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WO2025119207A1 - Composés antiviraux et compositions et utilisations correspondantes - Google Patents

Composés antiviraux et compositions et utilisations correspondantes Download PDF

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Publication number
WO2025119207A1
WO2025119207A1 PCT/CN2024/136699 CN2024136699W WO2025119207A1 WO 2025119207 A1 WO2025119207 A1 WO 2025119207A1 CN 2024136699 W CN2024136699 W CN 2024136699W WO 2025119207 A1 WO2025119207 A1 WO 2025119207A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
virus
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Inventor
Gongxin HE
Kai Hou
Hao Wu
Xiubo TANG
Wenyuan Fan
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Shanghai Curegene Pharmaceutical Co Ltd
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Shanghai Curegene Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present disclosure generally relates to compounds which exhibit activity in the inhibition of RNA polymerase as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions comprising the same.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East Respiratory Syndrome coronavirus
  • Ebola virus etc.
  • SARS-CoV-2 the global pandemic caused by SARS-CoV-2 has resulted in severe respiratory illness throughout the world, wherein severe cases progress to pneumonia and multiorgan failure, which have led to millions of deaths worldwide.
  • Coronaviruses are highly susceptible to mutate into prevalent variants.
  • Coronaviruses are positive-strand RNA viruses encoding 16 nonstructural proteins (nsp1 to nsp16) . A number of the nonstructural proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC) .
  • the main replicase-transriptase protein is the RNA-dependent RNA polymerase (RdRp) , which is directly involved in the replication and transcription of RNA from an RNA strand.
  • RdRps are highly conserved throughout variants and viruses, making it a desirable drug target for managing various RNA-viral infections.
  • Remdesivir a monophosphoramidate prodrug of the nucleoside GS-441524, originally developed to treat Ebola virus infections, inhibits the RdRp of SARS-CoV-2. It was the first antiviral approved or authorized for emergency use to treat COVID-19 in several countries. Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe disease and it prevents disease progression in outpatients (Beigel J. H., et al. Remdesivir for the treatment of covid-19 -final report. N. Engl. J. Med. 2020; 383 (19) : 1813-1826. ; Gottling R.L., et al.
  • Remdesivir is effective against different variants of concern of SARS-CoV-2 (Vangeel L., et al. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022 Feb; 198: 105252. ) .
  • Remdesivir has several drawbacks, such as, limited to intravenous administration, short plasma half-life, uncorrelated plasma exposure and clinical efficacy, low delivery in lung (Sun D. Remdesivir for treatment of COVID-19: combination of pulmonary and IV administration may offer additional benefit.
  • RNA polymerase inhibitor with good oral and pulmonary bioavailability, and high conversion rate to its monophosphate and triphosphate.
  • the present disclosure provides compounds which are capable of inhibiting RNA polymerase, the pharmaceutical compositions comprising these compounds and methods for the use of such compounds or pharmaceutical compositions for treatment of viral infections.
  • the present disclosure provides a compound having Formula (I) or Formula (II) : or a pharmaceutically acceptable salt thereof, wherein Base is a naturally occurring or modified pyrimidine base or purine base; Q is CH 2 , CHD or CD 2 ; R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a , -NO 2 , -N (R a ) 2 , -C (O) N (R a ) 2 , -C (O) R a , -OC (O) R a , -C (O) OR a , -S (O) R a , -S (O) 2 R a , -S (O) OR a , -S (O) 2 (OR a ) , and -S (O) 2 N (R a ) 2
  • a compound having a formula selected from: or a pharmaceutically acceptable salt thereof having a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for treating a viral infection.
  • linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent.
  • -NR (CR’ R” ) -includes both -NR (CR’ R” ) -and - (CR’ R” ) NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described herein.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • Examples of “C 1-10 alkyl” include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkyl groups contain 9 to 30 carbon atoms. In some embodiments, alkyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.
  • alkylcycloalkyl refers to an alkyl attached to cycloalkyl, including -alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to -alkyl-cycloalkyl.
  • alkylheterocyclyl refers to an alkyl attached to heterocyclyl, including -alkyl-heterocyclyl and alkyl-heterocyclyl-. In some embodiments, alkylheterocyclyl refers to -alkyl-heterocyclyl.
  • alkylaryl refers to an alkyl attached to aryl, including -alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to -alkyl-aryl.
  • alkylheteroaryl refers to an alkyl attached to heteroaryl, including -alkyl-heteroaryl and alkyl-heteroaryl-. In some embodiments, alkylheteroaryl refers to -alkyl-heteroaryl.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In some embodiments, alkenyl groups contain 9 to 30 carbon atoms.
  • alkenyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.
  • alkenyl group examples include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkoxyl refers to an alkyl group attached to oxygen (-O-alkyl) .
  • alkoxyl groups contain 1 to 10 carbon atoms.
  • alkoxyl groups contain 1 to 9 carbon atoms.
  • alkoxyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • Example of alkoxyl group include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • alkynyl refers to a linear or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In some embodiments, alkynyl groups contain 9 to 30 carbon atoms.
  • alkynyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • amino refers to -NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.
  • aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl group may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system.
  • the polycyclic ring system it may include fused or spiro ring system.
  • a polycyclic aryl may comprise an aromatic ring fused to one or more additional rings such as cycloalkyl or aryl ring.
  • the aryl is a C 6 -C 12 aryl.
  • the aryl is a C 6 -C 11 aryl. In some embodiments, the aryl is C 6 -C 10 aryl. In some embodiments, the aryl is a C 6 -C 9 aryl. In some embodiments, the aryl is a C 6 -C 8 aryl.
  • Aryl includes, but are not limited to, aryl groups derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted at one or more ring positions with substituents as described herein.
  • zido refers to -N 3 .
  • cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring. In the case of polycyclic carbocyclic ring system, it may include fused (for example, fused with another cycloalkyl ring) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. In some embodiments, the cycloalkyl is partially saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • the cycloalkyl is a 3-to 12-membered cycloalkyl. In some embodiments, the cycloalkyl is a 3-to 10-membered cycloalkyl. In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted at one or more ring positions with substituents as described herein.
  • cyano refers to -CN.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl substituted with one or more halogens.
  • the haloalkyl may contain 1 to 6 carbon atoms.
  • the haloalkyl may contain 1 to 4 carbon atoms.
  • the haloalkyl may contain 1 to 3 carbon atoms. Examples of haloalkyl include, but not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl and tetrafluoroethyl.
  • heteroatom refers to nitrogen, oxygen, sulfur, phosphorus or silicon, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heteroaryl refers to an aromatic ring having, in addition to carbon atoms, one or more heteroatoms which may be optionally oxidized or quaternized.
  • the heteroaryl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. In the case of the polycyclic ring system, it may include fused or spiro ring system.
  • a polycyclic heteroaryl may comprise a heteroaryl ring fused to one or more additional rings such as cycloalkyl, heterocyclyl, aryl or heteroaryl ring, or an aryl ring fused to one or more additional rings such as heterocyclyl or heteroaryl ring.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • heteroaryl examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiopheny
  • heterocyclyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur, which may be optionally oxidized or quaternized.
  • the heterocyclyl is fully saturated.
  • the heterocyclyl is partially unsaturated.
  • the heterocyclyl group may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system.
  • a polycyclic heterocyclyl may comprise a heterocyclyl ring fused to one or more additional rings such as cycloalkyl or heterocyclyl ring, or a cycloalkyl ring fused to one or more heterocyclyl ring.
  • heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydro
  • the heterocyclyl is a 3-to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 9-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 7-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-to 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5-to 6-membered heterocyclyl.
  • a heterocyclyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like.
  • substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like.
  • the heterocyclyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocyclyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocyclyl is optionally substituted with halogen.
  • 3-to 12-membered heterocyclyl refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.
  • hydroxyl refers to -OH.
  • naturally occurring amino acid side chain and “naturally occurring amino acid side chain” refer to side chain of any of the naturally occurring amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) usually in the S-configuration (i.e., the L-amino acid) .
  • the naturally occurring amino acids i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyros
  • partially saturated or “partially unsaturated” refers to a radical that includes at least one double or triple bond.
  • the term “partially saturated” or “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • purine base or “pyrimidine base” comprises, but is not limited to, adenine, N 6 -alkylpurines, N 6 -acylpurines (wherein acyl is C (O) (alkyl, aryl, alkylaryl, or arylalkyl) ) , N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -allylaminopurine, N 6 -thioallyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2-and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including
  • Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2, 6-diaminopurine, and 6-chloropurine.
  • the purine and pyrimidine bases are linked to the ribose sugar, or analog thereof, through a nitrogen atom of the base. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • substituents include, but are not limited to, the functional groups as described herein, such as halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like, each of which may also be similarly substituted.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution when used in conjunction with groups such as alkylaryl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.
  • the present disclosure provides a compound having Formula (I) or Formula (II) : or a pharmaceutically acceptable salt thereof, wherein Base is a naturally occurring or modified pyrimidine base or purine base; Q is CH 2 , CHD or CD 2 ; R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a , -NO 2 , -N (R a ) 2 , -C (O) N (R a ) 2 , -C (O) R a , -OC (O) R a , -C (O) OR a , -S (O) R a , -S (O) 2 R a , -S (O) OR a , -S (O) 2 (OR a ) , and -S (O) 2 N (R a ) 2
  • the Base is selected from the group consisting of:
  • the Base is selected from the group consisting of:
  • R 1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl, or haloalkyl. In some embodiments, R 1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) , or C 1-6 haloalkyl (such as C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl) .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • C 1-6 haloalkyl such as C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl
  • R 1 is cyano
  • each of R 21 , R 22 , R 31 , R 32 , and R 4 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) , haloalkyl (such as C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl) , or -OC (O) R a .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • haloalkyl such as C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or
  • each of R 21 , R 22 , R 31 , R 32 is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) or -OC (O) R a .
