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WO2024233812A1 - Inhibiteurs de la gmp-amp synthase cyclique et leurs utilisations - Google Patents

Inhibiteurs de la gmp-amp synthase cyclique et leurs utilisations Download PDF

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WO2024233812A1
WO2024233812A1 PCT/US2024/028639 US2024028639W WO2024233812A1 WO 2024233812 A1 WO2024233812 A1 WO 2024233812A1 US 2024028639 W US2024028639 W US 2024028639W WO 2024233812 A1 WO2024233812 A1 WO 2024233812A1
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alkyl
salt
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Ramsay Beveridge
Stephane Ciblat
Patrick Cyr
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Ventus Therapeutics US Inc
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Ventus Therapeutics US Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

Definitions

  • cGAMP is the first cyclic dinucleotide in metazoans, and cGAMP functions as an endogenous secondary messenger that induces interferon production in response to cytosolic DNA.
  • cGAMP synthase (cGAS) is an enzyme that intervenes in the synthesis of cyclic GMP-AMP and belongs to the nucleotidyltransferase family. Overexpression of cGAS activates the transcription factor IRF3 and induces IFN ⁇ in a STING-dependent manner. Knockdown of cGAS inhibits IRF3 activation and IFN ⁇ induction by DNA transfection or DNA virus infection.
  • cGAS binds to DNA in the cytoplasm and catalyzes cGAMP synthesis. These findings indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP. [004] The critical role of cGAS in cytosolic DNA sensing has been established in different pathogenic bacteria, viruses, and retroviruses (US 2021/0155625). Additionally, cGAS is essential in various other biological processes, such as cellular senescence and recognition of ruptured micronuclei in the surveillance of potential cancer cells. [005] There is a need for therapeutic agents that target cGAS.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C 1–6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”).
  • an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3– pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6).
  • alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In some embodiments, the alkyl group is an unsubstituted C1–10 alkyl (e.g., –CH3). In some embodiments, the alkyl group is a substituted C1–10 alkyl.
  • Haloalkyl refers to a substituted alkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1–8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C 1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1–4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C 1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
  • haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include –CF 3 , –CF 2 CF 3 , – CF 2 CF 2 CF 3 , –CCl 3 , –CFCl 2 , –CF 2 Cl, and the like.
  • Alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C 2–10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”).
  • an alkenyl group has 2 to 3 carbon atoms (“C2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1– butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like.
  • C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C2–10 alkenyl. In some embodiments, the alkenyl group is a substituted C2–10 alkenyl.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2– 10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1– butynyl).
  • Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C 2–10 alkynyl. In some embodiments, the alkynyl group is a substituted C 2–10 alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3–14 carbocyclyl”) and zero heteroatoms in the non– aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3–10 carbocyclyl”).
  • a carbocyclyl group has 3 to 9 ring carbon atoms (“C 3–9 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3–7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10 carbocyclyl”).
  • Exemplary C3–6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3–8 carbocyclyl groups include, without limitation, the aforementioned C3–6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3–10 carbocyclyl groups include, without limitation, the aforementioned C3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H– indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon–carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons designate the number of carbons in the polycyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3–14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3–14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3–14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”). Examples of C 5–6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C3–14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3–14 cycloalkyl.
  • “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 14–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • N-O N-oxide
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes (i) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused (e.g., spiro-fused or ring fused) or bridged with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or (ii) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the polycyclic ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1– 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyr
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2– naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designate the number of carbon atoms in the polycyclic ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6–14 aryl.
  • the aryl group is a substituted C 6–14 aryl.
  • Heteroaryl refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes polycyclic ring systems wherein the heteroaryl ring, as defined above, (i) is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, or (ii) is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the fused polycyclic ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a ring heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a ring heteroatom (e.g., 2–indolyl) or the ring that does not contain a ring heteroatom (e.g., 5–indolyl).
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5–14 membered heteroaryl.
  • the heteroaryl group is a substituted 5–14 membered heteroaryl.
  • Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • “Ortho” position refers to the 2-position on an aryl or heteroaryl ring, relative to the 1- position which is the point of attachment.
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, – Br), or iodine (iodo, –I) radicals.
  • “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
  • alkylene is the divalent moiety of alkyl
  • haloalkylene is the divalent moiety of haloalkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkylene may be a C 1-6 alkylene, which may be linear or branched.
  • An alkylene may further be a C 1-4 alkylene.
  • Exemplary C 1-4 alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, - CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Salt refers to any and all salts, including pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a “free base” refers to a neutral non-ionized form of a compound which is not a salt or pharmaceutically acceptable salt.
  • a “leaving group” is an art–understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501–502).
  • Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and sulfonyl substituted hydroxyl groups (e.g., -O-tosyl, -O-mesyl, and -O-besyl).
  • a “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.
  • the patient or subject is a human.
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of the compound sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition in a subject in need thereof.
  • An effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. [035] “Disease”, “disorder”, “condition”, or “state” are used interchangeably herein.
  • Treating” or “treat” or “treatment” describes the management and care of a subject in need thereof, for the purpose of combating a disease, condition, or disorder in the subject, and includes the administration of a compound, or a pharmaceutically acceptable salt thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • references to “treating” or “treatment” include the alleviation of established symptoms of a condition, and therefore includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • “Modulate”, “modulating” and the like refer to the ability of a compound to change the activity of a particular biological process (e.g., cGAS activity) in a cell relative to a control.
  • “Inhibition”, “inhibiting”, “inhibit” and “inhibitor”, and the like refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process (e.g., cGAS activity) in a cell relative to a control.
  • the phrase “at least one” refers to one instance or more than one instance.
  • Ring A is a 5-membered monocyclic heteroaryl
  • the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 1A ; each R 1A is independently -OR 1B ; each R 1B is independently hydrogen or C 1 -C 4 alkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen or -OR 1F ; and each R 1F is independently hydrogen or C 1 -C 3 alkyl; -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A ; each R 1A is independently -OR 1B ; each R 1B is independently hydrogen or C1-C4 alkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen or -OR 1F ; each R 1F is independently hydrogen or C 1 - C 3 alkyl substituted with 0, 1, 2,
  • the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1 -C 6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C 1 -C 4 alkyl substituted with 0 R 1D ; -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond; or -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E ; each R 3A is independently C 1 -C 3 alkyl, halogen, -L 1 -CN, or -L 1 -OR 3B
  • the compound is of Formula (I′): or a pharmaceutically acceptable salt thereof, wherein a nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.
  • compounds of Formula (I) comprising the combination of an -OR 1 group at the C3 position of the pyrone ring, an aryl or heteroaryl moiety at the C4 position of the pyrone ring, and a 5-membered monocyclic heteroaryl Ring A, show improvement in one or more desirable drug-like properties, such as improvement in unbound clearance, permeability, bioavailability, hcGAS potency, and/or solubility.
  • Applicants have additionally found incorporating at least one -L 1 -OR 3B group, -L1-CN group, or halogen group, which are exemplary substituents of group R 3A , particularly at one or both ortho positions to the point of attachment of Ring C to the pyrone ring, may show additional improvements in one or more of these desirable properties.
  • inclusion of an additional ortho -L 1 - OR 3B group (e.g., -OCH 3 ) or halogen group to Compound 1 (“A2” activity) provides Compound 44 (“A1” activity) and Compound 41 (“A1” activity) with improved cGAS potency.
  • Non- limiting examples include Compound 24A*, comprising an ortho -CN and ortho C 1 -C 3 alkyl group, and Compound 45, comprising an ortho -CN and ortho halogen group, each with “A1” activity.
  • the compound of Formula (I) is of Formula (I′′): and pharmaceutically acceptable salts thereof, wherein n is 0, 1, 2, or 3.
  • -L 1 - OR 3B is ortho to the point of attachment to the pyrone ring.
  • Ring C further comprises a second R 3A group ortho to the point of attachment selected from halogen, -L 1 -OR 3B , or -L 1 -CN, and optionally comprises additional R 3A groups, wherein n is 0, 1, or 2.
  • the compound of Formula (I) is of Formula (I′′′): and pharmaceutically acceptable salts thereof, wherein n is 0, 1, 2, or 3.
  • -L 1 - CN is ortho to the point of attachment to the pyrone ring.
  • Ring C further comprises a second R 3A group ortho to the point of attachment selected from halogen, -L 1 -OR 3B , or -L 1 -CN, and optionally comprises additional R 3A groups, wherein n is 0, 1, or 2. [049] Additional embodiments are further described below and herein.
  • R 1 is C1-C6 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C1-C4 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C1- C3 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C1-C2 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . [052] In some embodiments, R 1 is C2-C6 alkenyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C2-C4 alkenyl substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is C 2 -C 3 alkenyl substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is C 2 -C 6 alkynyl substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is C 2 -C 4 alkynyl substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is C 2 -C 3 alkynyl substituted with 0, 1, 2, or 3 R 1A .
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(C 3 -C 4 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(C 5 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L3-(7- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L3-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L3-(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is C1-C6 alkyl substituted with 0 R 1A .
  • each R 1B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D .
  • R 1 is C1-C6 alkyl substituted with 1 R 1A ;
  • R 1A is halogen, -OR 1B , -N(R 1B )2, -(C1-C3 alkylene)-OR 1B , or -(C1-C3 alkylene)-SR 1B ;
  • each R 1B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ;
  • each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; and each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
  • R 1 is C1-C6 alkyl substituted with 1 R 1A ; R 1A is -OR 1B ; and R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0 R 1D .
  • R 1 is C1-C6 alkyl substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is C1-C3 alkyl or C1-C3 haloalkyl substituted with 1 R 1D ; R 1D is -OR 1F ; and R 1F is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl substituted with 1 R 1D ;
  • R 1D is -OR 1F ; and
  • R 1F is hydrogen.
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl substituted with 1 R 1D ;
  • R 1D is -OR 1F ;
  • R 1F is C 1 -C 3 alkyl.
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ; and
  • R 1B is hydrogen or C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ; R 1A is -OR 1B ; and R 1B is hydrogen. [065] In some embodiments, R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ; R 1A is -OR 1B ; and R 1B is C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C 1 -C 3 alkyl substituted with 1 R 1D ;
  • R 1D is -OR 1F ;
  • R 1F is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C 1 -C 3 alkyl substituted with 1 R 1D ;
  • R 1D is -OR 1F ; and
  • R 1F is hydrogen.
  • R 1 is C1-C6 alkyl substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C1-C3 alkyl substituted with 1 R 1D ;
  • R 1D is -OR 1F ;
  • R 1F is C 1 -C 3 alkyl.
  • R 1 is C 1 -C 6 alkyl substituted with 2 R 1A ; each R 1A is independently -OR 1B ; each R 1B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl independently substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; and each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
  • R 1 is C1-C6 alkyl substituted with 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C1-C3 alkyl substituted with 0 R 1D .
  • R 1 is C1-C6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C1-C3 alkyl substituted with 0 R 1D .
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 0 R 1A ;
  • L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is substituted with 0, 1, 2, 3, or 4 R 1E ;
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ;
  • R 1A is halogen, -OR 1B , -N(R 1B )2, -(C1-C3 alkylene)-OR 1B , or -(C1-C3 alkylene)-SR 1B ;
  • R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ;
  • each R 1D is independently halogen, -OR 1F , or -N(R 1F )2;
  • each R 1F is independently hydrogen, C1-C3 alkyl, or C1- C3 haloalkyl;
  • L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is substituted with 0,
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is halogen; and L 3 is bond.
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ;
  • R 1A is -OR 1B ;
  • R 1B is C 1 -C 3 alkyl substituted with 0 R 1D ;
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 1A ; each R 1A is halogen, -OR 1B , -N(R 1B ) 2 , -(C 1 -C 3 alkylene)-OR 1B , or -(C 1 -C 3 alkylene)-SR 1B ; each R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; each R 1F is independently hydrogen, C1-C3 alkyl, or C1- C3 haloalkyl; L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alky
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 1A ; each R 1A is -OR 1B ; each R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0 R 1D ; and L3 is C1-C3 alkylene or -(C1-C3 alkylene)-O-, wherein the alkylene is substituted with 0 R 1E .
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 1A ; each R 1A is -OR 1B ; each R 1B is hydrogen or C1-C3 alkyl substituted with 0 R 1D ; and L3 is C1-C3 alkylene substituted with 0 R 1E .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ;
  • L3 is a bond, C1-C3 alkylene, or -(C1-C3 alkylene)-O-, wherein the alkylene is substituted with 0, 1, 2, 3, or 4 R 1E ;
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L3 is a bond.
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ;
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; L 3 is C 1 -C 3 alkylene substituted with 1 R 1E ; and R 1E is -(C 1 -C 3 alkylene)- OR 1B , or -OR 1B .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; L 3 is C 1 -C 3 alkylene substituted with 1 R 1E ; R 1E is -(C 1 -C 3 alkylene)-OR 1B .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; L 3 is C 1 -C 3 alkylene substituted with 1 R 1E ; and R 1E is -OR 1B .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ;
  • R 1A is halogen, -OR 1B , -N(R 1B ) 2 , -(C 1 -C 3 alkylene)-OR 1B , or -(C 1 -C 3 alkylene)-SR 1B ;
  • R 1B is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ;
  • each R 1D is independently halogen, -OR 1F , or -N(R 1F )2;
  • each R 1F is independently hydrogen, C1-C3 alkyl, or C 1 -C 3 haloalkyl;
  • L 3 is a bond, C 1 -C 3 alkylene, or -(C 1 -C 3 alkylene)-O-, where
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ;
  • R 1A is -(C1-C3 alkylene)-SR 1B ;
  • R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ;
  • each R 1D is independently halogen, -OR 1F , or -N(R 1F )2;
  • each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
  • L3 is C1-C3 alkylene substituted with 0 R 1E .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ;
  • R 1A is -(C1-C3 alkylene)-SR 1B ;
  • R 1B is C1-C3 alkyl substituted with 0 R 1D ;
  • L3 is C1-C3 alkylene substituted with 0 R 1E .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ; R 1A -(C1-C3 alkylene)-OR 1B ; R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; and L3 is C1-C3 alkylene substituted with 0 R 1E .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ;
  • R 1A is -(C1-C3 alkylene)-OR 1B ;
  • R 1B is hydrogen;
  • L3 is C1-C3 alkylene substituted with 0 R 1E .
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ; R 1A -(C1-C3 alkylene)-SR 1B ; R 1B is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; each R 1F is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 1A ;
  • R 1A is -(C 1 -C 3 alkylene)-SR 1B ;
  • R 1B is hydrogen; and
  • L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • At least one R 1A is independently halogen, -OR 1B , -N(R 1B ) 2 , or –(C 1 -C 3 alkylene)-OR 1B . [098] In some embodiments, at least one R 1A is independently halogen, -OR 1B , or -N(R 1B ) 2 . [099] In some embodiments, at least one R 1A is independently halogen. [100] In some embodiments, at least one R 1A is independently -OR 1B or -N(R 1B ) 2 .
  • at least one R 1C is independently hydrogen.
  • at least one R 1C is independently C1-C3 alkyl.
  • at least one R 1C is independently C1-C3 haloalkyl.
  • at least one R 1C is independently -OR 1F .
  • at least one R 1C is independently -OCH3.
  • at least one R 1A is independently -(C1-C3 alkylene)-OR 1B .
  • At least one R 1A is independently -(C1-C3 alkylene)-SR 1B .
  • at least one R 1B is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
  • at least one R 1B is independently hydrogen.
  • At least one R 1B is independently C1-C3 alkyl or C1-C3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F )2; and each R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.
  • at least one R 1B is independently C1-C3 alkyl or C1-C3 haloalkyl substituted with 0 R 1D .
  • At least one R 1B is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl substituted with 1 R 1D ;
  • R 1D is halogen, -OR 1F , or -N(R 1F ) 2 ; and each R 1F is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • At least one R 1B is independently C 1 -C 3 alkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F ) 2 ; and each R 1F is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • at least one R 1B is independently C 1 -C 3 alkyl substituted with 0 R 1D .
  • At least one R 1B is independently C 1 -C 3 alkyl substituted with 1 R 1D ; R 1D is -OR 1F ; and R 1F is C 1 -C 3 alkyl.
  • at least one R 1B is independently C 1 -C 3 haloalkyl substituted with 0, 1, 2, 3, or 4 R 1D ; each R 1D is independently halogen, -OR 1F , or -N(R 1F ) 2 ; and each R 1F is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • At least one R 1D is independently halogen, -OR 1F , or -N(R 1F ) 2 . [125] In some embodiments, at least one R 1D is independently halogen. [126] In some embodiments, at least one R 1D is independently -OR 1F or -N(R 1F ) 2 . [127] In some embodiments, at least one R 1D is independently -OR 1F . [128] In some embodiments, at least one R 1D is independently -OH. In some embodiments, at least one R 1D is independently -O(C1-C3 alkyl). [129] In some embodiments, at least one R 1D is independently -N(R 1F )2.
  • At least one R 1F is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl. [131] In some embodiments, at least one R 1F is independently hydrogen. [132] In some embodiments, at least one R 1F is independently C1-C3 alkyl or C1-C3 haloalkyl. [133] In some embodiments, at least one R 1F is independently C1-C3 alkyl. [134] In some embodiments, at least one R 1F is independently C1-C3 haloalkyl. [135] In some embodiments, at least one R 1E is independently -(C1-C3 alkylene)-OR 1B or -OR 1B .
  • At least one R 1E is independently -(C1-C3 alkylene)-OR 1B .
  • at least one R 1E is independently -OR 1B .
  • R 1 is -CH3, -CH2-C(CH3)2-CH2OCH3, -CH2CH2OH, or -CH2CH2OCH3.
  • R 1 is -CH3.
  • R 1 is -CH2-C(CH3)2-CH2OCH3.
  • R 1 is -CH2CH2OH.
  • R 1 is -CH2CH2OCH3.
  • the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.
  • the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.
  • the heterocyclyl ring when R 1 is -L 3 -(7- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R 1 is -L 3 -(7- to 10-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S. [144] In some embodiments, when R 1 is -L 3 -(4- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.
  • the heterocyclyl ring when R 1 is -L 3 -(4- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S. [145] In some embodiments, when R 1 is -L 3 -(5- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R 1 is -L 3 -(5- to 6-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S.
  • R 1 when R 1 is -L 3 -(4- to 10-membered heterocyclyl), the heterocyclyl ring is selected from: [147] In some embodiments, when R 1 is -L 3 -(C 3 -C 6 carbocyclyl), the carbocyclyl ring is selected . [148] In some embodiments, R 1 is selected from: [149] As generally described herein, Ring C is a C6-C10 aryl or 5- to 10-membered heteroaryl. [150] In some embodiments, Ring C is a monocyclic C6 aryl (phenyl). In some embodiments, Ring C is phenyl, and n is 0.
  • Ring C is phenyl, and n is 1. In some embodiments, Ring C is phenyl, and n is 2. In some embodiments, Ring C is phenyl, and n is 3. In some embodiments, Ring C is phenyl, and n is 4. [151] In some embodiments, Ring C is of the formula (i-c): (i-c). In some embodiments, Ring C is of one of the following formulae: [152] In some embodiments, Ring C is a monocyclic 5- to 6-membered heteroaryl. [153] In some embodiments, Ring C is 6-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O.
  • Ring C is 6- membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N and O. In some embodiments, Ring C is 6-membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N and O. In some embodiments, Ring C is 6-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring N atoms. In some embodiments, Ring C is 6-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring N atoms. In some embodiments, Ring C is 6- membered heteroaryl, wherein the heteroaryl has 1 ring N atom. [154] In some embodiments, Ring C is a pyridine ring.
  • Ring C is of the formula (ii-c): (ii-c). In some embodiments, Ring C is of the formula (ii-c), and n is 0. In some embodiments, Ring C is of the formula (ii-c), and n is 1. In some embodiments, Ring C is of the formula (ii-c), and n is 2. In some embodiments, Ring C is of the formula (ii-c), and n is 3. In some embodiments, Ring C is of the formula (ii-c), and n is 4. [155] In some embodiments, Ring C is of one of the following formulae: , , [156] In some embodiments, Ring C is of the formula (iii-c): (iii-c).
