(trifluoromethylsulfonyloxy)naphthalen-2- yl)acetate (65 mg, 0.129 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (65 mg, 0.258 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl)[2-(2- aminoethylphenyl)]palladium(II) - methyl-t-butyl ether adduct (Strem, 9 mg, 0.013 mmol), cesium fluoride (98 mg, 0.645 mmol) and flushed with nitrogen. Dimethoxyethane (2 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120°C for 40 minutes. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert- butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolm^
2-yl)acetate. LCMS-ESf (m/z): [M+H]+ calcd for C30H29F3NO4: 524.54; Found: 524.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-4,5,7-trifluoro-3-methylnaphthalen-2-yl)acetate, was also isolated. LCMS- ESI+ (m/z): [M+H]+ calcd for C30H29F3NO4: 524.54; Found: 524.1.
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2- ((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4,5,7-trifluoro-3-methylnaphthalen-2- yl)acetate (10 mg) and 1M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 40°C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSC^), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound. 1H-NMR: 400 MHz, (CD3OD) δ: 8.64 (d, J = 5.47 Hz, 1H), 8.12 (d, J - 8.21 Hz, 1H), 7.68 (d, J = 5.47 Hz, 1H), 7.45 (d, J = 8.21 Hz, 1H), 7.17 (m, 1H), 6.43 (m, 1H), 5.14 (s, 1H), 4.69 (m, 2H), 3.61 (t, J = 6.2 Hz, 2H), 2.59 (d, J = 3.12 Hz 3H), 0.84 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25F3N04: 496.49; Found: 496.1. Preparation of (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-
4,5,7-trifluoro-3-methylnaphthalen-2-yl)acetic acid: A solution of (S)-ethyl 2-tert-butoxy-2- ((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4,5,7-trifluoro-3-methylnaphthalen-2- yl)acetate (16 mg) and 1M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and ethanol (1.0 mL) was heated at 40°C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give the desired compound. 1H-NMR: 400 MHz, (CD3OD) δ: 8.64 (d, J - 5.47 Hz, 1H), 7.84 (d, J = 8.21 Hz, 1H), 7.78 (d, J = 5.48 Hz, 1H), 7.45 (d, J = 8.21 Hz, 1H), 7.22 (m, 1H), 6.43 (m, 1H), 5.17 (s, 1H), 4.69 (m, 2H), 3.63 (t, J = 6.2 Hz, 2H), 2.62 (d, J = 3.12 Hz 3H), 0.94 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25F3 04: 496.49; Found: 496.1. Example 24. (S)-2-tert-Butoxy-2-((R)- 10-(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7- yl)phenanthren-9-yl)acetic acid
Figure imgf000182_0001
phenanthren-9-ol ethyl 2-hydroxy-2-(10- hydroxyphenanthren-9-yl)acetate
Figure imgf000182_0002
ethyl 2-oxo-2-(10- (S)-ethyl 2-terf-butoxy-2-(10- (trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy)phenant
phenanthren-9-yl)acetate hren-9-yl)acetate
Figure imgf000182_0003
(S)-ethyl 2-ferf-butoxy-2-((R)- (S)-2-fert-butoxy-2-((R)-10-(2,3- 10-(2,3-dihydropyrano[4,3,2- dihydropyrano[4,3,2-cie]quinolin-7-yl)
de]quinolin-7-yl) phenanthren-9-yl)acetic acid
phenanthren-9-yl)acetate Preparation of ethyl 2-hydroxy-2-(10-hydroxyphenanthren-9-yl)acetate: Prepared by the similar method to make ethyl 2-(6-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2- hydroxyacetate in Example 20, using phenanthren-9-ol instead of 6-bromo-3-methylnaphthalen- l-ol. 1H-NMR: 400 MHz, (CDC13) δ: 8.90 (s, 1H), 8.66-8.62 (m, 2H), 8.40 (d, J = 4.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.71-7.49 (m, 4H), 6.23 (s, 1H), 4.14-4.08 (m, 2H), 3.81 (bs, 1H), 1.11 (t, J = 7.4Hz, 3H).
Preparation of ethyl 2-oxo-2-(10-(trifluoromethylsulfonyloxy)phenanthren-9-yl)acetate: Prepared by the similar method to make ethyl 2-(6-bromo-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate in Example 20, using ethyl 2- hydroxy-2-(10-hydroxyphenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-l-hydroxy-3- methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: 400 MHz, (CDC13) δ: 8.77-8.74 (m, 2H), 8.25 (d, J - 4.0 Hz, 1H), 7.87-7.84 (m, 2H), 7.81-7.77 (m, 2H), 7.70-7.67 (m, 2H), 4.44-4.38 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). 17F-NMR: 400 MHz, (CDC13) δ: -73.18 (s).
Preparation of (S)-ethyl 2-tert-butoxy-2-(10 (trifluoromethylsulfonyloxy)phenanthren-9- yl)acetate: Prepared by the similar method to make (S)-ethyl 2-(6-bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate in Example 20, using ethyl 2- oxo-2-( 10-(trifluoromethylsulfonyloxy)phenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-3 - methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CDCI3) δ: 8.74-8.69 (m, 2H), 8.41 (d, J - 4.4 Hz, 1H), 8.19 (d, J = 4.2 Hz, 1H), 7.79-7.61 (m, 4H), 6.00 (s, 1H), 4.189-4.14 (m, 1H), 4.05-4.00 (m, 1H), 1.25 (s, 9H), 1.03 (t, J = 7 Hz, 3H). Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-10-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)phenanthren-9-yl)acetate: Prepared the similar method to make (S)-ethyl 2-(6-bromo-3- methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (S)-ethyl 2-(6- bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate, using ethyl 2-oxo-2-(10-(trifluoromethylsulfonyloxy)phenanthren-9-yl)acetate instead of ethyl 2-(6- bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H31N04: 506.6; Found: 506.1.
Preparation of (S)-2-tert-butoxy-2-((R)-10-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)phenanthren-9-yl)acetic acid: Prepared by the similar method to make (S)-2-tert-butoxy-2- ((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2- yl)acetic acid, using (S)-ethyl 2-tert-butoxy-2-((R)-10-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)phenanthren-9-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyl-6-(prop-l-ynyl)naphthalen-2-yl)acetate. 1H- NMR: 400 MHz, (CDC13) δ: 8.80 (d, J = 4.4 Hz, 1H), 8.68 (d, J = 3.8 Hz, 2H), 8.54 (d, J = 2.2 Hz, 1 H), 7.64-7.60 (m, 3H), 7.54-7.50 (m, 1H), 7.23-7.16 (m, 3H), 6.78 (d, J = 4.2 Hz, 1H),
5.30 (s, 1H), 4.58 (t, J = 5.8 Hz, 2H), 3.36 (t, J = 5.6 Hz, 2H), 0.938 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH27N04: 478.5; Found: 478.1. Example 25. (2S)-2-((R)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1 -methoxy-2-methylpropan-2-yloxy)acetic acid
Preparation of (S)-2-( 1 -( 1 -chloro-3 -methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2- methylpropyl acetate.
Figure imgf000184_0001
3-methylnaphthalen-2-ol 1 -chloro-3-methylnaphthalen-2-ol
Figure imgf000184_0002
1-chloro-3-methylnaphthalen-2- yl trifluoromethanesulfonate 1-chloro-3-methyl-2-vinylnaphthalene
Figure imgf000184_0003
(S)-1-(1-chloro-3- (S)-1-(1-chloro-3-methylnaphthalen- methylnaphthalen-2-yl)ethane- 2-yl)-2-(trityloxy)ethanol
1 ,2-diol
Figure imgf000184_0004
(S)-ethyl 2-(1-(1-chloro-3- methylnaphthalen-2-yl)-2- (S)-2-( 1 -( 1 -chloro-3-methy Inaphthalen- (trityloxy)ethoxy)-2-methylpropanoate 2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-1-ol
Figure imgf000184_0005
(S)-2-(1-(1-chloro-3- methylnaphthalen-2-yl)-2- (trityloxy)ethoxy)-2-methylpropyl
acetate Preparation of l-chloro-3-methyl-naphthalen-2-ol: To a solution of N-chlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at -78 °C was added zirconium(IV) chloride (2.80g, 12.01 mmol), followed by 3-methyl-naphthalen-2-ol (CombiBlocks, 9.5g, 60.05 mmol) under argon. The reaction mixture was stirred at -78 °C for 5 minutes, the cooling bath was removed and the reaction was stirred at room temperature for 5 h. The reaction was quenched with saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H20, extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3-methyl-naphthalen-2-ol. 1H NMR (400 MHz, CDC13) δ 8.01 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.52 (dd, J = 8.2, 8.2 Hz, 1H), 7.36 (dd, J = 8.2, 8.2 Hz, 1H), 5.99 (s, 1H), 2.47 (s, 3H).
Preparation of trifluoro-methanesulfonic acid l-chloro-3-methyl-naphthalen-2-yl ester: To a solution of l-chloro-3-methyl-naphthalen-2-ol (9.05 g, 46.98 mmol) in dichloromethane (235 mL) at -78°C was added trifluoromethanesulfonic anhydride (11.9 mL, 70.47 mmol), followed by 2,6-lutidine (8.2 mL, 70.47 mmol). The reaction mixture was stirred for 3 h to give a yellow solution, which was diluted with dichloromethane and washed with H20 brine. The organic layer was dried (MgS04), filtered, concentrated and purified by flash column
chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give trifluoro-methanesulfonic acid 1 -chloro-3-methyl-naphthalen-2-yl ester. 1H NMR (400 MHz, CDC13) δ 8.26 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.64-7.58 (m, 2H), 2.59 (s, 3H). 1 F NMR (377 MHz, CDCb) δ -72.9.
Preparation of l-chloro-3-methyl-2 -vinyl-naphthalene: To a solution of trifluoro- methanesulfonic acid l-chloro-3-methyl-naphthalen-2-yl ester (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added dichlorobis(triphenylphosphine) palladium(II) under argon. The reaction mixture was heated at 50 °C for 20 h, then heated at 90 °C for 8 h. The reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgS04), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3 -methyl -2 -vinyl- naphthalene contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2x). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1- chloro-3-methyl-2-vinyl-naphthalene. 1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.59-7.48 (m, 2H), 6.90 (dd, J = 18.0, 1 1.8 Hz, 1H), 5.73 (d, J = 11.8 Hz, 1H), 5.53 (d, J = 18.0 Hz, 1H), 2.50 (s, 3H).
Preparation of l-(l-chloro-3-methyl-naphthalen-2-yl)-ethane-l,2-diol: A biphasic mixture of AD mix-a (6.907 g) in tert-butanol (24.5 mL)/H20 (24.5 mL) was cooled to 0°C and l-chloro-3-methy 1-2- vinyl-naphthalene (1.00 g, 4.93 mmol) was added. The reaction mixture was stirred for 8 h at 0 °C. Sodium sulfite (7.4 g) was added at 0 °C and the reaction was stirred for 40 minutes to give a white mixture. The mixture was diluted with dichloromethane and H20. The mixture was extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give l-(l-chloro-3-methyl-naphthalen-2-yl)-ethane-l,2-diol. 1H NMR (400 MHz, CDC13) δ 8.27 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.56-7.47 (m, 2H), 5.70 (dd, J = 9.4, 3.9 Hz, 1H), 4.11 (dd, J = 10.5, 10.5 Hz, 1H), 3.80 (dd, J = 11.6, 3.9 Hz, 1H), 2.66 (s, 3H).
Preparation of (S)-l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethanol: A suspension of (S)-l-(l-chloro-3-methylnaphthalen-2-yl)ethane-l,2-diol (6.70 grams, 28.2 mmol) and CH2C12 (67 mL) was treated with pyridine (4.78 mL, 59.2 mmol) at 23 °C. Trityl chloride (8.28 g, 29.6 mmol) was added and the reaction was stirred for 24 h. The reaction was washed with 1.0 M aq CuS04 monohydrate (3 x 50 mL), H20 (2 x 50 mL), and brine (50 mL). The final organic layer was dried over Na2S04, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 20% ethyl
acetate/hexanes) to give (S)-l-(l-c oro-3-memylnaphthalen-2-yl)-2-(trityloxy)ethanol. 1H NMR (400 MHz, CDC13) 6 8.22 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 6H), 7.30-7.20 (m, 9H), 5.93-5.77 (m, broad, 1H), 3.59 (dd, J = 9.4, 9.0 Hz, 1H), 3.52 (dd, J = 9.4, 5.0 Hz, 1H), 2.85 (d, broad, J = 4.3 Hz, 1H), 2.52 (s, 3H).
Preparation of (S)-ethyl 2-(l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2- methylpropanoate: A slurry of (S)-l-(l-chloro-3-methylnaphthalen- 2-yl)-2-(trityloxy)ethanol (10.8 grams, 22.5 mmol) and DMF (40 mL) was treated with NaH (60% w/w in mineral oil, 11.3 mmol) at 23 °C . After 5 min, ethyl-(2-bromovalerate) (1.65 mL, 11.3 mmol) was added. After 30 min had passed, more NaH (60% w/w in mineral oil, 11.3 mmol) was added. After stirring for 5 min, additional ethyl-(2-bromovalerate) (1.65 mL, 11.3 mmol) was added. Again, after 30 min had passed, more NaH (60% w/w in mineral oil, 11.3 mmol) was added. After stirring for 5 min, additional ethyl-(2-bromovalerate) (1.65 mL, 11.3 mmol) was added. Once more, after 30 min had passed, more NaH (60% w/w in mineral oil, 11.3 mmol) was added. After stirring for 5 min, additional ethyl-(2-bromo valerate) (1.65 mL, 11.3 mmol) was added. The reaction was stirred for another hour. Saturated aq. NLL;C1 (100 mL) was added, followed by H20 (100 mL). After stirring for 10 min, the reaction was extracted with EtOAc (200 mL). The organic extract was washed with 5% w/v aq. LiCl (3x 100 mL). The final organic phase was dried over Na2S04, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 20% ethyl
acetate/hexanes) to give (S)-ethyl 2-(l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)- 2-methylpropanoate. 1H NMR (400 MHz, CDC13) δ 8.30 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.57-7.38 (m, 2H), 7.49 (s, 1H), 7.36-7.32 (m, 6H), 7.21-7.14 (m, 9H), 5.94 (dd, J = 6.7, 6.7 Hz, 1H), 3.93-3.74 (m, 2H), 3.61 (dd, J = 9.0, 7.0 Hz, 1H), 3.33 (dd, J - 9.0, 5.3 Hz, 1H), 2.52 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H), 0.99 (dd, J = 7.0, 7.0 Hz, 3H). Additionally, starting material ((S)-l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethanol) was recovered. Yield was not determined.
Preparation of (S)-2-(l-(l-chloro-3-methylnaphthalen- 2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-l-ol: A solution of (S)-ethyl 2-(l-(l-chloro-3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropanoate (1.58 g, 2.66 mmol) in diethyl ether (62 mL) was treated with DIBAL-H (1.0 M in hexanes, 13.3 mL, 13.3 mmol) at 23 °C. After 5 min, aq. Rochelle's salt (excess) was added dropwise over 5 min until bubbling ceased. The quenched reaction was agitated manually for 1 min to ensure full quenching. The system transitioned from a slurry to a gel. 50% w/v aw KOH (10 mL) was added, followed by H20 (40 mL), and the reaction was manually agitated until magnetic stirring was achievable (the reaction transitioned from a gel to a biphasic solution). After 15 min of stirring the reaction was extracted with diethyl ether (3x 30 mL). Combined organic layers were dried quickly over MgS04 for 1 min and promptly filtered and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-2-(l- (1 -chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-l -ol. 1H NMR (400 MHz, CDC13) δ 8.23 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.52-7.38 (m, 9H), 7.31-7.18 (m, 9H), 5.87 (dd, J = 9.5, 3.9 Hz, 1H), 3.76 (d, AB-spin system, J = 11.8 Hz, 1H), 3.60 (dd, J = 9.6, 9.6 Hz, 1H), 3.32 (d, AB-spin system, J = 11.8 Hz, 1H), 3.26 (dd, J = 9.8, 3.9 Hz, 1H), 2.49(s, 3H), 1.16 (s, 3H), 1.02 (s, 3H).
Preparation of (S)-2-(l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2- methylpropyl acetate: At 23 °C, a flask containing (S)-2-(l-(l-chloro-3-methylnaphthalen-2-yl)-
2- (trityloxy)ethoxy)-2-methylpropan-l-ol (1.31 g, 2.21 mmol) was charged with Ac20 (5.00 mL) immediately followed by pyridine (5.00 mL). 4-(N,N-dimethylamino)-pyridine (20 mg,
0.164 mmol) was added. After 1.5 h, the reaction was poured onto 50 mL of crushed ice and H20. A white precipitate developed. EtOAc (50 mL) was added after several hours had passed. Solid NaHC03 was added portionwise (bubbling) until the aq. layer had a pH of 9. The slurry was extracted with EtOAc (2x 25 mL). The combined organic layers were washed with 1.0 M aq. CuS04 monohydrate (3x 25 mL) and H20 (25 mL). The final organic phase was dried over Na2S04, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-2-(l-(l-chloro-
3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate. 1H NMR (400 MHz, CDC13) δ 8.25 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52-7.41 (m, 9H), 7.26-7.16 (m, 9H), 5.99 (dd, J = 8.2, 4.7 Hz, 1H), 4.02 (app. s, 2H), 3.55 (dd, J = 8.6, 8.4 Hz, 1H), 3.12 (dd, J = 9.8 Hz, 4.7 Hz, 1H), 2.52 (s, 3H), 1.86 (s, 3H), 1.32 (s, 3H), 1.15 (s, 3H).