  • R a is alkyl. In certain embodiments, R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R a is methyl.
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, azido, or haloalkyl (such as C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl) .
  • haloalkyl such as C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl
  • the Base is and is
  • the Base is is
  • the compound has a Formula (Ia) : or a pharmaceutically acceptable salt thereof, wherein Q, R 1 to R 6 , R 21 , R 22 , R 31 , R 32 , L 1 , L 2 and Base are defined supra.
  • each R 5 is independently selected from hydrogen or C 1-6 alkyl (such as C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) .
  • each R 5 is independently C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, both R 5 are methyl. In certain embodiments, both R 5 are ethyl.
  • one R 5 is hydrogen, and the other R 5 is C 1-6 alkyl. In certain embodiments, one R 5 is hydrogen, and the other R 5 is C 1-6 alkyl, C 1-5 alkyl, C 1- 4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • both R 5 are hydrogen.
  • two R 5 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more R 5a .
  • two R 5 taken together with the nitrogen atom to which they are bound form a 5-to 12-membered heterocyclyl (such as 5-to 11-membered heterocyclyl, 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered heterocyclyl, 5-to 7-membered heterocyclyl or 5-to 6-membered heterocyclyl) optionally substituted with one or more R 5a .
  • two R 5 taken together with the nitrogen atom to which they are bound form a heterocyclyl selected from the group consisting of: each of which is optionally substituted with one or more R 5a .
  • R 5a is selected from alkyl or alkoxyl. In certain embodiments, R 5a is selected from C 1-6 alkyl (such as C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) or C 1-6 alkoxyl (such as C 1-5 alkoxyl, C 1-4 alkoxyl, C 1-3 alkoxyl or C 1-2 alkoxyl) . In certain embodiment, R 5a is methyl or
  • each R L is independently selected from hydrogen, deuterium, or alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) . In certain embodiments, both R L are hydrogen.
  • L 2 is selected from *-OC (O) -or *-OC (O) O-. In certain embodiments, L 2 is *-OC (O) O-.
  • R 6a is selected from C 8-20 alkyl or C 8-20 alkenyl, each of which is optionally substituted with one or more R b .
  • R 6a is selected from C 8-20 alkyl, C 8-18 alkyl, C 8-15 alkyl, C 8-13 alkyl, C 8-20 alkenyl, C 8-18 alkenyl, C 8-15 alkenyl or C 8-13 alkenyl, each of which is optionally substituted with one or more R b .
  • R 6a is selected from C 8-13 alkyl or C 8-13 alkenyl, each of which is optionally substituted with one or more R b .
  • R 6a is C 8-13 alkyl optionally substituted with one or more R b .
  • R 6b is selected from hydrogen, halogen or alkyl. In certain embodiments, R 6b is selected from hydrogen or alkyl. In certain embodiments, R 6b is hydrogen or methyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is C 1-6 alkyl. In certain embodiments, R 6b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl. In certain embodiments, R 6b is C 1- 3 alkyl. In certain embodiments, R 6b is methyl.
  • the compound has a Formula (IIa) : or a pharmaceutically acceptable salt thereof, wherein Q, R 1 to R 8 , R 21 , R 22 , R 31 , R 32 , L 1 , L 2 and Base are defined supra..
  • L 2 is selected from *-OC (O) -or *-OC (O) O-.
  • L 2 is *-OC (O) O-.
  • R 8 is selected from hydrogen or C 1-6 alkyl optionally substituted with one or more R b .
  • R 8 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl optionally substituted with one or more R b .
  • R 8 is C 1-3 alkyl optionally substituted with one or more R b .
  • R 8 is methyl or isopropyl.
  • G is -N (R a ) -**.
  • R a is selected from hydrogen or alkyl.
  • R a is alkyl.
  • R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • R a is methyl.
  • G is -N (R a ) C (R G ) 2 C (O) O-**.
  • each R G is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 6-12 aryl, 5-to 12-membered heteroaryl, (C 1-3 alkyl) (C 3-12 cycloalkyl) , (C 1-3 alkyl) (3-to 12-membered heterocyclyl) , (C 1-3 alkyl) (C 6-12 aryl) , (C 1-3 alkyl) (5-to 12-membered heteroaryl) and natural amino acid side chain, each of which is optionally substituted with one or more R b .
  • one of R G is hydrogen, and the other R G is selected from C 1-6 alkyl, C 6-12 aryl, (C 1-3 alkyl) (C 6-12 aryl) , (C 1-3 alkyl) (5-to 12-membered heteroaryl) or natural amino acid side chain, each of which is optionally substituted with one or more R b .
  • one of R G is hydrogen, and the other R G is (C 1-3 alkyl) (C 6-12 aryl) or (C 1-3 alkyl) (5-to 12-membered heteroaryl) , each optionally substituted with one or more R b .
  • R b is cyano, halogen, hydroxyl, or alkoxyl.
  • one of R G is hydrogen, and the other R G is selected from the group consisting of:
  • one of R G is hydrogen, and the other R G is natural amino acid side chain.