  • Ring C is of the formula (iii-c), and n is 0. In some embodiments, Ring C is of the formula (iii-c), and n is 1. In some embodiments, Ring C is of the formula (iii-c), and n is 2. In some embodiments, Ring C is of the formula (iii-c), and n is 3. In some embodiments, Ring C is of the formula (iii-c), and n is 4. [157] In some embodiments, Ring C is of one of the following formulae: , , [158] In some embodiments, Ring C is of the formula ( some embodiments, Ring C is of the formula (iv-c), and n is 0.
  • Ring C is of the formula (ii-c), and n is 1. In some embodiments, Ring C is of the formula (iv-c), and n is 2. In some embodiments, Ring C is of the formula (iv-c), and n is 3. In some embodiments, Ring C is of the formula (iv-c), and n is 4. [159] In some embodiments, Ring C is of one of the following formulae: . [160] In some embodiments, Ring C is 5-membered heteroaryl. In some embodiments, Ring C is 5- membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N, O, and S.
  • Ring C is 5-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is 5-membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N, O, and S. In some embodiments, Ring C is 5-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring heteroatoms independently selected from N and O. In some embodiments, Ring C is 5-membered heteroaryl, wherein the heteroaryl has 1 or 2 ring heteroatoms independently selected from N and O. In some embodiments, Ring C is 5-membered heteroaryl, wherein the heteroaryl has 1 ring heteroatom selected from N and O.
  • Ring C is an pyrazole ring. In some embodiments, Ring C is of the formula (v-c): (v-c). In some embodiments, Ring C is of the formula (v-c), and n is 0. In some embodiments, Ring C is of the formula (v-c), and n is 1. In some embodiments, Ring C is of the formula (v-c), and n is 2. In some embodiments, Ring C is of the formula (v-c), and n is 3. [162] In some embodiments, Ring C is of the formula: . [163] In some embodiments, Ring C is a pyrazole ring. In some embodiments, Ring C is of the formula (vi-c): (vi-c).
  • Ring C is of the formula (vi-c), and n is 0. In some embodiments, Ring C is of the formula (vi-c), and n is 1. In some embodiments, Ring C is of the formula (vi-c), and n is 2. In some embodiments, Ring C is of the formula (vi-c), and n is 3. [164] In some embodiments, Ring C is of the formula: . [165] In some embodiments, compounds of Formula (I) comprise at least one R 3A substituent -L1- OR 3B , and Ring C is substituted with 0, 1, 2, or 3 additional R 3A substituents. In some embodiments, the -L1-OR 3B group is ortho to the point of attachment of Ring C to the pyrone ring.
  • Ring C further comprises an additional R 3A group ortho to the point of attachment selected from halogen, -L1-OR 3B , or -L1-CN.
  • Ring C is of the formula: , , , ; wherein the halogen, -L 1 -OR 3B , and/or -L 1 -CN groups are each ortho to the point of attachment of Ring C to the pyrone ring.
  • compounds of Formula (I) comprise at least one R 3A substituent -L 1 - CN, and Ring C is substituted with 0, 1, 2, or 3 additional R 3A substituents.
  • the -L 1 -CN group is ortho to the point of attachment of Ring C to the pyrone ring.
  • Ring C further comprises an additional R 3A group ortho to the point of attachment selected from halogen, -L 1 -OR 3B , or -L 1 -CN. [168] In some embodiments, Ring C is of the formula:
  • n is 0, 1, or 2; or , wherein n is 0, 1, or 2; wherein the halogen, -L1-OR 3B , and/or -L1-CN groups are each ortho to the point of attachment of Ring C to the pyrone ring.
  • each R 3A is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogen, -L1-CN, -L1-SOR 3C , -L1-SO2R 3C , -L1-SR 3B , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C6-10aryl), or -L1-(5- to 10-membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R 3D .
  • each R 3A is independently C1-C3 alkyl, halogen, -L1-CN, -L1-SO2R 3C , -L1-OR 3B , -L1-N(R 3B )2, -L1-(C3-C6 carbocyclyl), -L1-(4- to 6-membered heterocyclyl), -L1-(C6-10aryl), or -L1-(5- to 10-membered heteroaryl), wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R 3D .
  • At least one R 3A is independently C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently C 1 -C 3 alkyl.
  • at least one R 3A is independently C 1 -C 3 alkyl substituted with 1 R 3D .
  • at least one R 3A is independently C 1 -C 3 alkyl substituted with 2 R 3D .
  • at least one R 3A is independently C 1 -C 3 alkyl substituted with 3 R 3D .
  • At least one R 3A is independently C1-C3 alkyl substituted with 4 R 3D . [177] In some embodiments, at least one R 3A is independently halogen. [178] In some embodiments, at least one R 3A is independently F or Cl. [179] In some embodiments, at least one R 3A is independently F. In some embodiments, at least one R 3A is independently Cl. [180] In some embodiments, at least one R 3A is independently -L1-CN, -L1-SO2R 3C , -L1-OR 3B , or -L1-N(R 3B )2. [181] In some embodiments, at least one R 3A is independently -L1-CN.
  • At least one R 3A is independently -CN. [183] In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-CN. [184] In some embodiments, at least one R 3A is independently -L1-SO2R 3C . [185] In some embodiments, at least one R 3A is independently -SO2R 3C . [186] In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-SO2R 3C . [187] In some embodiments, at least one R 3A is independently -L1-OR 3B . [188] In some embodiments, at least one R 3A is independently -OR 3B .
  • at least one R 3A is independently –(C1-C3 alkylene)-OR 3B .
  • At least one R 3A is independently -L1-(C3-C6 carbocyclyl), -L1-(4- to 6- membered heterocyclyl), -L1-(C6-10aryl), or -L1-(5- to 10-membered heteroaryl), wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -L1-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D .
  • At least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl). [195] In some embodiments, at least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 3D . [196] In some embodiments, at least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -L 1 - (C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 3 R 3D .
  • At least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 4 R 3D .
  • at least one R 3A is independently –(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently –(C 3 -C 6 carbocyclyl).
  • at least one R 3A is independently –(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 3D .
  • At least one R 3A is independently –(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 3D . In some embodiments, at least one R 3A is independently –(C3- C 6 carbocyclyl), wherein the carbocyclyl is substituted with 3 R 3D . In some embodiments, at least one R 3A is independently –(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 4 R 3D .
  • At least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl).
  • at least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 3D .
  • At least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 2 R 3D . In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 3 R 3D . In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 4 R 3D .
  • At least one R 3A is independently -L1-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -L1-(4- to 6-membered heterocyclyl).
  • at least one R 3A is independently -L1-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 3D .
  • at least one R 3A is independently -L1-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 2 R 3D .
  • At least one R 3A is independently -L1-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -L1-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 4 R 3D . [209] In some embodiments, at least one R 3A is independently –(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D . [210] In some embodiments, at least one R 3A is independently –(4- to 6-membered heterocyclyl).
  • At least one R 3A is independently –(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 3D .
  • at least one R 3A is independently –(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 2 R 3D .
  • at least one R 3A is independently –(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 3 R 3D .
  • at least one R 3A is independently –(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 4 R 3D .
  • At least one R 3A is independently –(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently –(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl).
  • at least one R 3A is independently –(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R 3D .
  • At least one R 3A is independently –(C1-C3 alkylene)-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 2 R 3D . In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 3 R 3D . In some embodiments, at least one R 3A is independently –(C1-C3 alkylene)-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 4 R 3D .
  • At least one R 3A is independently -L1-(C6-10 aryl) substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -L1-(C6 aryl) substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -L1-(C6 aryl).
  • at least one R 3A is independently -L1-(C6 aryl) substituted with 1 R 3D .
  • at least one R 3A is independently -L1-(C6 aryl) substituted with 2 R 3D .
  • At least one R 3A is independently -L1-(C6 aryl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -L1-(C6 aryl) substituted with 4 R 3D . [222] In some embodiments, at least one R 3A is independently –(C6 aryl) substituted with 0, 1, 2, 3, or 4 R 3D . [223] In some embodiments, at least one R 3A is independently –(C6 aryl). [224] In some embodiments, at least one R 3A is independently –(C6 aryl) substituted with 1 R 3D .
  • At least one R 3A is independently –(C6 aryl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently –(C6 aryl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently –(C 6 aryl) substituted with 4 R 3D . [226] In some embodiments, at least one R 3A is independently –(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 0, 1, 2, 3, or 4 R 3D . [227] In some embodiments, at least one R 3A is independently –(C 1 -C 3 alkylene)-(C 6 aryl).
  • At least one R 3A is independently –(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 1 R 3D .
  • at least one R 3A is independently –(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 2 R 3D .
  • at least one R 3A is independently –(C 1 -C 3 alkylene)- (C 6 aryl) substituted with 3 R 3D .
  • at least one R 3A is independently –(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 4 R 3D .
  • At least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl).
  • at least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl) substituted with 1 R 3D .
  • at least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl) substituted with 2 R 3D .
  • At least one R 3A is independently -L 1 -(5- to 10- membered heteroaryl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -L1-(5- to 10-membered heteroaryl) substituted with 4 R 3D . [234] In some embodiments, at least one R 3A is independently –(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D . [235] In some embodiments, at least one R 3A is independently –(5- to 10-membered heteroaryl).
  • At least one R 3A is independently –(5- to 10-membered heteroaryl) substituted with 1 R 3D .
  • at least one R 3A is independently –(5- to 10-membered heteroaryl) substituted with 2 R 3D .
  • each R 3A is independently –(5- to 10-membered heteroaryl) substituted with 3 R 3D .
  • at least one R 3A is independently –(5- to 10-membered heteroaryl) substituted with 4 R 3D .
  • At least one R 3A is independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3A is independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl).
  • at least one R 3A is independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 1 R 3D .
  • At least one R 3A is independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -(C1-C3 alkylene)-(5- to 10-membered heteroaryl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(5- to 10-membered heteroaryl) substituted with 4 R 3D .
  • two R 3A groups are joined, with the atoms to which they are attached, to form C 6 aryl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, or 4- to 6-membered heterocyclyl.
  • two R 3A groups are joined, with the atoms to which they are attached, to form C 6 aryl.
  • two R 3A groups are joined, with the atoms to which they are attached, to form 5- to 6-membered heteroaryl.
  • two R 3A groups are joined, with the atoms to which they are attached, to form C 3 -C 6 carbocyclyl.
  • each R 3B is independently hydrogen, C 1 -C 3 alkyl, C 3 -C 6 carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3B is independently hydrogen.
  • each R 3B is independently C 1 -C 3 alkyl, C 3 -C 6 carbocyclyl, or 4- to 6- membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3D .
  • each R 3B is independently C1-C3 alkyl, C3-C6 carbocyclyl, or 4- to 6- membered heterocyclyl.
  • at least one R 3B is independently C1-C3 alkyl substituted with 0, 1, 2, 3, or 4 R 3D .
  • At least one R 3B is independently C1-C3 alkyl. [253] In some embodiments, at least one R 3B is independently C1-C3 alkyl substituted with 1 R 3D . [254] In some embodiments, at least one R 3B is independently C1-C3 alkyl substituted with 2 R 3D . [255] In some embodiments, at least one R 3B is independently C1-C3 alkyl substituted with 3 R 3D . [256] In some embodiments, at least one R 3B is independently C1-C3 alkyl substituted with 4 R 3D .
  • At least one R 3B is independently C3-C6 carbocyclyl substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3B is independently C3-C6 carbocyclyl.
  • at least one R 3B is independently C3-C6 carbocyclyl substituted with 1 R 3D .
  • at least one R 3B is independently C3-C6 carbocyclyl substituted with 2 R 3D .
  • at least one R 3B is independently C3-C6 carbocyclyl substituted with 3 R 3D .
  • At least one R 3B is independently C3-C6 carbocyclyl substituted with 4 R 3D .
  • at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3B is independently 4- to 6-membered heterocyclyl.
  • at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 1 R 3D .
  • at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 2 R 3D .
  • At least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 3 R 3D .
  • at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 4 R 3D .
  • each R 3C is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • at least one R 3C is independently C 1 -C 3 alkyl.
  • at least one R 3C is independently C1-C3 haloalkyl.
  • each R 3D is independently halogen, -OR 3E , -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • each R 3D is independently halogen or -OC1-C3 alkyl.
  • at least one R 3D is independently halogen.
  • at least one R 3D is independently F or Cl.
  • at least one R 3D is independently F.
  • at least one R 3D is independently Cl.
  • at least one R 3D is independently -OR 3E .
  • At least one R 3D is independently -OC1-C3 alkyl. [279] In some embodiments, at least one R 3D is independently -CN. [280] As generally defined herein, each R 3E is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl. [281] In some embodiments, at least one R 3E is independently hydrogen. [282] In some embodiments, at least one R 3E is independently C1-C3 alkyl. [283] In some embodiments, at least one R 3E is independently C1-C3 haloalkyl.
  • each L1 is independently a bond, C1-C3 alkylene, or C1-C3 haloalkylene. [285] In some embodiments, each L1 is independently a bond or C1-C3 alkylene. [286] In some embodiments, at least one L1 is independently a bond. [287] In some embodiments, at least one L1 is independently C1-C3 alkylene. [288] In some embodiments, at least one L1 is independently branched C1-C3 alkylene. [289] In some embodiments, at least one L1 is independently C1 alkylene. In some embodiments, at least one L 1 is independently C 2 alkylene.
  • At least one L 1 is independently C 3 alkylene.
  • at least one R 3A is independently -CN, -SO 2 CH 3 , -PO(CH 3 ) 2 , -OCH 3 , -OCHF 2 , -CH 3 , F, Cl, -OCH 2 CH 2 OCH 3 , -CH 2 CN, -CH 2 OH, -CH 2 OCH 3 , or -OCH 2 CH 2 CN.
  • at least one R 3A is independently -CN, -OCH 3 , -OCHF 2 , -CH 3 , or Cl.
  • at least one R 3A is independently -CN.
  • At least one R 3A is independently -SO 2 CH 3 . In some embodiments, at least one R 3A is independently -PO(CH 3 ) 2 . In some embodiments, at least one R 3A is independently -OCH 3 . In some embodiments, at least one R 3A is independently -OCHF 2 . In some embodiments, at least one R 3A is independently -CH 3 . In some embodiments, at least one R 3A is independently F. In some embodiments, at least one R 3A is independently Cl. In some embodiments, at least one R 3A is independently -OCH 2 CH 2 OCH 3 . In some embodiments, at least one R 3A is independently -CH 2 CN.
  • At least one R 3A is independently -CH 2 OH. In some embodiments, at least one R 3A is independently -CH 2 OCH 3 . In some embodiments, at least one R 3A is independently -OCH 2 CH 2 CN.
  • Ring C is: . (b) Ring A, R 4 , L2, and m [292] As generally defined herein, Ring A is a 5-membered monocyclic heteroaryl. [293] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 nitrogen atom. [294] In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 2 nitrogen atoms.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 oxygen atom.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 nitrogen atom and 1 oxygen atom.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 sulfur atom.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 nitrogen atom and 1 sulfur atom.
  • Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, or thiazole ring.
  • Ring A is: [301] In some embodiments, Ring A is: . [302] In some embodiments, Ring A is: (ii-b). In some embodiments, Ring A is: In some embodiments, Ring A is: (v-b). In some embodiments, Ring A is: some embodiments, Ring A is: ii-b). In some embodiments, Ring A is: embodiments, Ring A is: (xiv-b).
  • each R 4 is independently halogen, -CN, -L2-OR 4A , -L2-N(R 4B )2, C1-C6 alkyl, or C1-C6 haloalkyl.
  • at least one R 4 is independently halogen.
  • at least one R 4 is independently -F or -Cl.
  • at least one R 4 is independently -F.
  • at least one R 4 is independently -Cl.
  • at least one R 4 is independently -CN.
  • at least one R 4 is independently -L2-OR 4A .
  • At least one R 4 is independently -OR 4A .
  • at least one R 4 is independently –(C1-C3 alkylene)-OR 4A .
  • at least one R 4 is independently –(C1 alkylene)-OR 4A .
  • at least one R 4 is independently –(C2 alkylene)-OR 4A .
  • at least one R 4 is independently –(C3 alkylene)-OR 4A .
  • at least one R 4 is independently -OH.
  • At least one R 4 is independently –(C1-C3 alkylene)-OH. [320] In some embodiments, at least one R 4 is independently –(C1 alkylene)-OH. [321] In some embodiments, at least one R 4 is independently –(C2 alkylene)-OH. [322] In some embodiments, at least one R 4 is independently –(C3 alkylene)-OH. [323] In some embodiments, at least one R 4 is independently -O(C 1 -C 3 alkyl). [324] In some embodiments, at least one R 4 is independently –(C 1 -C 3 alkylene)-O(C 1 -C 3 alkyl).
  • At least one R 4 is independently –(C 1 alkylene)-O(C 1 -C 3 alkyl). [326] In some embodiments, at least one R 4 is independently –(C 2 alkylene)-O(C 1 -C 3 alkyl). [327] In some embodiments, at least one R 4 is independently –(C 3 alkylene)-O(C 1 -C 3 alkyl). [328] In some embodiments, at least one R 4 is independently -N(R 4B ) 2 . [329] In some embodiments, at least one R 4 is independently -L 2 -N(R 4B ) 2 .
  • At least one R 4 is independently -(C 1 -C 3 alkylene)-N(R 4B ) 2 . [331] In some embodiments, at least one R 4 is independently -NH 2 . [332] In some embodiments, at least one R 4 is independently -L 2 -NH 2 . [333] In some embodiments, at least one R 4 is independently -L 2 -NHC(O)CH 3 . [334] In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-NH 2 . [335] In some embodiments, at least one R 4 is independently -NH(R 4B ).
  • At least one R 4 is independently -L 2 -NH(R 4B ). [337] In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-NH(R 4B ). [338] In some embodiments, at least one R 4 is independently -N(C1-C3 alkyl)2. [339] In some embodiments, at least one R 4 is independently -L 2 -N(C 1 -C 3 alkyl) 2 . [340] In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl) 2 .
  • At least one R 4 is independently C1-C6 alkyl.
  • at least one R 4 is independently methyl.
  • at least one R 4 is independently ethyl.
  • at least one R 4 is independently propyl.
  • at least one R 4 is independently isopropyl.
  • at least one R 4 is independently butyl.
  • at least one R 4 is independently isobutyl.
  • at least one R 4 is independently tert-butyl.
  • at least one R 4 is independently C1-C6 haloalkyl.
  • At least one R 4 is independently halomethyl. In some embodiments, at least one R 4 is independently haloethyl. In some embodiments, at least one R 4 is independently halopropyl. In some embodiments, at least one R 4 is independently halo-isopropyl. In some embodiments, at least one R 4 is independently halobutyl. In some embodiments, at least one R 4 is independently halo-isobutyl. In some embodiments, at least one R 4 is independently halo-tert-butyl.
  • each instance of R 4 is independently selected from the group consisting of -CH3, -CH2CH3, -CHF2, -CF3, -Cl, -CN, -NH2, and -CH2OH. [346] In some embodiments, at least one instance of R 4 is independently -CH3 or -CH2CH3. [347] In some embodiments, at least one instance of R 4 is independently -CHF2 or -CF3. [348] In some embodiments, Ring A is:
  • Ring A is selected from: [351] In some embodiments, Ring A is: . [352] In some embodiments, Ring A is: . [353] In some embodiments, Ring A is: . [354] As generally defined herein, each L 2 is independently a bond, C 1 -C 3 alkylene, or C 1 -C 3 haloalkylene. [355] In some embodiments, each L2 is independently a bond or C1-C3 alkylene. [356] In some embodiments, at least one L 2 is independently a bond. [357] In some embodiments, at least one L 2 is independently C 1 -C 3 alkylene.
  • At least one L2 is independently C1 alkylene. In some embodiments, at least one L2 is independently C2 alkylene. In some embodiments, at least one L2 is independently C3 alkylene. [359] As generally defined herein, m is 0, 1, or 2. [360] In some embodiments, m is 0. [361] In some embodiments, m is 1 or 2. [362] In some embodiments, m is 1. In some embodiments, m is 2.
  • Ring A is a group of formula (ii-b)
  • the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond.
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • Ring C is .
  • each instance of R 3A is independently -L 1 - CN, -L 1 -OR 3B , C 1 -C 3 alkyl (e.g., -CH 3 ), or halo (e.g., Cl).
