WO2024137607A1 - Thiadiazole derivatives as inhibitors of cyclic gmp-amp synthase and uses thereof - Google Patents

Thiadiazole derivatives as inhibitors of cyclic gmp-amp synthase and uses thereof Download PDF

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WO2024137607A1
WO2024137607A1 PCT/US2023/084787 US2023084787W WO2024137607A1 WO 2024137607 A1 WO2024137607 A1 WO 2024137607A1 US 2023084787 W US2023084787 W US 2023084787W WO 2024137607 A1 WO2024137607 A1 WO 2024137607A1
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compound
alkyl
independently
formula
salt
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French (fr)
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Ramsay Beveridge
Jason Burch
Stephane Ciblat
Patrick Cyr
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Ventus Therapeutics US Inc
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Ventus Therapeutics US Inc
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Priority to JP2025536183A priority Critical patent/JP2026501225A/ja
Priority to IL321525A priority patent/IL321525A/en
Priority to CN202380091713.0A priority patent/CN120530109A/zh
Priority to KR1020257024220A priority patent/KR20250131845A/ko
Priority to AU2023408761A priority patent/AU2023408761A1/en
Priority to EP23848029.7A priority patent/EP4638446A1/en
Publication of WO2024137607A1 publication Critical patent/WO2024137607A1/en
Priority to CONC2025/0007987A priority patent/CO2025007987A2/es
Priority to MX2025007158A priority patent/MX2025007158A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • cytosolic DNA Aberrant accumulation of cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also induce autoimmunity.
  • This DNA signaling pathway requires the stimulator of interferon genes (STING) adapter protein and the transcription factors NF-KB and IRF3, but the mechanism of DNA sensing was unclear until recently.
  • STING interferon genes
  • mammalian cytosolic extracts synthesize cyclic GMP-AMP (cGAMP) in vitro from ATP and GTP in the presence of DNA rather than RNA (W O 2014099824). DNA transfection or DNA virus infection of mammalian cells also trigger the production of cGAMP.
  • cGAMP cyclic GMP-AMP
  • cGAMP binds to STING, leading to IRF3 activation and induction of interferon-(3 (IFN(3).
  • IFN(3) interferon-(3 )
  • 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.
  • cGAS cytosolic DNA sensing
  • pathogenic bacteria viruses
  • retroviruses US 20210155625
  • cGAS is essential in various other biological processes, such as cellular senescence and recognition of ruptured micronuclei in the surveillance of potential cancer cells.
  • 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
  • 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 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2–6 alkyl”).
  • C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n–pentyl (C 5 ), 3– pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n–octyl (C 8 ) 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 C 1–10 alkyl (e.g., –CH 3 ). In some embodiments, the alkyl group is a substituted C 1–10 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”).
  • haloalkyl hydrogen atoms are replaced with fluoro to provide a 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”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1–butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • 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 C 2–10 alkenyl.
  • the alkenyl group is a substituted C 2–10 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) (“C 2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 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).
  • 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. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents In some 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 (“C 3–8 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 (“C 4–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5–10 carbocyclyl”).
  • Exemplary C 3–6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3–8 carbocyclyl groups include, without limitation, the aforementioned C 3–6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3–10 carbocyclyl groups include, without limitation, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H– indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), 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”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”).
  • 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”)
  • C 3 6 cycloalkyl In some groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • 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 C 3–14 cycloalkyl.
  • the cycloalkyl group is a substituted C 3–14 cycloalkyl.
  • 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 selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • 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]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][
  • 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) In some embodiments 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.
  • 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. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen oxygen and sulfur Unless otherwise 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.
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, – Br), or iodine (iodo, –I) radicals.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties). “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 “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use
  • Examples of 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts
  • 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 + (C 1–4 alkyl) 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 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.
  • 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 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 vehicle.
  • “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 vehicle.
  • the phrase “at least one” refers to one instance or more than one instance.
  • the articles "a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.
  • Ring A is a 5-membered monocyclic heteroaryl
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl are independently substituted with 0, 1, 2, 3, or 4 R 1A
  • each R 1A is independently halogen, -OR 1B , or - N(R 1B ) 2
  • each R 1B is independently hydrogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A
  • each R 2A is independently halogen, -OR 2B , or -N(R 2B ) 2 , wherein each R 2B is independently hydrogen, C 1 -C 3 alkyl,
  • 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 ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A , and each R 2A is independently -OR 2B , wherein each R 2B is independently hydrogen or C 1 -C 3 alkyl; R 3 is C 1 -C 10 alkyl, C 3 -C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3A ; or R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10- membered heterocyclyl independently substituted
  • compounds of Formula (I), comprising the combination of an - OR 1 group at the C 3 position of the pyrone ring, an amino moiety at the C 4 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 inhibitory activity, and/or solubility, compared to compounds absent that combination.
  • Applicants have additionally found that incorporating an -L 1 -OR 3B group, which is an exemplary substituent of group R 3 , may show additional improvements in one or more of these desirable properties.
  • the amino moiety at the C4 position of Formula (I) may be a group of formula (i-a), (ii-a), or (iii-a): wherein L 1 , R 3A , and R 3B are as defined herein; L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene; Ring B is a C 3 -C 10 carbocyclyl or 4- to 10-membered heterocyclyl; Ring C is a 5- to 10-membered heterocyclyl; and p is 0, 1, 2, or 3.
  • the compound is of Formula (I′): or a pharmaceutically acceptable salt thereof, wherein L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene, and p is 0, 1, 2, or 3.
  • the compound is of Formula (I′′):
  • the compound is of Formula (I′′′): or a pharmaceutically acceptable salt thereof, wherein Ring C is a 5- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.
  • the compound is of Formula (I′′′′): or a pharmaceutically acceptable salt thereof, wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety. Additional embodiments are further described below and herein.
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -L 3 -(C 3 -C 6 carbocyclyl), or -L 3 -(4- to 10-membered heterocyclyl), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 1A ; each R 1A is independently halogen, -OR 1B , -N(R 1B ) 2 , -SR 1B , -C
  • R 1 is C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 1 -C 4 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 1 - C 3 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 1 -C 2 alkyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 2 -C 6 alkenyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 2 -C 4 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 . In some embodiments, R 1 is C 2 -C 6 alkynyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 2 -C 4 alkynyl substituted with 0, 1, 2, 3, or 4 R 1A . In some embodiments, R 1 is C 2 -C 3 alkynyl substituted with 0, 1, 2, or 3 R 1A . In some embodiments, R 1 is C 1 -C 6 alkyl substituted with 0 R 1A .
  • R 1 is C 1 -C 6 alkyl substituted with 1 R 1A ;
  • R 1A is halogen, -OR 1B , or - N(R 1B ) 2 ; and each R 1B is independently 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 ; and
  • R 1B is hydrogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 1 is -L 3 -(C 3 carbocyclyl), wherein the carbocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(C 3 -C 6 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; and R 1A is -OR 1B .
  • R 1 is -L 3 -(C 3 -C 4 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; and R 1A is -OR 1B
  • R 1 is -L 3 -(C 3 OR 1B .
  • R 1 is -L 3 -(C 3 carbocyclyl), wherein the carbocyclyl is substituted with 1 R 1A ; L 3 is C 1 -C 3 alkylene; and R 1A is -OR 1B .
  • R 1 is -L 3 -(C 3-6 carbocyclyl)
  • the carbocyclyl ring is: .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 is -L 3 -(5-membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, 3, or 4 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, wherein the alkylene is substituted with 0 R 1E .
  • R 1 is -L 3 -(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene, wherein the alkylene is substituted with 0 R 1E .
  • R 1 is -L 3 -(6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is C 1 -C 3 alkylene, wherein the alkylene is substituted with 0 R 1E .
  • R 1 is -L 3 -(4- to 10-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is a bond.
  • R 1 is -L 3 -(5- to 6-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is a bond.
  • R 1 is -L 3 -(5-membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R 1A ; and L 3 is a bond.
  • 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. 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. In some embodiments, when R 1 is -L 3 -(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 -(6-membered heterocyclyl), 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 -(5-membered heterocyclyl), the heterocyclyl ring comprises 1 or 2 ring heteroatoms independently selected from O, N, and S. In some embodiments, when R 1 is -L 3 -(5-membered heterocyclyl), the heterocyclyl ring comprises 1 ring O atom.
  • the heterocyclyl ring is selected from: As generally described herein, L 3 is a bond, C 1 -C 3 alkylene, or -(C 1 -C 3 alkylene)-O-, wherein the alkylene is independently substituted with 0, 1, 2, 3, or 4 R 1E . In some embodiments, L 3 is a bond. In some embodiments, L 3 is C 1 -C 3 alkylene independently substituted with 0, 1, 2, 3, or 4 R 1E . In some embodiments, L 3 is C 1 -C 2 alkylene independently substituted with 0, 1, 2, 3, or 4 R 1E .
  • L 3 is C 1 alkylene independently substituted with 0, 1, or 2 R 1E . In some embodiments, L 3 is C 1 -C 3 alkylene independently substituted with 0 R 1E . In some embodiments, L 3 is C 1 -C 2 alkylene independently substituted with 0 R 1E . In some embodiments, L 3 is C 1 alkylene substituted with 0 R 1E . In some embodiments, at least one R 1A is independently halogen, -OR 1B , or -N(R 1B ) 2 . In some embodiments, at least one R 1A is independently halogen. In some embodiments, at least one R 1A is independently -OR 1B or -N(R 1B ) 2 .
  • At least one R 1B is independently hydrogen. In some embodiments, at least one R 1C is independently C 1 -C 3 alkyl. In some embodiments, at least one R 1C is independently C 1 -C 3 haloalkyl. In some embodiments, at least one R 1C is independently -OR 1B . In some embodiments, at least one R 1C is independently -OCH 3 . In some embodiments, R 1 is -CH 3 , -CH 2 -C(CH 3 ) 2 -CH 2 OCH 3 , -CH 2 CH 2 OH, or - CH 2 CH 2 OCH 3 . In some embodiments, R 1 is -CH 3 .
  • R 1 is -CH 2 -C(CH 3 ) 2 -CH 2 OCH 3 . In some embodiments, R 1 is -CH 2 CH 2 OH. In some embodiments, R 1 is -CH 2 CH 2 OCH 3 .
  • R 1 is selected from: As generally defined herein, R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A , each R 2A is independently halogen, -OR 2B , or -N(R 2B ) 2 , wherein each R 2B is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; R 3 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3A ; or R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10-membered heterocyclyl independently substituted with 0, 1, 2, 3,
  • R 2 is hydrogen or C 1 -C 6 alkyl, wherein the alkyl is independently substituted with 0, 1, 2, 3, or 4 R 2A , and each R 2A is independently halogen, -OR 2B , or -N(R 2B ) 2 , wherein each R 2B is independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A .
  • R 2 is hydrogen.
  • R 2 is C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A .
  • R 2 is C 1 -C 6 alkyl substituted with 0 R 2A . In some embodiments, R 2 is C 1 -C 6 alkyl substituted with 1 R 2A . In some embodiments, R 2 is C 1 -C 6 alkyl substituted with 2 R 2A . In some embodiments, R 2 is C 1 -C 6 alkyl substituted with 3 R 2A . In some embodiments, R 2 is C 1 -C 6 alkyl substituted with 4 R 2A . In some embodiments, at least one R 2A is independently halogen, -OR 2B , or -N(R 2B ) 2 . In some embodiments, at least one R 2A is independently halogen.
  • At least one R 2A is independently -OR 2B . In some embodiments, at least one R 2A is independently -OH. In some embodiments, at least one R 2A is independently -O(C 1 -C 3 alkyl). In some embodiments, at least one R 2B is independently hydrogen. In some embodiments, at least one R 2B is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments, at least one R 2B is independently C 1 -C 3 alkyl. In some embodiments, at least one R 2B is independently methyl. In some embodiments, at least one R 2B is independently ethyl. In some embodiments, at least one R 2B is independently propyl.
  • At least one R 2B is independently C 1 -C 3 haloalkyl.
  • R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6- or 7-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 1A .
  • R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 0 R 1A .
  • R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 1 R 1A . In some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6- membered heterocyclyl substituted with 2 R 1A . In some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 3 R 1A . In some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form a 6-membered heterocyclyl substituted with 4 R 1A .
  • R 1 and R 2 are joined, with the atoms to which they are attached, to form: , wherein x is 0, 1, 2, 3, or 4. In some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form: some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form: , wherein x is 0, 1, 2, 3, or 4. In some embodiments, R 1 and R 2 are joined, with the atoms to which they are attached, to form: some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.
  • R 3 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 carbocyclyl, or 4-10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3A .
  • R 3 is C 1 -C 10 alkyl, C 3 -C 10 carbocyclyl, or 4-10 membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3A .
  • R 3 is C 1 -C 10 alkyl substituted with 0, 1, 2, 3, or 4 R 3A . In some embodiments, R 3 is C 1 -C 10 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 is C 1 -C 10 alkyl substituted with 1 R 3A . In some embodiments, R 3 is methyl substituted with 1 R 3A .
  • R 3 is ethyl substituted with 1 R 3A . In some embodiments, R 3 is propyl substituted with 1 R 3A . In some embodiments, R 3 is isopropyl substituted with 1 R 3A . In some embodiments, R 3 is butyl substituted with 1 R 3A . In some embodiments, R 3 is isobutyl substituted with 1 R 3A . In some embodiments, R 3 is tert-butyl substituted with 1 R 3A . In some embodiments, R 3 is C 1 -C 10 alkyl substituted with 2 R 3A . In some embodiments, R 3 is methyl substituted with 2 R 3A .
  • R 3 is ethyl substituted with 2 R 3A . In some embodiments, R 3 is propyl substituted with 2 R 3A . In some embodiments, R 3 is isopropyl substituted with 2 R 3A . In some embodiments, R 3 is butyl substituted with 2 R 3A . In some embodiments, R 3 is isobutyl substituted with 2 R 3A . In some embodiments, R 3 is tert-butyl substituted with 2 R 3A . In some embodiments, R 3 is C 1 -C 10 alkyl substituted with 3 R 3A . In some embodiments, R 3 is methyl substituted with 3 R 3A .
  • R 3 is ethyl substituted with 3 R 3A . In some embodiments, R 3 is propyl substituted with 3 R 3A . In some embodiments, R 3 is isopropyl substituted with 3 R 3A . In some embodiments, R 3 is butyl substituted with 3 R 3A . In some embodiments, R 3 is isobutyl substituted with 3 R 3A . In some embodiments, R 3 is tert-butyl substituted with 3 R 3A . In some embodiments, R 3 is C 1 -C 10 alkyl substituted with 4 R 3A .