  • one of R G is hydrogen, and the other R G is selected from the group consisting of: -H, -CH 3 ,
  • both R G are methyl.
  • G is and X is -O-.
  • ring A is selected from the group consisting of:
  • R 7 is selected from C 8-20 alkyl or C 8-20 alkenyl, each of which is optionally substituted with one or more R b .
  • R 7 is selected from C 8-20 alkyl, C 10-20 alkyl, C 12-20 alkyl, C 14-20 alkyl, C 16-20 alkyl, C 8-20 alkenyl, C 10-20 alkenyl, C 12-20 alkenyl, C 14-20 alkenyl, or C 16-20 alkenyl, each of which is optionally substituted with one or more R b .
  • R 7 is selected from C 16-20 alkyl or C 16-20 alkenyl, each of which is optionally substituted with one or more R b .
  • R 7 is C 16-20 alkyl optionally substituted with one or more R b .
  • the present disclosure provides a compound selected from any compound set forth in Table 1.
  • Table 1
  • the compounds of present disclosure can comprise one or more asymmetric centers depending on substituent selection, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds provided herein may have an asymmetric carbon center, and thus compounds provided herein may have either the (R) or (S) stereo-configuration at a carbon asymmetric center. Therefore, compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the term “enantiomer” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the term “diastereomer” refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • a particular enantiomer may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as “optically enriched” .
  • “Optically enriched” means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90%by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99%by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
  • a derivatization can be carried out before a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound provided herein or it can be done on a final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
  • absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis.
  • VCD Vibrational Circular Dichroism
  • mixtures of diastereomers for example mixtures of diastereomers enriched with 51%or more of one of the diastereomers, including for example 60%or more, 70%or more, 80%or more, or 90%or more of one of the diastereomers are provided.
  • compounds provided herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole) .
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • Isotopically-enriched compounds of Formula (I) or Formula (II) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the present disclosure includes compounds of Formula (I) , (II) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (IIa) , (IIb) , (IIc) , (IId) or (IIe) wherein one or more hydrogens attached to a carbon atom is/are replaced by deuterium.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula (I) , (II) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (IIa) , (IIb) , (IIc) , (IId) or (IIe) when administered to a subject, such as mammal, particularly a human.
  • a subject such as mammal, particularly a human.
  • a subject such as mammal, particularly a human.
  • novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions. Synthesis of compounds
  • Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate.
  • the embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.
  • the reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.
  • the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • the present disclosure provides compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof, which are capable of inhibiting RNA polymerase.
  • the compounds of the present disclosure or a pharmaceutically acceptable salt thereof are useful as medicinal drugs, and particularly useful as therapeutic or prophylactic agent that are active against various viruses.
  • the compounds of the present disclosure are therapeutic or prophylactic agent active against caliciviruses, picornaviruses and coronaviruses.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • treatment is used synonymously with “therapy” .
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treatment of viral infection.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.
  • the compounds of the present disclosure have good inhibitory effect against various coronaviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effect against various coronaviruses with low cytotoxicity.
  • the compounds of the present disclosure have good inhibitory effect against various pneumoviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effect against various pneumoviruses with low cytotoxicity.
  • the compounds of the present disclosure can convert into triphosphate and maintain a high concentration of triphosphate in targeted tissue and cells, such as lung cell and respiratory epidermal cell.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treatment of coronavirus or pneumovirus infection.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a coronavirus infection.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a pneumovirus infection.
  • the compounds provided herein are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a compound selected from any one of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a first compound selected from any one of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • composition refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • the term “pharmaceutically acceptable excipient” refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets (such as orodispersible tablets or orally disintegrating tablets) pills, oral soluble films, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms.
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • aqueous or oily solutions may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the pharmaceutical compositions of the present disclosure may be in a form of formulation for nasal or pulmonary administration.
  • the formulation is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the amount of the compounds provided herein in the unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject) , the particular route of administration, the actual compound administered and its relative activity, and the severity of the subject's symptoms.
  • dosage levels of the pharmaceutical compositions of the present disclosure can be between 0.001-1000 mg/kg body weight/day, for example, 0.001-1000 mg/kg body weight/day, 0.001-900 mg/kg body weight/day, 0.001-800 mg/kg body weight/day, 0.001-700 mg/kg body weight/day, 0.001-600 mg/kg body weight/day, 0.001-500 mg/kg body weight/day, 0.001-400 mg/kg body weight/day, 0.001-300 mg/kg body weight/day, 0.001-200 mg/kg body weight/day, 0.001-100 mg/kg body weight/day, 0.001-50 mg/kg body weight/day, 0.001-40 mg/kg body weight/day, 0.001-30 mg/kg body weight/day, 0.001-20 mg/kg body weight/day, 0.001-10 mg/kg body weight/day, 0.001-5 mg/kg body weight/day, 0.001-1 mg/kg body weight/day, 0.001-0.5 mg/kg body weight
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure are formulated for oral administration.