  • each instance of R 4 is independently C 1-3 alkyl (e.g., -CH 3 ) or -NH 2 .
  • m is 1 or 2.
  • n is 1 or 2.
  • R 1 is C1-C6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C1-C3 alkyl substituted with 0 R 1D .
  • R 1 is -L3-(C3-C6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L3 is bond.
  • R 1 is -L3-(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L3 is C1-C3 alkylene substituted with 0 R 1E .
  • Ring C is .
  • each instance of R 3A is independently -L1- CN, -L1-OR 3B , C1-C3 alkyl (e.g., -CH3), or halo (e.g., Cl).
  • each instance of R 4 is independently C1-3 alkyl (e.g., -CH3) or -NH2.
  • m is 1 or 2.
  • n is 1 or 2.
  • Ring A is a group of formula (xvii-b)
  • the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond.
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L3 is C1-C3 alkylene substituted with 0 R 1E .
  • Ring C is .
  • each instance of R 3A is independently -L1- CN, -L1-OR 3B , C1-C3 alkyl (e.g., -CH3), or halo (e.g., Cl).
  • each instance of R 4 is independently C1-3 alkyl (e.g., -CH3) or -NH2.
  • m is 1 or 2.
  • n is 1 or 2.
  • Ring C is of the formula (i-c)
  • the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond.
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • each instance of R 3A is independently -L 1 -CN, -L 1 -OR 3B , C 1 -C 3 alkyl (e.g., -CH 3 ), or halo (e.g., Cl).
  • each instance of R 4 is independently C 1-3 alkyl (e.g., -CH 3 ) or -NH 2 .
  • Ring .
  • m is 1 or 2.
  • n is 1 or 2.
  • Ring C is of the Formula (ii-c), (iii-c), or (iv-c)
  • the compound of Formula (I) is of Formula (I-e-1), (I-e-2), or (I-e-3), respectively: or a pharmaceutically acceptable salt thereof.
  • R 1 is C1-C6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C1-C3 alkyl substituted with 0 R 1D .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond.
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • each instance of R 3A is independently -L 1 -CN, -L 1 -OR 3B , C 1 -C 3 alkyl (e.g., -CH 3 ), or halo (e.g., Cl).
  • each instance of R 4 is independently C 1-3 alkyl (e.g., -CH 3 ) or -NH 2 .
  • Ring .
  • m is 1 or 2.
  • n is 1 or 2.
  • Ring C is of the formula (v-c) or (vi-c)
  • the compound of Formula (I) is of Formula (I-f-1) or (I-f-2), respectively: or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl substituted with 0 R 1D .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; R 1A is -OR 1B ; R 1B is hydrogen, and L 3 is bond.
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene substituted with 0 R 1E .
  • each instance of R 3A is independently -L 1 -CN, -L 1 -OR 3B , C 1 -C 3 alkyl (e.g., -CH 3 ), or halo (e.g., Cl).
  • each instance of R 4 is independently C 1-3 alkyl (e.g., -CH 3 ) or -NH 2 .
  • m is 1 or 2.
  • n is 1 or 2.
  • the compound of Formula (I) is selected from any one of the compounds of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds of Table 1 or Table 2.
  • the compound of Formula (I) is a free base selected from any one of the compounds of Table 1 or Table 2.
  • the below Table 1 and Table 2 also provides the location of the Compound (#) in the Examples (Ex) by Example Number or as provided in Table A (TA) of the Examples. Table 1.
  • Compounds of Formula (I) Table 1.
  • Compounds of Formula (I) Table 1.
  • Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1.
  • Compounds of Formula (I) Table 1. Compounds of Formula (I) Table 1.
  • Table 1 Compounds of Formula (I) Table 1.
  • the compound is Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 17, Compound 22, Compound 24A*, Compound 24B*, Compound 40, Compound 43A*, Compound 43B*, Compound 44, Compound 45, Compound 46B, Compound 47B, Compound 55A*, Compound 55B*, Compound 62A*, Compound 62B*, Compound 63A*, Compound 63B*, Compound 71A*, Compound 71B*, or Compound 74, or a pharmaceutically acceptable salt of any of the foregoing. ii.
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • exemplary pharmaceutical acceptable carriers include excipients, diluents, and surfactants.
  • the compounds of the present disclosure, or pharmaceutical compositions comprising same can be administered in an amount effective to treat a disorder in a subject.
  • Administration can be accomplished via any mode of administration. Exemplary modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration modes.
  • the disclosed compounds and compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • the disclosed compounds and compositions can also be administered by intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular in a form suitable for these types of administration.
  • parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Illustrative pharmaceutical compositions may be tablets or gelatin capsules comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt
  • a diluent e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogen
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of modulating cGAS activity in a cell (e.g., in vitro or in vivo) comprising contacting the cell with an a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of modulating cGAS activity in a cell (e.g., in vitro or in vivo) comprising contacting the cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is associated with implicated cGAS activity.
  • the disease or disorder is a disease or disorder in which cGAS activity is implicated.
  • the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating cGAS activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating cGAS activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides compounds that function as modulators of cGAS activity.
  • modulation is inhibition.
  • the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an cGAS-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in cGAS.
  • the disease or disorder is cancer.
  • the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer.
  • the disease or disorder is a central nervous system disorder.
  • the central nervous system disorder is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis (ALS), multiple sclerosis, ataxia telangiectasia, or age-related macular degeneration.
  • the disease or disorder is kidney disease.
  • the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.
  • the chronic kidney disease is diabetic nephropathy.
  • the disease or disorder is a skin disease.
  • the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.
  • the disease or disorder is a rheumatic disease.
  • the rheumatic disease is dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.
  • the disease or disorder is a liver disease.
  • the liver disease is nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • the disease or disorder is a cardiovascular disease.
  • the cardiovascular disease is cardiomyopathy, atherosclerosis, or peripheral artery disease (PAD).
  • the disease or disorder is a metabolic disease.
  • the metabolic disease is obesity-induced insulin-resistance.
  • the disease or disorder is a cGAS-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in cGAS.
  • the disease or disorder is an inflammatory, allergic or autoimmune disease such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), Chilblain lupus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Aicardi Goutines syndrome, dermatomyositis, systemic sclerosis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, or Sjogren’s syndrome (SS).
  • SLE systemic lupus erythematosus
  • CLE cutaneous lupus erythematosus
  • Chilblain lupus Chilblain lupus
  • psoriasis insulin-dependent diabetes me
  • the disease or disorder is inflammation of any tissue or organ of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.
  • musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons.
  • musculoskeletal inflammation examples include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).
  • Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids.
  • ocular inflammation examples include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
  • inflammation of the nervous system examples include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, and schizophrenia.
  • Examples of inflammation of the vasculature or lymphatic system include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.
  • Examples of inflammatory conditions of the digestive system include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, and proctitis.
  • Examples of inflammatory conditions of the reproductive system include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo- ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.
  • the disease or disorder is an autoimmune conditions having an inflammatory component.
  • autoimmune conditions include systemic lupus erythematosus, cutaneous lupus erythematosus, acute disseminated alopecia universalise, Bechet’s disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, Goodpasture's syndrome.
  • Grave's disease Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, Aicardi Goutines syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
  • the disease or disorder is a T-cell mediated hypersensitivity diseases having an inflammatory component.
  • T-cell mediated hypersensitivity diseases having an inflammatory component.
  • Such conditions include contact hypersensitivity, contact dermatitis (including that due to poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (Celiac disease).
  • other inflammatory conditions include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xenografts, serum sickness, and graft vs host disease), acute
  • Sezary’s syndrome congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, crizis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukemia and lymphomas in adults, acute leukemia of childhood, regional enteritis
  • Hydroxyl protection with group R 1 may provide a compound of Formula (D), or salt thereof.
  • Deprotection of the alkyl ester of Formula (D), or salt thereof may provide a carboxylic acid compound of Formula (D), or salt thereof, wherein R a is hydrogen.
  • General Scheme 1 As depicted in General Scheme 2, reacting a hydrazine carbothioamide of Formula (G), or salt thereof, with a carboxylic acid containing compound of Formula (F-1), or salt thereof, or nitrile containing compound of Formula (F-2), or salt thereof, wherein R 4 and m are as defined herein, may provide a 1,3,4-thiadiazol-2-amine of Formula (H-1), or salt thereof.
  • amine compounds of Formula (H-2), wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety and wherein R 4 and m are as defined herein may be prepared by coupling a 5-halo-1,3,4-thiadiazol-2-amine of Formula (M), or salt thereof, wherein Y is Cl, Br, or I, with an amine of Formula (L), or salt thereof.
  • the compound of Formula (N), or salt thereof may then be deprotected to provide a carboxylic acid compound of Formula (N), or salt thereof, wherein R a is hydrogen.
  • General Scheme 4. [416] The above-described compounds of Formula (D) and (N), or salts thereof, wherein R a is hydrogen, C1-6 alkyl or C1-6 haloalkyl, and amine compounds of Formula (H-1) or (H-2), or salts thereof, each may be used as intermediates in preparing compounds of Formula (I), or salts thereof.
  • peptide coupling the amine of Formula (H-1), or salt thereof, with the compound of Formula (D), or salt thereof, wherein R a is hydrogen, C1-6 alkyl or C1-6 haloalkyl, may provide an amide compound of Formula (J-1), or salt thereof.
  • the amide compound of Formula (J-1), or salt thereof, may then be cross-coupled with an aryl or heteroaryl boronic acid or boronic ester (K-1), or salt thereof, or an aryl or heteroaryl stannane (K-2), or salt thereof, or an aryl or heteroaryl sulfonate (K- 3), or salt thereof, (also referred to herein as an “aryl boron reagent” or “aryl tin reagent” or “aryl sulfonate reagent”).
  • K-1 aryl or heteroaryl boronic acid or boronic ester
  • K-2 aryl or heteroaryl stannane
  • K- 3 aryl or heteroaryl sulfonate
  • the amide compound of Formula (J-2), or salt thereof may then be cross-coupled with aryl or heteroaryl boronic acid or boronic ester (K-1), or salt thereof, or an aryl or heteroaryl stannane (K-2), or salt thereof, or an aryl or heteroaryl sulfonate (K-3), or salt thereof, (also referred to herein as an “aryl boron reagent” or “aryl tin reagent” or “aryl sulfonate reagent”), to provide a compound of Formula (I′), or salt thereof, wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.
  • Biological Assays Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the compounds described herein can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the compounds described herein for activity, using techniques known in the art.
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, as well as assays for determining hcGAS potency and inhibitory activity, unbound clearance, solubility, and permeability.
  • the compounds of the instant disclosure may be tested for their human- cGAS (h-cGAS) inhibitory activity using known procedures, such as the methodology reported in Lama et al., Nature Communications (2019) 10:2261 (2019). See also Examples, Assay Methods section.
  • the compounds of the instant disclosure may be tested for unbound clearance (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63:12156-12170.
  • unbound clearance (Clu) may be calculated by dividing total clearance (‘CL’ in mL/min/kg) as measured in blood or plasma by the unbound fraction in plasma (fu).
  • CL total clearance
  • the solubility of compounds of the instant disclosure may be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrom. (2000) 35:71-76.
  • the kinetic solubility in physiologically relevant media may be measured using serial dilution and two hour incubation period, followed by filtration, and reported in uM by LC-MS/MS.
  • Thermodynamic solubility in physiologically relevant media may be measured by LC-MS/MS, after a twenty-four hour incubation, followed by filtration, and reported in mg/mL.
  • the permeability of compounds of the instant disclosure may be determined following known procedures, such as described in Wang et al. J Mass Spectrom. (2000) 35:71-76.
  • permeability across cell membranes may be measured using either Caco-2 or MDCK-MDR1 cell lines in Transwell plates, after measuring the compound in both apical and basolateral chambers, and reported as an apparent permeability Papp A-B in 10 -6 cm/s.
  • Ring A is a 5-membered monocyclic heteroaryl
  • Embodiment 2 The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I′): or a pharmaceutically acceptable salt thereof, wherein a nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.
  • Embodiment 3 The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl substituted with 0, 1, 2, 3, or 4 R 3A .
  • Embodiment 4 The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 6-membered heteroaryl, wherein the heteroaryl has 1 ring N atom.
  • Embodiment 1 The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 5-membered heteroaryl, wherein the heteroaryl has 2 ring N atoms.
  • Embodiment 6 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is: [435] Embodiment 7.
  • Embodiment 8. The compound of any one of the preceding Embodiments, wherein the compound is of Formula (I-e-1), (I-e-2), or (I-e-3):
  • Embodiment 9 The compound of any one of the preceding Embodiments, wherein the compound is of Formula (I-f-1) or (I-f-2): or a pharmaceutically acceptable salt thereof.
  • Embodiment 10 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein at least one R 3A is independently -CN, -OCH3, - OCHF2, -CH3, or Cl.
  • Embodiment 11 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is:
  • Embodiment 12 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is:
  • Embodiment 13 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6 alkyl substituted with 1 or 2 R 1A ; each R 1A is independently -OR 1B ; and each R 1B is independently hydrogen or C1-C3 alkyl substituted with 0 R 1D . [442] Embodiment 14.
  • Embodiment 18 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is:
  • Embodiment 19 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is: [448] Embodiment 20.
  • each R 4 is independently halogen, -CN, -L 2 -OR 4A , - L 2 -N(R 4B ) 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • Embodiment 22 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently halogen, -CN, -L 2 -OR 4A , - L 2 -N(R 4B ) 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • Embodiment 23 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is: .
  • Embodiment 24 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is: ,
  • Embodiment 25 The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A is: [454] Embodiment 26. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 1. [455] Embodiment 27. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 2. [456] Embodiment 28. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 1. [457] Embodiment 29.
  • Embodiment 30 The compound of Embodiment 1, wherein the compound is selected from those in Table 1 or Table 2, and pharmaceutically acceptable salts thereof.
  • Embodiment 31 A pharmaceutical composition comprising the compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 32 A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Embodiment 33 A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Embodiment 34 A method of preparing a compound of Formula (I): or a salt thereof, wherein Ring A, Ring C, R 1 , R 3A , R 4 , m, and n are defined in Embodiment 1, the method comprising peptide coupling of a compound of Formula (H-1), or salt thereof, with a compound of Formula (N), or salt thereof: wherein R a is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl, to provide a compound of Formula (I), or salt thereof.
  • Embodiment 35 The method of Embodiment 34, wherein the compound of Formula (H-1), or salt thereof, is of Formula (H-2): salt thereof, and wherein the method provides a compound of Formula (I′): [464] Embodiment 36.
  • Embodiment 34 or 35 further comprising cross-coupling a compound of Formula (K-1), (K-2), or (K-3), or salt thereof, with a compound of Formula (D), or salt thereof, (K-1) wherein: R a is C1-6 alkyl or C1-6 haloalkyl; R C is Ring C; X is Cl, Br, or I; each R is independently H, an optionally substituted C 1-6 alkyl, or two R groups are joined to form a 5-6 membered ring; and each R′ is independently an optionally substituted C 1-6 alkyl; to provide a compound of Formula (N), or salt thereof.
  • R a is C1-6 alkyl or C1-6 haloalkyl
  • R C is Ring C
  • X is Cl, Br, or I
  • each R is independently H, an optionally substituted C 1-6 alkyl, or two R groups are joined to form a 5-6 membered ring
  • each R′ is independently an optionally substituted C 1-6 alkyl; to
  • Embodiment 38 The method of Embodiment 37, wherein the compound of Formula (J-1), or salt thereof, is of Formula (J-2): (J-2), or salt thereof, and wherein the method provides a compound of Formula (I′): (I′), or salt thereof.
  • Embodiment 39 The method of Embodiment 37, further comprising peptide coupling of a compound of Formula (H-1), or salt thereof, with a compound of Formula (D), or salt thereof: to provide a compound of Formula (J-1), or salt thereof.
  • Embodiment 40 Embodiment 40.
  • Embodiment 38 further comprising peptide coupling of a compound of Formula (H-2), or salt thereof, with a compound of Formula (D), or salt thereof: to provide a compound of Formula (J-2), or salt thereof.
  • Embodiment 41 The method of Embodiment 34 or 39, further comprising reacting a hydrazine carbothioamide of Formula (G), or salt thereof, with a carboxylic acid containing compound of Formula (F-1), or salt thereof, or nitrile containing compound of Formula (F-2), or salt thereof: to provide a compound of Formula (H-1), or salt thereof.
  • Embodiment 42 Embodiment 42.
  • Embodiment 35 or 40 further comprising coupling a compound Formula (M), or salt thereof, wherein Y is Cl, Br, or I, with an amine of Formula (L), or salt thereof: (L) to provide a compound of Formula (H-2), or salt thereof.
  • LCMS Liquid Chromatography - Mass Spectrometry
  • Mobile phases of water and/or acetonitrile may contain a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), ammonia (NH3.H2O), or ammonium carbonate (NH4HCO3).
  • TFA trifluoroacetic acid
  • FA formic acid
  • NH3.H2O ammonia
  • NH4HCO3 ammonium carbonate
  • ESI or ES electrospray ionization
  • m/z mass/charge
  • RT retention time (minutes).
  • Purification/Separation Methods The synthetic methods describe purification and/or separation chromatographic methods which have been employed in the purification and/or isolation of the exemplified compounds.
  • Rf retention factor
  • RT retention time (minutes);
  • Prep-HPLC Preparative High-performance liquid chromatography.
  • Step 1 Into a solution of 5-hydroxy-6-oxopyran-2-carboxylic acid (180 g, 1153 mmol, 1 equiv) in methanol (MeOH) (2000 mL) was added H 2 SO 4 (10 mL, 56 mmol) at room temperature. Then the resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (EtOAc) (1000 mL) and the organic phase was washed water (3 x 300 mL), and dried over anhydrous Na2SO4.
  • EtOAc ethyl acetate
  • Step 2 To a stirred solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (1 g, 5.9 mmol, 1 equiv) in acetic acid (AcOH) (25 mL, 323 mmol) was added N-bromosuccinimide (NBS) (1.25 g, 7.02 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C then diluted with water (70 mL).
  • AcOH acetic acid
  • NBS N-bromosuccinimide
  • Step 3 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4 g, 16 mmol, 1 equiv) in dichloromethane (DCM) (50 mL) was added diisopropylethylamine (DIEA) (11 g, 85.1 mmol, 5 equiv) and methyl trifluoromethanesulfonate (TfOMe) (13 g, 79.2 mmol, 5 equiv) dropwise at room temperature. The resulting mixture was stirred for 4 h at room temperature. The mixture was then diluted with water (200 mL) and extracted with DCM (3 x 200 mL).
  • DCM dichloromethane
  • Step 5 A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (200 g, 1110 mmol, 1 equiv), diisopropylethylamine (DIEA) (431 g, 3333 mmol, 3 equiv) and pyrazole (90.76 g, 1333 mmol, 1.2 equiv) in 1,4-dioxane was stirred for 3 h at 80 °C. The resulting mixture was concentrated under vacuum and the residue was dissolved in tetrahydrofuran (THF). The mixture was filtered, and the filter cake was washed with THF.
  • DIEA diisopropylethylamine
  • pyrazole 90.76 g, 1333 mmol, 1.2 equiv
  • Step 6 A mixture of 5-(pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 g, 598 mmol, 1 equiv), tosic acid (TsOH) (20.60 g, 119.6 mmol, 0.2 equiv) and 2,5-hexanedione (102 g, 897 mmol, 1.5 equiv) in toluene was stirred for 2 h at 110 °C.
  • TsOH tosic acid
  • Step 7 A solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (50 g, 204 mmol, 1 equiv) in tetrahydrofuran (THF) was treated with n-butyl lithium (n-BuLi) (97.8 mL, 245 mmol, 1.2 equiv) for 1 h at -78 °C under N 2 (nitrogen gas) followed by the addition of methyl iodide (CH 3 I) (34.7 g, 245 mmol, 1.2 equiv) dropwise at -78 °C.