Preparation of 2-((S)- 1 -((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate and 2-((S)-l-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2- methylpropyl acetate.
Figure imgf000189_0001
2,3-dihydropyrano[4,3,2-de]quinolin-7- 2-((S)-1-((S)-1-(2,3-dihydropyrano
ylboronic acid, monohydrochloride [4,3,2-cfe]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- (trityloxy)ethoxy)-2-methylpropyl acetate
Preparation of 2-((S)-l-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate: A 100 mL round-bottom flash was charged with (S)-2-(l-(l-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2- methylpropyl acetate (1.32 g, 2.23 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, monohydrochloride (673 mg, 2.68 mmol), CsF (1.49 g, 9.81 mmol), and Buchwald's S- Phos Palladacycle precatalyst (Strem, 225 mg, 0.331 mmol). The vessel was evacuated under vacuum and backfilled with dry argon. Freshly distilled 1,2-dimethoxyethane (distilled from sodium/benzophenone, 20 mL) was introduced. With vigorous stirring, the flask was wrapped in foil and heated to 120 °C for 3 h. The reaction was cooled to 23 °C and added to brine (20 mL) and H20 (20 mL). EtOAc (30 mL) was introduced, followed by hexane (10 mL). The slurry was filtered over a pad of Celite. The filtrate now separated into two layers. The organic phase was collected. The aq. layer was extracted with EtOAc (3x 30 mL). Combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give two products: The first was 2-((S)-l-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2 -methylpropyl acetate. LCMS-ESI+: calc'd for C49H45N05: 728.3 (M+H+); Found: 728.3 (M+H+), 750.3 (M+Na)+. The second was 2-((S)-l- ((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate.
LCMS-ESf (m/z): [M+H]+ calcd for C49H45N05: 728.3; Found: 728.1.
Preparation of (2 S)-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-7-yl)-3 - methylnaphthalen-2-yl)-2-( 1 -methoxy-2-methyl ro an-2-yloxy)acetic acid.
Figure imgf000190_0001
2-((S)-1-((R)-1 -(2,3-dihydropyrano (2S)-2-((R)-1-(2,3-dihydropyrano
[4,3,2-de]quinolin-7-yl)-3- [4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- methylnaphthalen-2-yl)-2-(1-methoxy- (trityloxy)ethoxy)-2-methylpropyl acetate 2-methylpropan-2-yloxy)acetic acid
Preparation of (2S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid: A slurry of 2-((S)-l- ((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2- (trityloxy)ethoxy)-2-methylpropyl acetate (15 mg, 21 μηιοΐ), THF (1.5 mL), EtOH (absolute, 750 μΐ,), and H20 (750 μί) was treated with LiOH monohydrate (75 mg, excess) at 23 °C. After 1 h, the reaction was diluted with H20 (15 mL) and extracted with EtOAc (2x 15 mL).
Combined organic layers were dried over Na2S04, filtered, concentrated, treated with THF, and concentrated again to remove residual EtOAc.
DMF (750 μί) was introduced, followed by iodomethane (150 μί). The solution was treated with NaH (60% w/v in mineral oil, 30 mg, excess) at 23 °C. After 1.5 h, the reaction was quenched with saturated aq. NH4CI. After dilution with H20 (15 mL), the reaction was extracted with EtOAc (2x 15 mL). The combined organic layers were washed with 5% w/v aq. LiCl (3x 10 mL), dried (Na2S04), filtered, and concentrated.
MeOH (1.5 mL) was introduced followed by MsOH monohydrate (15 μί, excess) at 23 °C. After 30 min, saturated aq. NaHC03 (3 mL) was added in one portion (bubbling). After 10 min, H20 (10 mL) was added and the reaction was extracted with EtOAc (3x 15 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated. EtOAc was added, and again the solution was concentrated to remove residual methanol.
CH3CN (800 μί) and H20 (200 μί) were added, followed by H5I06 (30 mg, excess). Cr03 (7 mg, excess) was added at 23 °C with vigorous stirring. After 15 min, the reaction was directly purified on a CI 8 Gemini column (Eluent: H20/CH3CN 95:5→ 0:100 + 0.1% v/v TF A), giving (2S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid as its mono-trifluoroacetic acid salt. !H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.76-7.64 (m, 2H), 7.46 (dd, J = 8.4, 8.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 7.4, 7.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.53 (s, broad, 1H), 4.73-4.66 (m, 2H), 3.63-3.58 (m, 2H), 3.40-2.99 (m, 2H), 3.08 (s, 3H), 2.74 (s, 3H), 0.91 (s, broad, 3H), 0.88 (s, broad, 3H). 19F NMR (377 MHz, CD3OD) 6 -105.6 (s, IF), -77.5. LCMS-ESf (m/z): [M+H]+ calcd for C29H29NO5: 472.2; Found: 472.2. Example 26. (2S)-2-((S)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(l -metho -2-methylpropan-2-yloxy)acetic acid
Figure imgf000191_0001
2-((S)-1 -((S)-1 -(2,3-dihydropyrano (2S)-2-((S)-1-(2,3-dihydropyrano
[4,3,2-cte]quinolin-7-yl)-3- [4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- methylnaphthalen-2-yl)-2-(1-methoxy- (trityloxy)ethoxy)-2-methylpropyl acetate 2-methylpropan-2-yloxy)acetic acid
Preparation of (2S)-2-((S)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 - methylnaphthalen-2-yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid: Prepared in a manner similar to (2S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid in Example 25, except using 2-((S)-l-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate (Example 25) as the starting material. 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 8.2, 1H), 7.93 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.50-7.44 (m, 2H), 7.24 (dd, J = 7.8, 7.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.55 (s, broad, 1H), 4.71 (dd, J = 5.9, 5.9 Hz, 2H), 3.64 (dd, J = 5.9, 5.9 Hz, 2H), 3.38-3.00 (m, 2H), 3.07 (s, 3H), 2.73 (s, 3H), 0.95 (s, broad, 3H), 0.75 (s, broad, 3H). 19F NMR (377 MHz, CD3OD) δ -77.7. LCMS-ESf m/z): [M+H]+ calcd for C29H29NO5: 472.2; Found: 472.1.
Example 27. (2S)-2-((R)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1 -ethoxy-2-methylpropan-2-yloxy)acetic acid
Figure imgf000192_0001
2-((S)-1-((R)-1 -(2,3-dihydropyrano (2S)-2-((R)-1 -(2,3-dihydropyrano
[4,3,2-de]quinohn-7-yl)-3- [4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- methylnaphthalen-2-yl)-2-(1-ethoxy-
(trityloxy)ethoxy)-2-methylpropyl acetate 2-methylpropan-2-yloxy)acetic acid
Preparation of (2S)-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l-ethoxy-2-methylpropan-2-yloxy)acetic acid: Prepared in a manner similar to (2S)-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid in Example 25, using 2-((S)- 1 -((R)- 1 -(2,3-dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2- (trityloxy)ethoxy)-2-methylpropyl acetate as the starting material. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 5.5 Hz, IH), 7.92 (s, IH), 7.91 (d, J = 8.6 Hz, IH), 7.80-7.68 (m, 2H), 7.50-7.38 (m, 2H), 7.25 (dd, J = 8.2, 8.2 Hz, IH), 6.90 (d, J = 8.2 Hz, IH), 5.70 (s, broad, IH), 4.75-4.68 (m, 2H), 3.68-3.59 (m, 2H), 3.48-3.45 (m, IH), 3.48-3.08 (m, 2H), 3.16-3.13 (m, IH), 2.74 (s, 3H), 0.97 (s, broad, 3H), 0.94-0.84 (m, 6H). 19F NMR (377 MHz, CD3OD) δ -77.5. LCMS-ESI+ (m/z) [M+H]+ calcd for C3oH31N05: 486.2; Found: 486.2. Example 28. (2S)-2-((S)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1 -ethoxy-2-methylpropan-2-yloxy)acetic acid
Figure imgf000192_0002
2-((S)-1-((S)-1 -(2,3-dihydropyrano (2S)-2-((S)-1 -(2,3-dihydropyrano
[4,3,2-de]quinolin-7-yl)-3- [4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- methylnaphthalen-2-yl)-2-(1-ethoxy-
(trityloxy)ethoxy)-2-methylpropyl acetate 2-methylpropan-2-yloxy)acetic acid
Preparation of (2S)-2-((S)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 - methylnaphthalen-2-yl)-2-(l-ethoxy-2-methylpropan-2-yloxy)acetic acid: Prepared in a manner similar to (2S)-2-((S)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l-methoxy-2-methylpropan-2-yloxy)acetic acid using 2-((S)-l-((S)- l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2- (trityloxy)ethoxy)-2-methylpropyl acetate as the starting material. ). 1H NMR (400 MHz,
CD3OD) 6 8.57 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.63-7.59 (m, 1H), 7.497.37 (m, 2H), 7.21 (dd, J = 8.8, 8.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 5.58 (s, broad, 1H), 4.70-4.65 (m, 2H), 3.62-3.55 (m, 2H), 3.49-3.47 (m, 1H), 3.47-3.00 (m, 2H), 3.15-3.13 (m, 1H), 2.70 (s, 3H), 1.02-0.94 (m, 6H), 0.88 (s, broad, 3H). 19F NMR (377 MHz, CD3OD) δ -77.6. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH31N05: 486.2; Found: 486.1. Example 29. (S)-2-((R)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(2-methylpentan-2-yloxy)acetic acid
Preparation of (S)-ethyl 2-hydroxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy)- naphthalen-2-yl)acetate.
Figure imgf000193_0001
1 -(4-bromophenyl)propan-2-one ethyl 4-(4-bromophenyl)- 3-methylbut-2-enoate
Figure imgf000193_0002
7-bromo-3- 3-methylnaphthalen-1 -ol ethyl 2-hydroxy-2-(1-hydroxy- methylnaphthal -1 -ol 3-methylnaphthalen-2-yl)acetate
Figure imgf000193_0003
ethyl 2-fer/-butoxy-2-(1-hydroxy- 3-methylnaphthalen-2-yl)acetate ethyl 2-ferf-butoxy-2-(3-methyl- 1 -(trif luoromethylsulfonyloxy)
naphthalen-2-yl)acetate
Figure imgf000193_0004
(S)-ethyl 2-hydroxy-2-(3-methyl- ethyl 2-hydroxy-2-(3-methyl-1- ethyl 2-(3-methyl-1- 1 -(trif luoromethylsulfonyloxy) (trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate naphthalen-2-yl)acetate naphthalen-2-yl)-2-oxoacetate
Preparation of ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate: At 0 °C, a suspension of 60% w/w NaH/minerai oil (7.13 g, 0.176 mol) in THF (250 mL) was treated dropwise with a solution of triethylphosphonoacetate (39.5 g, 0.176 mol) in THF (72 mL) over a 30 min period. The reaction was stirred for another 30 min, and a solution of l-(4-bromophenyl)propan-2-one (25.0 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0 °C during addition. The reaction was allowed to warm to 23 °C as it was stirred overnight. The next day, saturated NH4CI (250 mL) was added. After 2 h, the reaction was diluted with H20 (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2 x 150 mL). Combined organic phases were dried (MgS04), filtered, and concentrated, giving crude 4-(4-bromophenyl)-3-methylbut-2-enoate as a mixture of E and Z geometric isomers. The residue was carried onward without further purification. The Ή NMR reported below was from a crude mixture containing both the E and Z isomer. !H NMR (400 MHz, CDC13) δ 7.43 (d, J = 8.6 Hz, 1.6H), 7.39 (d, J = 8.6 Hz, 0.4H), 7.12 (d, J - 8.2 Hz, 0.4H), 7.04 (d, J = 8.2 Hz, 1.6H), 4.42-4.21 (m, 2H), 3.96 (s, 0.4H), 3.38 (s, 1.6H), 2.10 (s, 2.4H), 1.77 (s, 0.6H), 1.37-1.23 (m, 3H).
Preparation of 7-bromo-3-methylnaphthalen-l-ol: A flask containing the crude ethyl 4- (4-bromophenyl)-3-methylbut-2-enoate from above (~ 30 grams) was treated with concentrated H2S04 (120 mL) and warmed to 50 °C for 2.5 h. The reaction was poured onto -500 mL of crushed ice. Once the ice had thawed, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated NaHC03, dried (MgS04), filtered, and concentrated to ~ 55 mL. The residue was treated with DCM and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. 1H NMR (400 MHz, CDC13) δ 8.29 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.6, 2.0 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H). Preparation of 3-methylnaphthalen-l-ol: A slurry of 7-bromo-3-methylnaphthalen-l-ol
(100 mg, 0.421 mmol), 10% w/w Pd/C (45 mg, 42.1 μπιοΐ Pd), and absolute EtOH (2.0 mL) was purged under vacuum and backfilled with ¾ from a balloon several times. The suspension was stirred under a balloon of H2 at 23 °C overnight. The reaction was filtered over Celite, the cake was washed with EtOAc. The filtrate was concentrated and dissolved in DCM. The solution was loaded onto a 12 g "gold" ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. Ή NMR (400 MHz, CDC13) δ 8.10 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.22 (s, 1H), 6.67 (s, 1H), 2.45 (s, 3H). Preparation of ethyl 2-hydroxy-2-(l-hydroxy-3-methylnaphthalen-2-yl)acetate: A flask containing DCM (5.0 mL) was charged with TiCl4 (1.0 M in DCM, 3.16 mL, 3.16 mmol). After cooling to -40 °C (dry ice/CH3CN bath), a solution of 3-methylnaphthalen-l-ol (500 mg, 3.16 mmol) in DCM (5.0 mL) was added drop wise over a 5 min period. The reaction turned deep violet. After 30 min, a solution of ethyl glyoxylate (323 mg, 3.16 mmol, distilled freshly from P205 under N2 from the 50% w/w toluene solution of ethyl glyoxylate) in DCM (2.0 mL) was added quickly. The reaction was warmed to 0 °C. After 1 h, glacial AcOH (1.0 mL) was added. 5 min later, CH3CN (5.0 mL) was introduced, followed by H20 (10 mL). The reaction transitioned from violet to yellow-orange. The reaction was warmed to 23 °C and stirred for 30 min. The reaction was diluted with ¾0 (15 mL) and extracted with DCM (3 x 20 mL). The combined extracts were washed with saturated NaHC03 (20 mL) (this decolorized the organic phase from orange to yellow), dried ( a2S04), filtered, concentrated, treated with DCM (10 mL), and concentrated again. The residue was dissolved in DCM and loaded onto a 24 g "gold" ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. 1H NMR (400 MHz, CDC13) δ 8.41 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8, 8.0 Hz, 1H), 7.40 (dd, J = 8.2, 8.0 Hz, 1H), 7.20 (s, 1H), 5.68 (s, 1H), 4.31-4.08 (m, 2H), 3.94 (s, broad, 1H), 2.52 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2-yl)acetate: A solution of ethyl 2-hydroxy-2-(l-hydroxy-3-methylnaphthalen-2-yl)acetate (622 mg, 2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70% HC104 (20 jiL) at 23 °C). After 3 h, the reaction was added slowly over 5 min to saturated NaHC03 (25 mL). The resulting system was extracted with DCM (3 x 15 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated. Hexane (10 mL) was added, and the mixture was concentrated again. The residue was dissolved in benzene. The solution was loaded onto a 24 g "gold" ISCO silica gel column and purified by flash chromatography (hexane→ ethyl acetate) giving the desired product. Ή NMR (400 MHz, CDC13) δ 9.00 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.2, 8.0 Hz, 1H), 7/39 (dd, J = 8.8, 8.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 1H), 4.25-4.06 (m, 2H), 2.59 (s, 3H), 1.33 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-tert-butoxy-2-(3 -methyl- l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2- yl)acetate (9.37 g, 29.7 mmol) in THF (250 mL) was treated with N-phenyltriflimide (12.7 g, 35.6 mmol) followed by Cs2C03 (19.3 g, 59.3 mmol). More THF (50 mL) was added to aide fluidity, and the reaction was stirred at 23 °C for 2 h. The reaction was added slowly to a premade mixture of saturated aq. Na2HP04 (400 mL) and 2 M aq. NaHS04 (120 mL). System was then stirred for 10 min, reaching a final pH of 8. It was extracted with 9:1 EtOAc/hexanes (3x 200 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated. Hexane was added and the slurry was concentrated again to remove residual THF. The mix was treated with benzene and purified by silica gel chromatography (hexane→ ethyl acetate) to give product that was contaminated with a small amount of PhNH(Tf). LCMS-ESF1" (m/z): [M- C4H9+H]+ calcd for C16H15F306S: 392.4; found: 392.6.