  • the unit dosage for oral administration contains one or more compounds provided herein in an amount from about 1 mg to about 1000 mg, for example from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 1000 mg, from about 400 mg
  • the pharmaceutical compositions of the present disclosure are formulated for oral administration in a treatment having a duration of more than 1 week, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than 1 year or even longer.
  • the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, e.g., administered intravenously, subcutaneously or intramuscularly via injection.
  • the unit dosage for parenteral administration contains one or more compounds provided herein in an amount from about 0.1 mg to about 500 mg of one or more compounds provided herein, for example from about 0.2 mg to about 500 mg, from about 0.3 mg to about 500 mg, from about 0.4 mg to about 500 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 20 mg to about 500 mg, from about 30 mg to about 500 mg, from about 40 mg to about 500 mg, from about 50 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5
  • the pharmaceutical composition intended to be administered by injection can be prepared by combining one or more compounds of the present disclosure with sterile, distilled water, sesame or peanut oil, aqueous propylene glycol, so as to form a solution.
  • the pharmaceutical composition may comprise a surfactant or other solubilizing excipient that is added to facilitate the formation of a homogeneous solution or suspension.
  • the pharmaceutical composition may further comprise one or more additional agents selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer, and an isotonizing agent.
  • the pharmaceutical composition intended to be administered by injection can be administered with a syringe.
  • the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the pharmaceutical composition provided herein.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of any compound described herein.
  • the viral infection is from an RNA virus.
  • the RNA virus is a single stranded or double stranded RNA virus.
  • the RNA virus is a positive sense RNA virus or a negative sense RNA virus or an ambisense RNA virus.
  • the viral infection is from a virus selected from the group consisting of Retroviridae virus, Lentiviridae virus, Coronaviridae virus, Picornaviridae virus, Caliciviridae virus, Flaviviridae virus, Togaviridae virus, Bomaviridae, Filoviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Deltavirus.
  • the viral infection is from a virus selected from the group consisting of Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatitis A, Norwalk virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Rubella virus, Ross River virus, Sindbis virus, Chikungunya virus, Boma disease virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Nipah virus, Hendra virus, Newcastle disease virus, Human respiratory syncytial virus, Rabies virus, Lassa virus, Hantavirus, Crimean-Congo hemorrhagic fever virus, Influenza, Hepatitis D virus, Enterovirus 71, Coxsakie Virus, and Norovirus.
  • a virus selected from the group consisting of Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatit
  • the viral infection is a coronavirus infection.
  • the coronavirus is selected from the group consisting of 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV) , severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) , SARS-CoV-2 (COVID-19) , and Feline coronavirus (FCoV) .
  • MERS Middle East Respiratory Syndrome
  • SARS severe acute respiratory syndrome
  • FCoV Feline coronavirus
  • the coronavirus is SARS-CoV-2.
  • the coronavirus is feline coronavirus.
  • the feline coronavirus is feline enteric coronavirus (FECV) or feline infectious peritonitis virus (FIPV) .
  • the viral infection is a pneumovirus infection.
  • the pneumovirus is Human respiratory syncytial virus (RSV) .
  • the pneumovirus is human metapneumo virus (HMPV) .
  • the viral infection is from a DNA virus.
  • the DNA virus is a single stranded or double stranded DNA virus.
  • the DNA virus is a positive sense DNA virus or a negative sense DNA virus or an ambisense DNA virus.
  • the virus is a Myoviridae, Podoviridae, Siphoviridae, Alloherpesviridae, Herpesviridae (including human herpes virus, and Varicella Zozter virus) , Malocoherpesviridae, Lipothrixviridae, Rudiviridae, Adenoviridae, Ampullaviridae, Ascoviridae, Asfarviridae (including African swine fever virus) , Baculoviridae, Cicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Hytrosaviridae, Iridoviridae, Maseilleviridae, Mimiviridae, Nudiviridae, Nimaviridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Plasmavi
  • methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins.
  • described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting vims release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.
  • the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, comprising administrating an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to the subject.
  • the compounds of the present disclosure can also be used in combination with one or more additional therapeutic or prophylactic agents.
  • methods for treating viral infections in a subject in need thereof comprising administering to the subject a compound disclosed herein, as a first active ingredient, and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents, as a second active ingredient.
  • pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.
  • the second active ingredient include one or more additional therapeutic agents from the same class or group and/or one or ore more additional therapeutic agents from different classes or groups.
  • the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other.
  • Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the second active ingredient can be an antibiotic, a protease inhibitor, an anti-viral agent, an anti-inflammatory agent, an immunomodulatory agent, a kinase inhibitor, an anti-metabolite agent, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e.g., EIDD-2801) , a neuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e.g., types I, II, and III) , or a nucleoside analogue.
  • a polymerase inhibitor e.g., EIDD-2801
  • a neuraminidase inhibitor e.g., a reverse transcriptase inhibitor
  • a viral entry inhibitor e.g., an integrase inhibitor, interferons (e.g., types I, II, and III)
  • interferons e.g
  • the second active ingredient is an antibiotic.