  • n-BuLi n-butyl lithium
  • CH 3 I methyl iodide
  • Step 8 To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazole (7 g, 27 mmol, 1 equiv) in tetrahydrofuran (THF) (14 mL) and H2O (28 mL) at room temperature was added trifluoroacetic acid (TFA) (28 mL). The resulting mixture was stirred for 2 h at 50 °C then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • TFA trifluoroacetic acid
  • Step 9 To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (12 g, 48.2 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (150 mL) was added hydroxybenzotriazole (HOBt) (13.02 g, 96.38 mmol, 2 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (27.81 g, 145.05 mmol, 3 equiv) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (9 g, 49.7 mmol, 1 equiv) at room temperature.
  • HOBt hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • EDCI 1-ethyl-3-
  • Step 10 To a solution of 4-bromo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (100 mg, 0.24 mmol, 1 equiv) (“halo-pyrone reagent”) in N,N-dimethylformamide (DMF) (3 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) (40 mg, 0.055 mmol, 0.2 equiv), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (80 mg, 0.35 mmol, 1.4 equiv) (“aryl boron reagent”) and K 2 CO 3 (100 mg, 0.72 mmol, 3
  • Example 2 4-(2-(dimethylphosphoryl)phenyl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 3)
  • Step 1 To a stirred solution of 1-bromo-2-iodobenzene (500 mg, 1.77 mmol, 1 equiv) in N,N- dimethylformamide (DMF) (5 mL) was added palladium (II) acetate (Pd(OAc)2) (40 mg, 0.18 mmol, 0.1 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (205 mg, 0.35 mmol, 0.2 equiv), K3PO4 (566 mg, 2.67 mmol, 1.5 equiv) and (methylphosphonoyl)methane (
  • Step 2 To a stirred solution of 1-bromo-2-(dimethylphosphoryl)benzene (300 mg, 1.29 mmol, 1 equiv) in dioxane (3 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) (180 mg, 0.25 mmol, 0.2 equiv), potassium acetate (AcOK) (390 mg, 3.97 mmol, 3 equiv) and bis(pinacolato)diboron (3.30 g, 13.0 mmol, 10 equiv) at room temperature under nitrogen atmosphere.
  • Step 3 4-(2-(dimethylphosphoryl)phenyl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 3) was prepared according to Example 1, Step 10 using 2-[2-(dimethylphosphoryl)phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane as the “aryl boron reagent” and 4-bromo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of step 10, Example 1) as the “halo-pyrone reagent” and dioxane/H2O (10:1) as solvent in place of N,N-dimethylformamide (DMF).
  • Example 3 3-(2-methoxyethoxy)-4-(3-methoxypyridin-2-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 4)
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (5 g, 20 mmol, 1 equiv) and 2-methoxyethanol (2 g, 26 mmol, 1.3 equiv) in tetrahydrofuran (THF) was added triphenyl phosphine (PPh 3 ) (8 g, 30 mmol, 1.5 equiv) in portions at room temperature.
  • PPh 3 triphenyl phosphine
  • Step 2 A solution of methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate (1700 mg, 5.54 mmol, 1 equiv) in HCl (6M) (30 mL) was stirred for 3 h at 80 °C. The resulting mixture was then concentrated under reduced pressure and diluted with ethyl acetate (EtOAc) (200 mL), washed with brine (3 x 10 mL), and dried over anhydrous Na2SO4.
  • EtOAc ethyl acetate
  • Step 3 To a stirred solution of 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid (1200 mg, 4.09 mmol, 1 equiv) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 8, Example 1) (820 mg, 4.52 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (21 mL) was added hydroxybenzotriazole (HOBT) (1110 mg, 8.22 mmol, 2 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (2355 mg, 12.3 mmol, 3 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Step 4 To a stirred solution of 4-bromo-5-(2-methoxyethoxy)-N-[5-(5-methylpyrazol-1-yl)- 1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (80 mg, 0.18 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added 3-methoxy-2-(tributylstannyl)pyridine (“aryl tin reagent”) (110 mg, 0.28 mmol, 1.58 equiv), tetrakis (triphenylphosphine)palladium (0) (Pd(PPh3)4) (50 mg, 0.043 mmol, 0.25 equiv) and CuI (10 mg, 0.053 mmol, 0.30 equiv) at room temperature.
  • halo-pyrone reagent 80 mg, 0.18 mmol, 1 equi
  • Step 2 Into a 40 mL vial was added methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate (750 mg, 4.32 mmol, 1 equiv) and methanol (MeOH) (4.0 mL) at room temperature. To the above mixture was added NaOH (330 mg, 8.25 mmol, 2 equiv) in H 2 O (4.0 mL) at room temperature. The resulting mixture was stirred for an additional 2 h at 50 °C. The mixture was then acidified to pH 6 with HCl (3 M). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 30 mL).
  • EtOAc ethyl acetate
  • Step 3 Into a 40 mL vial was added 3-chloro-1-methylpyrrole-2-carboxylic acid (2.2 g, 13.8 mmol, 1 equiv), N,N-dimethylformamide (DMF) (20 mL), 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (15.7 g, 41.4 mmol, 3 equiv), diisopropylethylamine (DIEA) (5.42 g, 41.9 mmol, 3 equiv) and NH4Cl (2.97 g, 55.6 mmol, 4 equiv) at room temperature.
  • DIEA diisopropylethylamine
  • Step 4 Into a 40 mL vial was added 3-chloro-1-methylpyrrole-2-carboxamide (1.40 g, 8.83 mmol, 1 equiv), dichloroethane (DCE) (20 mL) and methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (6.29 g, 26.4 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The reaction was then quenched with water at room temperature and extracted with dichloromethane (DCM) (3 x 20 mL).
  • DCE dichloroethane
  • DCM dichloromethane
  • Step 5 A mixture of 3-chloro-1-methylpyrrole-2-carbonitrile (100 mg, 0.71 mmol, 1 equiv) and thiosemicarbazide (200 mg, 2.19 mmol, 3.1 equiv) in trifluoroacetic acid (TFA) (5 mL) was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by C18 reverse phase flash chromatography (acetonitrile (MeCN) in water, 30% to 40% gradient in 10 min; detector, UV 254 nm) to afford 5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4- thiadiazol-2-amine (45 mg, 26% yield).
  • TFA trifluoroacetic acid
  • Step 6 To a stirred solution of 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid (product of Step 2, Example 3) (300 mg, 1.02 mmol, 1 equiv) and 5-(3-chloro-1-methylpyrrol- 2-yl)-1,3,4-thiadiazol-2-amine (270 mg, 1.26 mmol, 1.23 equiv) in N,N-dimethylformamide (DMF) (6 mL) was added hydroxybenzotriazole (HOBT) (270 mg, 2 mmol, 1.95 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (600 mg, 3.13 mmol, 3.06 equiv) in portions at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Step 7 Into a 20 mL vial was added 4-bromo-N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4- thiadiazol-2-yl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (80 mg, 0.16 mmol, 1 equiv), 2,6-dimethoxyphenylboronic acid (“aryl boron reagent”) (36 mg, 0.2 mmol, 1.2 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl2) ⁇ CH2Cl2 complex (26.6 mg, 0.033 mmol, 0.2 equiv), K3PO4 (104 mg, 0.49 mmol, 3 equiv), dioxane (1.5 mL), and H2O (0.3 mL
  • Step 1 To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (6 g, 24.46 mmol, 1 equiv) in tetrahydrofuran (THF) (70 mL) was added n-butyl lithium (n-BuLi) (11.74 mL, 29.35 mmol, 1.2 equiv, 2.5 M) in portions at -78 °C under N2 (nitrogen gas). The resulting mixture was stirred for 1 h at -78 °C under N2.
  • THF tetrahydrofuran
  • Step 2 A mixture of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-iodopyrazol-1-yl)-1,3,4-thiadiazole (2 g, 5.39 mmol, 1 equiv), tris(dibenzylidenaceton)dipalladium(0) dibenzylidenacetone (Pd 2 (dba) 3 ) (494 mg, 0.539 mmol, 0.1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XantPhos) (624 mg, 1.078 mmol, 0.2 equiv), Cs 2 CO 3 (3.53 g, 10.8 mmol, 2 equiv) and acetamide (962 mg, 16.3 mmol, 3 equiv) in dioxane (25 mL) was stirred for 1 h at 120 °C under N 2 then concentrated under vacuum.
  • Step 3 To a stirred solution of N- ⁇ 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2- yl]pyrazol-3-yl ⁇ acetamide (1.10 g, 3.64 mmol, 1 equiv) in tetrahydrofuran (THF) (4 mL) and H2O (4 mL) was slowly added trifluoroacetic acid (TFA) (8 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature then volatiles removed under a stream of N2. The residue was then diluted with dichloromethane (DCM) (3 mL).
  • DCM dichloromethane
  • Step 4 To a stirred solution of 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid (product of Step 2, Example 3) (300 mg, 1.02 mmol, 1 equiv) and N-(1-(5-amino-1,3,4- thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (253 mg, 1.13 mmol, 1.1 equiv) in acetonitrile (MeCN) (6 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (575 mg, 2.05 mmol, 2 equiv) and N-methylimidazole (NMI) (842 mg, 10.2 mmol, 10 equiv) in portions at room temperature.
  • MeCN acetonitrile
  • TCFH chloro-N,N,N′,N′
  • Step 5 To a stirred solution of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2- yl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (300 mg, 0.60 mmol, 1 equiv) and 2,6-dimethoxyphenylboronic acid (“aryl boron reagent”) (164 mg, 0.90 mmol, 1.5 equiv) in dioxane (3 mL) and H 2 O (0.6 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) (87 mg, 0.12 mmol, 0.2 equiv) and K 3 PO 4 (382 mg, 1.80 mmol, 3 equiv) in portions at room temperature.
  • Step 6 To N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 6-Ac) (200 mg, 0.36 mmol, 1 equiv) was added conc. HCl (5 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. Water was then added and the resulting solids collected by filtration and washed with water (3 x 20 mL).
  • Example 6 4-(3-cyanopyridin-2-yl)-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 7)
  • Step 1 To a stirred solution of 2-bromopyridine-3-carbonitrile (3 g, 16 mmol, 1 equiv) and methyl 3-(sodiooxysulfinyl)propanoate (8.56 g, 49.2 mmol, 3 equiv) in DMSO (20 mL) was added CuI (9.37 g, 49.2 mmol, 3 equiv) at room temperature.
  • Step 2 To a stirred solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylate (product of Step 1, Example 3) (2.7 g, 8.8 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (30 mL) was added palladium (II) acetate (Pd(OAc) 2 ) (0.5 g, 2.2 mmol, 0.2 equiv), butylbis[(3R,5S,7s)-adamantan-1-yl]phosphane (cataCXiumA) (0.9 g, 2.5 mmol, 0.3 equiv), K2CO3 (3.6 g, 26 mmol, 3 equiv) and methyl 3-(3-cyanopyridin-2-ylsulfonyl)propanoate (2.70 g, 10.6 mmol, 1.2 equiv) at room temperature.
  • Step 3 To a stirred solution of methyl 4-(3-cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6- oxopyran-2-carboxylate (100 mg, 0.30 mmol, 1 equiv) in tetrahydrofuran (THF) (5 mL) was added trimethyltin hydroxide (170 mg, 0.94 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure to provide crude 4- (3-cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid, which was used directly in the next step without further purification.
  • THF tetrahydrofuran
  • Step 4 To a stirred solution of 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 8, Example 1; “ADT amine reagent”) (65 mg, 0.36 mmol, 1.19 equiv) in acetonitrile (MeCN) (2 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (130 mg, 0.46 mmol, 1.54 equiv), N-methylimidazole (NMI) (50 mg, 0.61 mmol, 2.03 equiv) and 4-(3- cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) (95 mg, 0.30 mmol, 1 e
  • Step 2 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- cyano-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 8-Ac) (30 mg, 0.05 mmol, 1 equiv) in EtOH (1 mL) was added conc. HCl (1 mL) at 0 °C. The resulting mixture was then stirred for 2 h at room temperature then concentrated under vacuum.
  • Example 8 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3-cyanopyridin-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 9) and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3-cyanopyridin-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H- pyran-6-carboxamide (Compound 9-Ac) [513] Step 1: To a stirred solution of 4-(3-cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylic acid (product of Step 3, Example 6; “aryl-pyrone reagent”) (100 mg, 0.32 mmol, 1
  • Step 2 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3-cyanopyridin-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 9) was prepared according to Step 2 of Example 7 by acidic deprotection of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)- 4-(3-cyanopyridin-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 9-Ac).
  • Example 9 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-4-(3- methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 10) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo- 2H-pyran-6-carboxamide (Compound 10-Ac)
  • Step 1 To a stirred solution of methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylate (product of Step 1, Example 3) (500 mg, 1.63 mmol, 1 equiv) in toluene (6 mL) was added tetrakis (triphenylphosphine)palladium (0) (Pd(PPh3)4) (376 mg, 0.32 mmol, 0.2 equiv), CuI (106 mg, 0.56 mmol, 0.34 equiv) and 3-methoxy-2-(tributylstannyl)pyridine (1.30 g, 3.27 mmol, 2 equiv) at room temperature under nitrogen atmosphere.
  • Step 2 A solution of methyl 3-(2-methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H- pyran-6-carboxylate (400 mg, 1.19 mmol, 1 equiv) in hydrochloric acid (8 mL, 6 M) was stirred for 1 h at 80 °C then cooled to rt and concentrated under reduced pressure to afford crude 3-(2- methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxylic acid (390 mg, 100% yield) which was used directly in the next step without further purification.
  • Step 3 To a solution of 3-(2-methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6- carboxylic acid (“aryl-pyrone reagent”) (320 mg, 1 mmol, 1 equiv) in MeCN (6 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (545 mg, 1.94 mmol, 2 equiv) and N-methylimidazole (NMI) (320 mg, 3.89 mmol, 4 equiv) and N-(1-(5-amino-1,3,4- thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5; “ADT amine reagent”) (257 mg, 1.14 mmol
  • Example 10 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dicyanophenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 12) and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dicyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran- 6-carboxamide (Compound 12-Ac)
  • Step 1 To a solution of isophthalonitrile (2 g, 16 mmol, 1 equiv) in tetrahydrofuran (THF) (100 mL) was added a solution of lithium diisopropyl amide (LDA) (12.8 mL of a 2M solution in n- hexane, 25.6 mmol, 1.6 equiv) in n-hexane dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at -78 °C then tributyltin chloride (Bu 3 SnCl) (6.7 g, 21 mmol, 1.3 equiv) was added at -78 °C.
  • LDA lithium diisopropyl amide
  • Step 2 To a stirred solution of methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylate (product of Step 1, Example 3) (3 g, 9.8 mmol, 1 equiv) and 2- (tributylstannyl)isophthalonitrile (6.12 g, 14.7 mmol, 1.50 equiv) in toluene (30 mL) was added tetrakis (triphenylphosphine)palladium (0) (Pd(PPh3)4) (2.3 g, 2.0 mmol, 0.2 equiv) and CuI (0.95 g, 5.0 mmol, 0.51 equiv) at room temperature.
  • Pd(PPh3)4 tetrakis (triphenylphosphine)palladium (0)
  • Step 3 To a solution of methyl 4-(2,6-dicyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran- 6-carboxylate (1.7 g, 4.8 mmol, 1 equiv) in tetrahydrofuran (THF) (10 mL) was added trimethylstannanol (0.9 g, 5.0 mmol, 1 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature then poured into water and acidified to pH 5 with HCl (aq.).
  • THF tetrahydrofuran
  • Step 4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dicyanophenyl)-3- (2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 12-Ac) was prepared according to Step 3 of Example 9 using 4-(2,6-dicyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylic acid in place of 3-(2-methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6- carboxylic acid as the “aryl-pyrone reagent” and using N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H- pyrazol-5-y
  • Step 1 Into a solution of methyl 5-hydroxy-6-oxopyran-2-carboxylate (25 g, 147 mmol, 1 equiv) in acetic acid (AcOH) (300 mL) was added N-iodosuccinimide (NIS) (39 g, 173 mmol, 1.18 equiv) in portions at room temperature. The resulting mixture was stirred for 20 h at 80 °C then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (EtOAc) (1 L) and washed with water (3 x 100 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • EtOAc ethyl acetate
  • Step 2 Into a solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20 g, 67.6 mmol, 1 equiv) in dichloromethane (DCM) (250 mL) was added diisopropylethylamine (DIEA) (26 g, 201 mmol, 3 equiv) at room temperature. To the above mixture was added triflate ester (33 g, 201 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature then poured into water and extracted with DCM (3 x 500 mL).
  • DCM dichloromethane
  • Step 4 A solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (2.60 g, 8.78 mmol, 1 equiv), hydroxybenzotriazole (HOBT) (1.80 g, 13.3 mmol, 1.5 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (3.60 g, 18.8 mmol, 2.1 equiv) and 5-(5-methylpyrazol- 1-yl)-1,3,4-thiadiazol-2-amine (product of Step 8, Example 1) (1.40 g, 7.72 mmol, 0.9 equiv) in N,N-dimethylformamide (DMF) (40 mL) was stirred for 1 h at room temperature.
  • DMF N,N-dimethylformamide
  • Step 5 To a solution of 3-iodo-2H-pyrazole-4-carbonitrile (1 g, 4.6 mmol, 1 equiv) and K2CO3 (1.26 g, 9.13 mmol, 2 equiv) in acetonitrile (MeCN) (12 mL) was added methyl iodide (MeI) (1.94 g, 13.7 mmol, 3 equiv) dropwise at room temperature and then the resulting solution was stirred for 1 h at room temperature. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (EtOAc) (4 x 30 mL).
  • MeI methyl iodide
  • Step 6 A solution of tricyclohexylphospine (PCy3) (130 mg, 0.46 mmol, 0.2 equiv) and bis (dibenzylideneacetone)palladium(0) (Pd(dba)2) (280 mg, 0.49 mmol, 0.21 equiv) in 1,4-dioxane (5 mL) was stirred for 30 min at room temperature under nitrogen atmosphere.
  • PCy3 tricyclohexylphospine
  • Pd(dba)2 bis (dibenzylideneacetone)palladium(0)
  • Step 7 A solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-4- carbonitrile (“aryl boron reagent”) (500 mg, 2.14 mmol, 1 equiv), [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(DtBPF)Cl 2 ) (285 mg, 0.44 mmol, 0.2 equiv), Cs 2 CO 3 (1.40 g, 4.29 mmol, 2 equiv) and 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (product of Step 4, Example 11; “halo-pyrone reagent”) (800 mg, 1.74 mmol, 0.8
  • Example 12 (Ra)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6- methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 15A*), (Sa)- N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-methoxyphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 15B*), and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo- 2H
  • Step 1 A mixture of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2- methoxyethoxy)-6-oxopyran-2-carboxamide (product of Step 4, Example 5; “halo-pyrone reagent”) (365 mg, 0.73 mmol, 1 equiv), [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (95 mg, 0.15 mmol, 0.20 equiv), K3PO4 (466 mg, 2.20 mmol, 3 equiv) and 2-chloro-6-methoxyphenylboronic acid (“aryl boron reagent”) (822 mg, 4.41 mmol, 6 equiv) in N,N-dimethylformamide (DMF) (15.2 mL)
  • Steps 2-3 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- chloro-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 15- Ac) (300 mg, 0.54 mmol, 1 equiv) in tetrahydrofuran (THF) (1 mL) and water (1 mL) was added trifluoroacetic acid (TFA) (4 mL). The resulting solution was stirred for 3 h at 80 °C under nitrogen atmosphere.
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF trifluoroacetic acid
  • Example 13 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (2-hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 17) and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-(tert-butoxy)ethoxy)-4-(2,6-dimethoxyphenyl)-2-oxo- 2H-pyran-6-carboxamide (Compound 17-Ac-OtBu)
  • Step 1 Methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate was synthesized according to Step 1 of Example 11.
  • LCMS (ESI, m/z) 295 [M - 1] –.
  • Step 2 To a stirred mixture of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (1000 mg, 3.378 mmol, 10 equiv) and triphenyl phosphine (PPh 3 ) (1328 mg, 5.063 mmol, 1.500 equiv) in tetrahydrofuran (THF) (15 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1166 mg, 5.064 mmol, 1.500 equiv) in portions at 0 °C.