Preparation of ethyl 2-hydroxy-2-(3 -methyl- l-(trifluoromethylsulfonyl- oxy)naphthalen- 2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(3-methyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (6.0 grams, ~13 mmol, semi pure) in DCM (60 mL) was treated with TFA (6.0 mL) at 23 °C. The reaction was diluted with H20 (60 mL) and the organic phase collected. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated. The residue (5.5 grams) was used in the next reaction without further purification. 1H NMR (400 MHz, CDC13): δ 8.08-8.06 (m, 1H), 7.81-7.78 (m, 1H), 7.69 (s, 1H), 7.62-7.55 (m, 2H), 5.81 (app. s, 1H), 4.35- 4.21 (m, 2H), 3.26 (app. s, broad, 1H), 2.50 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-(3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- oxoacetate: A solution of ethyl 2-hydroxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (5.5 g, crude) in DCM (160 mL) was treated with Dess-Martin periodinane (7.18 g, 16.9 mmol) at 23 °C. After 1 h, the reaction was added slowly over 5 min to 10% Na2S203 (100 mL). After 30 min, the reaction was extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated. The residue was treated with benzene, filtered, and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product in semi pure form. 1H NMR (400 MHz, CDC13): δ 8.11-8.08 (m, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.66-7.60 (m, 2H), 4.41 (q, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J = 7.4 Hz, 3H). 19F NMR (377 MHz, CDC13) δ - 73.3 (s). Preparation of (S)-ethyl 2-hydroxy-2-(3 -methyl- l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: Ethyl 2-(3 -methyl- 1 -(trifluoromethylsulfony loxy)naphthalen-2-yl)-2- oxoacetate (1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to -40 °C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine (219 mg, 7.5 mmol) and catecholborane (750 μΐ,, 7.04 mmol) were added and the mixture stirred at -40 °C. After 2 hrs at -40 °C the reaction was quenched by the addition of 15% Na2C03 (12 mL) and the mixture was allowed to warm to room temperature. The mixture was washed with 15% Na2C03 (8 x 12 mL) and saturated NH4CI (24 mL), organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Chromatography using silica gel using EtOAc in hexanes produced the desired (S)-ethyl 2-hydroxy-2-(3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCI3): δ 8.08-8.06 (m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80 (m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J = 2.4 Hz, 1H); 2.50 (s, 3H); 1.21 (t, J = 7.0 Hz, 3H).
Preparation of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- methylnaphthalen-2-yl)-2-(2-methylpentan-2-yloxy)acetic acid.
,2- ic
Figure imgf000198_0001
(S)-ethyl 2-hydroxy-2-(3-methyl-1 - (S)-ethyl 2-tert- CsF, 'S-phos
(trifluoromethylsulfonyloxy)naphth butoxy-2-(3-methyl-1 - palladacycle'
alen-2-yl)acetate (trifluoromethylsulfonyl DME
oxy)naphthalen-2- yl)acetate
Figure imgf000198_0002
(S)-ethyl 2-ferf-butoxy-2-((R)-1-(2,3- n- dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetate
Figure imgf000198_0003
(S)-ethyl 2-((R)-1-(2,3- dihydropyrano[4,3,2-de]quinolin- (S)-2-((ff)-1-(2,3-dihydropyrano[4,3,2- 7-yl)-3-methylnaphthalen-2-yl)-2- de]quinolin-7-yl)-3-methylnaphthalen-2- (2-methylpentan-2-yloxy)acetate yl)-2-(2-methylpentan-2-yloxy)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a stirring solution of (S)-ethyl 2- hydroxy-2-(3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (560 mg, 1.42 mmol) in t-BuOAc (32.0 mL, 381 mmol) was added 4 drops (catalytic) of 70% HC104 and the mixture allowed to stir at room temperature for 2 hrs. The mixture was quenched by dumping it into an icy solution of saturated NaHC03. Extraction with EtOAc (3 x 20 mL), drying with sodium sulfate and subsequent chromatography on silica gel using EtOAc in Hexanes gave (S)- ethyl 2-tert-butoxy-2-(3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H- NMR: 400 MHz, (CDC13): δ 8.06-8.03 (m, 1H); 7.81-7.78 (m, 1H); 7.67 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.25-4.10 (m, 2H); 2.55 (s, 3H); 1.21 (s, 9H), 1.17 (t, 3H). Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(3-methyl-l - (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (555 mg, 1.23 mmol) in freshly distilled DME (5.0 mL) was added to a 5- 10 mL microwave vial charged with a mixture of 2,3- dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (368 mg, 1.46 mmol); S-Phos Palladacycle (Strem, 155 mg, 0.23 mmol), and cesium fluoride (743 mg, 4.89 mmol). This heterogeneous mixture was then microwaved at 125 °C for 60 minutes. The mixture was then diluted 400% with EtOAc, extracted with saturated NH4CI, brine, and dried with sodium sulfate, filtered and concentrated. Chromatography via ISCO using a 15 μπι particle size silica gel column eluting with ethyl acetate/hexanes gave the desired atropisomer. 1H-NMR: 400 MHz, (CDCI3): δ 8.67 (d, J= 4.4 Hz, IH); 7.76 (d, J=8.0 Hz, IH); 7.72 (s, IH); 7.49 (d, J=8.0 Hz, IH); 7.36-7.33 (m, IH); 7.13-7.01 (m, 4H); 5.09 (s, IH); 4.58-4.52 (m, 2H); 4.03-3.78 (m, 2H); 3.38- 3.23 (m, 2H); 2.79 (s, 3H); 0.97-0.94 (m, 12H). LCMS-ESI+ (m/z): [M+H]+ calcd for
C30H32NO4: 470.23; Found: 470.39. The undesired atropisomer was also isolated. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32NO4: 470.23; Found: 470.39.
Preparation of (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate: To a solution of (S)-ethyl 2-tert-butoxy-2-((R)-l- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (49.0 mg, 0.104 mmol) in DCM (10 mL) was added TFA (650 iL, 0.0084 mmol) and reaction mixture was stirred at room temperature overnight. Mixture was quenched by pouring into an icy solution of saturated NaHC03 and extracted with EtOAc to give crude (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: δ 400 MHz, (CDCI3): 8.67 (d, J= 4.0 Hz, IH); 7.79-7.76 (m, 2H); 7.47 (d, J=7.6 Hz, IH), 7.38 (t, IH); 7.16-7.10 (m, 3H); 6.96 (d, J=8.4 Hz, IH); 5.36 (s, IH); 4.58-4.55 (m, 2H); 3.89-3.72 (m, 2H); 3.38-3.31 (m, 2H); 2.69 (s, 3H); 1.04 (t, 3H). LCMS-ESf (m/z): [M+H]+ calcd for C26H23N04: 414.16; Found: 414.1. Preparation of (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylpentan-2-yloxy)acetate: (S)-ethyl 2-((R)- 1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (21.2 mg, 0.415 mmol) was slurried in 2.5 mL of 2-methylpentan-2-yl acetate (preparation described in Example 30) and 2.5 mL of DCM and 70% perchloric acid (5 ) was added. The mixture was allowed to stir overnight at rt. The reaction was quenched by dumping it into icy saturated NaHC03. This mixture was extracted with EtOAc (3x 15 mL), dried with sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using EtOAc in hexanes gave rise to desired (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(2-methylpentan-2-yloxy)acetate. 1H-NMR: δ 400 MHz, (CDC13): 8.69 (s, 1H); 7.78-7.74 (m, 3H); 7.52-7.49 (m, 2H); 7.37-7.33 (m, 2H), 7.13-7.10 (m, 2H); 5.10 (s, 1H); 4.59 (t, 2H); 4.07-3.83 (m, 2H); 3.35 (s, 2H); 2.79 (s, 3H); 1.62-1.48 (m, 4H); 1.34-1.18 (m, 9H); 0.90 (t, 3H). LCMS-ESI+ m/z): [M+H]+calcd for C32H36N04: 498.26; Found: 498.11.
Preparation of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylpentan-2-yloxy)acetic acid: (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(2-methylpentan-2- yloxy)acetate (30 mg, 0.06 mmol) was dissolved in THF (9.0 mL), MeOH (3mL) and water (3.0 mL). Lithium hydroxide monohydrate (192 mg, 4.58 mmol) and was microwaved at 100 °C for 90 minutes. Mixture was then diluted 400 % with EtOAc, washed with water, brine, dried, filtered and concentrated in vacuo. Crude product was dissolved in MeOH and purified via PREP HPLC (5 μΜ Gemini C,8 column (100 x 30mm), (5 to 100% MeCN/H20 + 0.05%TFA) to give rise to the TFA salt of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylpentan-2-yloxy)acetic acid. 1H-NMR: 400 MHz, (CD3OD): 8.68-8.67(d, J=5.6 Hz, 1H); 7.98-7.94 (m, 2H), 7.88-7.81 (m, 2H); 7.56-7.49 (m, 2H); 7.19-7.26 (m, 1H); 6.946.92 (d, J=8.0 Hz, 1H); 5.22 (s, 1H); 4.78-4.69 (m, 2H); 3.70-3.67 (t, 2H); 2.79 (s, 3H); 1.37-1.26 (m, 2H); 1.21-1.09 (m, 2H), 0.94 (s,6H); 0.75 (t, 3H). 19F-NMR: 400 MHz, (CD3OD): -77.665. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32NO4: 469.57; Found: 470.12.
Example 30. (S)-2-((S)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(2-methylhexan-2-yloxy)acetic acid
Figure imgf000201_0001
(3-methyl-1- (S)-ethyl 2-(3-methyl-1- (trifluoromethylsulfonylo 2-methylhexan- (trifluoromethylsulfonyloxy)na
xy)naphthalen-2- 2-yl acetate phthalen-2-yl)-2-(2- yl)acetate methylhexan-2-yloxy)acetate
2,3-d
cte]
a LiOH
Figure imgf000201_0002
CsF, 'S-phos THF-H20-MeOH
palladacycle' (2S)-ethyl 2-(1-(2,3- DME dihydropyrano[4,3,2-cte]quinolin-7- yl)-3-methylnaphthalen-2-yl)-2-(2- ylhexan-2-yloxy)acetate
Figure imgf000201_0003
(S)-2-((fi)-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(2-methylhexan-2-yloxy)acetic acid
Preparation of (S)-ethyl 2-(3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- (2-methylhexan-2-yloxy)acetate: (S)-ethyl 2-hydroxy-2-(3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a stirring solution of (512 mg, 1.30 mmol) in 2-methylhexan-2-yl acetate (5.0 mL) was added 3 drops (catalytic) of HC104 and the mixture allowed to stir at room temp for 2.5 hrs. The mixture was quenched by pouring it into an icy solution of saturated NaHC03. Extraction with EtOAc (3 x 20 mL), drying with sodium sulfate and subsequent chromatography on silica gel using EtOAc in hexanes gave (S)-ethyl 2- (3-methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetate. 1H-NMR: δ 400 MHz, (CDC13): 8.05-8.03 (m, 1H); 7.81-7.79 (m, 1H); 7.68 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.26-4.11 (m, 2H); 2.55 (s, 3H); 1.54-1.39 (, 2H); 1.33-1.00 (m, 13H), 0.71 (t, 3H).
Preparation of (2S)-ethyl 2-(l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetate: (S)-ethyl 2-(3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetate (416 mg, 0.848 mmol) in freshly distilled DME (5.0 mL) was added to a 25 mL flask charged with a mixture of 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (236 mg, 0.938 mmol), S-Phos Palladacycle (Strem, 87 mg, 0.129 mmol), and cesium fluoride (386 mg, 2.54 mmol). This heterogeneous mixture was heated thermally at 120 °C for 60 minutes. The mixture was then diluted 400% with EtOAc, extracted with saturated NH4CI, brine, and dried with sodium sulfate, filtered and concentrated. Purification via ethyl acetate-hexane chromatography using an Isco 12 gram Gold silica gel column failed to completely separate the two atropisomers. Two atropisomer mixtures were obtained. The first eluting mixture, mixture A, was further purified via PRP HPLC (5 μΜ Gemini C18 column (100 x 30mm), (5 to 100% MeCN/H20 + 0.05%TFA) and resulting in enriched (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38N04: 512.65; Found: 512.17.
The later eluting mixture, mixture B, was carried forward without additional purification and was (S)-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2- (2-methylhexan-2-yloxy)acetic acid . LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38N04: 512.65; Found: 512.17.
Preparation of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid: (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(2-methylhexan-2- yloxy)acetate (15.6 mg, 0.0305 mmol) was dissolved in THF (3.0 mL), MeOH (1.0 mL) and water 1.0 mL. Lithium hydroxide monohydrate (102.1 mg, 2.43 mmol) was added and the mixture was and stirred at room temperature overnight. The mixture was then diluted 400 % with EtOAc, washed with water, brine, dried, filtered and concentrated in vacuo. Crude product was dissolved in MeOH and purified via PREP HPLC (5 μΜ Gemini C18 column (100 x 30mm), (5 to 100% MeCN/H20 + 0.05%TFA) to give (S)-2-((R)-l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid as a TFA salt. 1H-NMR: 400 MHz, (CD3OD): δ 8.66-8.65 (d, J=8.0 Hz, IH); 7.96-7.92 (m, 2H), 7.86-7.84 (d, J= 8.0 Hz, IH); 7.79-7.77 (d, J= 8.0 Hz, IH); 7.50-7.46 (m, 2H); 7.27-7.24 (t, IH); 6.91-6.89 (d, J=8.4 Hz, IH); 5.20 (s, IH); 4.76-4.69 (m, 2H); 3.67-3.64 (t, 2H); 2.77 (s, 3H); 1.21-1.10 (m, 2H); 0.93-0.87 (m, 6H), 0.81-0.77 (m, 3H).
19F-NMR: 400 MHz, (CD3OD): δ -77.595. LCMS-ESf (m/z): [M+H]+ calcd for C31H34N04: 484.2; Found: 484.12
Preparation of (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid: (S)-ethyl 2-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-memylnaphthalen-2-yl)-2-(2-methylhexan-2- yloxy)acetate (27.3 mg, 0.0534 mmol) was dissolved in THF (3.0 mL), MeOH (1.0 mL) and water 1.0 mL. Lithium hydroxide monohydrate (98.7 mg, 2.35 mmol) was added and the mixture was and stirred at room temperature overnight. The mixture was then diluted 400 % with EtOAc, washed with water, brine, dried, filtered and concentrated in vacuo. The crude product was dissolved in MeOH and purified via PREP HPLC (5 μΜ Gemini C18 column (100 x 30mm), (5 to 100% MeCN/H20 + 0.05%TFA) to give (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(2-methylhexan-2-yloxy)acetic acid as a TFA salt. 1H-NMR: 400 MHz, (CD3OD): δ 8.57-8.55 (d, J=5.6 Hz, IH); 8.15-8.13 (d, J= 7.2 Hz, IH); 7.96-7.90 (m, 2H), 7.67(m, IH); 7.48-7.44 (m, 2H); 7.24-7.20(m, IH), 6.91-6.88 (d, J=8.8 Hz, IH); 5.27 (s, IH); 4.71-4.68 (m, 2H); 3.61 (bs, 2H); 2.74 (s, 3H); 1.29-1.13 (m, 6H); 0.89 (s, 3H); 0.81-0.73(m, 6H)ppm.19F-NMR: δ 400 MHz, (CD3OD): -77.687. LCMS-ESf (m/z):
[M+H]+ calcd for C31H34N04: 484.2; Found: 484.13.
Preparation of 2-methylpentan-2-yl acetate and 2-methylhexan-2-yl acetate:
Figure imgf000203_0001
2-methylpentan-2-ol 2-methylpentan-2-yl acetate
Figure imgf000203_0002
2-methylhexan-2-ol 2-methylhexan-2-yl acetate
Preparation of 2-methylhexan-2-yl acetate: 2-Methylhexan-2-ol (30.0 g, 0.258 mol) treated with acetic anhydride (36.6 mL, 0.387 mol). Pyridine (30.0 mL, excess) was added dropwise over a 3 min period at 23 °C. Then 4-(N,N-dimethylamino)-pyridine (1.27 g, 10.0 mmol) was added. The reaction was heated to 70 °C for 16 h. The reaction was cooled to 23 °C and poured onto 300 mL of crushed ice. After 15 min of stirring, most of the ice had melted. Solid NaHC03 was added in portions (bubbling) until the pH was 9. The system was extracted with two portions of diethyl ether (100 mL, then 50 mL). The combined extracts were washed with 1.0 M aq. CuS04 monohydrate (4x 50 mL), dried over MgS04, and filtered. The filtrate was distilled at ambient pressure at a bath temperature of 80-100 °C to remove most of the diethyl ether. The resulting oil left in the pot was fractionally distilled through a Snyder column with 3 chambers under reduced pressure (6-8 mmHg). A small-volume forerun was collected and discarded (bp < 45 °C). The main fraction contained 2-methylhexan-2-yl acetate (bp 45-48 °C). Ή NMR (400 MHz, CDC13) δ 1.94 (s, 3H), 1.74-1.68 (m, 2H), 1.40 (s, 6H), 1.33-1.22 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H).
Preparation of 2-methylpentan-2-yl acetate: Prepared in a manner similar to 2- methylhexan-2-yl acetate, except using 2-methylpentan-2-ol. A 500 mL round bottom flask was charged with pyridine (30 mL), 2-methylpentanol (30 mL, 208 mmol) and was added followed by DMAP (1.213 g, 9.93 mmol). Acetic anhydride (46 mL, 417 mmol) was added slowly and the mixture heated at 70 °C for 20 hours. The reaction was quenched by pouring into a 10 °C Et20 bath on ice. 200 mL of water was added and the mixture was extracted with saturated CuS04 (4 x 50 mL). The mixture was then washed with water (2 x 200 mL), saturated NaHC03 (1 x 50 mL) and brine (1 x 50 mL). Mixture was dried with sodium sulfate, filtered and concentrated in vacuo. Distillation of the concentrate at 90 °C at reduced pressure (100 mtorr) resulted in 95% pure 2-methylpentan-2-yl acetate. 1H-NMR: 400 MHz, (CDC13): 1.91 (s, 3H); 1.69-1.5 (m, 2H); 1.37 (s, 6H); 1.31-1.25 (m, 2H); 0.87 (t J-7.2 Hz, 3H).