  • R 3 is C 3 -C 10 carbocyclyl substituted with 0 1 2 3 or 4 R 3A some embodiments, R 3 is C 5 carbocyclyl. In some embodiments, R 3 is C 6 carbocyclyl. In some embodiments, R 3 is C 7 carbocyclyl. In some embodiments, R 3 is C 8 carbocyclyl. In some embodiments, R 3 is C 9 carbocyclyl. In some embodiments, R 3 is C 10 carbocyclyl. In some embodiments, R 3 is C 3 -C 10 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 3 carbocyclyl substituted with 1 R 3A .
  • R 3 is C 4 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 5 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 6 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 7 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 8 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 9 carbocyclyl substituted with 1 R 3A . In some embodiments, R 3 is C 10 carbocyclyl substituted with 1 R 3A .
  • R 3 is C 3 -C 10 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 3 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 4 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 5 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 6 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 7 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 8 carbocyclyl substituted with 2 R 3A .
  • R 3 is C 9 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 10 carbocyclyl substituted with 2 R 3A . In some embodiments, R 3 is C 3 -C 10 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 3 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 4 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 5 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 6 carbocyclyl substituted with 3 R 3A .
  • R 3 is C 7 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 8 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 9 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 10 carbocyclyl substituted with 3 R 3A . In some embodiments, R 3 is C 3 -C 10 carbocyclyl substituted with 4 R 3A . In some embodiments, R 3 is 4- to 10-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R 3A . In some embodiments, R 3 is 4- to 10-membered heterocyclyl.
  • R 3 is a fused 6- to 10-membered heterocyclyl. In some embodiments, R 3 is a spiro 6- to 10-membered heterocyclyl. In some embodiments, R 3 is a bridged 4- to 10- membered heterocyclyl. In some embodiments, R 3 is 4-membered heterocyclyl. In some embodiments, R 3 is 5- membered heterocyclyl In some embodiments R 3 is 6-membered heterocyclyl In some In some embodiments, R 3 is 4-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 5-membered heterocyclyl substituted with 1 R 3A .
  • R 3 is 6- membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 7-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 8-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 9-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 10-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 3 is 4- to 10-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 4-membered heterocyclyl substituted with 2 R 3A .
  • R 3 is 5-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 6- membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 7-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 8-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 9-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 10-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 3 is 4- to 10-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 4-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 5-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 6- membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 7-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 8-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 9-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 10-membered heterocyclyl substituted with 3 R 3A .
  • R 3 is 4- to 10-membered heterocyclyl substituted with 4 R 3A .
  • R 3 is (R3A)p wherein L3 is C1-C10 alkylene, C2-C10 alkenylene, or C 2 -C 10 alkynylene, and p is 0, 1, 2, or 3.
  • R wherein Ring B is the C 3 -C 10 carbocyclyl or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is C 1 -C 10 alkyl. I b di t th i it 3 N R R2 i l t d f th i ti f
  • amino moiety selected from the group consisting of: ,
  • R R2 is .
  • R3 R2 is .
  • R3 R2 is .
  • group R 3 is of formula , wherein L3 is C1-C10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene, and p is 0, 1, 2, or 3.
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is , to provide an amino moiety of formula (i-a):
  • L 3 is C 1 -C 10 alkylene.
  • L 3 is C 1 -C 6 alkylene.
  • L 3 is C 1 -C 4 alkylene. In some embodiments, L 3 is C 1 -C 3 alkylene. In some embodiments, L 3 is C 2 -C 10 alkenylene. In some embodiments, L 3 is C 2 -C 10 alkynylene.
  • amino moieties of formula 3 R R2 which fall within the scope of formula (i-a) include, but are not limited to: In some embodiments, amino moieties of formula 3 N R R2 which fall within the scope of formula (i-a) include, but are not limited to: In some embodiments, R 2 is hydrogen or C 1 -C 6 alkyl, and R 3 is C 3 -C 10 carbocyclyl. In some embodiments, the amino moiety selected from the group consisting of: H F , H
  • the amino moiety is selected from the group consisting of: [0180] In some embodiments, the amino moiety selected from the group consisting of: , some embodiments, 3X 2 , some embodiments, R R is some embodiments, , R is . In some embodiments, . , R 2 is
  • R A R 2 2 is O'” . In some embodiments, R R
  • R 2 is hydrogen or Ci-Ce alkyl
  • R 3 is 4-10 membered heterocyclyl
  • amino moiety R 3' N ⁇ R 2 is selected from the group consisting of:
  • amino moiety R 3' N ⁇ R 2 is selected from the group consisting of:
  • R 3 is , wherein Ring B is the C3-C10 carbocyclyl or 4- to 10-membered heterocyclyl,
  • R 2 is hydrogen or
  • Ring B is the C3-C10 carbocyclyl or 4- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.
  • Ring B is a C3-C10 carbocyclyl or 4- to 10-membered heterocyclyl.
  • Ring B is a C3-C10 carbocyclyl.
  • Ring B is a monocyclic C 3 -C 8 carbocyclyl.
  • Ring B is a monocyclic C 5 -C 7 carbocyclyl.
  • Ring B is a bicyclic C 5 -C 8 carbocyclyl. In some embodiments, Ring B is a bicyclic C 9 -C 10 carbocyclyl. In some embodiments, Ring B is 4- to 10-membered heterocyclyl. In some embodiments, Ring B is monocyclic 4- to 8-membered heterocyclyl. In some embodiments, Ring B is monocyclic 4- to 6-membered heterocyclyl. In some embodiments, Ring B is monocyclic 5- to 6-membered heterocyclyl. In some embodiments, amino moieties R3 N R 2 which fall within the scope of formula (ii-a) include, but are not limited to:
  • amino moieties R 3 R 2 which fall within the scope of formula (ii-a) include, but are not limited to:
  • R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 3A .
  • R 2 and R 3 are joined, with the atom to which they are attached, to form a 4-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R 3A .
  • R 2 and R 3 are joined, with the atom to which they are attached, to form a 4-membered heterocyclyl. In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 4-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 4-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 4-membered heterocyclyl substituted with 3 R 3A .
  • R 2 and R 3 are joined, with the atom to which they are attached, to form a 5-membered heterocyclyl. In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 5-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 5-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 5-membered heterocyclyl substituted with 3 R 3A .
  • R 2 and R 3 are joined, with the atom to which they are attached, to form a 6-membered heterocyclyl. In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 6-membered heterocyclyl substituted with 1 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 6-membered heterocyclyl substituted with 2 R 3A . In some embodiments, R 2 and R 3 are joined, with the atom to which they are attached, to form a 6-membered heterocyclyl substituted with 3 R 3A . ome embodiments, the amino moiety 3 N In s R R2 is selected from the group consisting of:
  • R 2 and R 3 of the amino moiety of formula R 3 R 2 are joined to form an amino moiety of formula (iii-a) , wherein Li is a bond, C1-C3 alkylene, or
  • Ring C is a 5- to 10-membered heterocyclyl, and p is 0, 1, 2, or 3.
  • amino moieties R R which fall within the scope of formula (iii- a) include, but are not limited to:
  • At least one R 3A is independently C 1 -C 3 alkyl substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently C 1 -C 3 alkyl. In some embodiments, at least one R 3A is independently C 1 -C 3 alkyl substituted with 1 R 3D . In some embodiments, at least one R 3A is independently C 1 -C 3 alkyl substituted with 2 R 3D . In some embodiments, at least one R 3A is independently C 1 -C 3 alkyl substituted with 3 R 3D . In some embodiments, at least one R 3A is independently C 1 -C 3 alkyl substituted with 4 R 3D .
  • At least one R 3A is independently -CN. In some embodiments, at least one R 3A is independently –(C 1 -C 3 alkylene)-CN. In some embodiments, at least one R 3A is independently -L 1 -SO 2 R 3C . In some embodiments, at least one R 3A is independently -SO 2 R 3C . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-SO 2 R 3C . In some embodiments, at least one R 3A is independently -L 1 -PO(R 3C ) 2 . In some embodiments, at least one R 3A is independently -PO(R 3C ) 2 .
  • At least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl). In some embodiments, at least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl) substituted with 3 R 3D .
  • At least one R 3A is independently -L 1 -(C 3 -C 6 carbocyclyl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -(C 3 -C 6 carbocyclyl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(C 3 -C 6 carbocyclyl). In some embodiments, at least one R 3A is independently -(C 3 -C 6 carbocyclyl) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -(C 3 -C 6 carbocyclyl) substituted with 2 R 3D .
  • At least one R 3A is independently -(C 3 -C 6 carbocyclyl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -(C 3 -C 6 carbocyclyl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl).
  • At least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl) substituted with 3 R 3D .
  • At least one R 3A is independently -(C 1 -C 3 alkylene)-(C 3 -C 6 carbocyclyl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(4- to 6-membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(4- to 6-membered heterocyclyl).
  • At least one R 3A is independently -L 1 -(4- to 6-membered heterocyclyl) substituted with 1 R 3D In some embodiments, at least one R 3A is independently -(4- to 6-membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(4- to 6-membered heterocyclyl). In some embodiments, at least one R 3A is independently -(4- to 6-membered heterocyclyl) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -(4- to 6-membered heterocyclyl) substituted with 2 R 3D .
  • At least one R 3A is independently -(4- to 6-membered heterocyclyl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -(4- to 6-membered heterocyclyl) substituted with 4 R 3D . In some embodiments, at least one h R 3A is independently -(C 1 -C 3 alkylene)-(4- to 6- membered heterocyclyl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, 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) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 3 R 3D .
  • At least one R 3A is independently -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 6-10 aryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 6 aryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 6 aryl). In some embodiments, at least one R 3A is independently -L 1 -(C 6 aryl) substituted with 1 R 3D .
  • At least one R 3A is independently -L 1 -(C 6 aryl) substituted with 2 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 6 aryl) substituted with 3 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(C 6 aryl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -(C 6 aryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(C 6 aryl).
  • At least one R 3A is independently -(C 6 aryl) substituted with 1 R 3D . In some embodiments at least one R 3A is independently -(C 6 aryl) substituted with 2 R 3D In In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 6 aryl). In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 1 R 3D . In some embodiments, 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 . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(C 6 aryl) substituted with 4 R 3D . In some embodiments, at least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, 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 . In some embodiments, at least one R 3A is independently -L 1 -(5- to 10-membered heteroaryl) substituted with 2 R 3D . In some embodiments, 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 -L 1 -(5- to 10-membered heteroaryl) substituted with 4 R 3D .
  • At least one R 3A is independently -(5- to 10-membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(5- to 10-membered heteroaryl). In some embodiments, at least one R 3A is independently -(5- to 10-membered heteroaryl) substituted with 1 R 3D . In some embodiments, at least one R 3A is independently -(5- to 10-membered heteroaryl) substituted with 2 R 3D . In some embodiments, 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 . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(5- to 10- membered heteroaryl) substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(5- to 10- membered heteroaryl). In some embodiments, at least one R 3A is independently -(C 1 -C 3 alkylene)-(5- to 10- membered heteroaryl) substituted with 1 R 3D .
  • At least one R 3A is independently -(C 1 -C 3 alkylene)-(5- to 10- membered heteroaryl) substituted with 2 R 3D In some embodiments at least one R 3A is to form C 6 aryl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, or 4- to 6-membered heterocyclyl. In some embodiments, two R 3A groups are joined, with the atoms to which they are attached, to form C 6 aryl. In some embodiments, two R 3A groups are joined, with the atoms to which they are attached, to form 5- to 6-membered heteroaryl.
  • 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 C 1 -C 3 alkyl, C 3 -C 6 carbocyclyl, or 4- to 6- membered heterocyclyl.
  • at least one R 3B is independently C 1 -C 3 alkyl substituted with 0, 1, 2, 3, or 4 R 3D .
  • at least one R 3B is independently C 1 -C 3 alkyl.
  • At least one R 3B is independently C 1 -C 3 alkyl substituted with 1 R 3D . In some embodiments, at least one R 3B is independently C 1 -C 3 alkyl substituted with 2 R 3D . In some embodiments, at least one R 3B is independently C 1 -C 3 alkyl substituted with 3 R 3D . In some embodiments, at least one R 3B is independently C 1 -C 3 alkyl substituted with 4 R 3D . In some embodiments, at least one R 3B is independently C 3 -C 6 carbocyclyl substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3B is independently C 3 -C 6 carbocyclyl.
  • At least one R 3B is independently C 3 -C 6 carbocyclyl substituted with 1 R 3D . In some embodiments, at least one R 3B is independently C 3 -C 6 carbocyclyl substituted with 2 R 3D . In some embodiments at least one R 3B is independently C 3 -C 6 carbocyclyl substituted with 3 substituted with 0, 1, 2, 3, or 4 R 3D . In some embodiments, at least one R 3B is independently 4- to 6-membered heterocyclyl. In some embodiments, 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 . In some embodiments, at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 3 R 3D . In some embodiments, at least one R 3B is independently 4- to 6-membered heterocyclyl substituted with 4 R 3D . As generally defined herein, each R 3C is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments, at least one R 3C is independently C 1 -C 3 alkyl. In some embodiments, at least one R 3C is independently C 1 -C 3 haloalkyl.
  • each R 3D is independently halogen, -OR 3E , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In another aspect, each R 3D is independently halogen, -OR 3E , -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, each R 3D is independently halogen or -OC 1 -C 3 alkyl. In some embodiments, at least one R 3D is independently halogen. In some embodiments, at least one R 3D is independently F or Cl. In some embodiments, at least one R 3D is independently F. In some embodiments, at least one R 3D is independently Cl.
  • At least one R 3D is independently -OR 3E . In some embodiments, at least one R 3D is independently -OC 1 -C 3 alkyl. In some embodiments, at least one R 3D is -CN. As generally defined herein, each R 3E is independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some embodiments, each R 3E is independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, at least one R 3E is independently hydrogen. In some embodiments, at least one R 3E is independently C 1 -C 3 alkyl.
  • At least one R 3E is independently C 1 -C 3 haloalkyl.
  • each L 1 is independently a bond, C 1 -C 3 alkylene, or C 1 -C 3 haloalkylene
  • at least one L 1 is independently C 1 alkylene.
  • at least one L 1 is independently C 2 alkylene.
  • at least one L 1 is independently C 3 alkylene.
  • Ring A, R 4 , L 2 , and m As generally defined herein, Ring A is a 5-membered monocyclic heteroaryl.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 or 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 ring nitrogen atom. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 2 ring nitrogen atoms. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 ring oxygen atom. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 ring nitrogen atom and 1 ring oxygen atom.
  • Ring A is a 5-membered monocyclic heteroaryl comprising 1 ring sulfur atom. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl comprising 1 ring nitrogen atom and 1 ring sulfur atom. In some embodiments, Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, or thiazole ring. In some embodiments, Ring A is: In some embodiments, Ring A is: In some embodiments, Ring A is: (ii-b). In some embodiments, Ring A is: In some embodiments, Ring A is: (v-b).