  • DBAD di-tert-butyl azodicarboxylate
  • Step 3 Into a solution of methyl 5-[2-(tert-butoxy)ethoxy]-4-iodo-6-oxopyran-2-carboxylate (2 g, 5.0 mmol, 1 equiv) in tetrahydrofuran (THF) (5 mL) was added trimethyltin hydroxide (990 mg, 5.48 mmol, 1.08 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 4 A solution of 5-[2-(tert-butoxy)ethoxy]-4-iodo-6-oxopyran-2-carboxylic acid (289 mg, 0.76 mmol, 1 equiv) in MeCN (5 mL) was added N-methylimidazole (NMI) (186 mg, 2.27 mmol, 3 equiv), N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5)(170 mg, 0.76 mmol, 1 equiv) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (110 mg, 0.39 mmol, 1.50 equiv).
  • NMI N-methylimidazole
  • TCFH chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate
  • Step 5 A solution of 5-[2-(tert-butoxy)ethoxy]-N-[5-(5-acetamidopyrazol-1-yl)- 1,3,4- thiadiazol-2-yl]-4-iodo-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (159 mg, 0.27 mmol, 1 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl2)•CH2Cl2 complex (44 mg, 0.054 mmol, 0.20 equiv), K3PO4 (172 mg, 0.81 mmol, 3 equiv) and 2,6- dimethoxyphenylboronic acid (“aryl boron reagent”) (98 mg, 0.54 mmol, 2 equiv) in a mixture solution of 1,4-dioxane (5 mL) and H2
  • Step 6 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-(tert- butoxy)ethoxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 17-Ac- OtBu) (100 mg, 0.17 mmol, 1 equiv) in isopropanol (iPrOH) (6 mL) was added conc. HCl (1 mL). The resulting solution was stirred for 5 h at 60 °C then cooled to rt and concentrated under reduced pressure.
  • iPrOH isopropanol
  • Example 14 N-(5-(3-fluoro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 18) [541] Steps 1-6: 4-bromo-N-(5-(3-fluoro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide was prepared according to Steps 1-6 of Example 4 using methyl 3-fluoro-1H-pyrrole-2-carboxylate acid in place of methyl 3-chloro-1H-pyrrole-2- carboxylate.
  • Step 7 To a stirred solution of 4-bromo-N-[5-(3-fluoro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol- 2-yl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (40 mg, 0.085 mmol, 1 equiv) and 3-methoxy-2-(tributylstannyl)pyridine (“aryl tin reagent”) (150 mg, 0.38 mmol, 4.5 equiv) in N,N-dimethylformamide (DMF) (1 mL) was added tetrakis (triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ) (30 mg, 0.026 mmol, 0.3 equiv) and CuI (7 mg, 0.04 mmol,
  • Example 15 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,4-dimethoxypyridin-3- yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 19) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,4-dimethoxypyridin-3-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 19-Ac) [543] Steps 1-3: 4-(2,4-dimethoxypyridin-3-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid was prepared according to Steps 1-3 of Example 6 using 3-bromo-2,4-dime
  • Step 5 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,4-dimethoxypyridin-3- yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 19) was prepared according to Step 2 of Example 8 from acidic deprotection of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-4-(2,4-dimethoxypyridin-3-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxamide (Compound 19-Ac).
  • Example 16 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- ((1,3-dimethoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 20) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-((1,3- dimethoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 20-Ac)
  • Step 1 To a stirred solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (product of Step 1, Example 11) (500 mg, 1.69 mmol, 1 equiv) and 1,3-dimethoxypropan-2-ol (304 mg, 2.53 mmol, 1.50 equiv) in tetrahydrofuran (THF) (5 mL) was added triphenyl phosphine (PPh 3 ) (665 mg, 2.53 mmol, 1.5 equiv) and diethyl azodicarboxylate (DEAD) (441 mg, 2.53 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere.
  • PPh 3 triphenyl phosphine
  • DEAD diethyl azodicarboxylate
  • Step 2 A solution of methyl 5-[(1,3-dimethoxypropan-2-yl)oxy]-4-iodo-6-oxopyran-2- carboxylate (300 mg, 0.753 mmol, 1 equiv), 2,6-dimethoxyphenylboronic acid (274 mg, 1.51 mmol, 2 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl2) (110 mg, 0.151 mmol, 0.2 equiv) and K 2 CO 3 (3.12 g, 2.26 mmol, 3 equiv) in dioxane (3 mL) and H 2 O (0.3 mL) was stirred for 2 h at 70 °C under nitrogen atmosphere.
  • Step 3 To a solution of methyl 4-(2,6-dimethoxyphenyl)-5-[(1,3-dimethoxypropan-2-yl)oxy]- 6-oxopyran-2-carboxylate (110 mg, 0.269 mmol, 1equiv) in tetrahydrofuran (THF) (2 mL) was added trimethylstannanol (97 mg, 0.54 mmol, 2 equiv). The mixture was stirred for 1 h at room temperature under nitrogen atmosphere then concentrated under vacuum.
  • THF tetrahydrofuran
  • Step 4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-((1,3-dimethoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide
  • Compound 20-Ac was prepared according to Step 1 of Example 8 using 4-(2,6-dimethoxyphenyl)-5-[(1,3- dimethoxypropan-2-yl)oxy]-6-oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) in place of 4-(3- cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid and coupling with N-(1-(5- amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step
  • Example 17 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxypropoxy)-4-(3- methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 21) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxypropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo- 2H-pyran-6-carboxamide (Compound 21-Ac)
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (1000 mg, 4.016 mmol, 1 equiv), 3-methoxypropan-1-ol (434 mg, 4.82 mmol, 1.2 equiv) and triphenyl phosphine (PPh 3 ) (1578 mg, 6.016 mmol, 1.5 equiv) in tetahydrofuran (THF) (15 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1386 mg, 6.019 mmol, 1.5 equiv) in portions at 0 °C under nitrogen atmosphere.
  • DBAD di-tert-butyl azodicarboxylate
  • Steps 2-4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxypropoxy)- 4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 21-Ac) was prepared according to Steps 1-3 of Example 9 using methyl 4-bromo-5-(3-methoxypropoxy)-6-oxopyran-2- carboxylate in place of methyl 4-bromo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate.
  • Example 18 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (2-morpholinoethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 22) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2-morpholinoethoxy)-2-oxo- 2H-pyran-6-carboxamide (Compound 22-Ac) [554] Step 1: To a solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (500 mg, 2.01 mmol, 1 equiv) in tetrahydrofuran (THF) (12.5 mL) was added triphenyl pho
  • DBAD di-tert-butyl azodicarboxylate
  • Step 2 To a solution of methyl 4-bromo-5-[2-(morpholin-4-yl)ethoxy]-6-oxopyran-2- carboxylate (345 mg, 0.95 mmol, 1 equiv) in 1,4-dioxane (15.0 mL) and H2O (3.0 mL) was added 2,6-dimethoxyphenylboronic acid (258 mg, 1.42 mmol, 1.49 equiv), [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (124 mg, 0.19 mmol, 0.2 equiv) and KF (166 mg, 2.85 mmol, 3 equiv) at room temperature.
  • Step 3 A solution of methyl 4-(2,6-dimethoxyphenyl)-5-[2-(morpholin-4-yl)ethoxy]-6- oxopyran-2-carboxylate (243 mg, 0.58 mmol, 1 equiv) in conc. HCl (12 mL) was stirred for 1 h at 80 °C.
  • Step 4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-(2-morpholinoethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 22-Ac) was prepared according to was prepared according to Step 1 of Example 8 using 4-(2,6-dimethoxyphenyl)-5-[2- (morpholin-4-yl)ethoxy]-6-oxopyran-2-carboxylic acid as the “aryl-pyrone reagent” in place of 4- (3-cyanopyridin-2-yl)-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid and using N-(1-(5-amino- 1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide as the “ADT amine reagent”.
  • Step 5 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2- morpholinoethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 22) was prepared according to Step 2 of Example 8 by acidic deprotection of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol- 2-yl)-4-(2,6-dimethoxyphenyl)-3-(2-morpholinoethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 22-Ac).
  • Example 19 4-(2-cyano-6-methoxyphenyl)-N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 23) [559]
  • Step 1 Into a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (5 g, 20 mmol, 1 equiv) in tetrahydrofuran (THF) (100 mL) was added n-butyl lithium (n-BuLi) (8.97 mL, 22.4 mmol, 1.1 equiv) dropwise over 5 min at -78 °C.
  • n-BuLi n-butyl lithium
  • Step 2 To a stirred solution of 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole- 3-carbaldehyde (700 mg, 2.56 mmol, 1equiv) in dichloromethane (DCM) (5 mL) was added diethylaminosulfur trifluoride (DAST) (826 mg, 5.12 mmol, 2equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was then quenched by the addition of Water (2 mL) at room temperature and extracted with ethyl acetate (EtOAc) (3 x 50 mL).
  • EtOAc ethyl acetate
  • Step 3 Into a solution of 2-[5-(difluoromethyl)pyrazol-1-yl]-5-(2,5-dimethylpyrrol-1-yl)- 1,3,4-thiadiazole (300 mg, 1.02 mmol, 1equiv) in tetrahydrofuran (THF) (1 mL) and H 2 O (0.5 mL) was added trifluoroacetic acid (TFA) (0.5 mL) at 0 °C. The resulting mixture was stirred for 2 h at 60 °C under air atmosphere.
  • Step 4 4-bromo-N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide prepared according to Step 3 of Example 3 using 5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-amine in place of 5-(5-methylpyrazol-1-yl)- 1,3,4-thiadiazol-2-amine.
  • LCMS (ES, m/z) 491.9 [M+H]+.
  • Step 5 4-(2-cyano-6-methoxyphenyl)-N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide
  • Compound 23 prepared according to Step 1 of Example 7 using 4-bromo-N-(5-(5-(difluoromethyl)-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide as the “halo-pyrone reagent” in place of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2-methoxyethoxy)-6- oxopyran-2-carboxamide and 2-
  • Example 20 (Ra)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- methylphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 24A*), (Sa)-N- (5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6-methylphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 24B*), and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6-methylphenyl)-3-(2-methoxyethoxy)-2-oxo-2H- pyran-6-carboxamide (
  • Step 1 Methyl 4-iodo-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate was prepared according to Steps 1-2 of Example 1 and Step 1 of Example 3 using methyl 3-hydroxy-4-iodo-2-oxo- 2H-pyran-6-carboxylate in place of methyl 3-hydroxy-4-bromo-2-oxo-2H-pyran-6-carboxylate.
  • LCMS (ES, m/z) 354.8 [ M+H]+.
  • Step 2 Methyl 4-(2-cyano-6-methylphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxylate was prepared according to Step 2 of Example 18 using methyl 4-iodo-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate in place of methyl 4-bromo-5-[2-(morpholin-4- yl)ethoxy]-6-oxopyran-2-carboxylate and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile in place of 2,6-dimethoxyphenylboronic acid.
  • Steps 3-4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- methylphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 24-Ac) was prepared according to Steps 3-4 of Example 16 using methyl 4-(2-cyano-6-methylphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate in place of methyl 4-(2,6-dimethoxyphenyl)-5-[(1,3- dimethoxypropan-2-yl)oxy]-6-oxopyran-2-carboxylate to
  • Step 2 Into a solution of 2-(5-chloropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4- thiadiazole (880 mg, 3.15 mmol, 1 equiv) in tetrahydrofuran (THF) (1 mL) and H 2 O (2 mL) was added trifluoroacetic acid (TFA) (2 mL) at room temperature. The resulting mixture was stirred for 3 h at 60 °C then concentrated under reduced pressure.
  • Step 3 To a solution of 5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (200 mg, 0.99 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (10 mL) was added hydroxybenzotriazole (HOBT) (380 mg, 2.81 mmol, 2.83 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (148 mg, 0.77 mmol, 0.78 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • Step 4 To a solution of 5-[2-(tert-butoxy)ethoxy]-N-[5-(5-chloropyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-4-iodo-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (280 mg, 0.495 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (7 mL) and H2O (0.7 mL) was added 2-cyano-6- methoxyphenylboronic acid (“aryl boron reagent”) (392 mg, 2.213 mmol, 4.5 equiv), K3PO4 (314 mg, 1.48 mmol, 3 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (97 mg, 0.15
  • the reaction mixture was then irradiated in a microwave reactor for 20 min at 120 °C under a nitrogen atmosphere.
  • the mixture was cooled to rt and diluted with ethyl acetate (EtOAc) (100 mL) and washed with water (3 x 10 mL).
  • EtOAc ethyl acetate
  • the organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 5 To a solution of 4M HCl in 1,4-dioxane (8 mL) was added 3-(2-(tert-butoxy)ethoxy)- N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6-methoxyphenyl)-2-oxo-2H- pyran-6-carboxamide (Compound 26-OtBu) (130 mg, 0.228 mmol, 1 equiv). The resulting solution was stirred for 1 h at 80 °C then cooled to rt and concentrated under reduced pressure.
  • Compound 26-OtBu 3-(2-(tert-butoxy)ethoxy)- N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6-methoxyphenyl)-2-oxo-2H- pyran-6-carbox
  • Step 2 A mixture of bis (dibenzylideneacetone)palladium(0) (Pd(dba)2) (44 mg, 0.077 mmol, 0.10 equiv) and tricyclohexylphospine (PCy3) (52 mg, 0.18 mmol, 0.2 equiv) in dioxane (2 mL) was stirred for 30 min at room temperature under nitrogen atmosphere.
  • Pd(dba)2 bis (dibenzylideneacetone)palladium(0)
  • PCy3 tricyclohexylphospine
  • Step 3 To a stirred mixture of 2-[2-methoxy-6-(2-methoxyethoxy)phenyl]-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (100 mg, 0.324 mmol, 1 equiv) and 4-bromo-N-[5-(5- acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2-methoxyethoxy)-6- oxopyran-2-carboxamide (135 mg, 0.270 mmol, 0.8 equiv) in dioxane (1.2 mL) and H2O (0.2 mL) was added [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (35 mg, 0.054 mmol, 0.17 equiv) and K2CO3 (75 mg
  • Step 4 A solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- methoxy-6-(2-methoxyethoxy)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 27-Ac) (28 mg, 0.047 mmol, 1 equiv) in conc. HCl (1 mL) was stirred overnight at room temperature.
  • Step 2 Under nitrogen, to a solution of 3,5-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (500 mg, 1.89 mmol, 1 equiv) in 1,4-dioxane (15 mL) and H 2 O (2.5 mL) was added methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (product of Step 1, Example 3) (579 mg, 1.88 mmol, 1equiv), [1,1′-bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II) (Pd(dtbpf)Cl 2 ) (246 mg, 0.38 mmol, 0.2 equiv) and Cs 2 CO 3 (1.23 g, 3.78 mmol, 2equiv) at room temperature.
  • Step 3 A solution of methyl 4-(3,5-dimethoxypyridin-4-yl)-5-(2-methoxyethoxy)-6-oxopyran- 2-carboxylate (120 mg, 0.33 mmol, 1 equiv) in HCl (2 mL, 6 M) was stirred for 1 h at 80 °C.
  • Steps 4-5 To a solution of 4-(3,5-dimethoxypyridin-4-yl)-5-(2-methoxyethoxy)-6-oxopyran- 2-carboxylic acid HCl salt (60 mg, 0.17 mmol, 1 equiv) in dichloromethane (DCM) (2.5 mL) was added (COCl) 2 (87 mg, 0.68 mmol, 4 equiv) and N,N-dimethylformamide (DMF) (one drop) at 0 °C.
  • DCM dichloromethane
  • COCl chloromethane
  • DMF N,N-dimethylformamide
  • aryl-pyrone reagent 4-(3,5-dimethoxypyridin-4-yl)-5-(2-methoxyethoxy)-6-oxopyran- 2-carbonyl chloride
  • aryl-pyrone reagent 60 mg, 0.16 mmol, 1 equiv
  • DCM DCM
  • N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide product of Step 3, Example 5; “ADT amine reagent” (40 mg, 0.18 mmol, 1.1 equiv) and triethylamine (TEA) (33 mg, 0.33 mmol, 2 equiv) at room temperature and the resulting mixture was stirred for 1 h at room temperature.
  • Step 6 A solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3,5- dimethoxypyridin-4-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 28-Ac) (56 mg, 0.10 mmol, 1 equiv) in conc. HCl (2 mL) was stirred for 4 h at room temperature.
  • Example 24 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxy-2,2- dimethylpropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 29) and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxy-2,2- dimethylpropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 29- Ac)
  • Step 1 To a stirred solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (product of Step 1, Example 11) (1 g, 3.4 mmol, 1 equiv), 3-methoxy-2,2-dimethylpropan-1-ol (0.48 g, 4.05 mmol, 1.2 equiv) and triphenyl phosphine (PPh 3 ) (1.33 g, 5.07 mmol, 1.5 equiv) in tetrahydrofuran (THF) (10 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1.56 g, 6.76 mmol, 2 equiv) in portions at 0 °C under nitrogen atmosphere.
  • DBAD di-tert-butyl azodicarboxylate
  • Step 2 Into a solution of methyl 4-iodo-5-(3-methoxy-2,2-dimethylpropoxy)-6-oxopyran-2- carboxylate (400 mg, 1.01 mmol, 1 equiv) in tetrahydrofuran (THF) (8 mL) was added trimethylstannanol (366 mg, 2.02 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 40 °C then cooled to rt and quenched with water (20 mL).
  • THF tetrahydrofuran
  • Step 3 To a stirred solution of 4-iodo-5-(3-methoxy-2,2-dimethylpropoxy)-6-oxopyran-2- carboxylic acid (400 mg, 1.05 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (8 mL) was added hydroxybenzotriazole (HOBT) (283 mg, 2.09 mmol, 2 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (402 mg, 2.10 mmol, 2 equiv) and N-(1-(5-amino-1,3,4- thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5) (305 mg, 1.36 mmol, 1.30 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylaminoprop
  • Step 4 A solution of N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-(3- methoxy-2,2-dimethylpropoxy)-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (200 mg, 0.34 mmol, 1 equiv), 3-methoxy-2-(tributylstannyl)pyridine (“aryl tin reagent”) (259 mg, 0.65 mmol, 2 equiv), tetrakis (triphenylphosphine)palladium (0) (Pd(PPh3)4) (78 mg, 0.067 mmol, 0.2 equiv), CuI (20 mg, 0.105 mmol, 0.31 equiv) and CsF (100 mg, 0.66 mmol, 1.94 e
  • halo-pyrone reagent 200 mg, 0.34 mmol, 1 equiv
  • Step 5 A solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3- methoxy-2,2-dimethylpropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 29-Ac) (60 mg, 0.105 mmol, 1 equiv) in conc. HCl (5 mL) was stirred for 6 h at room temperature.
  • Example 25 4-(4-cyano-1-methyl-1H-pyrazol-3-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 31) and 4-(4-iodo-1-methyl- 1H-pyrazol-3-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H- pyran-6-carboxamide (Compound 16) [589] Step 1: A solution of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1000 mg, 4.806 mmol, 1.5 equiv), methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (1000 mg,
  • Step 2 To a solution of methyl 5-methoxy-4-(1-methylpyrazol-3-yl)-6-oxopyran-2- carboxylate (800 mg, 3.03 mmol, 1equiv) in acetic acid (AcOH) (12 mL) was added N- iodosuccinimide (NIS) (1362 mg, 6.054 mmol, 2 equiv). The resulting solution was stirred for 3 h at 40 °C then cooled to rt and diluted with ethyl acetate (EtOAc) (200 mL). The solution was washed with water (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • NMS N- iodosuccinimide
  • Step 3 To a solution of methyl 4-(4-iodo-1-methylpyrazol-3-yl)-5-methoxy-6-oxopyran-2- carboxylate (300 mg, 0.77 mmol, 1equiv) in tetrahydrofuran (THF) (6 mL) was added trimethylstannanol (279 mg, 1.54 mmol, 2.01 equiv) and the resulting mixture was stirred for 5 h at 40 °C.