Example 31. (S)-2-((R)-l-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)acetic acid and (R)-2-((S)-l-(2,3- dihydropyrano[4,3 ,2-de]quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2- methylpropan-2-yloxy)acetic acid.
Figure imgf000205_0001
3-Methyl- 1-Chloro-3-methyl- Trifluoro-methanesulfonic 1-Chloro-3-methyl-2- naphthalen-2-ol naphthalen-2-ol acid 1-chloro-3-methyl- vinyl-naphthalene naphthalen-2-yl ester
Figure imgf000205_0002
(R)-1-(1-chloro-3- ( ?)-2-{1-chloro-3-methylnaphthalen- (R)-2-<1-chloro-3- methylnaphthalen- 2-yl)-2-hydroxyethyl methylnaphthalen-
2-yl)ethane-1 ,2-diol 4-methylbenzenesulfonate 2-yl)oxirane
Figure imgf000205_0003
2-( 1 -chloro-3-methy Inaphthalen- 2-(1-chloro-3-methylnaphthalen- 2,3-dihydropyrano[4,3,2- 2-yl)-2-( 1 ,1 ,1 -trifluoro-2- 2-yl)-2-{1 ,1 ,1 -trifluoro-2- de]quinolin-7-ylboronic methylpropan-2-yloxy)ethanol methylpropan-2-yloxy)ethyl pivalate acid, HCI salt
Figure imgf000205_0004
a mixture of (S)-2-((/?)-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(1 ,1 ,1- trifluoro-2-methylpropan-2-yloxy)ethyl pivalate and
(R)-2-((S)-1-(2,3-dihydropyrano[4,3,2--ye]quinolin-7- yl)-3-methylnaphthalen-2-yl)-2-(1 ,1 ,1 -trifluoro-2- methylpropan-2-yloxy)ethyl pivalate
Figure imgf000206_0001
a mixture of (S)-2-((R)-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(1 ,1 ,1- trifluoro-2-methylpropan-2-yloxy)ethanol and (R -2- ((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(1 ,1 ,1 -trif luoro-2- methylpropan-2-yloxy)ethanol
Figure imgf000206_0002
a mixture of (S)-2-(( ?)-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(1 ,1 ,1- trifluoro-2-methylpropan-2-yloxy)acetic acid and
(R)-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)-2-(1 ,1 ,1-tr'ifluoro-2- methylpropan-2-yloxy)acetic acid
Figure imgf000206_0003
(S)-2-((/¾-1-(2,3-dihydropyrano[4,3,2- (/?)-2-((S)-1-(2,3-dihydropyrano[4,3,2- de quinolin-7-y -3-methylnaphthalen- de]quinolin-7-yl)-3-methylnaphthalen-
2-yl)-2-(1 ,1 ,1-trifluorc)-2-methylpropan- 2-yl)-2-(1 ,1 ,1-trifluoro-2-methylpropan- 2-yloxy)acetic acid 2-yloxy)acetic acid
Preparation of l-chloro-3-methyl-naphthalen-2-ol: To a solution of N-chlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at -78 °C was added zirconium(IV) chloride (2.80g, 12.01 mmol), followed by 3-methyl-naphthalen-2-ol (CombiBlocks, 9.5g, 60.05 mmol) under argon. The reaction mixture was stirred at -78 °C for 5 minutes, the cooling bath was removed and the reaction was stirred at room temperature for 5 h. The reaction was quenched with saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H20, extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3-methyl-naphthalen-2-ol.
Preparation of trifluoro-methanesulfonic acid l-chloro-3-methyl-naphthalen-2-yl ester: To a solution of l-chloro-3 -methyl -naphthalen-2-ol (9.05 g, 46.98 mmol) in dichloromethane (235 mL) at -78°C was added trifluoromethanesulfonic anhydride (11.9 mL, 70.47 mmol), followed by 2,6-lutidine (8.2 mL, 70.47 mmol). The reaction mixture was stirred for 3 h to give a yellow solution, which was diluted with dichloromethane and washed with H20/brine. The organic layer was dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give trifluoro-methanesulfonic acid l-chloro-3-methyl-naphthalen-2-yl ester.
Preparation of l-chloro-3 -methyl-2-vinyl-naphthalene: To a solution of trifluoro- methanesulfonic acid l-chloro-3 -methyl-naphthalen-2-yl ester (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added dichlorobis(triphenylphosphine) palladium(II) under argon. The reaction mixture was heated at 50 °C for 20 h, then heated at 90 °C for 8 h. The reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgS04), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give l-chloro-3 -methyl-2- vinyl- naphthalene contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2x). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1- chloro-3-methyl-2 -vinyl-naphthalene.
Preparation of (R)-l-(l-chloro-3-methylnaphthalen-2-yl)ethane-l,2-diol: A biphasic mixture of AD-mix-β (45.7 g, , excess) in tert-butanol (147 mL)/H20 (147 mL) was cooled to 0°C and l-chloro-3 -methyl-2- vinyl-naphthalene (4.46 g, 22.0 mmol) was added. The reaction mixture was stirred for 7 days at 0 °C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2S04, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)- 1-( l-chloro-3 - methylnaphthalen-2-yl)ethane-l,2-diol. 1H-NMR: 400 MHz, (CDC13) δ 8.27 (d, J = 8.4 Hz, 1H), 7.73 (d, J - 7.6 Hz, 1H), 7.57-7.50 (m, 3H), 5.70 (dd, J = 10.0, 4.0 Hz, 1H), 4.11 (t, J = 10.4 Hz, 1H), 3.79 (dd, J = 1 1.6, 4.0 Hz, 1H), 2.66 (s, 3 H).
Preparation of (R)-2-(l-chloro-3-methylnaphthalen-2-yl)-2-hydroxy ethyl 4- methylbenzenesulfonate: To a stirred solution of (R)-l-(l-chloro-3-methylnaphthalen-2- yl)ethane-l,2-diol (2.30 g, 9.74 mmol) in CH2C12 (97 mL), dibutyltinoxide (48.5 mg, 0.19 mmol), p-toluenesulfonyl chloride (2.08 g, 10.90 mmol), and Et3N (1.60 mL, 11.58 mmol) were added at room temperature. ). After stirring for 15 h, the reaction mixture was quenched with saturated aqueous NH4CI, and then diluted with CH2C12. The organic phase was washed with brine, dried over Na2S04, filtered and concentrated and purified by flash column
chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-2-(l-chloro-3- methylnaphthalen-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate. 1H-NMR: 400 MHz,
(CDCI3) δ 8.18 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.57-7.54 (m, 5H), 5.82 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 10.0, 6.8 Hz, 1H), 4.35 (dd, J = 10.4, 5.6 Hz, 1H), 2.59 (s, 3 H), 2.29 (s, 3H).
Preparation of (R)-2-(l-chloro-3-methylnaphthalen-2-yl)oxirane: To a solution of (R)-2- (l-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (1.38 g, 3.54 mmol) in THF (39 mL) at 0 °C was added potassium tert-butoxide (3.90 mL of 1.0 M solution in THF, 3.90 mmol). After stirring for 1 h, the reaction mixture was quenched with saturated aqueous Ν¾0, and then diluted with EtOAc. The organic phase was washed with water and brine, dried over Na2S04, filtered and concentrated and purified by flash column
chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (R)-2-(l-chloro-3- methylnaphthalen-2-yl)oxirane. 1H-NMR: 400 MHz, (CDC13) δ 8.26 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57-7.48 (m, 3H), 4.13 (t, J = 3.6 Hz, 1H), 3.34 (t, J - 5.6 Hz, 1H), 2.97 (dd, J = 5.2, 2.8 Hz, 1H), 2.64 (s, 3 H).
Preparation of 2-( 1 -chloro-3-methylnaphthalen-2-yl)-2-( 1 ,1,1 -trifluoro-2-methylpropan- 2-yloxy)ethanol: To a stirred solution of (R)-2-(l-chloro-3-methylnaphthalen-2-yl)oxirane (340 mg, 1.56 mmol) and 2-trifluoromethyl-2-propanol (4.3 mL, 38.97 mmol) in CH2C12 (4.3 mL), boron trifluoride diethyl etherate (1.9 mL, 15.60 mmol) was added at 0 °C. The reaction mixture was stirred for 16 h at 0 °C and allowed to warm to room temperature overnight. The mixture was quenched with saturated aqueous NaHC03, and then diluted with CH2C12. The organic phase was washed with brine, dried over Na2S04, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(l-chloro-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDC13) δ 8.27 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.90 (dd, J = 9.6, 4.4 Hz, 1H), 3.98 (t, J = 11.2 Hz, 1H), 3.66 (dd, J = 12.0, 4.0 Hz, 1H), 2.69 (s, 3 H), 2.18 (br s, 1H), 1.45 (s, 3H), 1.19 (s, 3H).
Preparation of 2-( 1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan- 2-yloxy)ethyl pivalate: To a stirred solution of trimethylacetyl chloride (0.17 mL, 1.36 mmol) and 4-(Dimethylamino)pyridine (55 mg, 0.45 mmol) in pyridine (2.4 mL, 29.48 mmol), 2-(l- chloro-3-methylnaphthalen-2-yl)-2-(l ,1,1 -trifluoro-2-methylpropan-2-yloxy)ethanol (157 mg, 0.45 mmol) in CH2C12 (2.4 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2- (1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDC13) δ 8.26 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58-7.48 (m, 3H), 6.05 (dd, J = 8.4, 5.2 Hz, 1H), 4.50 (dd, J = 11.2, 8.4 Hz, 1H), 4.21 (dd, J = 11.2, 4.8 Hz, 1H), 2.73 (s, 3 H), 1.43 (s, 3H), 1.19(s, 3H), 1.16 (s, 9H). Preparation of a mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate and (R)-2- ((S)- 1 -(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro- 2-methylpropan-2-yloxy)ethyl pivalate: 2-( 1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro- 2-methylpropan-2-yloxy)ethyl pivalate (82 mg, 0.19 mmol) in freshly distilled DME (7.0 mL) was added to a microwave vial charged with a mixture of 2,3-dihydropyrano[4,3,2-i e]quinolin- 7-ylboronic acid, HC1 salt (77mg, 0.31 mmol), SPhos precatalyst (Strem, 14 mg, 0.02 mmol), and CsF (155 mg, 1.02 mmol). This heterogeneous mixture was then microwaved at 120 °C for 90 minutes. The mixture was then diluted with EtOAc, extracted with saturated NaHC03, brine, and dried over Na2S04, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes) to give a mixture of (S)-2-((R)-l-(2,3- dihydropyrano [4,3 ,2-de quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2- methylpropan-2-yloxy)ethyl pivalate and (R)-2-((S)-l-(2,3-dihydropyrano[4,3,2-i e]quinolin-7- yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H- NMR: 400 MHz, (CDC13) δ 8.63 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 7.20-7.12 (m, 3H), 7.07 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 5.2 Hz, 1H), 4.58-4.52 (m, 2H), 4.42 (d, J = 5.2 Hz, 2H), 3.31 (t, J = 5.2 Hz, 2H), 2.79 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.89 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35F3N04: 566.25; Found: 566.2.
Preparation of a mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-ife]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethanol and (R)-2-((S)- 1 - (2,3-dihydropyrano[4,3,2-<ie]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l ,l,l-trifluoro-2- methylpropan-2-yloxy)ethanol: To a stirred solution of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-( 1,1 ,1 -trifluoro-2-methylpropan-2-yloxy)ethyl pivalate and (R)-2-((S)-l -(2,3-dihy(kopyrano[4,3,2-^e]quinolin-7-yl)-3-methylnaphthalen-2-yl)- 2-(l ,l,l-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate (45 mg, 0.08 mmol) in THF (3.5 mL) and methanol (3.5 mL) was added 1 M NaOH solution (3.5 mL, excess). The reaction mixture was stirred at 50 °C overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2S04, filtered and concentrated and purified by flash column
chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give a mixture of (S)-2-((R)-l- (2,3 -dihydropyrano [4,3 ,2-<ie]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2- methylpropan-2-yloxy)ethanol and (R)-2-((S)-l -(2,3-dihydropyrano[4,3,2-ife]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1,1 ,1 -trifluoro-2-methylpropan-2-yloxy)ethanol as a yellow oil. 1H- NMR: 400 MHz, (CDC13) δ 8.67 (d, J = 4.4 Hz, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.18-7.1 1 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H), 4.82 (t, J = 7.6 Hz, 1H), 4.60 (t, J = 5.6 Hz, 2H), 3.80 (m, 2H), 3.36 (t, J = 5.6 Hz, 2H), 2.80 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H27F3N03: 482.20; Found: 482.1.
Preparation of a mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-(ie]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)acetic acid and (R)-2-((S)-l- (2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l , 1 ,1 -trifluoro-2- methylpropan-2-yloxy)acetic acid: To a solution of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2- £ e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l,l ,l-trifluoro-2-methylpropan-2-yloxy)ethanol and (R)-2-((S)- 1 -(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-( 1,1 ,1- trifluoro-2-methylpropan-2-yloxy)ethanol (26 mg, 0.05 mmol) in wet acetonitrile (0.75%wt H20) was added Η5ΙΟ^Γ03 (0.439 M stock solution in wet acetonitrile, 0.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 45 min. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) to give a mixture of (S)-2- ((R)- 1 -(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l ,1,1 -trifluoro- 2-methylpropan-2-yloxy)acetic acid and (R)-2-((S)-l-(2,3-dihydropyrano[4,3,2-ife]quinolin-7- yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)acetic acid as TFA salt. 1H-NMR: 400 MHz, (CD3OD) δ 8.65 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84-7.81 (m, 2H), 7.54-7.50 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.31-7.27 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.47 (s, 1H), 4.79-4.65 (m, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.76 (s, 3H), 1.25 (s, 3H), 1.00 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25F3N04: 496.18, Found: 496.1.
Preparation of (S)-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)acetic acid: Separation by chiral HPLC, using a Chiralpak AZ-H column (4.6x250 mm) and an isocratic solvent system of 70% heptane and 30% isopropyl alcohol provides (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l , 1 , 1 -trifluoro-2-methylpropan-2-yloxy)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ 8.54 (d, J - 4.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 6.8 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.58-4.61 (m, 2H), 3.43 (t, J = 6.0 Hz, 2H), 2.68 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H). LCMS-ESf (m/z): [M+H]+ calcd for C28H25F3N04: 496.18, Found: 496.1.
Preparation of (R)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)acetic acid: Separation by chiral HPLC, using a Chiralpak AZ-H column (4.6x250 mm) and an isocratic solvent system of 70% heptane and 30% isopropyl alcohol (R)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ 8.54 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 6.8 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.58-4.61 (m, 2H), 3.43 (t, J = 6.0 Hz, 2H), 2.68 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H). LCMS-ESf (m/z): [M+H]+ calcd for C28H25F3N04: 496.18, Found: 496.1. Example 32. (S)-2-( 1 , 1 -Difluoro-2-methylpropan-2-yloxy)-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2- i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid and (R)-2-(l,l-difluoro-2-methylpropan- 2-yloxy)-2-((S)- 1 -(2,3 -dihydropyrano [4,3 ,2-i/e]quinolin-7-yl)-3 -methylnaphthalen-2-yl)acetic acid
Figure imgf000212_0001
ethyl 2,2-difluoroacetate benzyl alcohol benzyl 1 ,1 -difluoro-2- 2,2- methylpropan-2-ol difluoro
acetate
Figure imgf000212_0002
1-Chloro-3-methyl-2- 2-(1-chloro-3- 1 ,1 -difluoro-2- vinyl-naphthalene methylnaphthalen-2- methylpropan-2-ol
yl)oxirane
Figure imgf000212_0003
2-(1 -chloro-3-methylnaphthalen- 2-(1 -chloro-3-methylnaphthalen-2- 2,3-dihydropyrano[4,3,2- 2-yl)-2-( 1 , 1 -dif luoro-2- yl)-2-(1 , 1 -dif luoro-2-methylpropan- cfe]quinolin-7-ylboronic methylpropan-2-yloxy)ethanol 2-yloxy)ethyl pivalate acid, HCI salt
Figure imgf000212_0004
a mixture of (S)-2-(1 ,1 -difluoro-2-methylpropan-2- yloxy)-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)ethyl pivalate and {R)- 2-(1 , 1 -dif luoro-2-methylpropan-2-yloxy)-2-((S)-1 - (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethyl pivalate
Figure imgf000213_0001
a mixture of (S)-2-(1 ,1-difluoro-2-methylpropan-2- yloxy)-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)ethanol and (R)- 2-(1 ,1-difluoro-2-methylpropan-2-yloxy)-2-((S)-1- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethanol
Figure imgf000213_0002
a mixture of (S)-2-(1 ,1-difluoro-2-methylpropan- 2-yloxy)-2-((f?)-1-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid
and (R)-2-(1 ,1-difluoro-2-methylpropan-2-yloxy)-2- ((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3-methylnaphthalen-2-yl)acetic acid