  • Ring A is: S N (vii-b). In some embodiments, Ring A is: (xiii-b). In some embodiments, Ring A is: (xiv-b). In some embodiments, Ring A is a 5-membered monocyclic heteroaryl directly linked to the thiadiazole via an N atom, as provided in formula (xvii-b): not limited to: (iii-b).
  • 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, wherein R 4A and R 4B are each independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl; each L 2 is a bond, C 1 -C 3 alkylene, or C 1 -C 3 haloalkylene; and m is 0, 1 or 2.
  • 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.
  • 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 -L 2 -OR 4A .
  • At least one R 4 is independently -OR 4A . In some embodiments, at least one R 4 is independently –(C 1 -C 3 alkylene)-OR 4A . In some embodiments, at least one R 4 is independently –(C 1 alkylene)-OR 4A . In some embodiments, at least one R 4 is independently –(C 2 alkylene)-OR 4A . In some embodiments, at least one R 4 is independently –(C 3 alkylene)-OR 4A . In some embodiments, at least one R 4 is independently -OH. In some embodiments, at least one R 4 is independently –(C 1 -C 3 alkylene)-OH.
  • At least one R 4 is independently –(C 2 alkylene)-O(C 1 -C 3 alkyl). In some embodiments, at least one R 4 is independently -NH 2 . In some embodiments, at least one R 4 is independently -L 2 -NH 2 . In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-NH 2 . In some embodiments, at least one R 4 is independently -NH(R 4B ). In some embodiments, at least one R 4 is independently -L 2 -NH(R 4B ). In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-NH(R 4B ).
  • At least one R 4 is independently -N(C 1 -C 3 alkyl) 2 . In some embodiments, at least one R 4 is independently -L 2 -N(C 1 -C 3 alkyl) 2 . In some embodiments, at least one R 4 is independently -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl) 2 . In some embodiments, at least one R 4 is independently C 1 -C 6 alkyl. In some embodiments, at least one R 4 is independently methyl. In some embodiments, at least one R 4 is independently ethyl. In some embodiments, at least one R 4 is independently propyl. In some embodiments, at least one R 4 is independently isopropyl.
  • At least one R 4 is independently butyl. In some embodiments, at least one R 4 is independently isobutyl. In some embodiments, at least one R 4 is independently tert-butyl. In some embodiments, at least one R 4 is independently C 1 -C 6 haloalkyl. In some embodiments, 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.
  • At least one R 4 is independently halo-isobutyl. In some embodiments, at least one R 4 is independently halo-tert-butyl. In some embodiments, each instance of R 4 is independently selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -Cl, -CN, -NH 2 , and -CH 2 OH. In some embodiments, at least one instance of R 4 is independently -CH 3 or -CH 2 CH 3 . In some embodiments, at least one instance of R 4 is independently -CHF 2 or -CF 3 .
  • Ring A is selected from the group consisting of: In some embodiments, Ring A ring systems of formula (xvii-b) are selected from the group consisting of: As generally defined herein, each L 2 is independently a bond, C 1 -C 3 alkylene, or C 1 -C 3 haloalkylene. In some embodiments, each L 2 is independently a bond or C 1 -C 3 alkylene. In some embodiments, at least one L 2 is independently a bond. In some embodiments, at least one L 2 is independently C 1 -C 3 alkylene. In some embodiments, at least one L 2 is independently C 1 alkylene. In some embodiments, at least one L 2 is independently C 2 alkylene.
  • At least one L 2 is independently C 3 alkylene.
  • m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.
  • variables Ring A, R 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4 , R 4A , R 4B , R 4C , L 1 , L 2 , L 3 , and m can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables Ring A, R 1 , R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 2 , R 2A , R 2B , x, R 3 , R 3A , R 3B , R 3C , R 3D ,
  • Ring A is
  • the amino moiety at the C 4 position is a group of formula (i-a). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-b). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-c). In certain embodiments, R 1 is methyl (-CH 3 ). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound is of Formula (I-a) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • Ring A is a group of formula (iv-b)
  • the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt thereof.
  • the amino moiety at the C 4 position is a group of formula (i-a).
  • the amino moiety at the C 4 position is a group of formula (i-b).
  • the amino moiety at the C 4 position is a group of formula (i-c).
  • R 1 is methyl (-CH 3 ).
  • R 2 is hydrogen.
  • m is 1 or 2.
  • the compound is of Formula (I-b) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • Ring A is a group of formula (v-b)
  • the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof
  • the amino moiety at the C 4 wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
  • the amino moiety at the C 4 position is a group of formula (i-a).
  • the amino moiety at the C 4 position is a group of formula (i-b). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-c). In certain embodiments, R 1 is methyl (-CH 3 ). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound is of Formula (I-d) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2. In some embodiments, wherein Ring A is a group of formula (vii-b), the compound of Formula (I) is of Formula (I-e): or a pharmaceutically acceptable salt thereof. In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-a).
  • the amino moiety at the C 4 position is a group of formula (i-b). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-c). In certain embodiments, R 1 is methyl (-CH 3 ). In certain embodiments, R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound is of Formula (I-e) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2. In some embodiments, wherein Ring A is a group of formula (xiii-b), the compound of Formula (I) is of Formula (I-f): formula (i-c). In certain embodiments, R 1 is methyl (-CH 3 ).
  • R 2 is hydrogen. In certain embodiments, m is 1 or 2. In some embodiments, the compound is of Formula (I-f) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2. In some embodiments, wherein Ring A is a group of formula (xiv-b), the compound of Formula (I) is of Formula (I-g): or a pharmaceutically acceptable salt thereof.
  • the amino moiety at the C 4 position is a group of formula (i-a). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-b). In certain embodiments, the amino moiety at the C 4 position is a group of formula (i-c).
  • R 1 is methyl (-CH 3 ).
  • R 2 is hydrogen.
  • m is 1 or 2.
  • the compound is of Formula (I-g) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • Ring A is a group of formula (ii-b) and the amino moiety at the C 4 position is a group of formula (i-a)
  • the compound of Formula (I) is of Formula (I-a-1): or a pharmaceutically acceptable salt thereof, wherein L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene, and p is 0, 1, 2, or 3.
  • the compound is of Formula (I-a-1) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • Ring A is a group of formula (ii-b) and the amino moiety at the C 4 position is a group of formula (ii-a)
  • the compound of Formula (I) is of Formula (I-a-2): a-2) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • the compound of Formula (I) is of Formula (I-a-3): or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4- to 10-membered heterocyclyl and p is 0, 1, 2, or 3.
  • the compound is of Formula (I-a-3) wherein R 1 is methyl and m is 1 or 2.
  • the compound of Formula (I) is of Formula (I-f-1): or a pharmaceutically acceptable salt thereof, wherein L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene, and p is 0, 1, 2, or 3.
  • the compound is of Formula (I-f-1) wherein R 1 is methyl, R 2 is hydrogen, and m is 1 or 2.
  • the compound of Formula (I) is of Formula (I-f-2): or a pharmaceutically acceptable salt thereof, wherein Ring B is C 3 -C 10 carbocyclyl, or 4- to 10- or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4- to 10-membered heterocyclyl and p is 0, 1, 2, or 3.
  • the compound is of Formula (I-f-3) wherein R 1 is methyl and m is 1 or 2.
  • R 1 and R 2 are cyclized to form a 6-membered heterocyclic ring
  • the compound of Formula (I) is selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is selected from any one of the compounds of 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.
  • Table 1 and Table 2 also provides the location of the compound in the Examples (Ex) by Example Number (Ex) or as provided in Table A (TA) of the Examples The Asterix (*) next
  • the compound is Compound 3*, Compound 4*, Compound 10, Compound 21*, Compound 22*, Compound 67a*, Compound 67b*, Compound 73, Compound 74, Compound 77, Compound 83, Compound 107a*, Compound 107b*, Compound 108a*, Compound 108b*, Compound 114, Compound 121, Compound 127, Compound 161, Compound 182, Compound 196, Compound 197, Compound 213, or a pharmaceutically acceptable salt of any of the foregoing.
  • the present disclosure provides a pharmaceutical composition 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 compound of the present disclosure, or pharmaceutical composition 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, 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.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • 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 lub
  • 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 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 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 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). In some aspects, 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. In some aspects, 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). In some aspects, 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. In some embodiments, modulation is inhibition.
  • the disease or disorder is inflammation, an autoimmune 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 is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury spinal cord injury amyotrophic lateral sclerosis (ALS) multiple sclerosis ataxia
  • 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).
  • 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 mellitus
  • IDDM insulin-dependent diabetes mellitus
  • SS Sjogren's syndrome
  • 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 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.
  • 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.
  • Such 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 pancreatiti
  • 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 a cyano containing compound of Formula (F-2), or salts 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 amide compound of Formula (J-1), or salt thereof may then be cross-coupled with an amine of Formula (K), or salt thereof, to provide a compound of Formula (I), or salt thereof.
  • General Scheme 5 Alternatively, as depicted in General Scheme 6, peptide coupling of the amine of Formula (H-2), or salt thereof, with the compound of Formula (D), or salt thereof, wherein R a is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, may provide an amide compound of Formula (J-2), or salt thereof.
  • the amide compound of Formula (J-2), or salt thereof may then be cross-coupled with an amine of Formula (K), or salt thereof, 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.
  • General Scheme 6 Compounds of Formula (J-1) and (J-2), and salts thereof, are also referred to herein as the “halo-pyrone reagent”s, and compounds of Formula (K), and salts thereof, are also referred to herein as the “amine reagent”s.
  • peptide coupling of the amine 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 may provide a compound of Formula (I), or salt thereof.
  • General Scheme 7 peptide coupling of the amine of Formula (H-2), 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, may provide a compound of Formula (I′′′′), or salt General Scheme 8.
  • amino-pyrone reagent compounds of Formula (H-1) and (H-2), and salts thereof, are also referred to as the “ADT amine reagent”s.
  • a bicyclic compound of Formula (I-BC-a) and (I-BC-b) may be formed from conversion of the terminal -OH of R 1 to a leaving group (LG), as defined herein, followed by cyclization.
  • the leaving group is a sulfonyl substituted hydroxyl group, such as -O-tosyl, -O-mesyl, or O-besyl.
  • General Scheme 9. v. 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. For example, 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. Furthermore, high-throughput screening can be used to speed up analysis using such assays.
  • 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, Biological Assay Methods.
  • 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 vi. Additional Embodiments Embodiment 1.
  • Ring A is a 5-membered monocyclic heteroaryl
  • Embodiment 2 The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-membered monocyclic heteroaryl; R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl are independently substituted with 0, 1, 2, 3, or 4 R 1A ; each R 1A is independently halogen, -OR 1B , or - N(R 1B ) 2 ; and each R 1B is independently hydrogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A , and each R 2A is independently halogen, -OR 2B , or -N(R 2B ) 2 , wherein each R 2B is independently hydrogen, C 1 -C 3 alkyl, or
  • Embodiment 3 The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the amino moiety is a group of formula (i-a), (ii-a), or (iii-a): wherein: L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene; Ring B is a C 3 -C 10 carbocyclyl or 4- to 10-membered heterocyclyl; Ring C is a 5- to 10-membered heterocyclyl; and p is 0, 1, 2, or 3.
  • Embodiment 1 or 2 wherein the compound is of Formula (I′): or a pharmaceutically acceptable salt thereof, wherein L 3 is C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 - C 10 alkynylene, and p is 0, 1, 2, or 3.
  • Embodiment 5 The compound of Embodiment 1 or 2, wherein the compound is of Formula (I′′): membered heterocyclyl, and p is 0, 1, 2, or 3.
  • Embodiment 1 The compound of Embodiment 1 or 2, wherein the compound is of Formula (I′′′′): or a pharmaceutically acceptable salt thereof, wherein the nitrogen atom of the heteroaryl Ring A is directly linked to the thiadiazole moiety.
  • Embodiment 8 The compound of any one of Embodiments 1-7, 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 .
  • Embodiment 8 The compound of Embodiment 8, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 , -CH 2 -C(CH 3 ) 2 -CH 2 OCH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , Embodiment 10.
  • R 1 is -CH 3 , -CH 2 -C(CH 3 ) 2 -CH 2 OCH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3
  • Embodiment 10 is hydrogen.
  • Embodiment 11 The compound of any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 10 alkyl substituted with 0, 1, 2, 3, or 4 R 3A .
  • Embodiment 15 The compound of any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof wherein R 3 is C 3 -C 10 carbocyclyl substituted with 0 1 2 3 or 4 R 3A acceptable salt thereof, wherein R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 3A .
  • Embodiment 15 The compound of any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10-membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 3A .
  • Embodiment 20 The compound of any one of Embodiments 1-19, or pharmaceutically acceptable salt thereof, wherein Ring A is: Embodiment 22.
  • Embodiment 23 Embodiment 23.
  • each R 4 is independently -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -Cl, -CN, -NH 2 , or -CH 2 OH.
  • Embodiment 24 The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond or C 1 -C 3 alkylene.
  • Embodiment 25 The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond or C 1 -C 3 alkylene.
  • Embodiment 26 is a pharmaceutically acceptable salt thereof, wherein each R 4 is independently -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -Cl, -CN, -NH 2 , or -CH 2 OH.
  • Embodiment 27 The compound of any one of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein m is 2.
  • Embodiment 28 The compound of Embodiment 20, or a pharmaceutically acceptable salt thereof, wherein Ring A is: or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.
  • Embodiment 31 The compound of any one of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • Embodiment 28 The compound of Embodiment 20, or a pharmaceutically acceptable salt thereof, wherein Ring A is: or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.
  • 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 ; and each R 1B is independently hydrogen or C 1 -C 3 alkyl;
  • R 2 is hydrogen or C 1 -C 6 alkyl substituted with 0, 1, 2, 3, or 4 R 2A , and each R 2A is independently -OR 2B , wherein each R 2B is independently hydrogen or C 1 -C 3 alkyl;
  • R 3 is C 1 -C 10 alkyl, C 3 -C 10 carbocyclyl, or 4- to 10-membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are independently substituted with 0, 1, 2, 3, or 4 R 3A ; or R 2 and R 3 are joined, with the atom to which they are attached, to form a 4- to 10- membered heterocyclyl independently substituted with 0, 1, 2, 3, or 4 R 3A
  • Embodiment 32 The compound of Embodiment 1 or 2, wherein the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • Embodiment 33 The compound of Embodiment 32, wherein the compound is Compound 3, Compound 4 Compound 10 Compound 21 Compound 22 Compound 67a Compound 67b Embodiment 34.
  • Embodiment 35 Embodiment 35.
  • Embodiment 34 wherein the compound of Formula (H-1), or salt thereof, is of Formula (H-2): r salt thereof, and wherein the method provides a compound of Formula (I′′′′): r salt thereof.
  • Embodiment 36 The method of Embodiment 34, wherein the compound of Formula (H-1), or salt thereof, is of Formula (H-2): r salt thereof, and wherein the method provides a compound of Formula (I′′′′): r salt thereof.