  • the antibiotic can be selected from the group consisting of a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor.
  • the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, ne
  • the second active ingredient can be a protease inhibitor.
  • the protease inhibitor can be selected from the group consisting of nafamostat, camostat, gabexate, epsilon-aminocapronic acid, aprotinin, amprenavir, indinavir, nelfinavir, nirmatrelvir, s-217622, EDP-235, PBI-0451, ritonavir, and saquinavir.
  • the second active ingredient can be an anti-viral agent.
  • the anti-viral agent can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, sime
  • the second active ingredient can be an anti-inflammatory agent.
  • the anti-inflammatory agent can be selected from the group consisting of anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide) , NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.
  • pranlukast tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists) , adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo) , DPI antagonists, DP2 antagonists, PI3K delta inhibitors, GGK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors, bronchodilators (e.g. .
  • muscarinic antagonists beta-2 agonists
  • methotrexate and similar agents
  • monoclonal antibody therapy such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents
  • cytokine receptor therapies e.g. etanercept and similar agents
  • antigen non-specific immunotherapies e.g.
  • cytokines/chemokines interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents
  • suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents.
  • the second active ingredient can be an immunomodulatory agent.
  • the immunomodulatory agent can be selected from the group consisting of anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9) , CD40 agonist therapeutics including but not limited to SGN-40, CP-870, 893 or R07009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenz
  • the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.
  • a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol,
  • the second active ingredient can be a kinase inhibitor.
  • the kinase inhibitor can be selected from the group consisting of erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib
  • the compound in Table 1 may be separated by prep-HPLC or Chiral HPLC to give a pair of isomers comprising Compound No. -P1 and Compound No. -P2.
  • the compound designated as “-P1” is firstly eluted from the column of prep-HPLC or Chiral HPLC and the compound designated as “-P2” is secondly eluted.
  • the structure of a pair of separated Compound No.-P1 and Compound No. -P2 was shown by marking a “*” near the chiral central atom of the corresponding Compound No. structure.
  • 1-P1 and 1-P2 could be:
  • the compound in Table 1 may be separated by Chiral HPLC to give four isomers comprising Compound No. -P1, Compound No. -P2, Compound No. -P3 and Compound No. -P4.
  • Example 1 Synthesis of Intermediates 1.1 Synthesis of Intermediate 1a:
  • HPLC a pair of isomers with the ratio about 50: 50.
  • Compound 11
  • the compound was separated by Chiral HPLC to give a pair of isomers with the ratio ⁇ 50: 50.
  • the compound 62 was separated by Chiral HPLC to give a pair of isomers 62-P1 and 62-P2.
  • the compound 64 was separated by Chiral HPLC to give a pair of isomers 64-P1 and 64-P2:
  • Anti-virial activity assay The MRC5 cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of 20000 cells/well and cultured at 37 °Cand 5%CO 2 . After incubation for 24 hours, the test compounds and a positive control (Remdesivir) were diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted virus was added. The resulting cell culture are incubated for additional 3 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE. The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • Inhibition (%) (Raw data CPD -Average VC) / (Average CC -Average VC) *100.
  • test compounds a positive control (Remdesivir) and Reference Compound 1 (octyl ( ( (2R, 3S, 4R, 5R) -5- (4-aminopyrrolo [2, 1-f] [1, 2, 4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphoryl) -L-alaninate) were serially diluted in DMSO and added into 384-well plates 0.3 ⁇ l per well (8 doses, 3 fold, in duplicate wells) .
  • the replicon RNA was generated in vitro transcript.
  • Huh7 cells transfected with purified SARS-CoV-2 replicon RNAs were seeded 4000/well in 384 microplates containing serially diluted compounds, then cultured at 37°C and 5%CO 2 for 1 day. The final volume of the cell culture was 60 ⁇ l per well, and the final concentrations of DMSO in the test plates was 0.5%.
  • Fluorescence intensity was determined using Acumen Cellista (TTP LabTech) , and the antiviral activity of compounds was calculated based on the inhibition of expression of GFP. Cell viability was measured with CellTiter Glo following the manufacturer’s manual.
  • Raw data CPD values of the sample-treated wells
  • Average ZPE average value of virus control
  • Average HPE average value of medium control (medium only) wells.
  • the human hepatocellular carcinoma cell line HepG2 and human lung adenocarcinoma cell line were used to evaluate the drug cell uptake and intracellular nucleoside triphosphates.
  • Cells were incubated in 6 well plate at 37°C in a 5%CO2 -95%air atmosphere over allow the cells to attach.
  • the cell density was 2x106/well for HepG2 and 1x106/well for A549.
  • the incubation medium for HepG2 and A549 were Eagle's Minimum Essential Medium (EMEM) and F-12K, respectively, both containing 2%Fetal bovine serum (FBS) .