Figure imgf000213_0003
(S)-2-(1 ,1-difluoro-2- (R)-2-(1 ,1-difluoro-2- methylpropan-2-yloxy)-2-((R)-1 - methylpropan-2-yloxy)-2-((S)-1 - (2,3-dihydropyrano[4,3,2-de] (2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-3-methylnaphthalen- quinolin-7-yl)-3-methylnaphthalen- 2-yl)acetic acid 2-yl)acetic acid
Preparation of benzyl 2,2-difluoroacetate: To a dried round bottom flask was added ethyl 2,2-difluoroacetate (25 g, 0.20 mol), benzyl alcohol (62.6 mL, 0.60 mol) and boron trifluoride etherate (2.5 mL, 0.02 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 75 °C overnight. The mixture was quenched with saturated aqueous NaHC03, and then diluted with EtOAc. The organic phase was washed with brine, dried over Na2S04, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give benzyl 2,2-difluoroacetate. 1H-NMR: 400 MHz, (CDC13) δ 7.39-7.29 (m, 4H), 5.93 (t, J = 52.8 Hz, 1H), 5.31 (s, 2H).
Preparation of l,l-difluoro-2-methylpropan-2-ol: To a stirred solution of
methylmagnesium bromide (70.2 mL of 3.0 M solution in Et20, 0.21 mol) was added benzyl 2,2-difluoroacetate (13.7 g, 0.07 mol) in Et20 (40.2 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and quenched with ice water and hydrochloric acid. The ethereal layer was separated, washed with saturated NaHC03 and brine, dried over Na2S04, filtered and distilled to give l,l-difluoro-2-methylpropan-2-ol. 1H-NMR: 400 MHz, (CDC13) δ 5.52 (t, J = 56.4 Hz, 1H), 1.28 (t, J = 1.6 Hz, 6H).
Preparation of 2-(l-chloro-3-methylnaphthalen-2-yl)oxirane: To a stirred solution of 1- chloro-3-methyl-2-vinyl-naphthalene (3.0 g, 14.8 mmol) in CH2C12 (120 mL) was added 3- chloroperoxybenzoic acid (3.8 g, 22.0 mmol) at 0 °C and allowed to warm to room temperature overnight. The reaction mixture was washed with NaHC03, brine, dried over Na2S04, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(l-chloro-3-methylnaphthalen-2-yl)oxirane. 1H-NMR: 400 MHz, (CDCI3) δ 8.26 (d, J = 7.2 Hz, 1H), 7.74 (dd, J = 7.2, 2.0 Hz, 1H), 7.57-7.48 (m, 3H), 4.13 (t, J = 3.6 Hz, 1H), 3.34 (t, J = 5.6 Hz, 1H), 2.97 (dd, J = 5.2, 2.8 Hz, 1H), 2.64 (s, 3 H).
Preparation of 2-( 1 -chloro-3-methylnaphthalen-2-yl)-2-( 1 , 1 -difluoro-2-methylpropan-2- yloxy)ethanol : Compound 2-( 1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1 , 1 -difluoro-2- methylpropan-2-yloxy)ethanol was prepared following the procedure used to prepare 2-(l- chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethanol of Example 31, except that 1 , 1 -difluoro-2-methylpropan-2-ol ( 10 eq) was used instead of 2-trifluoromethyl- 2-propanol (25 eq). 1H-NMR: 400 MHz, (CDC13) δ 8.27 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.85 (dd, J = 9.2, 3.6 Hz, 1H), 5.61 (t, J = 56.4 Hz, 1H), 3.94 (dd, J = 11.6, 9.6 Hz, 1H), 3.65 (dd, J = 11.6, 4.4 Hz, 1H), 2.69 (s, 3 H), 2.18 (br s, 1H), 1.32 (s, 3H), 1.10 (s, 3H).
Preparation of 2-( 1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1 , 1 -difluoro-2-methylpropan-2- yloxy)ethyl pivalate: Compound 2-(l-chloro-3-methylnaphthalen-2-yl)-2-(l,l-difluoro-2- methylpropan-2-yloxy)ethyl pivalate was prepared following the procedure used to prepare 2-(l- chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethyl pivalate of Example 31, except that 2-(l-chloro-3-methylnaphthalen-2-yl)-2-(l,l-difluoro-2-methylpropan- 2-yloxy)ethanol was used instead of 2-(l -chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2- methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDC13) δ 8.27 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.56-7.50 (m, 2H), 6.01 (dd, J = 8.4, 4.8 Hz, 1H), 5.53 (t, J = 56.4 Hz, 1H), 4.47 (dd, J = 11.6, 8.4 Hz, 1H), 4.19 (dd, J = 11.6, 5.6 Hz, 1H), 2.72 (s, 3 H), 1.27 (s, 6H), 1.16 (s, 9H).
Preparation of a mixture of (S)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethyl pivalate and (R)-2-(l,l- difluoro-2-methylpropan-2-yloxy)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethyl pivalate: Mixture of (S)-2-(l,l-difluoro-2-methylpropan-2-yloxy)- 2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethyl pivalate and (R)-2-(l,l-difluoro-2-memylpropan-2-yloxy)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)ethyl pivalate was prepared following the procedure used to prepare the mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2- e]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate and (R)-2- ((S)- 1 -(2,3 -dihydropyrano [4,3 ,2- e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro- 2-methylpropan-2-yloxy)ethyl pivalate of Example 31, except that 2-(l-chloro-3- methylnaphthalen-2-yl)-2-( 1 , 1 -difluoro-2-methylpropan-2-yloxy)ethyl pivalate was used instead of 2-( 1 -chloro-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDC13) δ 8.64 (d, J = 3.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.41-7.36 (m, 1H), 7.26-7.08 (m, 4H), 5.37 (t, J = 56.8 Hz, 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.58-4.52 (m, 2H), 4.39 (d, J = 5.6 Hz, 2H), 3.32 (t, J = 5.2 Hz, 2H), 2.78 (s, 3H), 0.94 (s, 6H), 0.89 (s, 9H); LCMS-ESI+ m/z):
Preparation of a mixture of (S)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2-((R)-l-(2,3- dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol and (R)-2-(l , 1 - difluoro-2-methylpropan-2-yloxy)-2-((S)-l-(2,3-dihydropyrano[4,3,2-iie]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethanol: Mixture of (S)-2-(l,l-difluoro-2-methylpropan-2- yloxy)-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 -methylnaphthalen-2-yl)ethanol and (R)-2-( 1 , 1 -difluoro-2-methylpropan-2-yloxy)-2-((S)- 1 -(2,3-dihydropyrano [4,3 ,2- i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol was prepared following the procedure used to prepare the mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2-methylpropan-2-yloxy)ethanol and (R)-2-((S)- 1 - (2,3-dihydropyrano[4,3,2-i e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l ,1 , 1 -trifIuoro-2- methylpropan-2-yloxy)ethanol of Example 31, except that the mixture of (S)-2-(l,l-difluoro-2- methylpropan-2-yloxy)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethyl pivalate and (R)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2-((S)-l- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethyl pivalate was used instead of the mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate and (R)-2- ((S)-l-(2,3-dihydropyrano[4,3,2-^e]quinolm^
2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDC13) δ 8.71 (d, J = 4.8 Hz, 1H), 7.79-7.75 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.39-7.34 (m, 1H), 7.22-7.10 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 5.43 (t, J = 56.0 Hz, 1H), 4.77 (t, J = 8.0 Hz, 1H), 4.61 (t, J = 5.6 Hz, 2H), 3.84 (dd, J = 11.6, 6.8 Hz, 1H), 3.72 (dd, J = 11.6, 8.4 Hz, 1H), 3.37 (t, J = 6.0 Hz, 2H), 2.78 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H); LCMS-ESf m/z):
Preparation of a mixture of (S)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2-((R)-l-(2,3- dihydropyrano[4,3,2-ife]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid
and (R)-2-(l , 1 -difluoro-2-methylpropan-2-yloxy)-2-((S)-l -(2,3-dihydropyrano[4,3,2- iie]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid: Mixture of (S)-2-(l,l-difluoro-2- methylpropan-2-yloxy)-2-((R)-l-(2,3-dihydropyrano[4,3,2-ife]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid and (R)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2- ((S)-l-(2,3-dihydropyrano[4,3,2-i e]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid was prepared following the procedure used to prepare the mixture of (S)-2-((R)-l-(2,3- dihydropyrano [4,3 ,2-i/e]quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro-2- methylpropan-2-yloxy)acetic acid and (R)-2-((S)-l-(2,3-dihydropyrano[4,3,2-ife]quinolin-7-yl)- 3-methylnaphthalen-2-yl)-2-(l,l,l-trifluoro-2-methylpropan-2-yloxy)acetic acid of Example 31, except that of (S)-2-(l,l-difluoro-2-methylpropan-2-yloxy)-2-((R)-l-(2,3-dihydropyrano[4,3,2- i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol and (R)-2-(l , 1 -difluoro-2-methylpropan-2- yloxy)-2-((S)-l-(2,3-dihydropyrano[4,3,2-i e]quinolin-7-yl)-3-methylnaphthalen-2- yl)ethanolwas used instead of the mixture of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2- <ie]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l , 1 , 1 -trifluoro-2-methylpropan-2-yloxy)ethanol and (R)-2-((S)-l -(2,3-dihydropyrano[4,3,2-i e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l , 1,1- trifluoro-2-methylpropan-2-yloxy)ethanol. LCMS-ESI* (m/z): [M+H]+ calcd for C28H26F2N04: 478.19; Found: 478.1.
Preparation of (S)-2-( 1 , 1 -difluoro-2-methylpropan-2-yloxy)-2-((R)- 1 -(2,3- dihydropyrano[4,3,2- e]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid: Compound (S)-2- (1,1 -difluoro-2-methylpropan-2-yloxy)-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-ife]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid was prepared following the procedure used to prepare (S)-2- ((R)-l-(2,3-dihydropyrano[4,3,2- e]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(l,l,l-trifluoro- 2-methylpropan-2-yloxy)acetic acid of Example 31. 1H-NMR: 400 MHz, (CD3OD) δ 8.65 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.53-7.45 (m, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 5.40 (t, J = 56.8 Hz, 1H), 4.77-4.60 (m, 2H), 3.67 (t, J = 5.6 Hz, 2H), 2.76 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H26F2N04: 478.19; Found: 478.1. Preparation of (R)-2-( 1 , 1 -difluoro-2-methylpropan-2-yloxy)-2-((S)- 1 -(2,3 - dihydropyrano[4,3,2-i/e]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid: Compound (R)-2- (l,l-difluoro-2-memylpropan-2-yloxy)-2-((S)-l-(2,3-dihydropyrano[4,3,2- e]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid was prepared following the procedure used to prepare (R)-2- ((S)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-( 1,1,1 -trifluoro- 2-methylpropan-2-yloxy)acetic acid of Example 31. 1H-NMR: 400 MHz, (CD3OD) δ 8.65 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.53-7.45 (m, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 5.40 (t, J = 56.8 Hz, 1H), 4.77-4.60 (m, 2H), 3.67 (t, J - 5.6 Hz, 2H), 2.76 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H26F2N04: 478.19; Found: 478.1.
Examples 33-106. The compounds of Examples 33-106 where prepared following similar synthetic procedures as those procedures described in Examples 1-32 and Example 107.
HPLC Method
Column Phenomenex Kinetex C18 (2.6 urn ΙΟθΑ, 4.6 x 100 mm)
Flow Rate 2.5 mL/min
Solvent A MilliQ H2O + 0.1% TFA
Solvent B ACN +0.1% TFA
Gradient %B 2-98 Gradient time 8.5 min Wavelength 214 nm
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
219
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Example 107. Synthetic method for the preparation of (.S)-2-tert-butoxy-2-((i?)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid One embodiment provides methods and intermediates to prepare (<S)-2-tert-butoxy-2- ((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 ,6-dimethylnaphthalen-2-yl)acetic acid as described hereinbelow.
Figure imgf000232_0001
1 -m-toly lpropan-2-one ethyl 3-methyl-4-m- ethyl 3-methyl-4- tol lbut-2-enoate m-tol lbutanoate
Figure imgf000232_0002
3-methyl-4-m- 3,6-dimethyl-3,4- 2,2-dibromo-3,6-dimethyl-3,4- tolylbutanoic acid dihydronaphthalen-1 (2H)-one dihydronaphthalen-1 (2H)-one
Figure imgf000232_0003
2-bromo-3,6- 3,6-dimethylnaphthalen-1-ol ethyl 2-hydroxy-2-(1-hydroxy- dimethylnaphthalen-1 -ol 3,6-dimethylnaphthalen-2-yl)
acetate
Figure imgf000232_0004
ethyl 2-triethylsilyloxy-2-(1- hydroxy-3,6- dimethylnaphthalen-2-yl)
acetate
Figure imgf000232_0005
ethyl 2-(3,6-dimethyl-1- (S)-ethyl 2-(3,6-dimethyl-1- (S)-ethyl 2-ferf-butoxy-2-(3,6-dimethyl- (trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy) 1 -(trif luoromethylsulf onyloxy) naphthalen-2-yl)-2-oxoacetate naphthalen-2-yl)-2- naphthalen-2-yl)acetate
hydroxy acetate
Figure imgf000232_0006
(S)-ethyl 2-ierf-butoxy-2-((R)-1 -(2,3- dihydropyrano[4,3,2-c/e]quinolin-7-yl)- (S)-2-ieri-butoxy-2-((R)-1-(2,3- 3,6-dimethylnaphthalen-2-yl)acetate dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid Preparation of ethyl 3-methyl-4-m-tolylbut-2-enoate. A three neck flask was charged with NaHMDS (1M in THF, 59 mL, 59 mmol) under an atmosphere of Ar and cooled to an internal temperature of 0 °C. Triethyl phosphonoacetate (10.1 mL, 50.6 mmol) was diluted in THF (41 mL) and added via additional funnel at a rate to maintain a temperature < 5 °C. The resulting yellow-orange solution was allowed to stir for 15 minutes at 0 °C following completion of addition. Following addition of l-/w-tolylpropan-2-one (5 g, 33.7 mmol, diluted in 50 mL THF) via addition funnel, the resulting mixture was allowed to stir at 0 °C for 60 minutes before removing cooling and allowing the reaction to warm to room temperature over 1.5 hours. The reaction was slowly quenched with water, and the resulting aqueous phase extracted thoroughly with EtOAc. The combined organics were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The resulting oil was eluted on Yamazen silica gel chromatography (0-15% EtO Ac/hex) to afford an approximately 85:15 E:Z mixture. LCMS- ESI+ (m/z): [M+H]+ calcd for Ci4H1902: 219.3; found: 219.3.
Preparation of ethyl 3 -methyl -4-w-tolylbutanoate. Ethyl 3-methyl-4-wz-tolylbutanoate (50 g, 229 mmol) was taken up in EtO Ac (1 L) and treated with Rh (5% on alumina, 24 g catalyst). The atmosphere was replaced with H2 and the reaction left under balloon pressure of H2 overnight with vigorous stirring. The next morning, the H2 atmosphere was replaced with air and Celite (25 g) was added with stirring. After 10 min, the reaction slurry was filtered through a pad of Celite and the filtrate concentrated to the desired compound that was used in the next step without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H2102: 221.3; found: 221.2. Preparation of 3-methyl-4-w-tolylbutanoic acid. The material from the previous preparation was taken up in a 1/1 mixture of THF/EtOH (250 mL each), treated with a solution of LiOH«H20 (46.5 g, 1.1 mol) in water (250 mL) and heated to 50 °C. After 2.5 hours, the solution was cooled to 0 °C, diluted with EtOAc (300 mL) and treated with 2M HC1 (300 mL). The solution was further adjusted to pH ~ 3 using aliquots of concentrated HC1. The resulting aqueous layer was extracted with EtOAc. The combined organics were washed with brine and allowed to stand over anhydrous Na2S04 for 72 hours. The EtOAc was removed in vacuo and the resulting oil taken up in hexanes and allowed to stand over anhydrous Na2S04 overnight. Following concentration, the material was taken up in CHC13 and concentrated again to afford 3- methyl-4-m-tolylbutanoic acid. 1H-NMR: 400 MHz, (CDC13) δ: 7.18 (t, J = 8 Hz, 1H); 7.02 (d, J - 8 Hz, 1H); 6.99 (s, 1H); 6.97 (d, J = 8 Hz, 1H); 2.61 (dd, J - 13.6, 6.8 Hz, 1H); 2.50 (dd, J = 14, 7 Hz, 1H); 2.40 (dd, J = 14.8, 5.6 Hz, (1H); 2.34 (s, 3H); 2.28 (m, 1H); 2.18 (dd, J = 16, 8 Hz, 1H); 0.99 (d, J = 6.4 Hz, 3H).
Preparation of 3,6-dimethyl-3,4-dihydronaphthalen-l (2H)-one. 3-Methyl-4-m- tolylbutanoic acid (20.6 g, 107 mmol, dissolved in 125 mL DCM) was added slowly to triflic acid (250 g, 1.7 mol) that was pre-cooled to 0 °C under an Ar atmosphere. After 30 minutes, the volume of the reaction is doubled with DCM and poured slowly onto 1.5 L crushed ice. The resulting icy slurry is allowed to stir and come to room temperature over 1 hour. The resulting aqueous layer was extracted with DCM and the combined organics dried over anhydrous MgS04, filtered and concentrated in vacuo. The procedure was repeated once and the two lots of crude product were combined and purified via elution on Isco silica gel column