  • Embodiment 34 or 35 further comprising cross-coupling a compound of Formula (K), or salt thereof, with a compound of Formula (D), or salt thereof, H N(R2)(R3) (K) or a salt thereof, wherein Ring A, R 1 , R 2 , R 3 , R 4 , and m are defined in Embodiments 1 or 2, the method comprising cross-coupling of the amine of Formula (K), or salt thereof, with a compound of Formula (J-1), or salt thereof: H N(R2)(R3) (K) wherein X is Cl, Br, or I, to provide a compound of Formula (I), or salt thereof.
  • Embodiment 38 Embodiment 38.
  • 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′′′′): 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 The method of Embodiment 38, further comprising peptide coupling of a to provide a compound of Formula (J-2), or salt thereof.
  • Embodiment 41 Embodiment 41.
  • Embodiment 33 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 The method of 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: N N H N 4 H2N S Y A ( M) (R )m ( L) to provide a compound of Formula (H-2), or salt thereof.
  • Embodiment 43 Embodiment 43.
  • Embodiments 36, 39, and 40 further comprising: (a) protecting a compound of Formula (A), or salt thereof, to provide an alkyl ester of Formula (B): or salt thereof, wherein R a is C 1-6 alkyl or C 1-6 haloalkyl; (b) halogenating the compound of Formula (B), or salt thereof, to provide a compound of Formula (C): or salt thereof, wherein R 1 is as defined in Embodiment 1; and (d) optionally, deprotecting the compound of Formula (D), or salt thereof, to provide a carboxylic acid of Formula (D), wherein R a is hydrogen.
  • Embodiment 44 protecting a compound of Formula (A), or salt thereof, to provide an alkyl ester of Formula (B): or salt thereof, wherein R a is C 1-6 alkyl or C 1-6 haloalkyl; (b) halogenating the compound of Formula (B), or salt thereof, to provide a compound of Formula (C): or salt thereof,
  • the method of Embodiment 44, wherein the compound of Formula (I-BC- a), or salt thereof, is of Formula (I-BC-b): and the compound of Formula (P-1) is of Formula (P-2):
  • Embodiment 47 A pharmaceutical composition comprising the compound of any one of Embodiments 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 48 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 Embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 47.
  • Embodiment 49 Embodiment 49.
  • Embodiment 48 wherein the disease or disorder is inflammation, an autoimmune 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.
  • Embodiment 50 Embodiment 50.
  • a method of modulating cGAS activity comprising contacting a cell with a compound of any one of Embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 47.
  • EXEMPLIFICATION In order that this disclosure may be more fully understood, the following Examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.
  • Analytical Methods Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts ( ⁇ ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans.
  • Typical NMR solvents scattering as well as positive ion electrospray ionization.
  • MS range was 100 - 1000 Da.
  • Mobile phases of water and/or acetonitrile (MeCN) may contain a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate (NH 4 HCO 3 ).
  • 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.
  • Step 3 To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (4.0 g, 16 mmol, 1.0 equiv) in dichloromethane (DCM) (50 mL) was added diisopropylethylamine (DIEA) (11.0 g, 85.1 mmol, 5.30 equiv) and methyl trifluoromethanesulfonate (TfOMe) (13.0 g, 79.2 mmol, 4.93 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
  • Example 1 - Part B Preparation of 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine S 1 A i f b 134 hi di l 2 i (200 1110 l 10 i ) filter cake was washed with tetrahydrofuran (THF). The filtrate was concentrated under reduced pressure to afford 5-(pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 g, 54 % yield), which was used directly in the next step without further purification.
  • THF tetrahydrofuran
  • Step 2 A mixture of 5-(pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 g, 598 mmol, 1.0 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 3 A solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (50.0 g, 204 mmol, 1.0 equiv) in 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. The resulting mixture was stirred for 2 h at room temperature under N 2 .
  • n-BuLi n-butyl lithium
  • CH 3 I methyl iodide
  • Step 4 To a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazole (7.0 g, 27 mmol, 1.0 equiv) in tetrahydrofuran (THF) (14 mL) and H 2 O (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
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • H 2 O 28 mL
  • THF tetrahydrofuran
  • TFA trifluoroacetic acid
  • Example 1 - Part C Preparation of 4-((1,3-dimethoxypropan-2-yl)amino)-3-methoxy-N-(5-(5- Step 1: To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (12.0 g, 48.2 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (150 mL) was added hydroxybenzotriazole (HOBt) (13.02 g, 96.38 mmol, 2.00 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (27.81 g, 145.05 mmol, 3.01 equiv) and 5-(5- methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Example 1, Part B, Step 4) (9.00
  • Step 2 To a stirred solution of 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide (also referred to herein as 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, 0.243 mmol, 1.00 equiv) (“halo-pyrone reagent”) in N,N-dimethylformamide (DMF) (3.5 mL) was added 1,3-dimethoxypropan-2-amine (“amine reagent”) (60 mg, 0.50 mmol, 2.1 equiv), 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (40 mg, 0.0
  • the resulting mixture was stirred for 3 h at 100 °C under N 2 (nitrogen gas).
  • the resulting mixture was filtered, and the filter cake was washed with acetonitrile (1 x 3 mL) and the filtrate was concentrated under reduced pressure.
  • Example 3 4-(((cis)-2-hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 23, rac-23), 4-(((1S,2R)-2- hydroxycyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2- oxo-2H-pyran-6-carboxamide (Compound 23a*) and 4-(((1R,2S)-2-hydroxycyclopentyl)amino)- 3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6- carboxamide (Compound 23b
  • Example 4 N-(5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 136)
  • Step 1 To a stirred solution of 4-chlorothiophene-3-carbonitrile (270 mg, 1.88 mmol, 1.00 equiv) in trifluoroacetic acid (TFA) (3.00 mL) was added thiosemicarbazide (257 mg, 2.82 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C.
  • TFA trifluoroacetic acid
  • Step 3 N-(5-(4-Chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 136) was prepared from 4- bromo-N-[5-(4-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the “halo-pyrone reagent” and 2-methoxyethan-1-amine as the “amine reagent” according to the procedure outlined for the preparation of Compound 23 in Example 3.
  • Example 5 N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((cis)-2- hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7, rac-7), N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2-hydroxycyclopentyl)amino)-3- methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7a*) and N-(5-(3-chlorothiophen-2-yl)- 1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6- carboxamide (Compound 7b*) Compound 7
  • Step 3 N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2- hydroxycyclopentyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7a*) and N- (5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2-hydroxycyclopentyl)amino)-3- methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 7b*) were prepared as a racemic mixture according to Example 1, Part C, Step 2 using cis-2-aminocyclopentan-1-ol hydrochloride as the “amine reagent” and 4-bromo-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3
  • Example 6 (R)-4-((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 21*) and (S)-4- ((1-cyclopropyl-2-methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 22*) (R)4((1 l l2 (S)4((1 l l2 1.18 equiv) in portions at room temperature.
  • Step 2 Into a solution of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (20.0 g, 67.6 mmol, 1.00 equiv) in dichloromethane (DCM) (250 mL) was added diisopropylethylamine (DIEA) (26.0 g, 201 mmol, 2.98 equiv) at room temperature. To the above mixture was added triflate ester (33.0 g, 201 mmol, 2.98 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, 1.00 equiv), hydroxybenzotriazole (HOBT) (1.80 g, 13.3 mmol, 1.52 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (3.60 g, 18.8 mmol, 2.14 equiv) and 5-(5- methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Example 1, Part B, Step 4) (1.40 g, 7.72 mmol, 0.88 equiv) in N,N-dimethylformamide (DMF) (40 mL) was stirred for 1 h at room temperature.
  • DMF N,N-dimethylformamide
  • Step 5 A mixture of 4-iodo-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2- yl)-2-oxo-2H-pyran-6-carboxamide as the “halo-pyrone reagent” (100 mg, 0.218 mmol, 1 equiv), (2-dicyclohexylphosphino-2′ 6′-diisopropoxy-11′-biphenyl)[2-(2′-amino-11′- N,N-dimethylformamide (DMF) (5.0 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere.
  • DMF 2-(2′-amino-11′- N,N-dimethylformamide
  • the crude material was further purified by Prep- HPLC with the following conditions (X Select CSH Prep C18 OBD Column, 19*250 mm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: acetonitrile (MeCN); flow rate: 20 mL/min; gradient: 25% B to 30% B in 8 min, 30% B; wave length: 254 nm; RT1(min): 8), and thendried in an oven under reduced pressure to afford 70 mg of racemic 4-((1-cyclopropyl-2- methoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H- pyran-6-carboxamide.
  • Example 7 4-(((cis)-2-hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 26, rac-26), 4-(((1S,2R)-2- hydroxycycloheptyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2- oxo-2H-pyran-6-carboxamide (Compound 26a*) and 4-(((1R,2S)-2-hydroxycycloheptyl)amino)- 3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6- carboxamide (Com
  • Example 9 4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3-methoxy-N-(5-(5-methyl-1H- Compound 29 4-((1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)amino)-3-methoxy-N-(5-(5-methyl- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)- 2 -oxo-2H-pyran-6-carboxamide
  • 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2- yl]-6-oxopyran-2-carboxamide product of Example 1, Part C, Step 1; “halo-pyrone reagent”) (100 mg, 0.24 mmol, 1.00 equiv) (“halo-pyrone reagent”), 4-aminote
  • Example 10 N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)- 3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 131)
  • Compound 131 N-(5-(3-chloro-1-methyl-1 H- pyrrol-2-yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)-3- methoxy-2-oxo-2 H-pyran-6- c arboxamide
  • Step 1 Into a 250mL round-bottom flask were added methyl 3-chloro-1H-pyrrole-2- carboxylate (2.40 g, 15.0 mmol, 1.00 equiv) and tetrahydrofuran (THF) (20 mL, 247 mmol, 16.4 equiv) at room temperature.
  • THF tetrahydrofur
  • Step 2 Into a 40 mL vial was added methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate (750 mg, 4.32 mmol, 1.00 equiv) and methanol (MeOH) (4.0 mL, 99 mmol, 23 equiv) at room temperature. To the above mixture was added NaOH (330 mg, 8.25 mmol, 1.91 equiv) in H 2 O (4.0 mL, 222 mmol, 51.4 equiv) 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).
  • Step 3 Into a 40 mL vial was added 3-chloro-1-methylpyrrole-2-carboxylic acid (2.20 g, 13.8 mmol, 1.00 equiv), N,N-dimethylformamide (DMF) (20 mL), 1- [Bis(dimethylamino)methylene] 1H 123 triazolo[45 b]pyridinium 3 oxid hexafluorophosphate with brine (3 x 30 mL) then concentrated under reduced pressure.
  • 3-chloro-1-methylpyrrole-2-carboxylic acid (2.20 g, 13.8 mmol, 1.00 equiv)
  • DMF N,N-dimethylformamide
  • Step 4 Into a 40 mL vial was added 3-chloro-1-methylpyrrole-2-carboxamide (1.40 g, 8.83 mmol, 1.00 equiv), dichloroethane (DCE) (20 mL) and methyl N- (triethylammoniumsulfonyl)carbamate (Burgess reagent) (6.29 g, 26.4 mmol, 2.99 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, 1.00 equiv) and thiosemicarbazide (200 mg, 2.19 mmol, 3.09 equiv) in trifluoroacetic acid (TFA) (5.00 mL, 67.3 mmol, 94.6 equiv) was stirred for 16 h at 80 °C.
  • TFA trifluoroacetic acid
  • Step 6 Into a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (770 mg, 3.09 mmol, 1.00 equiv) in acetonitrile (MeCN) (20 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (960 mg, 3.42 mmol, 1.11 equiv), N-methylimidazole (NMI) (900 mg, 11.0 mmol, 3.54 equiv) and 5-(3-chloro-1- methylpyrrol-2-yl)-1,3,4-thiadiazol-2-amine (616 mg, 2.87 mmol, 0.93 equiv) at room temperature.
  • MeCN acetonitrile
  • TCFH chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphat
  • Example 11 N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2- hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 53*) and N- (5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-(((1R,2S)-2- hydroxycyclobutyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 54*) N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)- N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)- 1,3,4-thiadiazol-2-yl)-4-(((1S,2R)-2- 1,
  • Example 12 4-(((1R,2S)-2-cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 73*) and 4-(((1S,2R)-2- cyanocyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2- oxo-2H-pyran-6-carboxamide (Compound 74*) Compound 73* Compound 74* 4-(((1R,2S)-2-cyanocyclopentyl)amino)-3- 4-(((1S,2R)-2-cyanocyclopentyl)amino)- methoxy-N-(5-(5-methyl-1H-pyr
  • Example 13 3-methoxy-4-((2-methoxyethyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 75 3-methoxy-4-((2- methoxyethyl)amino)-N-(5- (5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo- 2 H-pyran-6-carboxamide
  • Compound 75 was prepared according to Example 1, Part C, Step 2 using 4-iodo-3-methoxy-N-(5-(
  • Example 15 (R)-4-((2-methoxy-1-phenylethyl)amino)-3-(2-methoxyethoxy)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 200) Compound 200 (R)-4-((2-methoxy-1-phenylethyl)amino)-3-(2- methoxyethoxy)-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6- c arboxamide Step 1: To a stirred solution of methyl 4-bromo-5-hydroxy-6-oxopyran-2-carboxylate (product of Example 1, Part A, Step 2) (5.0 g, 20 mmol, 1.0 equiv) and 2-methoxyethanol (2.0 g, 26 m
  • DBAD di-tert-butyl azodicarboxylate
  • Step 3 To a stirred solution of 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (1200 mg, 4.09 mmol, 1.00 equiv) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (also referred to as 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-amine) (product of Example 1, Part B, Step 4) (820 mg, 4.52 mmol, 1.11 equiv) in N,N-dimethylformamide (DMF) (21 mL) was added hydroxybenzotriazole (HOBT) (1110 mg, 8.22 mmol, 2.01 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (2355 mg, 12.3 mmol, 3.00 equiv) at room temperature.