  • EMEM Eagle's Minimum Essential Medium
  • FBS 2%Fetal bovine serum
  • the culture medium was removed and 2.5mL fresh medium which containing test compound at 1 ⁇ M was add to each well for incubation at 37°C in a 5%CO 2 -95%air atmosphere.
  • remove the culture medium remove the culture medium and wash the cells with 3mL ice-cold PBS twice.
  • the cells were digested from the plate wells with 600 ⁇ L ice-cold 70%methanol. The cell lysates were then centrifuged at 4°C, 13000rpm for 5min.
  • Anti-virial activity assay The Hep-2 cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of 6000 cells/well and cultured at 37 °Cand 5%CO 2 . After incubation for 24 hours, the test compounds and a positive control (Remdesivir) were diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted RSV A2 virus was added. The final concentration of DMSO in the assay medium is 0.5%. The resulting cell culture are incubated for 5 days.
  • the supernatant of antiviral activity test plate was removed, and the intracellular viral protein expression was detected by anti-RSV F antibody ELISA assay.
  • the antiviral activity of the tested compounds was calculated based on the virus replication inhibition rate of the tested compounds at different concentrations.
  • Inhibition (%) (Raw data CPD -Average VC) / (Average CC -Average VC) *100.
  • Cytotoxicity assay The cytotoxicity of compounds is assessed under the same method as in the anti-virial activity assay, but without the step of virus infection. Cell viability is measured with CCK8 following the manufacturer’s manual.
  • Viability (%) (Raw data CPD -Average MC) / (Average CC -Average MC) *100.
  • Raw data CPD values of the sample-treated wells
  • Average VC average value of virus control
  • Average CC average value of cell control (cells without virus infection or compound treatment)
  • Average MC average value of medium control (medium only) wells.
  • EC 50 and CC 50 values was calculated using the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response --Variable slope (four parameters) .
  • Tables 2-4 show the results of exemplary compounds of the present disclosure for Assays 3-5, respectively. It shows the compounds of present disclosure have good inhibitory effect against various coronaviruses and respiratory syncytial viruses with low cytotoxicity, show higher stability in human liver and produce more triphosphorylated products in lung cells.
  • Table 2 In vitro anti-viral activities against SARS-CoV-2 Replicon for exemplary compounds 1 A: ⁇ 100nM, B: 100nM-1000nM, D: ⁇ 1000nM Table 3 Intracellular nucleoside triphosphates for exemplary compounds 1 A: ⁇ 500nM, B: 200 ⁇ 500nM, C: ⁇ 200nM.
  • Table 4 In vitro anti-viral activities against RSV A2 for exemplary compounds 1 A: ⁇ 100nM, B: 100nM-1000nM, C: ⁇ 1000nM Assay 5: Rat tissue distribution
  • the compounds or positive control (remdesivir) were administrated at 20mg/kg dose level via intravenous injection. After each specified time points (1, 3, 8 and 24 hour) , 3 animals were sacrificed to collect lung and liver samples.
  • Test compounds were dissolved in saline at 1mg/mL and serial diluted in saline as working solution with desired concentration.
  • Rat whole blood was transferred to a 50mL tube and centrifuge the blood at 2000rmp for 10 minutes, then discard the supernatant.
  • RBC washed red blood cell
  • A ⁇ 10%, B: 10% ⁇ 30%; C: >30%
  • LLC-MK2 cell The in vitro anti-HMPV activity and cytotoxicity were evaluated using LLC-MK2 cell as follows.
  • Anti-viral activity assay The LLC-MK2 cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of 10,000 cells/well and cultured at 37 °C and 5%CO 2 . After overnight incubation, the test compounds and a positive control (ALS-8112) were diluted with assay medium containing 5 ⁇ g/ml trypsin and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium containing 5 ⁇ g/ml trypsin diluted HMPV virus was added. The final concentrations of DMSO and trypsin in the assay medium were 0.5%and 2.5 ⁇ g/ml, respectively.
  • the resulting cell culture was incubated at 33 °C and 5%CO 2 for 3 days.
  • the GFP intensity was measured by Acumen Cellista.
  • the antiviral activity of the tested compounds was calculated based on the virus replication inhibition rate of the tested compounds at different concentrations.
  • Inhibition (%) (Raw data CPD -Average VC) / (Average CC -Average VC) *100.
  • Cytotoxicity assay The cytotoxicity of compounds was assessed under the same method as in the anti-viral activity assay, but without the step of virus infection. Cell viability was measured with CCK8 following the manufacturer’s manual.
  • Viability (%) (Raw data CPD -Average MC) / (Average CC -Average MC) *100.
  • Raw data CPD values of the sample-treated wells
  • Average VC average value of virus control (cells infected with virus, without compound treatment) wells
  • Average CC average value of cell control (cells without virus infection or compound treatment)
  • Average MC average value of medium control (medium only) wells.
  • Table 7 shows the compounds of present disclosure have good inhibitory effect against HMPV with low cytotoxicity.

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Abstract

La présente invention concerne des composés qui présentent une activité inhibitrice de l'ARN polymérase ainsi que des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement d'infections virales par administration de ces composés ou compositions pharmaceutiques.