  • THF tetrahydrofuran
  • Step 4 To a stirred solution of 4-(4-iodo-1-methylpyrazol-3-yl)-5-methoxy-6-oxopyran-2- carboxylic acid (“aryl-pyrone reagent”) (200 mg, 0.53 mmol, 1equiv), hydroxybenzotriazole (HOBT) (143 mg, 1.06 mmol, 1.99 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (207 mg, 1.08 mmol, 2.03 equiv) in N,N-dimethylformamide (DMF) (5 mL) was added 5- (5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Step 8, Example 1; “ADT amine reagent”) (116 mg, 0.64 mmol, 1.20 equiv) at room temperature.
  • aryl-pyrone reagent 200 mg, 0.53 mmol, 1equiv
  • Step 5 A mixture of 4-(4-iodo-1-methyl-1H-pyrazol-3-yl)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 16) (100 mg, 0.18 mmol, 1equiv), CuCN (32 mg, 0.36 mmol, 1.93 equiv), [1,1′- bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) (14 mg, 0.019 mmol, 0.1 equiv) and tris(dibenzylidenaceton)dipalladium(0) dibenzylidenacetone (Pd 2 (dba) 3 ) (17 mg, 0.019 mmol, 0.1 equiv) in N,N-dimethylformamide (Compound 16)
  • Example 26 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-(cyanomethyl)-6- methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 32), N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-(cyanomethyl)-6-methoxyphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 32-Ac), and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-(hydroxymethyl)-6-methoxyphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6
  • Step 1 A solution of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2- methoxyethoxy)-6-oxopyran-2-carboxamide (product of Step 4, Example 5; (“halo-pyrone reagent”)) (300 mg, 0.601 mmol, 1 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) ⁇ CH 2 Cl 2 complex (88 mg, 0.11 mmol, 0.2 equiv), K 2 CO 3 (254 mg, 1.84 mmol, 3 equiv) and 7-methoxy-3H-2,1-benzoxaborol-1-ol (“aryl boron reagent”) (120 mg, 0.732 mmol, 1.2 equiv) in dioxane (6 mL
  • Step 2 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- (hydroxymethyl)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 37-Ac) (150 mg, 0.27 mmol, 1 equiv) in dichloromethane (DCM) (4 mL) was added methanesulfonyl methanesulfonate (240 mg, 1.38 mmol, 5 equiv) and triethylamine (TEA) (80 mg, 0.79 mmol, 3 equiv) and the solution was stirred for 2 h at room temperature.
  • DCM dichloromethane
  • TEA triethylamine
  • Step 3 To a solution of [2-(6-([5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]carbamoyl- 3-(2-methoxyethoxy)-2-oxopyran-4-yl)-3-methoxyphenyl]methyl methanesulfonate (100 mg, 0.16 mmol, 1equiv) in acetonitrile (MeCN) (5 mL) was added tetramethylammonium fluoride (TMAF) (59 mg, 0.633 mmol, 4 equiv) and trimethylsilyl cyanide (TMSCN) (188 mg, 1.90 mmol, 12 equiv).
  • TMAF tetramethylammonium fluoride
  • TMSCN trimethylsilyl cyanide
  • Step 4 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- (cyanomethyl)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 32-Ac) (80 mg, 0.14 mmol, 1equiv) in ethanol (EtOH) (1 mL) was added conc. HCl (1 mL). The resulting solution was stirred for 3 h at room temperature then concentrated under reduced pressure.
  • Step 1 To a solution of 2,2-dimethylpropane-1,3-diol (1 g, 9.62 mmol, 1equiv) in dichloromethane (DCM) (20 mL) was added imidazole (1.96 g, 28.8 mmol, 3 equiv) and tert- butyl(chloro)diphenylsilane (TBDPSCl) (2.63 g, 9.60 mmol, 1 equiv). The resulting solution was stirred at rt for 3 h then washed with water and concentrated under reduced pressure.
  • DCM dichloromethane
  • TBDPSCl tert- butyl(chloro)diphenylsilane
  • Step 2 To a solution of 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropan-1-ol (300 mg, 0.88 mmol, 1equiv), methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (261 mg, 1.05 mmol, 1.2 equiv) and triphenyl phosphine (PPh3) (344 mg, 1.31 mmol, 1.5 equiv) in tetrahydrofuran (THF) (10 mL) was added diethyl azodicarboxylate (DEAD) (228 mg, 1.31 mmol, 1.5 equiv) at 0 °C.
  • THF tetrahydrofuran
  • DEAD diethyl azodicarboxylate
  • Step 3 To a solution of methyl 4-bromo-5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2- dimethylpropoxy ⁇ -6-oxopyran-2-carboxylate (500 mg, 0.87 mmol, 1 equiv) in tetrahydrofuran (THF) (10 mL) was added trimethylstannylhydroxide (315 mg, 1.74 mmol, 2 equiv). The resulting mixture was stirred for 2 h at room temperature then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 4 To a solution of 4-bromo-5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -6- oxopyran-2-carboxylic acid (400 mg, 0.72 mmol, 1 equiv) and N-(1-(5-amino-1,3,4-thiadiazol-2-yl)- 1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5) (176 mg, 0.79 mmol, 1.1 equiv) in acetonitrile (MeCN) (5 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (300 mg, 1.07 mmol, 1.5 equiv) and N-methylimidazole (NMI) (176 mg, 2.14 mmol, 3 equiv).
  • MeCN acetonitrile
  • TCFH chloro
  • Step 5 To a solution of 4-bromo-5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -N- [5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (300 mg, 0.392 mmol, 1 equiv), 3-methoxy-2-(tributylstannyl)pyridine (“aryl tin reagent”) (234 mg, 0.588 mmol, 1.5 equiv) and bis(tri-tert-butylphosphine)palladium(0) (Pd(t- Bu3P)2) (40 mg, 0.078 mmol, 0.20 equiv) in 1,4-dioxane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere.
  • halo-pyrone reagent 300
  • Step 6 To a solution of 5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -N-[5-(5 acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-(3-methoxypyridin-2-yl)-6-oxopyran-2- carboxamide (60 mg, 0.076 mmol, 1 equiv) in tetrahydrofuran (THF) (3 mL) was added conc. HCl (1.5 mL). The resulting solution was stirred for 1 h at 60 °C under nitrogen atmosphere then cooled to rt and concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Example 28 (Sa)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6- methoxyphenyl)-3-(2-hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 34A*), (Ra)- N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-methoxyphenyl)-3-(2- hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 34B*), and N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-(tert-butoxy)ethoxy)-4-(2-chloro-6-methoxyphenyl)-2- oxo-2
  • Step 1 To a stirred solution of 5-[2-(tert-butoxy)ethoxy]-N-[5-(5-acetamidopyrazol-1-yl)- 1,3,4-thiadiazol-2-yl]-4-iodo-6-oxopyran-2-carboxamide (product of Step 4 of Example 13; “halo- pyrone reagent”) (100 mg, 0.017 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (2 mL) and H2O (0.5 mL) was added 2-chloro-6-methoxyphenylboronic acid (“aryl boron reagent”) (100 mg, 0.054 mmol, 3 equiv), [1,1′-bis(diphenylphosphino)ferrocene] dichloro palladium(II) (Pd(dppf)Cl2) (30 mg, 0.004 mmol, 0.2 equiv) and K 2 CO 3
  • Step 1 A solution of methyl 4-bromo-5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2- dimethylpropoxy ⁇ -6-oxopyran-2-carboxylate (product of Step 2 of Example 27) (560 mg, 0.976 mmol, 1 equiv), 2,6-dimethoxyphenylboronic acid (355 mg, 1.952 mmol, 2 equiv), [1,1′- bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl2) ⁇ CH2Cl2 complex (159 mg, 0.195 mmol, 0.2 equiv) and K2CO3 (404 mg, 2.928 mmol, 3 equiv) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere.
  • 1,4-dioxane 10 m
  • Step 2 To a solution of methyl 5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -4- (2,6-dimethoxyphenyl)-6-oxopyran-2-carboxylate (490 mg, 0.777 mmol, 1equiv) in tetrahydrofuran (THF) (10 mL) was added Me 3 SnOH (1.21 g, 1.554 mmol, 2equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere.
  • THF tetrahydrofuran
  • Step 3 To a solution of 5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -4-(2,6- dimethoxyphenyl)-6-oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) (440 mg, 0.713 mmol, 1 equiv) and N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5; “ADT amine reagent”) (239 mg, 1.069 mmol, 1.5 equiv) in acetonitrile (MeCN) (10 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (300 mg, 1.069 mmol, 1.5 equiv) and N-methylimidazole (NMI) (234
  • Step 4 To a solution of 5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -4-(2,6- dimethoxyphenyl)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2- carboxamide (180 mg, 0.219 mmol, 1 equiv) in tetrahydrofuran (THF) (4 mL) was added conc. HCl (2 mL) and the mixture was stirred for 1 h at room temperature.
  • THF tetrahydrofuran
  • Example 30 (Sa)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6- methoxyphenyl)-3-(2-hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 37A*) and (Ra)- N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-methoxyphenyl)-3-(2- hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 37B*)
  • Step 1 A solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- (hydroxymethyl)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 37-Ac; product of Step 1 of Example 26) (40 mg, 0.072 mmol, 1 equiv) in conc. HCl (1 mL) was stirred for 3 h at room temperature.
  • Example 31 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (methoxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 39) and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (methoxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 39- Ac)
  • Step 1 To a solution of 2-bromo-3-(hydroxymethyl)benzonitrile (2 g, 9.4 mmol, 1 equiv) in tetrahydrofuran (THF) (80 mL) was added NaH (723 mg, 18.10mmol, 1.92 equiv, 60% in mineral oil) at 0 °C, and then the resulting mixture was stirred for 5 min at 0 °C. To the above mixture was then added CH3I (5.36 g, 37.7 mmol, 4equiv) at room temperature and the resulting mixture was stirred for 1 h at room temperature.
  • THF tetrahydrofuran
  • Step 2 3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile was prepared according to Step 2 of Example 22 using 2-bromo-3-(methoxymethyl)benzonitrile in place of 2-bromo-1-methoxy-3-(2-methoxyethoxy) benzene.
  • Step 3 To a solution of 3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (800 mg, 2.93 mmol, 1equiv) in dioxane (18 mL) and H2O (3 mL) was added methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (product of Step 1, Example 3) (900 mg, 2.93 mmol, 1 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl 2 ) (380 mg, 0.583 mmol, 0.2 equiv) and Cs 2 CO 3 (1.91 g, 5.86 mmol, 2
  • Steps 4-5 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (methoxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide
  • Compound 39-Ac was prepared according to Step 3-4 of Example 10 by hydrolysis of methyl 4-[2-cyano-6- (methoxymethyl)phenyl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (instead of methyl 4-(2,6- dicyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylate) to provide 4-(2-cyano-6- (methoxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid (the “aryl-
  • Example 32 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (3-hydroxypropoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 40) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(3-hydroxypropoxy)-2-oxo- 2H-pyran-6-carboxamide (Compound 40-Ac) [621] Step 1: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (1 g, 4.0 mmol, 1 equiv) and 3-[(tert- butyldimethylsilyl)oxy]propan-1-ol (1 g,
  • Step 2 methyl 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-(2,6-dimethoxyphenyl)-2-oxo- 2H-pyran-6-carboxylate was prepared according to Step 1 of Example 29 using methyl 4-bromo-5- ⁇ 3-[(tert-butyldimethylsilyl)oxy]propoxy ⁇ -6-oxopyran-2-carboxylate in place of methyl 4-bromo-5- ⁇ 3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -6-oxopyran-2-carboxylate.
  • Step 3 To a solution of methyl 5- ⁇ 3-[(tert-butyldimethylsilyl)oxy]propoxy ⁇ -4-(2,6- dimethoxyphenyl)-6-oxopyran-2-carboxylate (650 mg, 1.36 mmol, 1equiv) in tetrahydrofuran (THF) (9 mL) was added trimethylstannanol (365 mg, 2.02 mmol, 1.49 equiv). The resulting solution was stirred overnight at room temperature then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 4 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-(3-hydroxypropoxy)-2-oxo-2H-pyran-6-carboxamide
  • Compound 40-Ac was prepared according to Step 1 of Example 8 using 4-(2,6-dimethoxyphenyl)-5-(3-hydroxypropoxy)-6-oxopyran-2- carboxylic acid (“aryl-pyrone reagent”) in place of 4-(3-cyanopyridin-2-yl)-5-(2-methoxyethoxy)- 6-oxopyran-2-carboxylic acid and using N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5- yl)acetamide (product of Step 3, Example 5; “ADT amine reagent”).
  • Example 33 (S)-3-((1,4-dioxan-2-yl)methoxy)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol- 2-yl)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 43A*) and (R)-3- ((1,4-dioxan-2-yl)methoxy)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 43B*), and 3-((1,4-dioxan-2- yl)methoxy)-N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl
  • Step 1 Methyl 4-bromo-5-(1,4-dioxan-2-ylmethoxy)-6-oxopyran-2-carboxylate was prepared according to Step 1 of Example 3 using 1,4-dioxan-2-ylmethanol in place of 2-methoxyethanol.
  • LCMS (ES, m/z) 349.0 [M+H]+.
  • Step 2 Methyl 4-(2,6-dimethoxyphenyl)-5-(1,4-dioxan-2-ylmethoxy)-6-oxopyran-2- carboxylate was prepared according to Step 2 of Example 18 using methyl 4-bromo-5-(1,4-dioxan-2- ylmethoxy)-6-oxopyran-2-carboxylate in place of methyl 4-bromo-5-[2-(morpholin-4-yl)ethoxy]-6- oxopyran-2-carboxylate.
  • LCMS (ES, m/z) 407.2 [M+H]+.
  • Steps 3-4 3-((1,4-dioxan-2-yl)methoxy)-N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 43-Ac) was prepared following Steps 3-4 of Example 16 by hydrolysis of methyl 4-(2,6-dimethoxyphenyl)-5- (1,4-dioxan-2-ylmethoxy)-6-oxopyran-2-carboxylate (instead of methyl 4-(2,6-dimethoxyphenyl)-5- [(1,3-dimethoxypropan-2-yl)oxy]-6-oxopyran-2-carboxylate) to provide 3-((1,4-dioxan-2- yl)methoxy)-4-(2,6-dimethoxyphenyl
  • Example 34 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-cyanophenyl)- 3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 45), N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-chloro-6-cyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H- pyran-6-carboxamide (Compound 45-Ac), N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol- 2-yl)-4-(2-carbamoyl-6-chlorophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (
  • Step 1 To a solution of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2- methoxyethoxy)-6-oxopyran-2-carboxamide (product of Step 4, Example 5; “halo-pyrone reagent”) (200 mg, 0.401 mmol, 1 equiv) in dioxane (10 mL) was added 3-chloro-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (“aryl boron reagent”) (211 mg, 0.802 mmol, 2 equiv), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (XantphosPdCl 2 ) (61 mg, 0.08 mmol, 0.2 equiv), K 3 PO 4
  • Step 2 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- carbamoyl-6-chlorophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 25- Ac) (250 mg, 0.436 mmol, 1 equiv) in dichloroethane (DCE) (5 mL) was added methyl N- (triethylammoniumsulfonyl) carbamate (Burgess reagent) (208 mg, 0.872 mmol, 2 equiv) at room temperature.
  • DCE dichloroethane
  • Step 3 To a solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2- chloro-6-cyanophenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 45-Ac) (50 mg, 0.090 mmol, 1 equiv) in ethanol (EtOH) (1.5 mL) was added conc. HCl (4.5 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature then concentrated under reduced pressure.
  • Step 1 Methyl 5-[(2R)-2-(benzyloxy)propoxy]-4-iodo-6-oxopyran-2-carboxylate was prepared according to Step 1 of Example 3 using (R)-2-(benzyloxy)propan-1-ol in place of 2- methoxyethanol and methyl 4-iodo-5-hydroxy-6-oxopyran-2-carboxylate in place of methyl 3- hydroxy-4-bromo-2-oxo-2H-pyran-6-carboxylate.
  • LCMS (ES, m/z) 445.0 [M+H]+.
  • Step 2 Methyl 5-[(2R)-2-(benzyloxy)propoxy]-4-(2,6-dimethoxyphenyl)-6-oxopyran-2- carboxylate was prepared according to Step 2 of Example 18 using methyl 5-[(2R)-2- (benzyloxy)propoxy]-4-iodo-6-oxopyran-2-carboxylate in place of methyl 4-bromo-5-[2- (morpholin-4-yl)ethoxy]-6-oxopyran-2-carboxylate.
  • LCMS (ES, m/z) 455.0 [M+H]+.
  • Steps 3-4 (R)-N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2- (benzyloxy)propoxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 46A- Ac-OBn) was prepared following Steps 3-4 of Example 16 by hydrolysis of methyl 5-[(2R)-2- (benzyloxy)propoxy]-4-(2,6-dimethoxyphenyl)-6-oxopyran-2-carboxylate (instead of methyl 4-(2,6- dimethoxyphenyl)-5-[(1,3-dimethoxypropan-2-yl)oxy]-6-oxopyran-2-carboxylate) to provide (R)-3- (2-(benzyloxy)propoxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H
  • Step 5 (R)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-(2-hydroxypropoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 46A) was prepared by acidic deprotection of (R)-N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2- (benzyloxy)propoxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 46A- Ac-OBn) following Step 5 of Example 16.
  • Steps 6-10 (S)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2- hydroxypropoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 46B) was prepared following Steps 1- 5 of above Example 35, but using (2S)-2-(benzyloxy) propan-1-ol in place of (2R)-2-(benzyloxy) propan-1-ol for Step 1.
  • LCMS (ES, m/z) 515.1 [M+H]+.
  • Example 36 (S)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-((1-methoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 47A), (S)-N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-((1- methoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 47A-Ac), (R)-N-(5-(5- amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-((1-methoxypropan
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Step 2, Example 1) (2 g, 8.0 mmol, 1 equiv) in tetrahydrofuran (THF) (20 mL) was added (2R)-1-methoxypropan-2-ol (1.45 g, 16.1 mmol, 2 equiv) and triphenyl phosphine (PPh3) (6.36 g, 24.3 mmol, 3 equiv) at room temperature.
  • THF tetrahydrofuran
  • Step 2 A solution of methyl 4-bromo-5-([(2S)-1-methoxypropan-2-yl]oxy-6-oxopyran-2- carboxylate (2.5 g, 7.8 mmol, 1 equiv) in hydrogen chloride (10 mL, 6M) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by C18 reverse phase flash chromatography (mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide 4-bromo-5-([(2S)-1-methoxypropan-2-yl]oxy-6-oxopyran- 2-carboxylic acid (260 mg, 9.8% yield).
  • Step 3 To a stirred solution of 4-bromo-5-([(2S)-1-methoxypropan-2-yl]oxy-6-oxopyran-2- carboxylic acid (300 mg, 0.977 mmol, 1 equiv) in acetonitrile (MeCN) (6 mL) was added chloro- N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (420 mg, 1.50 mmol, 1.5 equiv), N-methylimidazole (NMI) (240 mg, 2.92 mmol, 3 equiv) and N-(1-(5-amino-1,3,4-thiadiazol-2-yl)- 1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5) (180 mg, 0.803 mmol, 0.8 equiv) at room
  • Step 4 To a stirred solution of 4-bromo-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2- yl]-5-([(2S)-1-methoxypropan-2-yl]oxy-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (90 mg, 0.175 mmol, 1 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl 2 ) (36 mg, 0.055 mmol, 0.3 equiv) in dioxane (1.5 mL) and H 2 O (0.3 mL) was added K2CO3 (73 mg, 0.528 mmol, 3 equiv) and 2,6-dimethoxyphenylboronic acid (“aryl boron reagent”) (
  • Step 5 A solution of (S)-N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-3-((1-methoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 47A-Ac) (20 mg, 0.035 mmol, 1 equiv) in conc. HCl (0.5 mL) was stirred for 2 h at room temperature.
  • Step 2 To a solution of 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)benzonitrile (900 mg, 2.76 mmol, 1 equiv) in dioxane (20 mL) was added bis(pinacolato)diboron (1057 mg, 4.165 mmol, 1.5 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl 2 ) ⁇ CH 2 Cl 2 complex (540 mg, 0.663 mmol, 0.2 equiv) and potassium acetate (KOAc) (836 mg, 8.52 mmol, 3 equiv) at room temperature.