  • HOBT hydroxybenzotriazo
  • Example 17 (S)-3-methoxy-4-(3-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 87)
  • Compound 87 Into a mixture of 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6- oxopyran-2-carboxamide (product of Example 1, Part C, Step 1; “halo-pyrone reagent”) (50 mg, 0.12 mmol, 1.0 equiv) and (3S)-3-(methoxymethyl)pyrrolidine (27 mg, 0.24 mmol, 2.00 equiv) (“amine reagent”) in N,N-dimethylformamide (DMF) (0.5 mL) was added 2- (dicyclo
  • Example 18 (R)-N-(5-(3-chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1- methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 94) (R)-N-(5-(3-chlorothiophen-2-yl)- 1,3,4-thiadiazol-2-yl)-3-methoxy-4- ((1-methoxypropan-2-yl)amino)-2- o xo-2H-pyran-6-carboxamide (R)-N-(5-(3-Chlorothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((1-methoxypropan-2- yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 94) was prepared according to Example 1, Part C,
  • Example 20 3-methoxy-4-(((cis)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 108, rac-108 3-methoxy- 4-(((trans)-3-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)- 2-oxo-2H-pyran-6-carboxamide
  • Compound 109, rac-109 3-methoxy-4-(((1S,3R)-3- methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H- pyran-6-car
  • Step 2 Into a solution of 5-methoxy-4-( ⁇ 3-methoxybicyclo[1.1.1]pentan-1-yl ⁇ amino)-N-[5- (5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (Compound 126-OMe) (80 mg, 0.180 mmol, 1.00 equiv) in dichloromethane (DCM) (3 mL) was added a solution of BBr 3 (0.80 mL, 0.80 mmol, 4.44 equiv) in DCM (1 M) at 0 °C. The resulting mixture was stirred for 30 mg, 15% yield).
  • DCM dichloromethane
  • Example 22 N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-4-((2- hydroxyethyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 129) and N-(5-(3- chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2- oxo-2H-pyran-6-carboxamide (Compound 129-OMe) HN pyrrol-2-yl)-1,3,4-thiadiazol-2- S2 yl)-4-((2-hydroxyethyl)amino)- OH 3-methoxy-2-oxo-2H-pyran-6- carboxamide Step 1: N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,
  • Step 2 Into a solution of N-[5-(3-chloro-1-methylpyrrol-2-yl)-1,3,4-thiadiazol-2-yl]-5- flash chromatography (acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford a crude product (40 mg) which was further purified by Prep-HPLC (YMC-Actus Triart C18 ExRS, 30*150 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and MeCN (15% MeCN up to 25% in 10 min); Detector, UV254nm) to afford N-(5-(3-chloro-1-methyl-1H-pyrrol-2- yl)-1,3,4-thiadiazol-2-yl)-4-((2-hydroxyethyl)amino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 129) (4.3 mg, 2.5% yield).
  • Example 23 4-((2-hydroxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 130) Step 1: To a stirred mixture of 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Example 1, Part C, Step 1; “halo-pyrone reagent”) (200 mg, 0.485 mmol, 1.00 equiv) and (2-aminoethoxy)(tert-butyl)dimethylsilane (“amine reagent”) (851 mg, 4.85 mmol, 10.0 equiv) in dioxane (5 mL) was added bis(tri-tert- butylphosphine)pal
  • Step 2 A solution of 4-( ⁇ 2-[(tert-butyldimethylsilyl)oxy]ethyl ⁇ amino)-5-methoxy-N-[5-(5- methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (30 mg, 0.059 mmol, 1.00 equiv) in HCl (4 M in 1,4-dioxane) (1.5 mL) was stirred for 1 h at room temperature.
  • Example 24 N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4- (((1R,2S)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 132*) and N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(((1S,2R)-2- methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 133*) Compound 132* Compound 133* N-(5-(3-chloro-1-methyl-1H- N-(5-(3-chloro-1-methyl-1H- pyrrol-2-yl)-1,3,4-thiadiazol-2- pyrrol-2-yl)-1
  • Step 2 Racemic N-(5-(3-chloro-1-methyl-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy- 4-(((1,2-cis)-2-methoxycyclobutyl)amino)-2-oxo-2H-pyran-6-carboxamide was prepared and its constituent enantiomers separated according to Example 14 using N-[5-(3-chloro-1-methylpyrrol-2- yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide as the “halo-pyrone reagent” and rac-(1,2-cis)-2-methoxycyclobutan-1-amine hydrochloride as the “amine reagent” to provide two enantiomers with arbitrarily assigned stereochemistry: N-(5-(3-chloro-1-methyl-1H- pyrrol-2-yl)-1,3,4-thiadia
  • Example 25 N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-5-methoxy-4-(2- methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (Compound 134) Cl S6 methoxy-4-(2- methoxyethylamino)-6- oxo-6H-pyran-2- c arboxamide Step 1: To a stirred solution of 5-bromo-1,3,4-thiadiazol-2-amine (13.8 g, 76.6 mmol, 1.00 equiv) and 4-fluoro-1H-pyrazole (7.96 g, 92.5 mmol, 1.21 equiv) in dioxane (80 mL) was added diisopropylethylamine (DIEA) (29.8 g, 231 mmol, 3.01 equiv) at room temperature.
  • DIEA diisoprop
  • Step 2 To a stirred solution of 5-(4-fluoropyrazol-1-yl)-1,3,4-thiadiazol-2-amine (5.0 g, 27 mmol, 1.0 equiv) and 2,5-hexanedione (4.62 g, 40.5 mmol, 1.50 equiv) in toluene (20 mL) was added tosic acid (TsOH) (0.93 g, 5.40 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred for 1 h at 100 °C then concentrated under reduced pressure.
  • TsOH tosic acid
  • Step 3 To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(4-fluoropyrazol-1-yl)-1,3,4- thiadiazole (1.0 g, 3.8 mmol, 1.0 equiv) in tetrahydrofuran (THF) (5 mL) was added lithium diisopropyl amide (LDA) (3.80 mL, 3.80 mmol, 1.00 equiv) at -78 °C under N 2 (nitrogen gas).
  • LDA lithium diisopropyl amide
  • Step 4 To a stirred solution of 2-(5-chloro-4-fluoropyrazol-1-yl)-5-(2,5-dimethylpyrrol-1- yl)-1,3,4-thiadiazole (200 mg, 0.672 mmol, 1.00 equiv) in H 2 O/THF (2:1, 3 mL) was added trifluoroacetic acid (TFA) (2 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 °C then concentrated under vacuum.
  • TFA trifluoroacetic acid
  • Step 5 To a stirred solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (113 mg, 0.45 mmol, 1.00 equiv) and 5-(5-chloro-4-fluoro-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-amine (100 mg, 0.45 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (10 mL) was added 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5- b]pyridine 3-oxide hexafluorophosphate(V) (HATU) (258 mg, 0.68 mmol, 1.50 equiv) and diisopropylethylamine (DIEA) (176 mg, 1.36 mmol, 3.00 equiv) at 0 o C under N 2 (nitro
  • Step 6 N-(5-(5-Chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-5-methoxy-4-(2- methoxyethylamino)-6-oxo-6H-pyran-2-carboxamide (Compound 134) was prepared according to Example 1, Part C, Step 2 using 4-bromo-N-(5-(5-chloro-4-fluoro-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-3-methoxy-2-oxo-2H-pyran-6-carboxamide as the “halo-pyrone reagent” and 2- methoxyethan-1-amine as the “amine reagent”.
  • Step 1 To a stirred solution of 2-chlorothiophene-3-carboxylic acid (1.0 g, 6.15 mmol, 1.0 equiv) in tetrahydrofuran (THF) (10 mL) was added carbonyldiimidazole (CDI) (1.50 g, 9.22 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added an ammonia in methanol solution (7N NH 3 /MeOH) (10 mL) dropwise over 1 h at room temperature. The resulting mixture was stirred for an additional 30 min at room temperature then concentrated under reduced pressure.
  • CDI carbonyldiimidazole
  • Step 2 To a stirred solution of 2-chlorothiophene-3-carboxamide (350 mg, 2.17 mmol, 1.00 equiv) in dichloroethane (DCE) (5 mL) was added methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (1.50 g, 6.50 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 1 h at 60 °C then concentrated under reduced pressure.
  • DCE dichloroethane
  • Step 5 To a stirred solution of 4-bromo-N-[5-(2-chlorothiophen-3-yl)-1,3,4-thiadiazol-2-yl]- 5-methoxy-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (160 mg, 0.357 mmol, 1.00 equiv) and 2-methoxyethan-1-amine (“amine reagent”) (32 mg, 0.43 mmol, 1.19 equiv) in N,N- dimethylformamide (DMF) (4 mL) was added CF 3 COONa (160 mg, 1.18 mmol, 3.30 equiv), 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (63 mg, 0.14 mmol, 0.38 equiv), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (160 mg, 1.05 mmol, 2.95 e
  • Step 2 To a stirred solution of 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (1.00 g, 3.87 mmol, 1.00 equiv), 4-methylthiophen-3-ylboronic acid (0.83 g, 5.81 mmol, 1.50 equiv) in dioxane (10 mL) was added [(2-Di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) (1.40 g, 1.55 mmol, 0.40 equiv), K 2 CO 3 (1.07 g, 7.75 mmol, 2.00 equiv) at room temperature.
  • Step 3 To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(4-methylthiophen-3-yl)-1,3,4- thi di l (400 145 l 100 i ) i t t h d f (THF) (60 L) dd d d i another 1 h. The reaction was then quenched by the addition of sat. NH 4 Cl (aq.) (10 mL) at 0 °C and extracted with ethyl acetate (EtOAc) (3 x 50 mL).
  • EtOAc ethyl acetate
  • Step 4 To a stirred solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(2-iodo-4-methylthiophen-3- yl)-1,3,4-thiadiazole (120 mg, 0.31 mmol, 1.00 equiv) in N,N-dimethylacetamide (DMAC) (3 mL) was added Zn(CN) 2 (72 mg, 0.61 mmol, 2.00 equiv), XantPhos (266 mg, 0.46 mmol, 1.50 equiv), PdCl 2 (82 mg, 0.46 mmol, 1.50 equiv) and diisopropylethylamine (DIEA) (79 mg, 0.61 mmol, 2.00 equiv) at room temperature.
  • DMAC N,N-dimethylacetamide
  • Step 6 To a stirred solution of 3-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylthiophene-2- carbonitrile (35 mg, 0.16 mmol, 1.00 equiv), 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (118 mg, 0.47 mmol, 3.00 equiv) in acetonitrile (MeCN) (1 mL) was added N-methylimidazole (NMI) (65 mg, 0.79 mmol, 5.00 equiv) and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (TCFH) (53 mg, 0.19 mmol, 1.20 equiv).
  • NMI N-methylimidazole
  • TCFH chloro-N,N,N',N'- tetramethylformamidinium hexafluor
  • Step 7 N-(5-(2-Cyano-4-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide
  • Compound 137 was prepared according to Example 1 Part C Step 2 using 4-bromo-N-[5-(2-cyano-4-methylthiophen-3-yl)-134-thiadiazol-
  • Example 28 N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2- methoxyethyl)amino]-6-oxopyran-2-carboxamide
  • Compound 138 Step 1: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3- carbonitrile (210 mg, 0.89 mmol,
  • Step 3 To a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (137 mg, 0.550 mmol, 1.00 equiv) in acetonitrile (MeCN) (4.7 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (233 mg, 0.83 mmol, 1.51 equiv) and N-methylimidazole (NMI) (136 mg, 1.66 mmol, 3.01 equiv) at room temperature. The resulting mixture was stirred for 30 min at room temperature.
  • Step 4 N-[5-(4-Cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2- methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 138) was prepared according to Example 1, Part C, Step 2 using 4-bromo-N-[5-(4-cyanothiophen-3-yl)-1,3,4-thiadiazol-2-yl]-5- methoxy-6-oxopyran-2-carboxamide as the “halo-pyrone reagent” and 2-methoxyethan-1-amine as the “amine reagent”.
  • LCMS (ES, m/z) 433.95 [M+1]+.
  • Step 2 To a stirred solution of 5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-amine (70 mg, 0.32 mmol, 1.0 equiv) and 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (160 mg, 0.64 mmol, 2.01 equiv) in acetonitrile (MeCN) (5 ml) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (270 mg, 0.96 mmol, 3.01 equiv) and N-methylimidazole (NMI) (270 mg, 3.29 mmol, 10.3 equiv) at room temperature.
  • MeCN acetonitrile
  • TCFH chloro-N,N,N',N'-tetramethylformamidinium hexafluoro
  • Step 3 N-(5-(4-chloroisothiazol-5-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 139) was prepared according to Example 1, Part C, Step 2 using 4-bromo-N-[5-(4-chloro-1,2-thiazol-5-yl)-1,3,4-thiadiazol-2-yl]-5- methoxy-6-oxopyran-2-carboxamide as “halo-pyrone reagent” and 2-methoxyethan-1-amine as the “amine reagent”.
  • Step 1 To a stirred solution of 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (product of Example 27, Step 1) (2.50 g, 9.68 mmol, 1.00 equiv) and 2-methylthiophen-3- ylboronic acid (1.66 g, 11.7 mmol, 1.21 equiv) in dioxane (18 mL) were added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ) (0.80 g, 1.09 mmol, 0.11 equiv), H 2 O (3 mL) and K 2 CO 3 (2.70 g, 19.5 mmol, 2.02
  • Step 3 To a stirred solution of 5-(2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-amine (500 mg, 2.54 mmol, 1.00 equiv) in trifluoroacetic acid (TFA) (20 mL) was added Br 2 (3.0 g, 19 mmol, 7.4 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was then quenched with sat.NaHSO 3 and extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers were washed with water and brine (3 x 5 mL), and dried over anhydrous Na 2 SO 4 .
  • TFA trifluoroacetic acid
  • Step 4 To a stirred solution of 5-(4,5-dibromo-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2- amine (700 mg, 1.97 mmol, 1.00 equiv) and 2,5-hexanedione (336 mg, 2.94 mmol, 1.49 equiv) in toluene (5 mL) was added tosic acid (TsOH) (112 mg, 0.65 mmol, 0.33 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C then concentrated under reduced pressure.
  • Step 5 To a stirred solution of 2-(4,5-dibromo-2-methylthiophen-3-yl)-5-(2,5- dimethylpyrrol-1-yl)-1,3,4-thiadiazole (600 mg, 1.38 mmol, 1.00 equiv) in acetic acid (AcOH) (5 mL) and H 2 O (5 mL) was added Zn (540 mg, 8.26 mmol, 5.96 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The mixture was then diluted with water and extracted with ethyl acetate (EtOAc) (3 x 50 mL).
  • EtOAc ethyl acetate
  • Step 6 To a stirred solution of 2-(4-bromo-2-methylthiophen-3-yl)-5-(2,5-dimethylpyrrol-1- yl)-1,3,4-thiadiazole (440 mg, 1.24 mmol, 1.00 equiv) in NMP (5 mL) was added CuCN (230 mg, 2.57 mmol, 2.07 equiv) at room temperature. The resulting mixture was stirred for 3 h at 150 °C. The mixture was then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water and brine (3 x 5 mL), and dried over anhydrous Na 2 SO 4 .