chromatography (0-15% EtOAc/hex) to afford 3,6-dimethyl-3,4-dihydronaphthalen-l(2H)-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H150: 175.3; found: 175.4.
Preparation of 2,2-dibromo-3,6-dimethyl-3,4-dihydronaphthalen-l (2H)-one. 3,6- Dimethyl-3,4-dihydronaphthalen-l(2H)-one (32.4 g, 186 mmol) was taken up in DCM (1.5 L and treated with a solution of Br2 (19.1 mL, 372 mmol) in DCM (300 mL) that was added via an addition funnel at room temperature over 2 hours. An additional 1.5 mL of Br2 was added and the reaction allowed to age another 1.5 hours. The reaction was concentrated in vacuo to produce 2,2-dibromo-3,6-dimethyl-3,4-dihydronaphthalen-l(2H)- that was used directly in the next procedure without further purification. LCMS-ESI+ (m/z) [M+H]+ calcd for C12H13Br20: 333.1; found: 333.2.
Preparation of 2-bromo-3 ,6-dimethylnaphthalen- 1 -ol. A solution of 2,2-dibromo-3 ,6- dimethyl-3,4-dihydronaphthalen-l(2H)-one (61.2 g, 184 mmol) in MeCN (1.5 L) was cooled to -40 °C internal temperature using a dry ice/acetone bath. l,8-Diazabicycloundec-7-ene (41.6 mL, 279 mmol) was added as a solution in MeCN (150 mL) and the reaction was allowed to warm to room temperature overnight. The majority of the reaction solvent was removed in vacuo and the residue taken up in EtOAc (1 L) and washed with 0.5 M HCl (1 L). The resulting aqueous layer was extracted with several portions of EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgS04 and concentration in vacuo, the resulting residue was absorbed directly onto 200 g silica gel and eluted on Isco silica gel column chromatography (0-20% EtO Ac/hex) to afford 2-bromo-3,6-dimethylnaphthalen-l-ol. LCMS- ESI+ (m/z): [M]+ calcd for Ci2HnBrO: 251.1; found: 251.4. Preparation of 3 ,6-dimethylnaphthalen- 1 -ol. A solution of 2-bromo-3 ,6- dimethylnaphthalen-l-ol (31.9 g, 127 mmol) in EtOH (1.3 L) was treated with Et3N (26.6 mL, 191 mmol) at room temperature. Pd/C (13.5 g, 12.7 mmol, 10% wt on C) was added in one portion and the atmosphere replaced with H2. The reaction was left under balloon pressure of H2 for 6 hours. After replacing the atmosphere with air, Celite (20 g) was added and the slurry stirred for 15 minutes before filtering the solution through a pad of Celite. The volatiles were removed in vacuo, and the residue was taken up in EtO Ac/water (250 mL each). The organics were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The resulting residue was purified on Isco silica gel column chromatography (0-35% EtO Ac/hex) to afford 3,6-dimethylnaphthalen-l-ol. LCMS-ESf (m/z): [M+H]+ calcd for Ci2H130: 173.1;
found: 173.4.
Preparation of ethyl 2-hydroxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. A solution of 3,6-dimethylnaphthalen-l-ol (4.76 g, 27.6 mmol) in DCM (345 mL) was cooled to 0 °C internal temperature. TiCl4 (1M in DCM, 36 mL, 36 mmol) was added at a rate to maintain the internal temperature at 0 °C to produce a dark purple solution that was allowed to stir at 0 °C for 20 min. Freshly distilled ethyl glyoxylate (3.66 g, 35.9 mmol) was gently warmed with a heat gun for 3 minutes prior to dilution in DCM (250 mL). The reagent solution was then added via addition funnel slowly. After 90 minutes, the reaction was poured onto 800 mL ice/500 mL saturated Rochelle's salt solution. The opaque orange slurry was allowed to come to room temperature over 2.5 hours and filtered through a Celite pad. The aqueous phase was extracted with DCM and the combined organics were washed with water, brine, and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, the resulting residue was purified via Yamazen silica gel column chromatography (3-35% EtO Ac/hex) to provide 2-hydroxy-2-(l- hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. LCMS-ESI+ (m/z): [M-OH]+ calcd for C16H,703: 257.3; found: 257.5.
Preparation of ethyl 2-triethylsilyloxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate. A solution of 2-hydroxy-2-(l-hydroxy-3,6-dimethylnaphthalen-2-yl) acetate (4.55 g, 16.6 mmol) in DCM (165 mL) at 0 °C was subsequently treated with imidazole (1.53 g, 22.4 mmol) and triethylsilyl chloride (3.2 mL, 19.1 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 1.5 hours. Water was added, and the resulting aqueous layer was extracted with DCM. The combined organics were washed with 1M HC1 and brine. Following drying over anhydrous MgS04, concentration in vacuo afforded the desired compound that was used without further purification.
Preparation of ethyl 2-triethylsilyloxy-2-(l-trifluoromethylsulfonyloxy-3,6- dimethylnaphthalen-2-yl) acetate. A solution of ethyl 2-triethylsilyloxy-2-(l-hydroxy-3,6- dimethylnaphthalen-2-yl) acetate (5.62 g of crude product from above, 14.5 mmol) in THF (58 mL) was treated with phenyl triflimide (7.75 g, 21.7 mmol) and Cs2C03 (11.8 g, 36.3 mmol) at room temperature. After 3 hours, the reaction was diluted with EtOAc and water. The resulting organics were washed with 1M NaOH and brine. Following drying over MgS04 and concentration in vacuo, the resulting residue was purified via Yamazen silica gel column chromatography (0- 10% EtO Ac/hex) to afford ethyl 2-triethylsilyloxy-2-( 1 - trifluoromethylsulfonyloxy-3,6-dimethylnaphthalen-2-yl) acetate. LCMS-ESI+ (m/z): [M+Na]+ calcd for C23H31F306SSiNa: 543.6; found: 543.0.
Preparation of ethyl 2-(3,6-dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- hydroxyacetate. A solution of ethyl 2-triethylsilyloxy-2-(l-trifluoromethylsulfonyl-oxy-3,6- dimethylnaphthalen-2-yl) acetate (~ 29 g) in THF (375 mL) was treated with 48% HF (71 mL, 1.96 mol) at room temperature and allowed to stir overnight. Solid NaHC03 was added in small portions until pH ~ 8 by test strip. Water and EtOAc were added, and the layers separated. The aqueous layer was slurried with Celite, filtered through a Celite pad and further extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgS0 , filtered and concentrated in vacuo. The resulting ethyl 2-(3 ,6-dimethyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate was used without further purification. LCMS-ESI+ (m/z): [M-OH]+ calcd for C17H16F305S: 389.4; found: 389.4. Preparation of ethyl 2-(3 ,6-dimethyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- oxoacetate. A solution of ethyl 2-(3 ,6-dimethyl- l-(trifluoromethylsulfonyloxy) naphthalen-2- yl)-2 -hydroxyacetate (~ 22.8 g, 56 mmol) in DCM (560 mL) was treated with solid Dess-Martin periodinane (35.7 g, 84.2 mmol) at room temperature. After 60 minutes, isopropyl alcohol (25 mL) was added and allowed to stir for 30 minutes. A mixture of saturated NaHC03 and saturated Na2S203 (100 mL each, diluted to 400 mL with water) was added and the resulting aqueous layer extracted with DCM. The combined organics were washed with water, brine and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, the residue was purified via Isco silica gel column chromatography (0-35% EtO Ac/hex) to afford ethyl 2 -(3 ,6- dimethyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CDC13) δ: 7.98 (d, J = 8.4 Hz, 1H); 7.66 (s, 1H); 7.61 (s, 1H); 7.47 (d, J = 8.4 Hz, 1H); 4.41 (q, J = 7.2 Hz, 2H); 2.55 (s, 3H); 2.49 (s, 3H); 1.40 (t, J = 8.4 Hz, 3H). Preparation of (S)-ethyl 2-(3 ,6-dimethyl- 1 -(trifluoromethylsulfonyloxy) naphthalen-2- yl)-2-hydroxyacetate. A solution of ethyl 2-(3,6-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (16.3 g, 40 mmol) in toluene (250 mL) cooled to an internal temperature of -40 °C was treated with (i?)-(+)-2-methyl-CBS- oxazaborolidine (5.6 g, 20.1 mmol). Freshly distilled catecholborane (4.7 mL, 44.2 mmol) was diluted with toluene (20 mL) and the solution added dropwise to the reaction over 30 minutes to produce a clear yellow solution. After an additional 15 minutes, saturated Na2C03 (300 mL) was added and the reaction allowed to warm to room temperature over 2.5 hours. The aqueous layer is extracted with EtO Ac and the combined organics are washed with saturated Na2C03 (3 X 300 mL), saturated NH4CI (300 mL) and brine. Following drying over anhydrous MgS04 and concentration in vacuo, the residue was purified using Isco silica gel column chromatography (10-75% EtOAc/hex) to produce (S)-ethyl 2-(3 ,6-dimethyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate that was determined to be 66% enantiomeric excess by HPLC analysis on a Chiralpak AS-H column with a 80:20 heptane/EtOH isocratic method. LCMS-ESI+ (m/z): [M+Na]+calcd for C17H17F306SNa: 429.3; found: 429.3.
Preparation of (S)-ethyl 2-tert-butoxy-2-(3 ,6-dimethyl- l-(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)acetate. A solution of (S)-ethyl 2-(3,6-dimethyl-l-(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (7.5 g, 18.5 mmol) in tBuOAc (100 mL) at room temperature was treated with perchloric acid (70%, 0.16 mL, 1.8 mmol) and allowed to stir at room temperature overnight. The reaction was slowly poured into ice-cold saturated NaHC03 (150 mL). The aqueous layer was extracted with EtO Ac and the combined organics washed with brine and dried over anhydrous MgS04 and filtered. Following concentration in vacuo, purification of the residue by Yamazen silica gel column chromatography (2-20-50% EtO Ac/hex) afforded (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-l-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. LCMS-ESI+ (m/z): [M+Na]+ calcd for C21H25F306SNa: 485.5; found: 485.8. Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3,6-dimethylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[4,3,2-de]qumolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate. A solution of (S)- ethyl 2-tert-butoxy-2-(3 ,6-dimethyl- 1 -(trifiuoromethylsulfonyl-oxy)naphthalen-2-yl)acetate (-0.5 g, 1.1 mmol) in 10.8 mL DME (freshly distilled from Na/benzophenone) was treated with 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (0.33 g, 1.3 mmol), SPhos precatalyst (Strem, 0.073 g, 0.1 1 mmol), and CsF (0.722 g, 4.8 mmol). The reaction tube was sealed and the reaction mixture sparged with Ar for 30 minutes prior to heating at 120 °C for 90 minutes in a microwave reactor. The reaction mixture was absorbed directly onto silica gel and purified via Yamazen silica gel column chromatography (3-50% EtOAc/hex) to afford (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2- yl)acetate (1H-NMR: 400 MHz, (CDC13) δ: 8.68 (br s, 1H); 7.64 (s, 1H); 7.54 (s, 1H); 7.49 (d, J = 8 Hz, 1H); 7.1 1 (d, J = 8 Hz, 1H); 7.08 (br s, 1H); 6.99-6.84 (m, 2H); 5.08 (s, 1H); 4.58 (t, J = 6 Hz, 2H); 3.98 (m, 1H); 3.82 (m, 1H); 3.34 (m, 2H); 2.78 (s, 3H); 2.42 (s, 3H); 0.97 (s, 9H); 0.97 (obscured t, 3H)) and (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate (1H-NMR: 400 MHz, (CDC13) δ: 8.64 (d, J = 4 Hz, 1H); 7.73 (d, J = 8 Hz, 1H); 7.60 (s, 1H); 7.53 (s, 1H); 7.1 1 (d, J = 8 Hz, 1H); 7.04 (d, J = 4 Hz, 1H); 6.93 (dd, J = 8, 1.2 Hz, 1H); 6.82 (d, J = 8 Hz, 1H); 5.12 (s, 1H); 4.57 (t, J = 5.6 Hz, 2H); 4.20-4.04 (m, 2H); 3.33 (m, 2H); 2.65 (s, 3H); 2.42 (s, 3H); 1.22 (t, J = 7.2 Hz, 3 H); 0.76 (s, 9H)).
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,6-dimethylnaphthalen-2-yl)acetic acid. (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid was prepared in a similar fashion to (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen- 2-yl)acetic acid of Example 16 substituting (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate with (S)-ethyl 2- tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 ,6-dimethylnaphthalen-2- yl)acetate (0.90 g, 1.9 mmol) with appropriate adjustments to scale to (S)-2-tert-butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimemylnaphthalen-2-yl)acetic acid (TFA salt). LCMS-ESf m/z): [M+H]+ calcd for C29H30NO4: 456.5; found: 456.5. 1H-NMR: 400 MHz, (CD3CN) δ: 8.55 (d, J = 5.6 Hz, 1H); 7.85 (s, 1H); 7.79 (d, J = 8 Hz, 1H); 7.68 (s, 1H); 7.62 (d, J = 5.6 Hz, 1H); 7.37 (d, J = 8 Hz, 1H); 7.1 1 (d, J = 9 Hz, 1H); 6.78 (d, J = 9 Hz, 1H); 5.15 (s, 1H); 4.69-4.58 (m, 2H); 3.54 (d, J = 6 Hz, 2H); 2.67 (s, 3H); 2.45 (s, 3H); 0.93 (s, 9H).
Example 108. The following illustrate representative pharmaceutical dosage forms, containing a compound disclosed herein ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 mg/tablet
Compound X= 100.0
Lactose 77.5
Povidone 15.0
Croscarmellose sodium 12.0
Microcrystalline cellulose 92.5
Magnesium stearate 3.0
300.0
(i Tablet 2 mg/tablet
Compound X= 20.0
Microcrystalline cellulose 410.0
Starch 50.0
Sodium starch glycolate 15.0
Magnesium stearate 5J)
500.0
(iii) Capsule mg/capsule
Compound X= 10.0
Colloidal silicon dioxide 1.5
Lactose 465.5
Pregelatinized starch 120.0
Magnesium stearate Q
600.0
(iv) Injection 1 (1 mg/ml) mg/ml
Compound X= (free acid form) 1.0
Dibasic sodium phosphate 12.0
Monobasic sodium phosphate 0.7
Sodium chloride 4.5
1.0 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg/mD mg/ml
Compound X= (free acid form) 10.0
Monobasic sodium phosphate 0.3
Dibasic sodium phosphate 1.1
Polyethylene glycol 400 200.0
1.0 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL (vi) Aerosol mg/can
Compound X= 20.0
Oleic acid 10.0
Trichloromonofluoromethane 5,000.0
Dichlorodifluoromethane 10,000.0
Dichlorotetrafluoroethane 5,000.0
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. All references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques.
However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
The use of the terms "a" and "an" and "the" and similar references in the context of this disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as, preferred, preferably) provided herein, is intended merely to further illustrate the content of the disclosure and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.
Alternative embodiments of the claimed disclosure are described herein, including the best mode known to the inventors for practicing the claimed invention. Of these, variations of the disclosed embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing disclosure. The inventors expect skilled artisans to employ such variations as appropriate (e.g., altering or combining features or embodiments), and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of individual numerical values is stated as approximations as though the values were preceded by the word "about" or "approximately." Similarly, the numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about" or "approximately." In this manner, variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have their plain and ordinary meanings to a person of ordinary skill in the art to which the disclosed subject matter is most closely related or the art relevant to the range or element at issue. The amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words "about" or "approximately" will serve to broaden a particular numerical value or range. Thus, as a general matter, "about" or "approximately" broaden the numerical value. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values plus the broadening of the range afforded by the use of the term "about" or "approximately." Thus, recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
It is to be understood that any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, a person of ordinary skill in the art most closely related to a particular range, ratio or range of ratios will appreciate that such values are unambiguously derivable from the data presented herein.