  • bis(pinacolato)diboron 1057 mg, 4.165 mmol, 1.5 equiv
  • Step 3 To a solution of 3-([(tert-butyldimethylsilyl)oxy]methyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (500 mg, 1.34 mmol, 1equiv) in N,N-dimethylformamide (DMF) (20 mL) was added N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-(2-methoxyethoxy)- 6-oxopyran-2-carboxamide (prepared following Steps 1-4 of Example 5, but using 4-iodo-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxylic acid instead of 4-bromo-3-(2-methoxyethoxy)-2-oxo- 2H-pyr
  • Step 4 A solution of 4-[2-cyano-6-(hydroxymethyl)phenyl]-N-[5-(5-acetamidopyrazol-1-yl)- 1,3,4-thiadiazol-2-yl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxamide (158 mg, 0.286 mmol, 1 equiv) in conc. HCl (10 mL) was stirred for 4 h at room temperature then concentrated under reduced pressure.
  • Example 38 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (hydroxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 50) and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-((1,3-bis(benzyloxy)propan-2- yl)oxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 50-Ac-OBn)
  • Step 1 Methyl 5-([1,3-bis(benzyloxy)propan-2-yl]oxy-4-bromo-6-oxopyran-2-carboxylate was prepared according to Step 1 of Example 3 using 1,3-bis(benzyloxy)propan-2-ol in place of 2- methoxyethanol.
  • LCMS (ES, m/z) 503.0 [M+H]+.
  • Step 2 To a solution of methyl 5-([1,3-bis(benzyloxy)propan-2-yl]oxy-4-bromo-6-oxopyran- 2-carboxylate (1.6 g, 3.2 mmol, 1 equiv) in dioxane (20 mL) and H2O (4 mL) was added 2,6- dimethoxyphenylboronic acid (578 mg, 3.18 mmol, 1equiv), [1,1′- bis(diphenylphosphino)ferrocene]dichloro palladium(II) (Pd(dppf)Cl2) ⁇ CH2Cl2 complex (517 mg, 0.64 mmol, 0.2 equiv) and Cs2CO3 (2071 mg, 6.358 mmol, 2 equiv) at room temperature.
  • Step 3 N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-((1,3- bis(benzyloxy)propan-2-yl)oxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 50-Ac-OBn) was prepared according to Step 4 of Example 16 using 5-([1,3- bis(benzyloxy)propan-2-yl]oxy-4-(2,6-dimethoxyphenyl)-6-oxopyran-2-carboxylic acid (“aryl- pyrone reagent”) in place of 4-(2,6-dimethoxyphenyl)-5-[(1,3-dimethoxypropan-2-yl)oxy]-6- oxopyran-2-carboxylic acid and N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H
  • Step 4 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (hydroxymethyl)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 50) was prepared by acidic deprotection of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3- ((1,3-bis(benzyloxy)propan-2-yl)oxy)-4-(2,6-dimethoxyphenyl)-2-oxo-2H-pyran-6-carboxamide (Compound 50-Ac-OBn) following Step 5 of Example 16.
  • Example 39 N-(5-(5-aminothiazol-4-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 51) and N-(5-(5-acetamidothiazol- 4-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6- carboxamide (Compound 51-Ac)
  • Step 1 To a solution of 5-bromo-1,3-thiazole-4-carbonitrile (1 g, 5.3 mmol, 1 equiv) in trifluoroacetic acid (TFA) (20 mL) was added thiosemicarbazide (968 mg, 10.6 mmol, 2 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C then cooled to rt and concentrated under reduced pressure.
  • TFA trifluoroacetic acid
  • Step 2 To a solution of 5-(5-bromo-1,3-thiazol-4-yl)-1,3,4-thiadiazol-2-amine (800 mg, 3 mmol, 1 equiv) in toluene (30 mL) was added 2,5-hexanedione (520 mg, 4.56 mmol, 1.5 equiv) and p-toluenesulfonic acid monohydrate (TsOH ⁇ H 2 O) (116 mg, 0.61 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 110 °C then cooled to rt and concentrated under reduced pressure.
  • TsOH ⁇ H 2 O p-toluenesulfonic acid monohydrate
  • Step 3 To a solution of 2-(5-bromo-1,3-thiazol-4-yl)-5-(2,5-dimethylpyrrol-1-yl)-1,3,4- thiadiazole (400 mg, 1.17 mmol, 1 equiv) in dioxane (8 mL) was added acetamide (346 mg, 5.86 mmol, 5equiv), tris(dibenzylidenaceton)dipalladium(0) dibenzylidenacetone (Pd 2 (dba) 3 ) (215 mg, 0.23 mmol, 0.20 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XantPhos) (136 mg, 0.23 mmol, 0.2 equiv) and Cs 2 CO 3 (764 mg, 2.34 mmol, 2 equiv) at room temperature.
  • acetamide 346 mg, 5.86 mmol, 5e
  • Step 4 To a solution of N-(4-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-1,3-thiazol-5- ylacetamide (300 mg, 0.94 mmol, 1 equiv) in tetrahydrofuran (THF) (5 mL) was added H2O (1 mL) and trifluoroacetic acid (TFA) (5 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 °C then cooled to rt and concentrated under reduced pressure.
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF tetra
  • Step 5 To a solution of 4-(2,6-dimethoxyphenyl)-5-(2-methoxyethoxy)-6-oxopyran-2- carboxylic acid (“aryl-pyrone reagent”, prepared following Step 3-4 of Example 31, but using 2,6- dimethoxyphenylboronic acid instead of 3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile) (101 mg, 0.29 mmol, 1 equiv) in acetonitrile (MeCN) (2 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (162 mg, 0.58 mmol, 2 equiv), N-methylimidazole (NMI) (47 mg, 0.58 mmol, 2 equiv) and N-[4-(5-amino-1,3,4- thione
  • Step 6 A solution of N-(5-(5-acetamidothiazol-4-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 51-Ac) (30 mg, 0.052 mmol, 1 equiv) in conc. HCl (2 mL) was stirred for 1 h at 40 °C. The mixture was then cooled to rt and concentrated under reduced pressure.
  • Example 40 (S)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-((1-hydroxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 55A*), (R)-N-(5-(5- amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-((1-hydroxypropan-2- yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 55B*), and N-(5-(5-acetamido-1H-pyrazol- 1-yl)-1,3,4-thiadiazol-2-yl)-3-((1-(tert-butoxy)propan-2-yl)oxy)-4-(2,6-dimethoxyphen
  • Example 41 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (3-hydroxy-3-methylbutoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 59) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(3-hydroxy-3- methylbutoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 59-Ac)
  • Steps 1-3 4-(2,6-dimethoxyphenyl)-5-(3-hydroxy-3-methylbutoxy)-6-oxopyran-2-carboxylic acid was prepared according to Steps 1-3 of Example 32 using 2,4-dihydroxy-2-methylbutane in place of 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol.
  • LCMS (ES, m/z) 379.1 [M+H]+.
  • Step 4 To a stirred mixture of 4-(2,6-dimethoxyphenyl)-5-(3-hydroxy-3-methylbutoxy)-6- oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) (60 mg, 0.16 mmol, 1 equiv) in N,N- dimethylformamide (DMF) (3.60 mL) was added a solution of propylphosphonic (T3P) in ethyl acetate (50% yield) (600 mg, 0.943 mmol, 6 equiv) and N-methylmorpholine (NMM) (96 mg, 0.95 mmol, 6 equiv) at room temperature.
  • aryl-pyrone reagent 4-(2,6-dimethoxyphenyl)-5-(3-hydroxy-3-methylbutoxy)-6- oxopyran-2-carboxylic acid
  • Step 5 To a stirred mixture of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4- (2,6-dimethoxyphenyl)-3-(3-hydroxy-3-methylbutoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 59-Ac) (20 mg, 0.034 mmol, 1 equiv) in MeOH (3.3 mL) was added acetyl chloride (0.55 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure.
  • Example 42 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3,5-dimethoxypyridin-2- yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 60) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3,5-dimethoxypyridin-2-yl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 60-Ac) [667] Steps 1-2: 4-(3,5-dimethoxypyridin-2-yl)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2- yl]-5-(2-methoxyethoxy)-6-o
  • Step 3 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(3,5-dimethoxypyridin-2-yl)- 3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 60) was prepared according to Step 2 of Example 7 by acidic deprotection of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol- 2-yl)-4-(3,5-dimethoxypyridin-2-yl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 60-Ac).
  • Example 43 (S)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)- 3-((1-hydroxy-3-methoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 62A*), (R)-N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-((1- hydroxy-3-methoxypropan-2-yl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 62B*), (S)-N- (5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(2-hydroxy
  • Step 1 To a solution of glycerin methyl ether (1 g, 9.4 mmol, 1 equiv) and 1H-imidazole (1.28 g, 18.8 mmol, 2 equiv) in dichloromethane (DCM) (20 mL) was added tert- butyl(chloro)diphenylsilane (2.85 g, 10.4 mmol, 1.1 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature then diluted with water (50 mL) and extracted with dichloromethane (DCM) (3 x 50 mL).
  • DCM dichloromethane
  • Step 2 To a solution containing the mixture of tert-butyl(2-hydroxy-3- methoxypropoxy)diphenylsilane and 2-((tert-butyldiphenylsilyl)oxy)-3-methoxypropan-1-ol from Step 1 (2.2 g, 6.4 mmol, 1.2 equiv), triphenyl phosphine (PPh 3 ) (2.10 g, 7.98 mmol, 1.5 equiv) and methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (product of Step 1, Example 11) (1.58 g, 5.34 mmol, 0.8 equiv) in tetrahydrofuran (THF) (25 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1.84 g, 7.98 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere.
  • DBAD di-tert-buty
  • Step 3 To a solution containing the mixture of methyl 5-( ⁇ 1-[(tert-butyldiphenylsilyl)oxy]-3- methoxypropan-2-yl ⁇ oxy)-4-iodo-6-oxopyran-2-carboxylate and methyl 3-(2-((tert- butyldiphenylsilyl)oxy)-3-methoxypropoxy)-4-iodo-2-oxo-2H-pyran-6-carboxylate from Step 2 (1.5 g, 2.4 mmol, 1 equiv) in tetrahydrofuran (THF) (15 mL) was added trimethylstannanol (872 mg, 4.82 mmol, 2 equiv).
  • THF tetrahydrofuran
  • Step 4 To a solution containing the mixture of 5-( ⁇ 1-[(tert-butyldiphenylsilyl)oxy]-3- methoxypropan-2-yl ⁇ oxy)-4-iodo-6-oxopyran-2-carboxylic acid and 3-(2-((tert- butyldiphenylsilyl)oxy)-3-methoxypropoxy)-4-iodo-2-oxo-2H-pyran-6-carboxylic acid from Step 3 (1.5 g, 2.5 mmol, 1 equiv), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (2.10 g, 7.39 mmol, 3 equiv) and N-methylimidazole (NMI) (1.42 g, 17.2 mmol, 7 equiv) in aceton
  • Step 5 A solution containing the mixture of 5-( ⁇ 1-[(tert-butyldiphenylsilyl)oxy]-3- methoxypropan-2-yl ⁇ oxy)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-6- oxopyran-2-carboxamide and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-((tert- butyldiphenylsilyl)oxy)-3-methoxypropoxy)-4-iodo-2-oxo-2H-pyran-6-carboxamide from Step 4 (“halo-pyrone reagent”) (400 mg, 0.49 mmol, 1 equiv), 2,6-dimethoxyphenyl
  • reaction mixture was then cooled to rt and directly purified by C18 reverse phase flash chromatography (mobile phase, MeCN in water (50mmol/L NH 4 HCO 3 ), 50% to 65% gradient in 15 min; detector, UV 254 nm) to provide a mixture of 5-( ⁇ 1-[(tert-butyldiphenylsilyl)oxy]-3- methoxypropan-2-yl ⁇ oxy)-4-(2,6-dimethoxyphenyl)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)-3-methoxypropoxy)-4-(2,6-dimethoxyphenyl)-2-
  • Steps 6-7 A solution containing the mixture of 5-( ⁇ 1-[(tert-butyldiphenylsilyl)oxy]-3- methoxypropan-2-yl ⁇ oxy)-4-(2,6-dimethoxyphenyl)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)-3-methoxypropoxy)-4-(2,6-dimethoxyphenyl)-2- oxo-2H-pyran-6-carboxamide from Step 5 (270 mg, 0.33 mmol, 1 equiv)
  • Steps 1-2 2-bromo-1-(2-(tert-butoxy)ethoxy)-3-methoxybenzene was prepared according to Step 1 of Example 22 using 2-(tert-butoxy)ethan-1-ol in place of 2-methoxyethanol.
  • 2-bromo-1-(2-(tert-butoxy)ethoxy)-3-methoxybenzene (1 g, 3.3 mmol, 1 equiv) in tetrahydrofuran (THF) (20 mL) was added n-butyl lithium (n-BuLi) (1.5 mL, 4.7 mmol, 1.1 equiv) dropwise at -78 °C under nitrogen atmosphere.
  • Step 3 A solution of 2-[2-(tert-butoxy)ethoxy]-6-methoxyphenylboronic acid (300 mg, 1.12 mmol, 1equiv), K2CO3 (464 mg, 3.36 mmol, 3equiv) and methyl 4-bromo-5-(2-methoxyethoxy)-6- oxopyran-2-carboxylate (product of Step 1, Example 3) (344 mg, 1.12 mmol, 1 equiv) in 1,4- dioxane (10 mL) and H2O (1 mL) was stirred for 1 h at 60 °C under nitrogen atmosphere then cooled to rt and concentrated under reduced pressure.
  • Step 4 A solution of methyl 4- ⁇ 2-[2-(tert-butoxy)ethoxy]-6-methoxyphenyl ⁇ -5-(2- methoxyethoxy)-6-oxopyran-2-carboxylate (330 mg, 0.733 mmol, 1equiv) and trimethyltin hydroxide (265 mg, 1.47 mmol, 2 equiv) in tetrahydrofuran (THF) (5 mL) was stirred overnight at room temperature under nitrogen atmosphere.
  • THF tetrahydrofuran
  • Step 5 To a stirred mixture of 4- ⁇ 2-[2-(tert-butoxy)ethoxy]-6-methoxyphenyl ⁇ -5-(2- methoxyethoxy)-6-oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) (260 mg, 0.596 mmol, 1 equiv) and N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (product of Step 3, Example 5; “ADT amine reagent”) (160 mg, 0.715 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (5 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (501 mg, 1.79 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere, and the reaction was stirred at r
  • Step 6 A solution of 4- ⁇ 2-[2-(tert-butoxy)ethoxy]-6-methoxyphenyl ⁇ -N-[5-(5- acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxamide (300 mg, 0.467 mmol, 1equiv) in HCl (4 mL of 4 M in 1,4-dioxane) was stirred for 2 h at room temperature then concentrated under reduced pressure to provide N-(5-(5-acetamido-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-4-(2-(2-hydroxyethoxy)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo- 2H-pyran-6-carboxamide (Compound 35-Ac) (220 mg, 80% yield) which was used in the
  • Step 7 To a stirred solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4- (2-(2-hydroxyethoxy)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 35-Ac) (70 mg, 0.12 mmol, 1 equiv) in dichloromethane (DCM) (3 mL) was added triethylamine (TEA) (36 mg, 0.36 mmol, 3 equiv), methanesulfonic anhydride (31 mg, 0.18 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere.
  • DCM dichloromethane
  • TEA triethylamine
  • methanesulfonic anhydride 31 mg, 0.18 mmol, 1.5 equiv
  • Step 8 To a stirred solution of 2-[2-(6- ⁇ [5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2- yl]carbamoyl ⁇ -3-(2-methoxyethoxy)-2-oxopyran-4-yl)-3-methoxyphenoxy]ethyl methanesulfonate (80 mg, 0.12 mmol, 1 equiv) in tetrahydrofuran (THF) (2 mL) was added tetrabutylammonium fluoride (TBAF) (47 mg, 0.18 mmol, 1.5 equiv) and trimethylsilyl cyanide (TMSCN) (24 mg, 0.24 mmol, 2 equiv) at room temperature under nitrogen atmosphere.
  • THF tetrahydrofuran
  • THF tetrabutylammonium fluoride
  • TMSCN trimethylsilyl cyanide
  • Step 9 To a stirred solution of N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4- (2-(2-cyanoethoxy)-6-methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 67-Ac) (30 mg, 0.05 mmol, 1 equiv) in MeOH (3 mL) was added AcCl (8 mg, 0.10 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature then concentrated under reduced pressure.
  • N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-(2-hydroxyethoxy)-6- methoxyphenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 35) may be prepared following above Step 9 of Example 44 by acidic deprotection of N-(5-(5-acetamido-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-(2-hydroxyethoxy)-6-methoxyphenyl)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 35-Ac).
  • Example 45 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (2-(2-hydroxyethoxy)ethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 68) [688]
  • Step 1 Methyl 4-bromo-5-(2- ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethoxy ⁇ ethoxy)-6-oxopyran-2- carboxylate was prepared according to Step 2 of Example 27 using 2- ⁇ 2-[(tert- butyldimethylsilyl)oxy]ethoxy ⁇ ethanol in place of 2,2-dimethylpropane-1,3-diol and di-tert-butyl azodicarboxylate (DBAD) in place of diethyl azodicarboxylate (DEAD).
  • DBAD di-tert-butyl azodica
  • Step 2 4-Bromo-3-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2H-pyran-6-carboxylic acid was prepared according to Step 3 of Example 27 using methyl 4-bromo-5-(2- ⁇ 2-[(tert- butyldimethylsilyl)oxy]ethoxy ⁇ ethoxy)-6-oxopyran-2-carboxylate in place of methyl 4-bromo-5- ⁇ 3- [(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropoxy ⁇ -6-oxopyran-2-carboxylate.
  • Step 3 To a stirred solution of 4-bromo-5-[2-(2-hydroxyethoxy)ethoxy]-6-oxopyran-2- carboxylic acid (450 mg, 1.39 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (5 mL) was added tert-butyl(chloro)diphenylsilane (TBDPSCl) (766 mg, 2.79 mmol, 2 equiv) and imidazole (284 mg, 4.18 mmol, 3 equiv) at room temperature.
  • DMF N,N-dimethylformamide
  • TBDPSCl tert-butyl(chloro)diphenylsilane
  • Steps 4-6 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (2-(2-hydroxyethoxy)ethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 68) was prepared according to Steps 3-5 of Example 36 using 4-bromo-5-(2- ⁇ 2-[(tert- butyldiphenylsilyl)oxy]ethoxy ⁇ ethoxy)-6-oxopyran-2-carboxylic acid in place of 4-bromo-5-([(2S)- 1-methoxypropan-2-yl]oxy-6-oxopyran-2-carboxylic acid.
  • Example 46 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3- (((1S,2S)-2-hydroxycyclopentyl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 71A*), N-(5- (5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(((1R,2R)-2- hydroxycyclopentyl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 71B*), and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6-dimethoxyphenyl)-3-(((1,2-trans)-2-
  • Steps 1-5 A trans mixture of N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-3-(((1,2-trans)-2-hydroxycyclopentyl)oxy)-2-oxo-2H-pyran-6-carboxamide (Compound 71) was prepared according to Steps 2-6 of Example 13 using (1,2-cis)-cyclopentane- 1,2-diol in place of 2-(t-butoxy)ethanol and methyl 4-bromo-3-hydroxy-2-oxo-2H-pyran-6- carboxylate in place of methyl 4-iodo-3-hydroxy-2-oxo-2H-pyran-6-carboxylate.
  • Step 6 The trans isomers of N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2,6- dimethoxyphenyl)-3-(((1,2-trans)-2-hydroxycyclopentyl)oxy)-2-oxo-2H-pyran-6-carboxamide
  • Example 47 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxy-2,2- dimethylpropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 73) and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxy-2-methylpropoxy)- 4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 73-Ac) [696] Step 1: Methyl 4-bromo-5-(2-methoxy-2-methylpropoxy)-6-oxopyran-2-carboxylate was prepared according to Step 1 of Example 24 using 2-methoxy-2-methylpropan-1-ol in place of 3- methoxy-2,
  • Step 2 Methyl 5-(2-methoxy-2-methylpropoxy)-4-(3-methoxypyridin-2-yl)-6-oxopyran-2- carboxylate was prepared according to Step 4 of Example 24 using methyl 4-bromo-5-(2-methoxy-2- methylpropoxy)-6-oxopyran-2-carboxylate in place of N-[5-(5-acetamidopyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-4-iodo-5-(3-methoxy-2,2-dimethylpropoxy)-6-oxopyran-2-carboxamide.