  • Step 8 To a stirred solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 6, Step 3) (192 mg, 0.649 mmol, 1.07 equiv) and 4-(5-amino-1,3,4-thiadiazol-2-yl)-5- methylthiophene-3-carbonitrile (120 mg, 0.608 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (5 mL) was added hydroxybenzotriazole (HOBT) (102 mg, 0.755 mmol, 1.24 equiv) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (141 mg, 0.736 mmol, 1.21 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1- ethyl-3-(3-dimethylaminopropyl)carbod
  • Step 9 N-(5-(4-Cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 140) was prepared according to Example 1, Part C, Step 2 using 2-methoxyethan-1-amine as the “amine reagent” and N-[5-(4- cyano-2-methylthiophen-3-yl)-1,3,4-thiadiazol-2-yl]-4-iodo-5-methoxy-6-oxopyran-2-carboxamide as the “halo-pyrone reagent”.
  • Example 31 N-(5-(5-ethyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 141)
  • Step 1 Into a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Example 1, Part B, Step 2) (6.0 g, 24 mmol, 1.0 equiv) in tetrahydrofuran (THF) (150 mL) was added n-butyl lithium (n-BuLi) (12 mL, 30 mmol, 1.2 equiv) in hexanes (2.5 M) dropwise over 15 min at -78 °C under N 2 (nitrogen gas).
  • n-BuLi n-butyl lithium
  • Step 2 Into a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-ethylpyrazol-1-yl)-1,3,4- thiadiazole (5000 mg, 19.28 mmol, 1.00 equiv) in THF (10 mL) were added H 2 O (20 mL) and trifluoroacetic acid (TFA) (20 mL) at room temperature. The resulting mixture was stirred for 4 h at 60 °C then concentrated under reduced pressure.
  • THF trifluoroacetic acid
  • Step 3 Into a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (200 mg, 0.80 mmol, 1.00 equiv) in acetonitrile (MeCN) (5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (270 mg, 0.96 mmol, 1.20 equiv), N-methylimidazole (NMI) (132 mg, 1.61 mmol, 2.00 equiv) and 5-(5- ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (157 mg, 0.80 mmol, 1.0 equiv) at room temperature.
  • MeCN acetonitrile
  • NCI N-methylimidazole
  • Example 1 Part C, Step 2 using 2-methoxyethan-1-amine as the “amine reagent” and 4-bromo-N- [5-(5-ethylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-6-oxopyran-2-carboxamide as the “halo- pyrone reagent”.
  • Example 32 (R)-N-(5-(5-(hydroxymethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4- ((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 142) pyran-6-carboxamide
  • Step 1 Into a solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Example 1, Part B, Step 2) (5.0 g, 20 mmol, 1.0 equiv) in tetrahydrofuran (THF) (100 mL) was added n-butyl lithium (n-BuLi) (8.97 mL, 22.4 mmol, 1.10 equiv) dropwise over 5 min at - 78 °C.
  • n-BuLi n-butyl lithium
  • Step 3 Into a solution of ⁇ 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazol-3- yl ⁇ methanol (3.3 g, 12 mmol, 1.0 equiv) in tetrahydrofuran (THF) (16 mL) was added H 2 O (16 mL) and trifluoroacetic acid (TFA) (20 mL) at room temperature. The resulting mixture was stirred for 5 h at 60 °C then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 4 Into a solution of 4-iodo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 6, Step 3) (2.25 g, 7.61 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (20 mL) was added hydroxybenzotriazole (HOBT) (1.54 g, 11.4 mmol, 1.50 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (2.92 g, 15.2 mmol, 2.00 equiv) and [2-(5-amino-1,3,4- thiadiazol-2-yl)pyrazol-3-yl]methanol (1.5 g, 7.6 mmol, 1.0 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Step 5 (R)-N-(5-(5-(Hydroxymethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4- ((1-methoxypropan-2-yl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 142) was prepared according to Example 1, Part C, Step 2 using (R)-1-methoxypropan-2-amine as the “amine reagent” and N- ⁇ 5-[5-(hydroxymethyl)pyrazol-1-yl]-1,3,4-thiadiazol-2-yl ⁇ -4-iodo-5-methoxy-6- oxopyran-2-carboxamide as the “halo-pyrone reagent”.
  • Step 1 To a stirred solution of 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole- 3-carbaldehyde (product of Step 1 of Example 32) (700 mg, 2.56 mmol, 1.00 equiv) in dichloromethane (DCM) (5 mL) was added diethylaminosulfur trifluoride (DAST) (826 mg, 5.12 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature under air atmosphere.
  • DCM dichloromethane
  • DAST diethylaminosulfur trifluoride
  • Step 2 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, 1.00 equiv) in tetrahydrofuran (THF) (1 mL) and H 2 O (0.5 mL) was added trifluoroacetic acid (TFA) (0.5 mL) at 0 °C.
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • H 2 O 0.5 mL
  • Step 4 N-(5-(5-(Difluoromethyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 144) was prepared according to Example 1, Part C, Step 2 using 4-bromo-N- ⁇ 5-[5-(difluoromethyl)pyrazol-1-yl]-1,3,4-thiadiazol- 2-yl ⁇ -5-methoxy-6-oxopyran-2-carboxamide as “halo-pyrone reagent” and 2-methoxyethan-1- amine as the “amine reagent”.
  • Example 34 N-(5-(3-cyanothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 145)
  • Step 1 A solution of thiophene-3-carbonitrile (500 mg, 4.58 mmol, 1.00 equiv) and 4,4'-Di- tert-butyl-2,2'-bipyridine (dtbpy) (123 mg, 0.458 mmol, 0.10 equiv), Bis(1,5-cyclooctadiene)di-mu- methoxydiiridium(I) [Ir(OMe)(COD)] 2 (304 mg, 0.458 mmol, 0.10 equiv) in hexanes (2 mL) was stirred for 2 min at room temperature under N 2 (nitrogen gas).
  • Steps 2 - 5 N-(5-(3-Cyanothiophen-2-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 145) was prepared according to Example 28 steps 1 – 4 using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3- carbonitrile in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile to provide 2-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-3-carbonitrile (product of Step 3 of this Example), followed by coupling with 4-bromo-3-methoxy-2-oxo-2H-pyran-6-carboxylic acid to provide 4-bromo-N-(5-(3-
  • Example 35 N-[5-(5-chloropyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2- methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 148) Step 1: A solution of 2-(2,5-dimethylpyrrol-1-yl)-5-(pyrazol-1-yl)-1,3,4-thiadiazole (product of Example 1, Part B, Step 2) (1000 mg, 4.077 mmol, 1.00 equiv) in tetrahydrofuran (THF) was added dropwise n-butyl lithium (n-BuLi) (2.4 mL, 6.0 mmol, 1.5 equiv) at -78 °C under N 2 (nitrogen gas).
  • n-BuLi n-butyl lithium
  • 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, 1.00 equiv) in THF (1 mL) and H 2 O (2 mL) was added trifluoroacetic acid (TFA) (2 mL, 27 mmol, 8.6 equiv) at room temperature. The resulting mixture was stirred for 3 h at 60 °C then concentrated under reduced pressure.
  • THF trifluoroacetic acid
  • Step 3 Into a solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (300 mg, 1.21 mmol, 1.00 equiv) and 5-(5-chloropyrazol-1-yl)-1,3,4- thiadiazol-2-amine (270 mg, 1.34 mmol, 1.11 equiv) in N,N-dimethylformamide (DMF) (3 mL) was added 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate(V) (HATU) (692 mg, 1.82 mmol, 1.51 equiv) and diisopropylethylamine (DIEA) (469 mg, 3.63 mmol, 3.01 equiv) at 0 o C under N 2 (nitrogen gas).
  • DMF N,N
  • Step 4 N-[5-(5-Chloropyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2- methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 148) was prepared according to Example 1, Part C, Step 2 using 4-bromo-N-(5-(5-chloro-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)- 3-methoxy-2-oxo-2H-pyran-6-carboxamide as “halo-pyrone reagent” and 2-methoxyethan-1-amine as the “amine reagent”.
  • Example 36 4-(bicyclo[1.1.1]pentan-1-ylamino)-3-(3-methoxy-2,2-dimethylpropoxy)-N-(5-(5- methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 149) resulting mixture was stirred for 30 min at 0 °C then methyl iodide (CH 3 I) (16.0 g, 113 mmol, 1.17 equiv) added at 0 °C. The resulting mixture was stirred overnight at room temperature then quenched with sat. NH 4 Cl (aq.) at room temperature.
  • CH 3 I methyl iodide
  • Step 2 To a stirred solution of 3-methoxy-2,2-dimethylpropan-1-ol (479 mg, 4.06 mmol, 2.02 equiv) and methyl 4-bromo-3-hydroxy-2-oxo-2H-pyran-6-carboxylate (product of Example 1, Part A, Step 4) (500 mg, 2.01 mmol, 1.00 equiv) in THF (5 mL) was added triphenylphosphine (PPh 3 ) (800 mg, 3.05 mmol, 1.52 equiv) at room temperature. To the above mixture was added DBAD (700 mg, 3.04 mmol, 1.51 equiv) at 0 °C.
  • DBAD 700 mg, 3.04 mmol, 1.51 equiv
  • Step 4 To a stirred solution of 4-bromo-3-(3-methoxy-2,2-dimethylpropoxy)-2-oxo-2H- pyran-6-carboxylic acid (310 mg, 0.925 mmol, 1.00 equiv) and 5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-amine (product of Example 1, Part B, Step 4) (260 mg, 1.44 mmol, 1.55 equiv) in N,N-dimethylformamide (DMF) (3 mL) was added 1-((dimethylamino)(dimethyliminio)methyl)- 1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate(V) (HATU) (530 mg, 1.39 mmol, 151 equiv) and diisopropylethylamine (DIEA) (180 mg 139 mmol 151 equiv) at room Step 5
  • Example 37 (R)-3-methoxy-4-(3-methoxy-2-oxopyrrolidin-1-yl)-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 150) pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo- 2 H-pyran-6-carboxamide Step 1: To a stirred solution of (3R)-3-hydroxypyrrolidin-2-one (390 mg, 3.86 mmol, 1.99 equiv) and methyl 4-iodo-5-methoxy-6-oxopyran-2-carboxylate (product of Example 6, Step 2) (600 mg, 1.94 mmol, 1.00 equiv) in dioxane (9 mL) was added [(2-dicyclohexylphosphino-2′,6′- bis(N,N-
  • Step 2 To a stirred solution of methyl 4-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]-5- methoxy- 6-oxopyran-2- carboxylate (50 mg, 0.18 mmol, 1.0 equiv) in dichloromethane (DCM) (0.6 mL) was added Ag 2 O (50 mg, 0.22 mmol, 1.22 equiv) and MeI (0.6 mL) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The resulting mixture was then filtered and the filter cake was washed with dichloromethane (DCM) (3 x 10 mL).
  • DCM dichloromethane
  • Step 3 To a stirred solution of methyl 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]- 6-oxopyran-2- carboxylate (40 mg, 0.14 mmol, 1.0 equiv) in tetrahydrofuran (THF) (1 mL) was added trimethyltin hydroxide (37 mg, 0.20 mmol, 1.52 equiv) at room temperature.
  • THF tetrahydrofuran
  • Step 4 To a stirred solution of 5-methoxy-4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]-6- oxopyran-2-carboxylic acid (“amino-pyrone reagent”) (80 mg, 0.28 mmol, 1.0 equiv) in N,N- dimethylformamide (DMF) (2 mL) was added hydroxybenzotriazole (HOBT) (60 mg, 0.44 mmol, 1.57 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (108 mg, 0.56 mmol, 1.99 equiv) and 5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Example 1, Part B, Step 4; “ADT amine reagent”) (50 mg, 0.28 mmol, 0.98 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • Example 38 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol- 1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 152)
  • Step 1 Methyl 3-methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6- carboxylate was prepared according to Example 6, Step 5 using methyl 4-iodo-5-methoxy-6- oxopyran-2-carboxylate (product of Example 6, Step 2) and 1-(methoxymethyl)cyclopentan-1- amine.
  • LCMS (ES, m/z) 312 [M+1]+.
  • Step 2-3 3-Methoxy-4-((1-(methoxymethyl)cyclopentyl)amino)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 152) was prepared according to Example 37, Steps 3-4 using methyl 3-methoxy-4-((1- (methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylate in place of methyl 5-methoxy- 4-[(3R)-3-methoxy-2-oxopyrrolidin-1-yl]- 6-oxopyran-2- carboxylate to provide 3-methoxy-4-((1- (methoxymethyl)cyclopentyl)amino)-2-oxo-2H-pyran-6-carboxylic acid as the “amino-pyrone reagent”, followed by coupling with 5-(5-methyl
  • Example 39 3-methoxy-4-(((cis)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 153, rac-153), 3-methoxy-4-(((1S,2R)-2-methoxycyclopentyl)(methyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-
  • Step 2 To a stirred solution of rac-methyl 5-methoxy-4- ⁇ [cis-2- methoxycyclopentyl]amino ⁇ -6-oxopyran-2-carboxylate (81 mg, 0.27 mmol, 1.0 equiv) in dimethylformamide (DMF) (5 mL) were added methyl iodide (360 mg, 2.54 mmol, 9.31 equiv) and tert-butoxypotassium (122 mg, 1.09 mmol, 3.99 equiv) at 0 °C. The resulting mixture was stirred overnight at room temperature.
  • DMF dimethylformamide
  • Example 40 N-(5-(3,5-dichloroisothiazol-4-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 156) 2H-pyran-6-carboxamide Step 1: To a mixture of (2-methoxyethyl) [(4-methoxyphenyl) methyl] amine (1000 mg, 5.12 100 °C under N 2 (nitrogen gas) then diluted with water (50 mL). The mixture was extracted with ethyl acetate (EtOAc) (3 x 150 mL).
  • EtOAc ethyl acetate
  • Step 2 To a mixture of methyl 5-methoxy-4-[(2-methoxyethyl) [(4-methoxyphenyl) methyl] amino]-6-oxopyran-2-carboxylate (190 mg, 0.503 mmol, 1.00 equiv) in tetrahydrofuran (THF) (2 mL) was added trimethyltin hydroxide (137 mg, 0.758 mmol, 1.50 equiv). The resulting mixture was stirred for 2 h at room temperature then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 3 To a mixture of 5-methoxy-4-[(2-methoxyethyl) [(4-methoxyphenyl) methyl] amino]- 6-oxopyran-2-carboxylic acid (“amino-pyrone reagent”) (190 mg, 0.523 mmol, 1.00 equiv) and 5- (3,5-dichloro-1,2-thiazol-4-yl)-1,3,4-thiadiazol-2-amine (133 mg, 0.525 mmol, 1.00 equiv) as the “ADT amine reagent” (which may be synthesized following Example 29, Step 1, but using 3,5- dichloroisothiazole-4-carboxylic acid instead of 3-chloro-1,2-thiazole-4-carboxylic acid) in acetonitrile (MeCN) (3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (300 mg, 1.
