[go: up one dir, main page]

WO2022262845A1 - Ester derivatives of n4-hydroxycytidine and use thereof - Google Patents

Ester derivatives of n4-hydroxycytidine and use thereof Download PDF

Info

Publication number
WO2022262845A1
WO2022262845A1 PCT/CN2022/099403 CN2022099403W WO2022262845A1 WO 2022262845 A1 WO2022262845 A1 WO 2022262845A1 CN 2022099403 W CN2022099403 W CN 2022099403W WO 2022262845 A1 WO2022262845 A1 WO 2022262845A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
virus
tautomer
compound
racemate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/099403
Other languages
French (fr)
Inventor
Zuchun Zhao
Kai Xu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Spring Sea Bio Pharmaceuticals Co Ltd
Original Assignee
Suzhou Spring Sea Bio Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Spring Sea Bio Pharmaceuticals Co Ltd filed Critical Suzhou Spring Sea Bio Pharmaceuticals Co Ltd
Priority to CN202280040667.7A priority Critical patent/CN117642410A/en
Publication of WO2022262845A1 publication Critical patent/WO2022262845A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A61K31/7064—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 containing condensed or non-condensed pyrimidines
    • A61K31/7068—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 containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • the present disclosure relates to ester derivatives of N 4 -hydroxycytidine (NHC) , to pharmaceutical compositions thereof, and to the use of the ester derivatives of N 4 -hydroxycytidine to treat viral infections.
  • the compounds can be administered orally to provide N 4 -hydroxycytidine.
  • N 4 -hydroxycytidine is a ribonucleoside analog with broad-spectrum antiviral activity against various unrelated RNA viruses including influenza, Ebola, CoV, and Venezuelan equine encephalitis virus (VEEV) and most importantly the human SARS-CoV-2 virus.
  • the oxime form of NHC mimics uridine, matching up with adenosine (left structure below) , while the other tautomer mimics cytidine and matches up with guanosine (right structure below) . Such mismatching might cause virus error catastrophe.
  • N 4 -hydroxycytidine (NHC) Molnupiravire/EIDD2801/MK4486 is currently under clinical trial for treating SARS-CoV-2, the virus that causes COVID-19.
  • the compound is under phase III clinical trial for treating early infected patients by SARS-CoV-2 with planned dose of 800mg twice a day [2] .
  • Both the high dose and BID dosing are required for sustained efficacious concentration of NHC in human body that can induce viral error catastrophe.
  • more and potentially better prodrugs i.e. smaller pills, less frequent dosing and more efficacious
  • NHC N 4 -hydroxycytidine
  • the present disclosure relates to certain ester prodrugs of NHC, combinations, pharmaceutical compositions, use and methods related thereto.
  • the present disclosure provides a compound of formula (I) :
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -, C 3-6 halocycloalkyl-O- (CH 2 ) n -, 3-6 membered heterocycloalkyl-O- (CH 2 ) n -and 3-6 membered haloheterocycloalkyl-O-
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • the present disclosure also provides the compound of the present invention for use as a medicament.
  • the present disclosure also provides the compound of the present invention for use in treating or preventing a RNA viral infection.
  • the present disclosure also provides a pharmaceutical composition, comprising the compound of the present invention and optionally comprising a pharmaceutically acceptable excipient.
  • the present disclosure also provides a kit for treating or preventing a RNA viral infection, comprising a pharmaceutical composition of the present disclosure and an instruction for use.
  • the present disclosure also provides use of the compound of the present invention in the manufacture of a medicament for treating or preventing a RNA viral infection.
  • the present disclosure also provides use of the compound of the present invention for treating or preventing a RNA viral infection.
  • the present disclosure also provides a method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
  • the present disclosure also provides a method for increasing bioavailability of N 4 -hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
  • the present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention, and at least one additional therapeutic agent.
  • the present disclosure also provides a process for the preparation of the compound of the present invention, and itermediates for preparing the compound of the present invention.
  • the compound of the present invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict with each other, the chemical structure is determinative of the identity of the compound.
  • the symbol herein means that the relevant structures are tautomers, which exist in equilibrium and are readily converted from one isomeric form to another.
  • the compound of the present invention may exist in oxime form and the other form. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds, especially the tautomer in oxime form and the tautomer in the other form. Regardless of the tautomer that is shown, and regardless of the nature of the equilibrium between tautomers, the compound of the present invention is understood by those skilled in the art to encompass both oxime form and the other form.
  • Bioavailability refers to the rate and amount of a drug that reaches the systemic circulation of a subject following administration of the drug or prodrug thereof to the subject and can be determined by evaluating, for example, the plasma or blood concentration-versus-time profile for a drug.
  • Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC) , the time to maximum concentration (Tmax ) , and the maximum drug concentration (Cmax ) , where Cmax is the maximum concentration of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject, and Tmax is the time to the maximum concentration (Cmax ) of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject.
  • AUC area under the curve
  • Tmax time to maximum concentration
  • Cmax maximum drug concentration
  • Prodrugs are derivatized forms of drugs that following administration are converted or metabolized to an active form of the parent drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a manner that enhances the therapeutic efficacy of a parent drug. For example, prodrugs are often used to enhance the oral bioavailability of a drug. To be therapeutically effective, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may need to be administered by other than oral routes, such as intravenously. Examples of prodrugs that can be used to improve bioavailability include esters, optionally substituted esters, branched esters, optionally substituted branched esters.
  • Metal intermediate refers to a compound that is formed in vivo by metabolism of a parent compound and that further undergoes reaction in vivo to release an active agent.
  • Compounds of Formula (I) are protected ester prodrugs that are metabolized in vivo to provide the corresponding metabolic intermediates such as N4-hydroxycytidine (NHC) . It is desirable that the reaction products or metabolites thereof not be toxic.
  • Subject refers to a mammal, for example, a human.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts, formed with inorganic acids and one or more protonable functional groups such as hydroxylamine within the parent compound. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • a salt can be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy
  • “Pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agents and includes both fixed and non-fixed combinations of the therapeutic agents.
  • the term “fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the agents in the body of the subject.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder, e.g. virus infection, (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease) .
  • preventing or “prevention” refers to reducing symptoms of the disease by taking the compound in a preventative fashion.
  • the application of a therapeutic for preventing or prevention of a disease of disorder is known as prophylaxis.
  • Compounds provided by the present disclosure can provide superior prophylaxis because of antiviral activities.
  • Treating” or “treatment” of a disease or disorder refers to arresting or ameliorating a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the development of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease.
  • Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both, and to inhibiting at least one physical parameter or manifestation that may or may not be discernible to the subject. “Treating” or “treatment” also refers to delaying the onset of the disease, e.g. virus infection, or at least one or more symptoms thereof in a subject who may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease.
  • the term “effective amount” as used herein refers to an amount of the compound of the present invention effective for “treating” or “preventing” , as defined above, virus infection in a subject.
  • the effective amount may cause any changes observable or measurable in a subject as described in the definition of “treating” , “treatment” , “preventing” , or “prevention” above.
  • the “effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the subject to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.
  • alkyl means a straight or branched chain saturated hydrocarbon moieties such as those containing from 1 to 6 carbon atoms (C 1-6 ) , preferably 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 ) .
  • C 1-6 alkyl refers to the alkyl having 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms.
  • Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl; while branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • cycloalkyl as used herein are referred to herein saturated cyclic hydrocarbon radical having 3-6 ring carbon atoms (C 3-6 ) , such as 5-6 ring carbon atoms (C 5-6 ) .
  • examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • halocycloalkyl herein refers to the cycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
  • heterocycloalkyl refers to a saturated ring having 3-6 ring atoms (3-6 membered) , 4-6 ring atoms (4-6 membered) or 5-6 ring atoms (5-6 membered) , with one or more of, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, preferably O, and the remaining ring atoms being carbon.
  • heterocycloalkyl examples include, but are not limited to, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, 1, 3-dioxolane moiety and the like.
  • the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl.
  • haloheterocycloalkyl herein refers to the heterocycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
  • halogen and “halo” refer to fluorine and chlorine.
  • haloalkyl refers to the alkyl as defined herein, in which one or more, for example 1, 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atom.
  • substituted refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents. ” The molecule can be multiply substituted.
  • Embodiment 1 A compound of Formula (I) :
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered halo3-6 membered haloheterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -, C 3-6 halocycloalkyl-O- (CH 2 ) n -, 3-6 membered 3-6 membered haloheterocycloalkyl-O- (CH 2 ) n -and 3-6
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • Embodiment 2 A compound according to Embodiment 1, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra is methyl substituted with Ra1, Ra2 and Ra3;
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 alkyl-O-C 1-6 alkyl-O- (CH 2 ) n -, C 1-6 haloalkyl-O- (CH 2 ) n -, C 3-6 cycloalkyl-O- (CH 2 ) n -and 3-6 membered heterocycloalkyl-O- (CH 2 ) n -,
  • Ra2 is C 1-6 alkyl or C 1-6 alkyl-O- (CH 2 ) n -, and
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 alkyl-O- (CH 2 ) n -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • n 0 or 1
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • Embodiment 3 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, provided that
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl
  • Ra1 is not any of H, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl.
  • Embodiment 4 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Raa is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-O-C 1-6 alkyl-, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl; preferably C 1-6 alkyl.