Claims

What is claimed is:
Figure imgf000242_0001
Figure imgf000242_0002
Figure imgf000242_0003
Figure imgf000243_0001
Figure imgf000243_0002
Figure imgf000243_0003
242
Figure imgf000244_0001
Figure imgf000244_0002
Figure imgf000244_0003
IJ43
Figure imgf000245_0001
Figure imgf000245_0002
Figure imgf000245_0003
IJ44
Figure imgf000246_0001
Figure imgf000246_0002
Figure imgf000246_0003
245
Figure imgf000247_0001
Figure imgf000247_0002

Figure imgf000248_0001

Figure imgf000249_0001

Figure imgf000250_0001
Figure imgf000250_0002
249
Figure imgf000251_0001
Figure imgf000251_0002
Figure imgf000251_0003
and salts thereof.
2. The compound of claim 1 selected from:
Figure imgf000252_0001
Figure imgf000253_0001
252
Figure imgf000254_0001
Figure imgf000254_0002
Figure imgf000254_0003
Figure imgf000254_0004
IJ53
Figure imgf000255_0001
IJ54
Figure imgf000256_0001
Figure imgf000256_0002
Figure imgf000256_0003
Figure imgf000256_0004
IJ55
Figure imgf000257_0001

Figure imgf000258_0001

Figure imgf000259_0001
Figure imgf000259_0002

Figure imgf000260_0001
Figure imgf000260_0002

Figure imgf000261_0001
Figure imgf000261_0002
260
Figure imgf000262_0001
Figure imgf000262_0002
Figure imgf000262_0003
261
Figure imgf000263_0001
and salts thereof.
Figure imgf000263_0002
Figure imgf000264_0001
Figure imgf000264_0002
IJ63
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000265_0003
IJ64
Figure imgf000266_0001
Figure imgf000266_0002
Figure imgf000266_0003
Figure imgf000266_0004
265
Figure imgf000267_0001
Figure imgf000267_0002
Figure imgf000267_0003
IJ66
Figure imgf000268_0001
Figure imgf000268_0002
Figure imgf000268_0003

Figure imgf000269_0001
Figure imgf000269_0002
268
Figure imgf000270_0001
Figure imgf000270_0002

Figure imgf000271_0001
Figure imgf000271_0002
and salts thereof.
4. The compound of claim 1 selected from:
Figure imgf000271_0003
Figure imgf000271_0004
Figure imgf000272_0001
Figure imgf000272_0002
Figure imgf000272_0003
Figure imgf000272_0004
271
Figure imgf000273_0001
Figure imgf000273_0002
272
Figure imgf000274_0001
Figure imgf000274_0002
IJ73
Figure imgf000275_0001
IJ74
Figure imgf000276_0001
Figure imgf000276_0002
275
Figure imgf000277_0001
Figure imgf000277_0002
and salts thereof.
5. The compound of claim 1 selected from:
Figure imgf000278_0001
IJ77
Figure imgf000279_0001
Figure imgf000279_0002

Figure imgf000280_0001
Figure imgf000280_0002

Figure imgf000281_0001
Figure imgf000281_0002
Figure imgf000281_0003
and salts thereof.
6. The compound of claim 1 selected from:
Figure imgf000282_0001
Figure imgf000282_0002
Figure imgf000282_0003
Figure imgf000282_0004
Figure imgf000283_0001
Figure imgf000283_0002
Figure imgf000283_0003
282
Figure imgf000284_0001
Figure imgf000284_0002
IJ83
Figure imgf000285_0001
Figure imgf000285_0002
Figure imgf000285_0003
IJ84
Figure imgf000286_0001
IJ85
Figure imgf000287_0001
IJ86
Figure imgf000288_0001
Figure imgf000288_0002
and salts thereof.
compound of claim 1 selected from:
Figure imgf000289_0001
Figure imgf000289_0002
Figure imgf000289_0003
Figure imgf000289_0004
IJ88
Figure imgf000290_0001
Figure imgf000290_0002
289
Figure imgf000291_0001
Figure imgf000291_0002
290
Figure imgf000292_0001
Figure imgf000292_0002
and salts thereof.
9. A pharmaceutical composition comprising a compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. A method of treating an HIV infection in a mammal comprising administering a compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, to the mammal.
11. A method for treating an HIV infection in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting HIV protease inhibiting compounds, HIV non-nucleoside 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, and other drugs for treating HIV, and combinations thereof.
12. A compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof for use in medical therapy.
13. The use of a compound as described in any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a mammal.
14. A compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.
15 Any invention described or claimed herein.
PCT/US2013/020172 2012-01-04 2013-01-03 Napthalene acetic acid derivatives against hiv infection WO2013103738A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/370,466 US9284323B2 (en) 2012-01-04 2013-01-03 Naphthalene acetic acid derivatives against HIV infection

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261583136P 2012-01-04 2012-01-04
US61/583,136 2012-01-04

Publications (1)

Publication Number Publication Date
WO2013103738A1 true WO2013103738A1 (en) 2013-07-11

Family

ID=47557554

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/020172 WO2013103738A1 (en) 2012-01-04 2013-01-03 Napthalene acetic acid derivatives against hiv infection

Country Status (2)

Country Link
US (1) US9284323B2 (en)
WO (1) WO2013103738A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014119636A1 (en) 2013-01-31 2014-08-07 塩野義製薬株式会社 Hiv replication inhibitor
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
WO2015147247A1 (en) * 2014-03-28 2015-10-01 塩野義製薬株式会社 Tricyclic derivative having hiv replication inhibitory activity
WO2016005878A1 (en) * 2014-07-08 2016-01-14 Viiv Healthcare Uk Limited Isoindoline derivatives for use in the treatment of a viral infection
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
CN106478504A (en) * 2016-09-29 2017-03-08 上海勋和医药科技有限公司 The method preparing Roxadustat intermediate
JP2017521458A (en) * 2014-07-22 2017-08-03 ヴィーブ ヘルスケア ユーケー リミテッド Isoindolinone derivatives useful as antiviral drugs
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX357940B (en) 2012-12-21 2018-07-31 Gilead Sciences Inc Polycyclic-carbamoylpyridone compounds and their pharmaceutical use.
TWI738321B (en) * 2014-12-23 2021-09-01 美商基利科學股份有限公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10800772B2 (en) 2016-09-28 2020-10-13 Gilead Sciences, Inc. Therapeutic compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311735A1 (en) * 2007-11-16 2010-12-09 Boehringer Ingleheim International Gmbh Inhibitors of human immunodeficiency virus replication
WO2012003498A1 (en) * 2010-07-02 2012-01-05 Gilead Sciences, Inc. 2 -quinolinyl- acetic acid derivatives as hiv antiviral compounds
WO2012003497A1 (en) * 2010-07-02 2012-01-05 Gilead Sciences, Inc. Napht- 2 -ylacetic acid derivatives to treat aids