  • Step 4 Into a 25 mL round-bottom flask was added N-[5-(3,5-dichloro-1,2-thiazol-4-yl)- 1,3,4-thiadiazol-2-yl]-5-methoxy-4-[(2-methoxyethyl) [(4-methoxyphenyl) methyl] amino]-6- oxopyran-2-carboxamide (50 mg, 0.084 mmol, 1.00 equiv) and trifluoroacetic acid (1 mL). The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure.
  • Step 2 To a stirred mixture of [2-(benzyloxy)ethyl](2-methoxyethyl)amine (430 mg, 2.05 mmol, 1.00 equiv) and methyl 4-bromo-5-methoxy-6-oxopyran-2-carboxylate (product of Example 1, Part A, Step 3) (443 mg, 1.68 mmol, 0.82 equiv) in N,N-dimethylformamide (DMF) (5 mL) was added (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate (RuPhos Palladacycle Gen3) (140 mg, 0.167 mmol, 0.08 equiv), 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (
  • Step 3 To a stirred mixture of 4- ⁇ [2-(benzyloxy)ethyl](2-methoxyethyl)amino ⁇ -5-methoxy- 6-oxopyran-2-carboxylic acid (“amino-pyrone reagent”) (180 mg, 0.477 mmol, 1.00 equiv) and 5- (5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Example 1, Part B, Step 4; “ADT amine reagent”) (83 mg, 0.46 mmol, 0.96 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added hydroxybenzotriazole (HOBT) (124 mg, 0.918 mmol, 1.92 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (264 mg, 1.38 mmol, 2.89 equiv).
  • amino-pyrone reagent 180 mg
  • Example 42 4-(((cis)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 159, rac-159), 4-(((1S,2R)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5- (5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 159a*) and 4-(((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-N-(5-(5- methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyr
  • Step 2 Into a solution of 4-((cis-2-hydroxycyclopentyl)(methyl)amino)-3-methoxy-2-oxo- 2H-pyran-6-carboxylic acid (40 mg, 0.14 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (2 mL) was added hydroxybenzotriazole (HOBT) (29 mg, 0.215 mmol, 1.52 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (54 mg, 0.282 mmol, 1.99 equiv) and 5-(5- methylpyrazol-1-yl)-1,3,4-thiadiazol-2-amine (product of Example 1, Part B, Step 4) (23 mg, 0.127 mmol, 0.90 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylamin
  • Example 43 3-methoxy-4-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 160) pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H- mg, 0.56 mmol, 0.19 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature then diluted with water (50 mL).
  • Step 2 To a solution of (3S,4S)-4-(dibenzylamino)oxolan-3-ol (760 mg, 2.68 mmol, 1.00 equiv) in tetrahydrofuran (THF) (10 mL) was added 60% NaH in mineral oil (220 mg, 5.50 mmol, 2.05 equiv) at 0 °C. The mixture was stirred for 30 min then methyl iodide (MeI) (1530 mg, 10.78 mmol, 4.02 equiv) was added and the mixture was allowed to warm to rt and stirred overnight. The reaction was quenched with water at room temperature and extracted with ethyl acetate (EtOAc) (3 x 70 mL).
  • EtOAc ethyl acetate
  • Step 3 To a solution of (3S,4S)-N,N-dibenzyl-4-methoxyoxolan-3-amine (350 mg, 1.18 mmol, 1.00 equiv) in tetrahydrofuran (THF) (20 mL) was added Pd/C (150 mg, 1.41 mmol, 1.20 equiv) and 2M HCl (5.5 mL, 11.00 mmol, 9.35 equiv). The mixture was stirred at room temperature for 2 h under H 2 (gas).
  • THF tetrahydrofuran
  • Step 4 3-Methoxy-4-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)amino)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 160 was prepared according to Example 6, Step 5 using 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 4 of Example 6) as “halo-pyrone reagent” and (3S,4S)-4-methoxytetrahydrofuran-3-amine hydrochloride as the “amine reagent”.
  • Step 1 To a stirred solution of L-phenylalaninol (1.0 g, 6.61 mmol, 1.0 equiv) in methanol (MeOH) (30 mL) was added di-tert-butyl decarbonate (Boc 2 O) (2.90 g, 13.3 mmol, 2.01 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature then concentrated under vacuum. The residue was dissolved with ethyl acetate (EtOAc) (100 mL) and washed with water (2 x 10 mL), and solids crashed out of the solution. The resulting solids were collected and dried in an oven under reduced pressure.
  • EtOAc ethyl acetate
  • Step 2 To a stirred solution of tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate (940 mg, 3.74 mmol, 1.00 equiv) in dimethylformamide (DMF) (19 mL) was added methyl iodide (MeI) (1594 mg, 11.23 mmol, 3.00 equiv) was stirred for 15 min at 0 °C. To the above mixture was added tert-butoxypotassium (630 mg, 5.61 mmol, 1.50 equiv) at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with sat.
  • DMF dimethylformamide
  • MeI methyl iodide
  • Step 4 (S)-3-Methoxy-4-((1-methoxy-3-phenylpropan-2-yl)amino)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 165 was prepared according to Example 6, Step 5 using 4-iodo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Step 4 of Example 6) as “halo-pyrone reagent” and (2S)-1-methoxy-3-phenylpropan-2-amine as the “amine reagent”.
  • Example 45 3-methoxy-4-(((2R,3S)-3-methoxybutan-2-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 166) 3 , , Cs 2 CO 3 , DMF S 4 Step 1: To a solution of (2S,3R)-3-aminobutan-2-ol hydrochloride (600 mg, 4.78 mmol, 1.00 equiv) in methanol (MeOH) (10 mL) was added anisaldehyde (1.95 g, 14.3 mmol, 3.00 equiv).
  • Step 2 To a solution of (2S,3R)-3- ⁇ bis[(4-methoxyphenyl)methyl]amino ⁇ butan-2-ol (1.10 g, 3.34 mmol, 1.00 equiv) in tetrahydrofuran (THF) (30 mL) was added NaH (60% in mineral oil, 262mg, 6.56 mmol, 2.00 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 0.5 h at 0 °C. To the above mixture was added methyl iodide (MeI) (948 mg, 6.68 mmol, 2.00 equiv) at 0 °C.
  • MeI methyl iodide
  • Step 4 3-Methoxy-4-(((2R,3S)-3-methoxybutan-2-yl)amino)-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 166) was prepared according to Example 1, Part C, Step 2 using (2R,3S)-3-methoxybutan-2-amine as the “amine reagent” and 4-bromo-5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Example 1, Part C, Step 1) as the “halo-pyrone reagent”.
  • Example 46 4-((2-hydroxy-2-methylcyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol- 1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 167, rac-167), 4- (((1S,2R)-2-hydroxy-2-methylcyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 134-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 167a*) and 4-(((1R2S)-2-
  • Step 2 Oxalic dichloride (2.70 g, 21.3 mmol, 1.20 equiv) was dissolved in dichloromethane (DCM) (50 mL) at room temperature and stirred for 5 min at -60 °C under N 2 (nitrogen gas). Then dimethylsulfoxide (DMSO) (1.66 g, 21.3 mmol, 1.20 equiv) was added dropwise at -60 °C under N 2 .
  • DCM dichloromethane
  • DMSO dimethylsulfoxide
  • Step 5 4-(((1S,2R)-2-Hydroxy-2-methylcyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 167a*) and 4- (((1R,2S)-2-hydroxy-2-methylcyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 167b*) were prepared as a racemic mixture according to Example 1, Part C, Step 2 using cis-(1-methyl,2-amino)- cyclopentan-1-ol as the “amine reagent” and 4-bromo-5-methoxy-N-[5-(5-methyl
  • Example 47 4-((2-cyclopropoxyethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 168) Step 1: To a stirred solution of cyclopropanol (1.00 g, 17.2 mmol, 1.00 equiv) in tetrahydrofuran (THF) was added sodium hydride (60% in mineral oil, 0.62 g) at 0 o C.
  • THF tetrahydrofuran
  • prep-TLC prep-Thin Layer Chromatography
  • Step 3 4-(2-Cyclopropoxyethylamino)-5-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)-6-oxo-6H-pyran-2-carboxamide (Compound 168) was prepared according to Example 1, Part C, Step 2 using 2-cyclopropoxyethanamine as the “amine reagent” and 4-bromo- 5-methoxy-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Example 1, Part C, Step 1) as the “halo-pyrone reagent”.
  • Example 48 4-(((1R, 2S)-2-(2,2-difluoroethoxy)cyclopentyl)amino)-3-methoxy-N-(5-(5-methyl- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 171)
  • Step 1 Into a solution of (1S,2R)-2-aminocyclopentan-1-ol hydrochloride (1.83 g, 13.35 mmol, 1.00 equiv) in acetonitrile (MeCN) (50 mL) was added benzyl bromide (BnBr) (6.30 g, 36.8 mmol, 2.76 equiv) and cesium carbonate (12.7 g, 39.0 mmol, 2.92 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 10 mL) and the filtrate was concentrated under reduced pressure.
  • MeCN acetonitrile
  • Step 2 Into a solution of (1S,2R)-2-(dibenzylamino)cyclopentan-1-ol (400 mg, 1.42 mmol, 1.00 equiv) in tetrahydrofuran (THF) (5 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS) (2.80 mL, 2.80 mmol, 1.97 equiv) dropwise at 0 °C. The mixture was stirred for 15 min at room temperature then to this was added 2,2-difluoroethyl trifluoromethanesulfonate (600 mg, 2.80 mmol, 1.97 equiv) dropwise at 0 °C.
  • LiHMDS lithium bis(trimethylsilyl)amide
  • Step 3 Into a solution of (1R,2S)-N,N-dibenzyl-2-(2,2-difluoroethoxy)cyclopentan-1-amine (200 mg, 0.579 mmol, 1.00 equiv) in methanol (MeOH) (4 mL) was added Pd/C (800 mg, 7.52 mmol, 13.0 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature under H 2 (gas). The mixture was then filtered and the filter cake was washed with methanol (MeOH) (3 x 4 mL).
  • MeOH methanol
  • Example 49 4-(((1S,2R)-2-(2,2-difluoroethoxy)cyclobutyl)amino)-3-methoxy-N-(5-(5-methyl- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 172*) and 4-(((1R,2S)-2-(2,2-difluoroethoxy)cyclobutyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 173*) ol hydrochloride to provide (1,2-cis)-2-(2,2-difluoroethoxy)cyclobutan-1-amine (“amine reagent”), followed by coupling with 4-iodo-3-methoxy-
  • Example 50 (R)-4-(2-(cyanomethyl)pyrrolidin-1-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1- yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 174) and (R)-4-(2- (hydroxymethyl)pyrrolidin-1-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2- yl)-2-oxo-2H-pyran-6-carboxamide (Compound 174-OH) , , 2-oxo-2H-pyran-6-carboxamide Step 1: Into a 30 mL sealed tube were added 4-bromo-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran
  • Step 2 To a stirred solution of (R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-3-methoxy-N-(5- (5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 174-OH) (240 mg, 0.555 mmol, 1.00 equiv) in dichloromethane (DCM) (10 mL) was added i h l i ( A) (36 03 6 l 064 i ) d h lf i h d id ( O) (192 (1-(3-methoxy-6-((5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)carbamoyl)-2-oxo-2H-pyran- 4-yl)pyrrolidin-2-yl)methyl methanesulfonate (100 mg,
  • Example 51 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1- ylamino)-3-(2-hydroxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 177) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1-ylamino)-3-(2-(tert- butoxy)ethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 177-Ac-OtBu) Compound 177-Ac-OtBu N-(5-(5-acetamido-1 H-pyrazol- 1-yl)-1,3,4-thiadiazol-2-yl)-4- (bicyclo[1.1.1]pentan-1- y
  • Step 2 A mixture of 2-(2,5-dimethylpyrrol-1-yl)-5-(5-iodopyrazol-1-yl)-1,3,4-thiadiazole (2.00 g, 5.39 mmol, 1.00 equiv), tris(dibenzylidenaceton)dipalladium(0) dibenzylidenacetone silica gel column chromatography, eluted with petroleum ether / ethyl acetate (PE/EtOAc) (8:1), to afford N- ⁇ 2-[5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]pyrazol-3-yl ⁇ acetamide (1.1 g, 67% yield).
  • PE/EtOAc petroleum ether / ethyl acetate
  • Step 4 To a stirred solution of methyl 4-bromo-5-[2-(tert-butoxy)ethoxy]-6-oxopyran-2- carboxylate (prepared following Example 15, Step 1, but using 2-tertbutoxyethanol instead of 2- methoxyethanol) (3.0 g, 8.59 mmol, 1.00 equiv) in tetrahydrofuran (THF) (30 mL) was added trimethyltin hydroxide (4.00 g, 22.12 mmol, 2.57 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature then concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 5 To a stirred solution of 4-bromo-5-[2-(tert-butoxy)ethoxy]-6-oxopyran-2-carboxylic acid (550 mg, 1.64 mmol, 1.00 equiv) in N,N-dimethylformamide (DMF) (6 mL) was added hydroxybenzotriazole (HOBT) (445 mg, 3.29 mmol, 2.01 equiv), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (943 mg, 4.92 mmol, 3.00 equiv) and N-[2-(5-amino- 1,3,4-thiadiazol-2-yl)pyrazol-3-yl]acetamide (product of Step 3 of this Example) (440 mg, 1.96 mmol, 1.20 equiv) at room temperature.
  • HOBT hydroxybenzotriazole
  • EDCI 1-ethyl-3-(3- dimethylaminopropyl)
  • Step 6 To a stirred solution of 4-bromo-5-[2-(tert-butoxy)ethoxy]-N-[5-(5- acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (“halo-pyrone reagent”) (250 mg, 0.462 mmol, 1.00 equiv) in dioxane (3 mL) was added ([1,1′-binaphthalene]-2,2′- diyl)bis(diphenylphosphane) (BINAP) (61 mg, 0.098 mmol, 0.21 equiv), [2'-(diphenylphosphanyl)- [11'-binaphthalen]-2-yl] diphenylphosphane; [2'-amino-[11'-biphenyl]-2-yl] palladio chromatography (MeCN in water, 0% to 100% gradient in
  • Example 52 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1- ylamino)-3-methoxy-2-oxo-2H-pyran-6-carboxamide (Compound 178) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1-ylamino)-3-methoxy-2-oxo-2H- pyran-6-carboxamide (Compound 178-Ac) Compound 178-Ac H 2 N - pyran-6-carboxamide Step 1: N-(5-(5-Acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan- 1-ylamino)-3-
  • Example 54 (R)-3-methoxy-4-((2-methoxy-1-(2-methoxyphenyl)ethyl)amino)-N-(5-(5-methyl- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 198*) and (S)-3-methoxy-4-((2-methoxy-1-(2-methoxyphenyl)ethyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-
  • Step 2 A solution of tert-butyl (2-((3-methoxy-6-((5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl)carbamoyl)-2-oxo-2H-pyran-4-yl)amino)ethyl)carbamate in HCl(4 M) in 1,4-dioxane (2 mL) was stirred for 0.5 h at room temperature then concentrated under vacuum.