  • Embodiment 9 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl-O-C 1-4 alkyl-, C 3-5 cycloalkyl and 4-6 membered heterocycloalkyl.
  • Embodiment 10 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluorosubstitued ethyl, flurosubstituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl or tetrahydro-2H-pyran-4-yl; preferably methyl, ethyl, propyl, isopropyl, oxetanyl and tetrahydro-2H-pyran-4-yl.
  • Raa is selected from the group consisting of methyl,
  • Embodiment 11 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.
  • Embodiment 12 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 and Ra3 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6 cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • Ra3 is either H or C 1-6 alkyl
  • Ra1 is not H or C 1-6 alkyl.
  • Embodiment 13 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 14 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra3 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 15 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • Ra2 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -, and
  • Ra3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 16 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-
  • Ra2 is C 1-6 alkyl
  • Ra3 is H or C 1-6 alkyl.
  • Embodiment 17 A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-CH 2 -
  • each of Ra2 and Ra3 is C 1-6 alkyl.
  • Embodiment 18 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • each of Ra2 and Ra3 is C 1-6 alkyl-O-CH 2 -.
  • Embodiment 19 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-CH 2 .
  • Ra2 and Ra3 are C 1-6 alkyl, and the other is C 1-6 alkyl-O-CH 2 .
  • Embodiment 20 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-
  • Ra2 and Ra3 is independently C 1-3 alkyl, preferably Ra2 and Ra3 are the same.
  • Embodiment 21 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is C 1-6 alkyl-O-or C 1-6 alkyl-O-CH 2 -
  • Ra2 and Ra3 are taken together with the carbon they attached to form a C 3-6 cycloalkyl.
  • Embodiment 22 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
  • Ra1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -;
  • Ra2 and Ra3 are taken together with the carbon they attached to form a 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
  • Ra1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-O-and C 1-6 alkyl-O-CH 2 -.
  • Embodiment 25 A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Ra1 is C 1-6 alkyl-O-.
  • Embodiment 27 A compound according to any of Embodiments 1-4 and 12, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • Embodiment 28 A pharmaceutical composition, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
  • Embodiment 29 Use of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a RNA viral infection.
  • Embodiment 30 The use according to Embodiment 29, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus or Barmah Forest virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus or Powassan virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-
  • Embodiment 31 A method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 32 The method according to Embodiment 31, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamm
  • Embodiment 33 The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Embodiment 34 The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use in treating or preventing a RNA viral infection.
  • Embodiment 35 The compound for use according to Embodiment 34, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a
  • Embodiment 36 A method for increasing bioavailability of N 4 -hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 37 A pharmaceutical combination, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  • Embodiment 38 The pharmaceutical combination according to Embodiment 37, wherein additional therapeutic agent is selected from the group consisting of:
  • the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus (including subtype H1N1, H3N2, H7N9, or H5N1) , influenza B virus or influenza C, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus, rotavirus, e.g., rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E;
  • alphavirus
  • the RNA virus is a human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus, orthomyxoviridae virus, paramyxoviridae virus, RSV virus, influenza A virus, influenza B virus, filoviridae virus, or Ebola virus.
  • the RNA virus is a human coronavirus, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with SARS-CoV-2/COVID-19 virus, influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , Dengue virus, Zika virus, chik
  • influenza A virus
  • the subject is diagnosed with SARS-CoV-2/COVID-19 virus including an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any variant SARS-CoV-2/COVID-19 virus that could be treated by formula (I) compound or pharmaceuticals contain formula (1) compound.
  • influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path) , and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainflu
  • the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis.
  • the compounds of the present invention can be formulated into a pharmaceutical composition.
  • the pharmaceutical composition includes: (a) an effective amount of the compound of the present invention; (b) a pharmaceutically acceptable excipient (for example, one or more pharmaceutically acceptable carriers) ; and optionally (c) at least one additional therapeutic agent.
  • a pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient (s) in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the subject being treated.
  • Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy.
  • ) including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compounds of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • buffers including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compounds of the present invention or pharmaceutical composition thereof) or
  • the compound of the invention can be administered in various known manners, such as orally, parenterally, by inhalation, or through the lungs, i.e., pulmonary administration, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.
  • parenterally as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.
  • Oral or parenteral administration is preferred, especially oral administration.
  • the compound of the invention may be administered in any convenient formulation, e.g., tablets, powders, capsules, pills, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, aqueous buffer, such as a saline or phosphate buffer etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and an addtional active agent.
  • the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 15 mg/kg of body weight.
  • the compound described herein can be administered adjunctively with at least one additional therapeutic agent.
  • the additional therapeutic agents include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents.
  • the antiviral agent is a non-CNS targeting antiviral compound.