  • Step 3 5-(2-methoxy-2-methylpropoxy)-4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxylic acid was prepared according to Step 2 of Example 24 using methyl 5-(2-methoxy-2-methylpropoxy)- 4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxylate in place of methyl 4-iodo-5-(3-methoxy-2,2- dimethylpropoxy)-6-oxopyran-2-carboxylate.
  • LCMS (ES, m/z) 350.1 [M+H]+.
  • Steps 4-5 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(3-methoxy-2,2- dimethylpropoxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 73 was prepared according to Steps 4-5 of Example 16 using 5-(2-methoxy-2-methylpropoxy)-4-(3- methoxypyridin-2-yl)-6-oxopyran-2-carboxylic acid (“aryl-pyrone reagent”) in place of 4-(2,6- dimethoxyphenyl)-5-[(1,3-dimethoxypropan-2-yl)oxy]-6-oxopyran-2-carboxylic acid, which was coupled with N-(1-(5-amino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-yl)acetamide (
  • Example 48 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (difluoromethoxy)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 74) and N-(5-(5-acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (difluoromethoxy)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 74- Ac) [700] Steps 1-2: Methyl 4-[2-cyano-6-(difluoromethoxy)phenyl]-5-(2-methoxyethoxy)-6-oxopyran- 2-carboxylate was prepared according to Steps 1-2 of Example 23 using 2-brom
  • Steps 3-5 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(2-cyano-6- (difluoromethoxy)phenyl)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 74) was prepared according to Steps 3-5 of Example 32 using methyl 4-[2-cyano-6- (difluoromethoxy)phenyl]-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate in place of methyl 5- ⁇ 3- [(tert-butyldimethylsilyl)oxy]propoxy ⁇ -4-(2,6-dimethoxyphenyl)-6-oxopyran-2-carboxylate.
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4.00 g, 16.1 mmol, 1.0 equiv), (2R)-1-(benzyloxy)propan-2-ol (4.00 g, 24.1 mmol, 1.5 equiv), triphenylphosphine (PPh 3 ) (6.32 g, 24.1 mmol, 1.5 equiv) in tetrahydrofuran (THF) (40 mL, 494 mmol, 30.7 equiv) was added di-tert-butyl azodicarboxylate (DBAD) (5.55 g, 24.1 mmol, 1.5 equiv) at 0 °C, and then the resulting mixture was stirred for 2 h at room temperature.
  • DBAD di-tert-butyl azodicarboxylate
  • Step 2 To a stirred solution of methyl 5- ⁇ [(2S)-1-(benzyloxy)propan-2-yl]oxy ⁇ -4-bromo-6- oxopyran-2-carboxylate (2.00 g, 5.04 mmol, 1.0 equiv) in tetrahydrofuran (THF) (20 mL) was added trimethyltin hydroxide (1.38 g, 7.58 mmol, 1.5 equiv) at room temperature, and then the resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 3 To a stirred solution of 5- ⁇ [(2S)-1-(benzyloxy)propan-2-yl]oxy ⁇ -4-bromo-6-oxopyran- 2-carboxylic acid (600 mg, 1.57 mmol, 1.0 equiv), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (653 mg, 2.33 mmol, 1.5 equiv) and N-methylimidazole (NMI) (381 mg, 4.64 mmol, 3.0 equiv) in acetonitrile (MeCN) (10 mL) was added N-[2-(5-amino-1,3,4- thiadiazol-2-yl)pyrazol-3-yl]acetamide (279 mg, 1.24 mmol, 0.79 equiv) at room temperature.
  • TCFH chloro-N,N,N′,N′-tetramethylformamidinium hexa
  • Step 4 To a stirred solution of 5- ⁇ [(2S)-1-(benzyloxy)propan-2-yl]oxy ⁇ -4-bromo-N-[5-(5- acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (200 mg, 0.0170 mmol, 1.0 equiv) in toluene (2 ml) were added 3-methoxy-2-(tributylstannyl)pyridine (70 mg, 0.018 mmol, 1.0 equiv), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (80 mg, 0.0030 mmol, 0.20 equiv) and copper(I) iodide (40 mg, 0.0050 mmol, 0.31 equiv) at room temperature.
  • Pd(PPh3)4 3-methoxy-2-(tributylstanny
  • Step 5 A solution of 5-([(2S)-1-(benzyloxy)propan-2-yl]oxy-N-[5-(5-acetamidopyrazol-1-yl)- 1,3,4-thiadiazol-2-yl]-4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxamide (50 mg, 0.081 mmol, 1.0 equiv) in concentrated HCl (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (1.00 g, 4.02 mmol, 1.0 equiv), triphenylphosphine (PPh3) (1.58 g, 6.02 mmol, 1.5 equiv) and cis-(1s,4s)- cyclohexane-1,4-diol (0.930 g, 8.03 mmol, 2.0 equiv) in tetrahydrofuran (THF) (20 mL) were added di-tert-butyl azodicarboxylate (DBAD) (1.39 g, 6.02 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere.
  • DBAD di-tert-butyl azodicarboxylate
  • Step 2 A solution of methyl 4-bromo-6-oxo-5-([trans-4-hydroxycyclohexyl]oxypyran-2- carboxylate (400 mg, 1.15 mmol, 1 equiv), [1,1′-Bis(di-tert-butylphosphino) ferrocene] dichloropalladium(II) (Pd(DtBPF)Cl 2 ) (158 mg, 0.242 mmol, 0.21 equiv), K 3 PO 4 (480 mg, 2.26 mmol, 2.0 equiv) and 2,6-dimethoxyphenylboronic acid (321 mg, 1.76 mmol, 1.5 equiv) in dioxane (6 mL) and H2O (1 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere.
  • Step 3 To a solution of methyl 4-(2,6-dimethoxyphenyl)-6-oxo-5-([trans-4- hydroxycyclohexyl]oxypyran-2-carboxylate (280 mg, 0.692 mmol, 1.0 equiv) and imidazole (95 mg, 1.40 mmol, 2.0 equiv) in acetonitrile (5 mL) was added tert-butyldiphenylchlorosilane (TBDPSCl) (286 mg, 1.04 mmol, 1.5 equiv) at room temperature, and then the resulting solution was stirred for 2 h at room temperature.
  • TBDPSCl tert-butyldiphenylchlorosilane
  • Step 4 To a stirred solution of methyl 4-(2,6-dimethoxyphenyl)-6-oxo-5-([trans-4-[(tert- butyldiphenylsilyl)oxy]cyclohexyl]oxypyran-2-carboxylate (320 mg, 0.498 mmol, 1.0 equiv) in tetrahydrofuran (THF) (7 mL) was added trimethyltin hydroxide (180 mg, 0.995 mmol, 2.0 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 5 To a solution of 4-(2,6-dimethoxyphenyl)-6-oxo-5-([(1r,4r)-4-[(tert- butyldiphenylsilyl)oxy]cyclohexyl]oxypyran-2-carboxylic acid (250 mg, 0.398 mmol, 1.0 equiv) in acetonitrile (MeCN) (5 mL) was added N-[2-(5-amino-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]acetamide (90 mg, 0.401 mmol, 1.01 equiv), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (167 mg, 0.595 mmol, 1.5 equiv) and N-methylimidazole (NMI) (163 mg, 1.98 mmol, 5.0 equiv) at room temperature, and then the acetonit
  • Step 6 A solution of 4-(2,6-dimethoxyphenyl)-N-[5-(5-acetamidopyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxo-5-([trans-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]oxypyran-2-carboxamide (100 mg, 0.120 mmol, 1.0 equiv) in concentrated HCl (3 mL) was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 2 To a solution of methyl 4-bromo-5- ⁇ [cis-3-hydroxycyclopentyl]oxy ⁇ -6-oxopyran-2- carboxylate (1.3 g, 3.902 mmol, 1 equiv) and Imidazole (540 mg, 7.932 mmol, 2.03 equiv)in DCM (15 mL) was added TBDPSCl (1.7 g, 6.185 mmol, 1.58 equiv) at room temperature, and then the resulting mixture was stirred for 1h at room temperature. The reaction was diluted with water (150 mL) at room temperature, extracted with ethyl acetate (EtOAc) (3 x 70 mL).
  • EtOAc ethyl acetate
  • Step 3 To a stirred solution of methyl 4-bromo-5- ⁇ [cis-3-[(tert- butyldiphenylsilyl)oxy]cyclopentyl]oxy ⁇ -6-oxopyran-2-carboxylate (500 mg, 0.875 mmol, 1 equiv), tetrakis (triphenylphosphine)palladium (0) (Pd(PPh3)4) (200 mg, 0.173 mmol, 0.20 equiv) and copper(I) iodide (35.0 mg, 0.184 mmol, 0.21 equiv) in dioxane (7.5 mL) was added 3-methoxy-2- (tributylstannyl)pyridine (700 mg, 1.76 mmol, 2.0 equiv) at room temperature under nitrogen, and then the resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere.
  • 3-methoxy-2- (tributylstannyl)pyridine 700 mg, 1.76
  • Step 4 To a stirred solution of methyl 5- ⁇ [cis-3-[(tert- butyldiphenylsilyl)oxy]cyclopentyl]oxy ⁇ -4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxylate (400 mg, 0.667 mmol, 1.0 equiv) in tetrahydrofuran (THF) (10 mL) was added trimethylstannanol (Me 3 SnOH) (200 mg, 1.11 mmol, 1.7 equiv) at room temperature, and then the resulting mixture was stirred for 1 h at 50 °C.
  • THF tetrahydrofuran
  • Me 3 SnOH trimethylstannanol
  • Step 5 To a stirred solution of 5- ⁇ [cis-3-[(tert-butyldiphenylsilyl)oxy]cyclopentyl]oxy ⁇ -4-(3- methoxypyridin-2-yl)-6-oxopyran-2-carboxylic acid (230 mg, 0.393 mmol, 1.0 equiv), chloro- N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) (165 mg, 0.588 mmol, 1.5 equiv) and N-methyl imidazole (NMI) (97 mg, 1.181 mmol, 3.01 equiv) in acetonitrile (6 mL) was added and N-[2-(5-amino-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]acetamide (69.0 mg, 0.308 mmol, 0.78 equiv) at room temperature, and then the resulting
  • Step 6 A solution of the RS-isomer* (60 mg, 0.076 mmol, 1.0 equiv) in con. HCl (4 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 7 A solution of the SR-isomer* (60 mg, 0.076 mmol, 1.0 equiv) in con. HCl (4 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Example 52 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(((1R,3R)-3- methoxycyclohexyl)oxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 113A*), N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(((1S,3S)-3- methoxycyclohexyl)oxy)-4-(3-methoxypyridin-2-yl)-2-oxo-2H-pyran-6-carboxamide (compound 113B*), N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-(((1S,3R)-3- methoxycyclohe
  • Step 1 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (1.00 g, 4.02 mmol, 1.0 equiv), 3-methoxycyclohexan-1-ol (626 mg, 4.81 mmol, 1.2 equiv) and triphenylphosphine (1.58 g, 6.02 mmol, 1.5 equiv) in tetrahydrofuran (THF) (10 mL) was added di- tert-butyl azodicarboxylate (DBAD) (1.38 g, 6.02 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature.
  • DBAD di- tert-butyl azodicarboxylate
  • Step 2 To a solution of 4-bromo-5-[(3-methoxycyclohexyl)oxy]-6-oxopyran-2-carboxylate (1.50 g, 2.49 mmol, 1.0 equiv, 60% purity), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) (576 mg, 0.498 mmol, 0.20 equiv) and copper(I) iodide (95 mg, 0.50 mmol, 0.20 equiv) in dioxane (40 mL) was added 3-methoxy-2-(tributylstannyl)pyridine (993 mg, 2.49 mmol, 1.0 equiv) dropwise at room temperature under vacuum, and then the resulting solution was stirred for 2 h at 100 °C under nitrogen atmosphere.
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
  • Step 3 A solution of methyl 5-[(3-methoxycyclohexyl)oxy]-4-(3-methoxypyridin-2-yl)-6- oxopyran-2-carboxylate (1.10 g, 2.82 mmol, 1.0 equiv) in HCl (30 mL, 6M) was stirred for 3 h at 80 °C. The resulting mixture was concentrated under reduced pressure to afford 5-[(3- methoxycyclohexyl)oxy]-4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxylic acid (900 mg, 85% yield).
  • Step 4 To a solution of 5-[(3-methoxycyclohexyl)oxy]-4-(3-methoxypyridin-2-yl)-6- oxopyran-2-carboxylic acid (1.00 g, 2.66 mmol, 1.0 equiv), hydroxybenzotriazole (HOBT) (540 mg, 4.00 mmol, 1.5 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.02 g, 5.33 mmol, 2.0 equiv) in N,N-dimethylformamide (DMF) (20 mL) was added N-[2-(5-amino-1,3,4- thiadiazol-2-yl)pyrazol-3-yl]acetamide (478 mg, 2.13 mmol, 0.80 equiv) in portions at room temperature, and then the resulting solution was stirred for 1 h at room temperature.
  • HOBT hydroxybenzotri
  • Step 5 A solution of N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-[(3- methoxycyclohexyl)oxy]-4-(3-methoxypyridin-2-yl)-6-oxopyran-2-carboxamide (Compound 113- Ac) (700 mg, 1.20 mmol, 1.0 equiv) in concentrated HCl (14 mL) was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • cGAS catalyzes the cyclization of ATP and GTP to produce cGAMP, which is the activating ligand of STING.
  • Human cGAS (hcGAS) inhibition can thus be quantified by measuring how much cGAMP is formed either indirectly, by monitoring ATP-depletion as in the hcGAS Kinase-Glo assay (as described below), or directly, such as using the hcGAS LCMS assay (as described below).
  • hcGAS Kinase-Glo assay Compounds may be tested for their human-cGAS (h-cGAS) inhibition activity using the methodology reported in Lama et al., “Development of human cGAS-specific small molecule inhibitors for repression of dsDNA-triggered interferon expression”, Nature Communications 10, Article number: 2261 (2019), with slight changes to some conditions as shown in Table B.
  • hcGAS LCMS assay Compounds were tested for their hcGAS inhibition activity using direct measurement of cGAMP production by LC/MS. Briefly, compounds were incubated with enzyme and substrates for 4 hours (see Table C), before the reaction was stopped with 3 volumes of 70/30 Acetonitrile/H2O mix containing 0.15 uM cGAMP- 13 C10 15 N5 as internal standard and mixed for 5 min. After centrifugation (3700 rpm, 10 min, 10° Celsius), 100 uL of each reaction was collected and mixed to equal volume of acetonitrile (MeCN).
  • MeCN acetonitrile
  • A represents an IC50 value ⁇ 0.005 ⁇ M (with A1 representing an IC50 value ⁇ 0.0005 ⁇ M, A2 representing an IC50 value > 0.0005 ⁇ M and ⁇ 0.001 ⁇ M, and A3 representing an IC50 value > 0.001 ⁇ M and ⁇ 0.005 ⁇ M); B represents an IC50 value ⁇ 0.005 ⁇ M and ⁇ 0.02 ⁇ M; C represents an IC50 value ⁇ 0.02 ⁇ M and ⁇ 0.06 ⁇ M; and D represents an IC50 value ⁇ 0.06 ⁇ M.
  • Activity Data obtained from the above described hcGAS LCMS assay method is provided in Table D. Dashed lines (--) indicate no data available.
  • the present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims or embodiments is introduced into another claim or embodiment.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • the present disclosure recites elements presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.
  • variable e.g., an R group
  • any variable e.g., an R group
  • that variable may be selected from a given list of two or more elements, unless otherwise stated or understood within the context of the present disclosure, that variable (e.g., the R group) at each repeated occurrence (e.g., 2 or more times) is independent of each other, being independently selected from that given list.

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Abstract

La présente invention concerne des composés de formule (I), ou un sel pharmaceutiquement acceptable de ceux-ci, le cycle A, R1, le cycle C, R3A, R4, m et n étant définis dans la description, des procédés de préparation, des procédés de traitement et des compositions pharmaceutiques les comprenant. La présente invention concerne en outre l'utilisation des composés de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci, dans le traitement de maladies et de troubles liés à la cGAS.
PCT/US2024/028639 2023-05-10 2024-05-09 Inhibiteurs de la gmp-amp synthase cyclique et leurs utilisations Pending WO2024233812A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763263A (en) 1995-11-27 1998-06-09 Dehlinger; Peter J. Method and apparatus for producing position addressable combinatorial libraries
WO2014099824A1 (fr) 2012-12-19 2014-06-26 Board Of Regents, The University Of Texas System Ciblage pharmaceutique d'une voie de signalisation de dinucléotide cyclique chez un mammifère
WO2020072492A1 (fr) * 2018-10-02 2020-04-09 Baruch S. Blumberg Institute Dérivés de benzamide utilisés en tant qu'agonistes de la voie cgaz-sting
US20210155625A1 (en) 2018-02-05 2021-05-27 The Rockefeller University 2,3,4,5-TETRAHYDRO-1H-PYRIDO[4, 3-b]INDOLE INHIBITORS OF cGAS FOR TREATING AUTOINFLAMMATORY DISEASES
WO2023081441A1 (fr) * 2021-11-08 2023-05-11 Ventus Therapeutics U.S., Inc. Composés hétérocycliques et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763263A (en) 1995-11-27 1998-06-09 Dehlinger; Peter J. Method and apparatus for producing position addressable combinatorial libraries
WO2014099824A1 (fr) 2012-12-19 2014-06-26 Board Of Regents, The University Of Texas System Ciblage pharmaceutique d'une voie de signalisation de dinucléotide cyclique chez un mammifère
US20210155625A1 (en) 2018-02-05 2021-05-27 The Rockefeller University 2,3,4,5-TETRAHYDRO-1H-PYRIDO[4, 3-b]INDOLE INHIBITORS OF cGAS FOR TREATING AUTOINFLAMMATORY DISEASES
WO2020072492A1 (fr) * 2018-10-02 2020-04-09 Baruch S. Blumberg Institute Dérivés de benzamide utilisés en tant qu'agonistes de la voie cgaz-sting
WO2023081441A1 (fr) * 2021-11-08 2023-05-11 Ventus Therapeutics U.S., Inc. Composés hétérocycliques et leurs utilisations

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
ALSENZKANSY, ADVANCED DRUG DELIVERY REVIEWS, vol. 59, 2007, pages 546 - 567
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
ELIEL, E.L.: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
JACQUES ET AL.: "Enantiomers, Racemates and Resolutions", 1981, WILEY INTERSCIENCE
LAMA ET AL.: "Development of human cGAS-specific small molecule inhibitors for repression of dsDNA-triggered interferon expression", NATURE COMMUNICATIONS, vol. 10, 2019, pages 2261 - 502, XP055825490, DOI: 10.1038/s41467-019-08620-4
LAMA LODOE ET AL: "Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression", NATURE COMMUNICATIONS, vol. 10, no. 1, 1 December 2019 (2019-12-01), XP055825490, Retrieved from the Internet <URL:https://www.nature.com/articles/s41467-019-08620-4.pdf> DOI: 10.1038/s41467-019-08620-4 *
LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS, INC.
MILLER ET AL., J. MED. CHEM., vol. 63, 2020, pages 12156 - 12170
SMITHMARCH: "March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS, INC.
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
WANG ET AL., J MASS SPECTROM., vol. 35, 2000, pages 71 - 76
WILEN ET AL., TETRAHEDRON, vol. 33, 1977, pages 2725
WILEN, S.H.: "Tables of Resolving Agents and Optical Resolutions", 1972, UNIV. OF NOTRE DAME PRESS, pages: 268
ZHAO WENFENG ET AL: "In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing", JOURNAL OF CHEMICAL INFORMATION AND MODELING, vol. 60, no. 6, 22 June 2020 (2020-06-22), US, pages 3265 - 3276, XP093146699, ISSN: 1549-9596, DOI: 10.1021/acs.jcim.0c00171 *

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