PCT/CN2024/136699 2023-12-04 2024-12-04 Composés antiviraux et compositions et utilisations correspondantes Pending WO2025119207A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142075A1 (fr) * 2011-04-13 2012-10-18 Merck Sharp & Dohme Corp. Dérivés de nucléosides à substitution 2'-azido et leurs procédés d'utilisation pour le traitement de maladies virales
WO2013039920A1 (fr) * 2011-09-12 2013-03-21 Idenix Pharmaceuticals, Inc. Composés de carbonyloxyméthylphosphoramidate substitué et compositions pharmaceutiques servant à traiter les infections virales
WO2014059901A1 (fr) * 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Dérivés nucléosides à substitution 2'-cyano et leurs méthodes d'utilisation pour le traitement de maladies virales
WO2015181624A2 (fr) * 2014-05-28 2015-12-03 Idenix Pharmaceuticals, Inc Dérivés de nucléosides pour le traitement du cancer
WO2016014527A2 (fr) * 2014-07-21 2016-01-28 Achillion Pharmaceuticals, Inc. Nucléotides stabilisés pour traitement médical
CN109651468A (zh) * 2018-12-20 2019-04-19 刘洪海 具有抑制病毒复制活性的核苷氨基磷酸酯类似物、制备方法及其药物用途
CN112194680A (zh) * 2020-09-29 2021-01-08 佛山科学技术学院 核苷酸氨基磷酸酯化合物、其药物组合物及其制备方法和应用
WO2021194828A1 (fr) * 2020-03-23 2021-09-30 Viiv Healthcare Company Composés utiles dans la thérapie du vih
WO2022271878A1 (fr) * 2021-06-22 2022-12-29 Rome Therapeutics, Inc. Phosphoramidates de 4-éthynyle-3-hydroxy-tétrahydrofuranyle-adénine et composés apparentés et leur utilisation dans le traitement d'états médicaux
WO2023207942A1 (fr) * 2022-04-25 2023-11-02 北京沐华生物科技有限责任公司 Médicament nucléosidique pour le traitement ou la prévention d'une infection à coronavirus, et son utilisation
CN118165034A (zh) * 2022-12-09 2024-06-11 深圳市塔吉瑞生物医药有限公司 核苷酸类化合物及其组合物及用途

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142075A1 (fr) * 2011-04-13 2012-10-18 Merck Sharp & Dohme Corp. Dérivés de nucléosides à substitution 2'-azido et leurs procédés d'utilisation pour le traitement de maladies virales
WO2013039920A1 (fr) * 2011-09-12 2013-03-21 Idenix Pharmaceuticals, Inc. Composés de carbonyloxyméthylphosphoramidate substitué et compositions pharmaceutiques servant à traiter les infections virales
WO2014059901A1 (fr) * 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Dérivés nucléosides à substitution 2'-cyano et leurs méthodes d'utilisation pour le traitement de maladies virales
WO2015181624A2 (fr) * 2014-05-28 2015-12-03 Idenix Pharmaceuticals, Inc Dérivés de nucléosides pour le traitement du cancer
WO2016014527A2 (fr) * 2014-07-21 2016-01-28 Achillion Pharmaceuticals, Inc. Nucléotides stabilisés pour traitement médical
CN109651468A (zh) * 2018-12-20 2019-04-19 刘洪海 具有抑制病毒复制活性的核苷氨基磷酸酯类似物、制备方法及其药物用途
WO2021194828A1 (fr) * 2020-03-23 2021-09-30 Viiv Healthcare Company Composés utiles dans la thérapie du vih
CN112194680A (zh) * 2020-09-29 2021-01-08 佛山科学技术学院 核苷酸氨基磷酸酯化合物、其药物组合物及其制备方法和应用
WO2022271878A1 (fr) * 2021-06-22 2022-12-29 Rome Therapeutics, Inc. Phosphoramidates de 4-éthynyle-3-hydroxy-tétrahydrofuranyle-adénine et composés apparentés et leur utilisation dans le traitement d'états médicaux
WO2023207942A1 (fr) * 2022-04-25 2023-11-02 北京沐华生物科技有限责任公司 Médicament nucléosidique pour le traitement ou la prévention d'une infection à coronavirus, et son utilisation
CN118165034A (zh) * 2022-12-09 2024-06-11 深圳市塔吉瑞生物医药有限公司 核苷酸类化合物及其组合物及用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GWENAËLLE SIZUN, CLAIRE PIERRA, JÉRÔME PEYRONNET, ERIC BADAROUX, CÉLINE RABESON, SAMIRA BENZARIA-PRAD, DOMINIQUE SURLERAUX, ANNA G: "Design, synthesis and antiviral evaluation of 2'-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor", FUTURE MEDICINAL CHEMISTRY, vol. 7, no. 13, 1 October 2015 (2015-10-01), UK , pages 1675 - 1700, XP009563391, ISSN: 1756-8927, DOI: 10.4155/fmc.15.96 *

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