Family Cites Families (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3895028A (en) 1972-09-12 1975-07-15 Tokyo Tanabe Co Alpha-(2-phenylbenzothiazol-5-yl)propionic acid
JPS4994667A (en) 1973-01-23 1974-09-09
FR2453163A1 (en) 1979-04-03 1980-10-31 Rolland Sa A BENZOTHIAZOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS
US4816570A (en) 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
GB8403739D0 (en) 1984-02-13 1984-03-14 Roussel Lab Ltd Chemical compounds
US4968788A (en) 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
JPH03287558A (en) 1990-04-05 1991-12-18 Teijin Ltd Enzyme inhibitor
DK0533833T3 (en) 1990-06-13 1996-04-22 Arnold Glazier Phosphorus prodrugs
EP0481214B1 (en) 1990-09-14 1998-06-24 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
MX9308016A (en) 1992-12-22 1994-08-31 Lilly Co Eli HUMAN IMMUNODEFICIENCY VIRUS PROTEASE INHIBITING COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL FORMULATION CONTAINING THEM.
US5733906A (en) 1993-10-12 1998-03-31 Eli Lilly And Company Inhibitors of HIV Protease useful for the treatment of Aids
ATE355380T1 (en) 1993-04-02 2006-03-15 Rigel Pharmaceuticals Inc METHOD FOR SELECTIVE INACTIVATION OF VIRAL REPLICATION
US5434188A (en) 1994-03-07 1995-07-18 Warner-Lambert Company 1-ether and 1-thioether-naphthalene-2-carboxamides as inhibitors of cell adhesion and as inhibitors of the activation of HIV
DE4428932A1 (en) 1994-08-16 1996-02-22 Hoechst Ag Substituted quinoline derivatives, process for their preparation and their use
EP1070040A1 (en) 1998-04-09 2001-01-24 Merck & Co., Inc. Oxidation process using periodic acid
WO2000063152A1 (en) 1999-02-22 2000-10-26 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Acetylated and related analogues of chicoric acid as hiv integrase inhibitors
US20020052323A1 (en) 2000-08-30 2002-05-02 Jinhai Wang Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents
EP1337853B1 (en) 2000-11-21 2009-01-07 Sunesis Pharmaceuticals, Inc. An extended tethering approach for rapid identification of ligands
FR2819507B1 (en) 2001-01-17 2007-09-28 Inst Rech Developpement Ird SUBSTITUTED QUINOLINES FOR THE TREATMENT OF PROTOZOAN AND RETROVIRUS CO-INFECTIONS
FR2839646B1 (en) 2002-05-17 2008-04-11 Bioalliance Pharma USE OF QUINOLINE DERIVATIVES WITH ANTI-INTEGRASE EFFECT AND APPLICATIONS THEREOF
EP1545518A1 (en) 2002-08-02 2005-06-29 Tibotec Pharmaceuticals Ltd. Broadspectrum 2-amino-benzothiazole sulfonamide hiv protease inhibitors
US7358249B2 (en) 2002-08-13 2008-04-15 Shionogi & Co., Ltd. Heterocyclic compounds having inhibitory activity against HIV integrase
EP1546331B2 (en) 2002-09-26 2016-01-13 K.U.Leuven Research & Development Integrase cofactor
EP3406596A1 (en) 2002-11-20 2018-11-28 Japan Tobacco Inc. 4-oxoquinoline compound and use thereof as hiv integrase inhibitor
UA80571C2 (en) 2002-11-22 2007-10-10 Lilly Co Eli Quinolinyl-pyrrolopyrazoles
ES2423800T3 (en) 2003-03-28 2013-09-24 Novartis Vaccines And Diagnostics, Inc. Use of organic compounds for immunopotentiation
AU2005257859A1 (en) 2004-05-21 2006-01-05 Merck & Co., Inc. Amino cyclopentyl heterocyclic and carbocyclic modulators of chemokine receptor activity
US7087610B2 (en) 2004-06-03 2006-08-08 Bristol-Myers Squibb Company Benzothiazole antiviral agents
JP2008503588A (en) 2004-06-22 2008-02-07 スミスクライン ビーチャム コーポレーション Chemical compound
TWI306401B (en) 2004-08-13 2009-02-21 Nat Health Research Institutes Benzothiazolium compounds
US20060094755A1 (en) 2004-10-28 2006-05-04 Bioflexis, Llc Novel quinoline-based metal chelators as antiviral agents
TWI370820B (en) 2005-04-27 2012-08-21 Takeda Pharmaceutical Fused heterocyclic compounds
WO2006124780A2 (en) 2005-05-12 2006-11-23 Kalypsys, Inc. Ih-benzo [d] imidazole compounds as inhibitors of b-raf kinase
US7473784B2 (en) 2005-08-01 2009-01-06 Bristol-Myers Squibb Company Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors
US7939545B2 (en) 2006-05-16 2011-05-10 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
JP2009538899A (en) 2006-05-30 2009-11-12 ファイザー・プロダクツ・インク Triazolopyridazine derivatives
JO2841B1 (en) 2006-06-23 2014-09-15 تيبوتيك فارماسيوتيكالز ليمتد 2-( substituted-amino)- benzothiazole sulfonamide HIV protease INHIBITORS
US8435774B2 (en) 2006-06-28 2013-05-07 Qiagen Gmbh Enhancing reactivation of thermostable reversibly inactivated enzymes
WO2008053478A2 (en) 2006-10-30 2008-05-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions and methods for inhibiting hiv-1 replication and integrase activity
RU2469032C2 (en) 2006-12-13 2012-12-10 Ф.Хоффманн-Ля Рош Аг 2-(piperidin-4-yl)-4-phenoxy- or phenylaminopyrimidine derivatives as non nucleoside reverse transcriptase inhibitors
RU2503679C2 (en) 2007-11-15 2014-01-10 Джилид Сайенсиз, Инк. Replication inhibitors of human immunodeficiency virus
CA2705318C (en) 2007-11-15 2013-12-31 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
JP5269087B2 (en) 2007-11-16 2013-08-21 ギリアード サイエンシス インコーポレーテッド Inhibitors of human immunodeficiency virus replication
GB0801940D0 (en) 2008-02-01 2008-03-12 Univ Leuven Kath Inhibitors of lentiviral replication
WO2009099982A1 (en) 2008-02-04 2009-08-13 Osi Pharmaceuticals, Inc. 2-aminopyridine kinase inhibitors
JP5743897B2 (en) 2008-11-20 2015-07-01 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーＧｌａｘｏＳｍｉｔｈＫｌｉｎｅ ＬＬＣ Compound
US8338441B2 (en) 2009-05-15 2012-12-25 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication
GB0908394D0 (en) 2009-05-15 2009-06-24 Univ Leuven Kath Novel viral replication inhibitors
JP2012532102A (en) 2009-06-30 2012-12-13 シガ・テクノロジーズ・インコーポレーテッド Treatment and prevention of dengue virus infection
GB0913636D0 (en) 2009-08-05 2009-09-16 Univ Leuven Kath Novel viral replication inhibitors
WO2011047129A1 (en) 2009-10-15 2011-04-21 Southern Research Institute Treatment of neurodegenerative diseases, causation of memory enhancement, and assay for screening compounds for such
WO2011076765A1 (en) 2009-12-23 2011-06-30 Katholieke Universiteit Leuven Novel antiviral compounds
US20110223131A1 (en) 2010-02-24 2011-09-15 Gilead Sciences, Inc. Antiviral compounds
US8846909B2 (en) 2010-05-24 2014-09-30 University Of Rochester Bicyclic heteroaryl kinase inhibitors and methods of use
US8633200B2 (en) 2010-09-08 2014-01-21 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
BR112013011737A2 (en) 2010-11-15 2016-08-09 Univ Leuven Kath compound, use of a compound pharmaceutical composition, and method of treating or preventing an HIV infection
RU2564445C2 (en) 2010-11-15 2015-10-10 ВииВ Хелткер ЮКей Лимитед Inhibitors of hiv replication
AR084457A1 (en) 2010-12-22 2013-05-15 Lundbeck & Co As H BICYCLE DERIVATIVES [3,2,1] OCTILAMIDE
US9029391B2 (en) 2011-01-24 2015-05-12 Viiv Healthcare Uk Limited Isoquinoline compounds and methods for treating HIV
CA2830838A1 (en) 2011-04-04 2012-11-10 Gilead Sciences, Inc. Process for the preparation of an hiv integrase inhibitor
WO2012138669A1 (en) 2011-04-04 2012-10-11 Gilead Sciences, Inc. Solid state forms of hiv inhibitor
EP2508511A1 (en) 2011-04-07 2012-10-10 Laboratoire Biodim Inhibitors of viral replication, their process of preparation and their therapeutical uses
ES2742261T3 (en) 2011-04-15 2020-02-13 Hivih Inhibitors of viral replication, its preparation process and its therapeutic uses
EP2699572B1 (en) 2011-04-21 2016-08-10 Origenis GmbH Heterocyclic compounds as kinase inhibitors
RS54044B1 (en) 2011-04-21 2015-10-30 Bayer Intellectual Property Gmbh Triazolopyridines
CN103492389B (en) 2011-04-21 2016-09-14 原真股份有限公司 Pyrazolo [4,3-d] pyrimidine as inhibitors of kinases
MX2013012266A (en) 2011-04-21 2013-11-22 Gilead Sciences Inc Benzothiazole compounds and their pharmaceutical use.
WO2013002357A1 (en) 2011-06-30 2013-01-03 塩野義製薬株式会社 Hiv replication inhibitor
US8791108B2 (en) 2011-08-18 2014-07-29 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
WO2013043553A1 (en) 2011-09-22 2013-03-28 Glaxosmithkline Llc Pyrrolopyridinone compounds and methods for treating hiv
WO2013058448A1 (en) 2011-10-20 2013-04-25 한국해양연구원 Marine medaka genes responding to the exposure of endocrine-disrupting chemicals, and method for diagnosing an aquatic eco-system contamination using same
EP2772480B2 (en) 2011-10-25 2020-12-09 Shionogi & Co., Ltd. Hiv replication inhibitor
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
CN117736134A (en) 2012-01-12 2024-03-22 耶鲁大学 Compounds and methods for enhancing degradation of target proteins and other polypeptides by E3 ubiquitin ligases
US8629276B2 (en) 2012-02-15 2014-01-14 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
US9034882B2 (en) 2012-03-05 2015-05-19 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
US9006235B2 (en) 2012-03-06 2015-04-14 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
WO2013157622A1 (en) 2012-04-19 2013-10-24 塩野義製薬株式会社 Hiv replication inhibitor
SG11201401189WA (en) 2012-04-20 2014-09-26 Gilead Sciences Inc Benzothiazol- 6 -yl acetic acid derivatives and their use for treating an hiv infection
ES2647437T3 (en) 2012-07-12 2017-12-21 Viiv Healthcare Uk Limited Compounds and procedures for treating HIV
US8906929B2 (en) 2012-08-16 2014-12-09 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
US20140094609A1 (en) 2012-10-03 2014-04-03 Gilead Sciences, Inc. Process for the preparation of an hiv integrase inhibitor
WO2014055618A1 (en) 2012-10-03 2014-04-10 Gilead Sciences, Inc. Solid state forms of hiv inhibitor: hemi-succinate of (2s)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl)acetic acid)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311735A1 (en) * 2007-11-16 2010-12-09 Boehringer Ingleheim International Gmbh Inhibitors of human immunodeficiency virus replication
WO2012003498A1 (en) * 2010-07-02 2012-01-05 Gilead Sciences, Inc. 2 -quinolinyl- acetic acid derivatives as hiv antiviral compounds
WO2012003497A1 (en) * 2010-07-02 2012-01-05 Gilead Sciences, Inc. Napht- 2 -ylacetic acid derivatives to treat aids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PENDRI ET AL.: "New first and second generation inhibitors of human immunodeficiency virus-1 integrase", EXPERT OPIN. THER. PATENTS, vol. 21, no. 8, 1 August 2011 (2011-08-01), pages 1173 - 1189, XP008141359, ISSN: 1354-3776, DOI: 10.1517/13543776.2011.586631 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9096586B2 (en) 2012-04-20 2015-08-04 Gilead Sciences, Inc. Therapeutic compounds
WO2014119636A1 (en) 2013-01-31 2014-08-07 塩野義製薬株式会社 Hiv replication inhibitor
WO2015147247A1 (en) * 2014-03-28 2015-10-01 塩野義製薬株式会社 Tricyclic derivative having hiv replication inhibitory activity
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
WO2016005878A1 (en) * 2014-07-08 2016-01-14 Viiv Healthcare Uk Limited Isoindoline derivatives for use in the treatment of a viral infection
US10112899B2 (en) 2014-07-08 2018-10-30 Viiv Healthcare Uk Limited Isoindoline derivatives for use in the treatment of a viral infection
JP2017521428A (en) * 2014-07-08 2017-08-03 ヴィーブ ヘルスケア ユーケー リミテッド Isoindoline derivatives for use in the treatment of viral infections
EA030204B1 (en) * 2014-07-08 2018-07-31 ВАЙВ ХЕЛТКЕР ЮКей ЛИМИТЕД Isoindoline derivatives for use in the treatment of a viral infection
JP2017521458A (en) * 2014-07-22 2017-08-03 ヴィーブ ヘルスケア ユーケー リミテッド Isoindolinone derivatives useful as antiviral drugs
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
US10870661B2 (en) 2015-05-29 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
CN106478504A (en) * 2016-09-29 2017-03-08 上海勋和医药科技有限公司 The method preparing Roxadustat intermediate
CN106478504B (en) * 2016-09-29 2020-04-21 上海勋和医药科技有限公司 Method for preparing Roxadustat intermediate
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Also Published As

Publication number Publication date
US9284323B2 (en) 2016-03-15
US20150111891A1 (en) 2015-04-23

Similar Documents

Publication Publication Date Title
WO2013103738A1 (en) Napthalene acetic acid derivatives against hiv infection
AU2014205315B2 (en) Therapeutic compounds for the treatment of viral infections
EP2943481B1 (en) (hetero)arylacetamide derivatives as antiretroviral agents
EP2943487B1 (en) 5-membered heteroaryls and their use as antiviral agents
CA2901502C (en) Amide compounds for the treatment of hiv
US10202353B2 (en) Therapeutic compounds
US9096586B2 (en) Therapeutic compounds
WO2013103724A1 (en) 2- (tert - butoxy) -2- (7 -methylquinolin- 6 - yl) acetic acid derivatives for treating aids
AU2017213517A1 (en) Compounds for the treatment of HIV
US20140296266A1 (en) Therapeutic compounds
TW200811167A (en) Modulators of pharmacokinetic properties of therapeutics
EP2699558A1 (en) Benzothiazole compounds and their pharmaceutical use
WO2015179448A1 (en) Therapeutic compounds
TW201016698A (en) Antiviral compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13700246

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 14370466

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13700246

Country of ref document: EP

Kind code of ref document: A1