  • Example 56 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2- methoxyethyl)amino)-2-oxo-2H-pyran-6-carboxamide (Compound 205) and N-(5-(5-acetamido- 1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-((2-methoxyethyl)amino)-2-oxo-2H-pyran- 6 carboxamide (Compound 205 Ac)
  • Step 1 A solution of 4-bromo-5-methoxy-6-oxopyran-2-carboxylic acid (product of Example 1, Part A, Step 4) (220 mg, 0.883 mmol, 1.00 equiv) in acetonitrile (MeCN) (3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (506 mg, 1.80 mmol, 2.04 equiv) and N-methylimidazole (NMI) (375 mg, 4.57 mmol, 5.17 equiv) was stirred for 5 min at room temperature.
  • MeCN acetonitrile
  • TCFH chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate
  • N-methylimidazole (NMI) 375 mg, 4.57 mmol, 5.17 equiv
  • Step 3 To a solution of N-[5-(5-acetamidopyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-5-methoxy-4- [(2-methoxyethyl)amino]-6-oxopyran-2-carboxamide (Compound 205-Ac) (60 mg, 0.133 mmol, 1.00 equiv) in H 2 O (0.6 mL) and tetrahydrofuran (THF) (0.6 mL) was slowly added trifluoroacetic acid (TFA) (1.2 mL) at 0 °C. The resulting solution was stirred overnight at 50 °C then concentrated under vacuum.
  • THF tetrahydrofuran
  • Example 57 4-((2-(difluoromethoxy)ethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 208) Step 1: To a stirred solution of benzyl N-(2-hydroxyethyl)carbamate (1.00 g, 5.12 mmol, 1.00 equiv) in dichloromethane (DCM) (6 mL) and H 2 O (6 mL) was added KHF 2 (1.20 g, 15.4 mmol, 3.00 equiv) and (bromodifluoromethyl)trimethylsilane (TMS-CF 2 Br) (4.16 g, 20.5 mmol, 400 equiv) at 0 °C The resulting mixture was stirred for 12 h at room temperature The mixture was [M+1]+.
  • DCM dichlorome
  • Step 2 Into a stirred solution of benzyl N-[2-(difluoromethoxy)ethyl]carbamate (600 mg, 2.45 mmol, 1.00 equiv) in methanol (MeOH) (30 mL) was added conc. HCl (0.2 mL) and Pd/C (100 mg, 0.940 mmol, 0.38 equiv). The resulting mixture was stirred for 4 h at room temperature under H 2 (gas). The mixture was then filtered and the filter cake was washed with MeOH (3 x 5 mL).
  • Step 3 4-((2-(Difluoromethoxy)ethyl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 208) was prepared according to Example 1, Part C, Step 2 using 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 of Example 6) as “halo- pyrone reagent” and 2-(difluoromethoxy)ethan-1-amine as the “amine
  • Example 58 4-((trans)-2,5-bis(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 209, rac-209), 4-((2R,5R)-2,5-bis(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 209a*) and 4-((2R,5R)-2,5- bis(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4- thiadiazol-2-yl
  • Step 2 To a stirred solution of trans-2,5-diethyl 1-[(4-methoxyphenyl)methyl]pyrrolidine- 2,5-dicarboxylate (4.0 g, 11.9 mmol, 1.00 equiv) in tetrahydrofuran (THF) (50 mL) was added LiAlH 4 (960 mg, 25.3 mmol, 2.12 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature then quenched with water (0.96 mL) at 0 °C.
  • THF tetrahydrofuran
  • Step 3 To a solution of trans-[5-(hydroxymethyl)-1-[(4-methoxyphenyl)methyl]pyrrolidin- 2-yl]methanol (400 mg, 1.59 mmol, 1.00 equiv) in tetrahydrofuran (THF) (8 mL) was added and NaH (128 mg, 3.20 mmol, 2.01 equiv, 60% in mineral oil).
  • THF tetrahydrofuran
  • Step 4 A solution of trans-2,5-bis(methoxymethyl)-1-[(4- methoxyphenyl)methyl]pyrrolidine (250 mg, 0.895 mmol, 1.00 equiv) in methanol (MeOH) (15 mL) was added Pd/C (100 mg, 0.940 mmol, 1.05 equiv) and conc. HCl (0.2 mL). The mixture was stirred for 1 h at room temperature under H 2 (gas). The resulting mixture was filtered, and the filter cake was washed with MeOH (6 mL). The filtrate was concentrated under reduced pressure to afford trans-2,5-bis(methoxymethyl)pyrrolidine hydrochloride (180 mg).
  • Example 59 N-(5-(5-amino-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1- ylamino)-3-(2-methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 210) and N-(5-(5- acetamido-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-4-(bicyclo[1.1.1]pentan-1-ylamino)-3-(2- methoxyethoxy)-2-oxo-2H-pyran-6-carboxamide (Compound 210-Ac)
  • Step 1 A solution of methyl 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylate (product of Example 15, Step 1) (1700 mg, 5.536 mmol, 1.00 equiv) in HCl (6M) (30 mL) was stirred for 3 h at 80 °C then concentrated under reduced pressure.
  • Step 2 To a stirred solution of 4-bromo-5-(2-methoxyethoxy)-6-oxopyran-2-carboxylic acid (300 mg, 1.02 mmol, 1.00 equiv) and N-[2-(5-amino-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]acetamide (product of Step 3 of Example 51) (253 mg, 1.13 mmol, 1.10 equiv) in acetonitrile (MeCN) (6 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (575 mg, 2.05 mmol, 2.00 equiv) and N-methylimidazole (NMI) (842 mg, 10.2 mmol, 10.0 equiv) at room temperature.
  • MeCN acetonitrile
  • TCFH chloro-N,N,N',N'-tetramethylform
  • Example 60 3-methoxy-4-((2S,3R)-3-methoxy-2-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(5- methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Step 1 To a solution of (2R,3R)-1-[(benzyloxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid (1000 mg, 3.770 mmol, 1.00 equiv) in methanol (MeOH) (10 mL) was added trimethylsilyldiazomethane (TMSCHN 2 ) (20 mL, 0.600 mmol) at room temperature.
  • MeOH methanol
  • TMSCHN 2 trimethylsilyldiazomethane
  • Step 2 To a solution of 1-benzyl 2-methyl (2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.11 g, 3.97 mmol, 1.00 equiv) in dichloromethane (DCM) (20 mL) was added was added methyl iodide (MeI) (1.69 g, 11.9 mmol, 3.00 equiv) and Ag 2 O (1.84 g, 7.95 mmol, 2.00 equiv). The resulting mixture was stirred overnight at room temperature in the dark.
  • DCM dichloromethane
  • Step 4 To a solution of benzyl (2S,3R)-2-(hydroxymethyl)-3-methoxypyrrolidine-1- carboxylate (400 mg, 1.51 mmol, 1.00 equiv) and potassium tert-butoxide (t-BuOK) (860 mg, 7.66 mmol, 5.08 equiv) in N,N-dimethylformamide (DMF) (15 mL) was added in methyl iodide (MeI) (1.12 g, 7.89 mmol, 5.23 equiv) at 0 °C. And then the resulting mixture was stirred for 1 h at room temperature.
  • DMF N,N-dimethylformamide
  • MeI methyl iodide
  • Step 6 3-Methoxy-4-((2S,3R)-3-methoxy-2-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(5- methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 211 was prepared according to Example 6, Step 5 using 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 of Example 6) as “halo-pyrone reagent” and (2S,3R)-3-methoxy-2-(methoxymethyl)pyrrolidine hydrochloride as the “amine reagent”.
  • Example 61 4-(((1S,2R)-2-(difluoromethoxy)cyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 212) c arboxamide Step 1: To a solution of (1R,2S)-2-aminocyclopentan-1-ol hydrochloride (300 mg, 2.18 mmol, 1.00 equiv) in dioxane (0.6 mL) and H 2 O (3 mL) was added benzyl chloroformate (Cbz-Cl) (558 mg, 3.27 mmol, 1.50 equiv) and Na 2 CO 3 (462 mg, 4.36 mmol, 2.00 equiv) at 0 °C.
  • Cbz-Cl benzyl chloroformate
  • Step 4 4-(((1S,2R)-2-(Difluoromethoxy)cyclopentyl)amino)-3-methoxy-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 212) was prepared according to Example 6, Step 5 using 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 of Example 6) as “halo-pyrone reagent” and (1S,2R)-2-(difluoromethoxy)cyclopentan-1-amine as the “amine reagent”.
  • Example 62 3-methoxy-4-(((1S,2R)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol- 1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 214*) and 3-methoxy-4- (((1R,2S)-2-methoxycyclopentyl)amino)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)- 2-oxo-2H-pyran-6-carboxamide (Compound 215*) Compound 214* Compound 215* 3-methoxy-4-(((1S,2R)-2- 3-methoxy-4-(((1R,2S)-2- methoxycyclopentyl)amino)-N-(5-(5-methyl- methoxycyclopentyl)a
  • Example 63 4-((2-oxaspiro[3.3]heptan-5-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide (Compound 56, rac-56), (S)-4-((2- oxaspiro[3.3]heptan-5-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2- yl)-2-oxo-2H-pyran-6-carboxamide (Compound 56a*), and (R)-4-((2-oxaspiro[3.3]heptan-5-
  • Step 2 To a stirred solution of N-benzyl-2-oxaspiro[3.3]heptan-5-amine (300 mg, 1.48 mmol 100 equiv) in tetrahydrofuran (THF) (5 mL) was added Pd/C (100 mg 094 mmol 064 provide 2-oxaspiro[3.3]heptan-5-amine oxalate (80 mg, 48% yield).
  • LCMS (ES, m/z) 114 [M+1]+.
  • Step 3 4-((2-Oxaspiro[3.3]heptan-5-yl)amino)-3-methoxy-N-(5-(5-methyl-1H-pyrazol-1-yl)- 1,3,4-thiadiazol-2-yl)-2-oxo-2H-pyran-6-carboxamide
  • Compound 56 was prepared as a racemic mixture (comprising Compounds 56a* and 56b*) according to Example 1, Part C, Step 2 using 2- oxaspiro[3.3]heptan-5-amine oxalate as the “amine reagent” and 4-bromo-5-methoxy-N-[5-(5- methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (product of Example 1, Part C, Step 1) as the “halo-pyrone reagent”.
  • Example 64 1-(1,3-dimethoxypropan-2-yl)-N-(5-(5-methyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2- yl)-5-oxo-1,2,3,5-tetrahydropyrano[3,4-b][1,4]oxazine-7-carboxamide (Compound 221) Compound 221 1-(1,3-dimethoxypropan-2-yl)-N-(5-(5-methyl-1H- pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-5-oxo-1,2,3,5- tetrahydropyrano[3,4-b][1,4]oxazine-7-carboxamide Step 1: To a stirred mixture of methyl 5-hydroxy-4-iodo-6-oxopyran-2-carboxylate (product of Step 1, Example 6) (1.00 g, 3.38 mmol, 1 equiv) and tripheny
  • Step 2 Into a 8 mL vial was added methyl 5-[2-(tert-butoxy)ethoxy]-4-iodo-6-oxopyran-2- carboxylate (380 mg, 0.959 mmol, 1 equiv) in tetrahydrofuran (THF) (2 mL) and trimethyltin hydroxide (180 mg, 0.995 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 3 Into a 40 mL vial was added 5-[2-(tert-butoxy)ethoxy]-4-iodo-6-oxopyran-2- carboxylic acid (370 mg, 0.968 mmol, 1 equiv), acetonitrile (MeCN) (5 mL), chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (TCFH) (461 mg, 1.643 mmol, 1.7 equiv), N- methylimidazole (NMI) (238 mg, 2.90 mmol, 3 equiv) and 5-(5-methylpyrazol-1-yl)-1,3,4- thiadiazol-2-amine (product of Example 1, Part B, Step 4) (180 mg, 0.993 mmol, 1 equiv) at room
  • Step 4 Into a 40 mL vial containing 5-[2-(tert-butoxy)ethoxy]-4-iodo
  • Step 5 Into a 50 mL round-bottom flask were added 5-[2-(tert-butoxy)ethoxy]-4-[(1,3- dimethoxypropan-2-yl)amino]-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2- carboxamide (150 mg, 0.280 mmol, 1 equiv) and HCl(gas) in 1,4-dioxane (5 mL) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 6 Into a 50 mL round-bottom flask was added 4-[(1,3-dimethoxypropan-2-yl)amino]-5- (2-hydroxyethoxy)-N-[5-(5-methylpyrazol-1-yl)-1,3,4-thiadiazol-2-yl]-6-oxopyran-2-carboxamide (150 mg, 0.312 mmol, 1 equiv), dichloromethane (DCM) (6 mL) and triethylamine (TEA) (95 mg, 0.94 mmol, 3 equiv) at room temperature.
  • DCM dichloromethane
  • TEA triethylamine
  • Step 7 Into a 40 mL vial was added 2-( ⁇ 4-[(13-dimethoxypropan-2-yl)amino]-6- ⁇ [5-(5- aqueous layer was extracted with DCM (3 x 5 mL), the organic layer concentrated under reduced pressure, and the residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to provide a crude product, which was further purified by Chiral-Prep-HPLC (XBridge Prep Phenyl OBD Column, 19*250 mm, 5 ⁇ m; mobile phase, water (0.05% trifluoroacetic acid (TFA)) and MeCN (35% MeCN up to 45% in 10 min); Detector, UV 254 nm) to provide 1-(1,3- dimethoxypropan-2-yl)-N-(5-(5-methyl-1H-pyra
  • 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 were 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.
  • results of the assay are reported in Table D with the following designations: A represents an IC 50 value ⁇ 0.005 ⁇ M; B represents an IC 50 value ⁇ 0.005 ⁇ M and ⁇ 0.02 ⁇ M; C represents an IC 50 value ⁇ 0.02 ⁇ M and ⁇ 0.06 ⁇ M; D represents an IC 50 value ⁇ 0.06 and ⁇ 0.2 ⁇ M; E represents an IC 50 value ⁇ 0.2.
  • A represents an IC 50 value ⁇ 0.005 ⁇ M
  • B represents an IC 50 value ⁇ 0.005 ⁇ M and ⁇ 0.02 ⁇ M
  • C represents an IC 50 value ⁇ 0.02 ⁇ M and ⁇ 0.06 ⁇ M
  • D represents an IC 50 value ⁇ 0.06 and ⁇ 0.2 ⁇ M
  • E represents an IC 50 value ⁇ 0.2.
  • 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
  • that variable e.g., the R group
  • that variable is independent of each essentially of, such elements and/or features.
  • those embodiments have not been specifically set forth in haec verba herein.
  • the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are understood to be included.

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