  • “Adjunctive administration” means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • the additional therapeutic agent (s) can be formulated for immediate release, controlled release, or combinations thereof.
  • antiviral agent such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiqui
  • antiviral agent such as abacavir, acyclovir, acyclovir,
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the prevention of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the treatment of SARS-CoV-2/COVID-19 infection.
  • the compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the prevention of SARS-CoV-2/COVID-19 infection.
  • the present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention and at least one additional therapeutic agent.
  • additional therapeutic agent include, but are not limited to, those agents mentioned above, preferably proxalutamide, Compound-X and PF-07321332.
  • reaction vessel was cooled to room temperature, and pH was adjusted with 4M HCl in dioxane (200 mL, 99%) to the point at which pH just changes from >12 to 7, indicating neutralization of excess sodium methoxide without protonating the sodium salt of the carboxylate.
  • the reaction mixture was filtered to remove salts, and the salt cake was washed twice with 5 mL of methanol.
  • the organic layer were dried with sodium sulfate and concentrated to afford compound (I-3) as a liquid (73g, 95%) which was of sufficient purity to be used without purification.
  • 1 H NMR (CD 3 OD) ⁇ 3.67 (q, 1H) , 3.33 (s, 3H) , and 1.33 ppm (d, 3H) .
  • 2-Ethoxyisobutyric acid was prepared according to reference (Ragan, John A.; Ide, Nathan D.; Cai, Weiling; Cawley, James J.; Colon-Cruz, Roberto; Kumar, Rajesh; Peng, Zhihui; Vanderplas, Brian C. [Organic process research and development, 2010, vol. 14, #6, p.
  • 2-Ethyl-2-bromo-butyric acid (I-61) is commercially available or can be prepared according to the procedure described by Doran; Shonle in Journal of Organic Chemistry, 1938, vol. 3, p. 195.
  • 1-Methyl-2, 2-Dimethoxy-isobutyric acid (I-142) was prepared from commercially available 2, 2-bis (hydroxymethyl) propanoic acid according to Reference Example 14 of EP1437352.
  • 1 ⁇ (hydroxymethyl) cyclopropane ⁇ 1 ⁇ carboxylic acid methyl ester (I-223) was prepared according to the procedure described in Reference example 22-1 of US9546155. The hydroxy group was then alkylated with Methyl iodide using the similar process described by Shen, Peng-Xiang; et al., in Journal of the American Chemical Society, 2018, vol. 140, #21, p. 6545 -6549. The ester is then hydrolyzed to afford 1 ⁇ (methoxymethyl) cyclopropane ⁇ 1 ⁇ carboxylic acid (I-225) .
  • 1-Hydroxy-2, 2-Diethoxy-isobutyric acids ethyl ester (I-249) was prepared according to the procedure described by Bernardon, C. et al. In Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 1502 -1505. The hydroxy group was then alkylated with Methyl iodide followed by ester hydrolysis using the similar process described in Reference example K-19 in US10040791 to afford 1-Methoxy-2, 2-Diethoxy-isobutyric acid (I-251) .
  • methyl 2-methoxylacetate (I-289) was alkylated with dibromoethane in the same manner as those described in Example 26 3A of US10464914 to afforded the 1-methoxycyclopropanecarboxylic acid methyl ester which was then hydrolyzed under basic condition to afford the corresponding acid (I-291) .
  • the acid (I-291) was then trnasformed to the corresponding anhydride (I-292) according to the process of Preparation 2 to afford it as an oil.
  • N4-hydroxycytidine (NHC) or 1- (3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -4- (hydroxyamino) pyrimidin-2-one.
  • the following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-268) , (I-271) , (I-274) , (I-143) , (I-149) , (I-152) , (I-155) , (I-188) , (I-191) , (I-194) , (I-197) , (I-252) , (I-255) , (I-258) , (I-261) , (I-160) , (I-163) , (I-166) , (I-169) , (I-200) , (I-203) , (I-206) , (I-209) , (I-278) , (I-281) , (I-174) , (I-177) , (I-212) , (I-215) , (I-285) , (I-288) , (I-182) , (I-185) , (I-218) and (I-221) .
  • Molnupiravir is prepared according to the process of example 10 of US2020276219 using 2’, 3’-O-isopropylidene-uridine (I-318) and isobutyric anhydride to afford it as a white solid.
  • 1H NMR 400 MHz, D 2 O
  • Plasma Incubations Plasma incubations were conducted in duplicate in 96-well plate at 37°C.
  • Plasma was prewarmed in a total volume of 198 ⁇ L for 5 min at 37°C, then added 2 ⁇ L of 100 ⁇ M test compound into an incubation well containing plasma, pipette-mixed to achieve a homogenous suspension and immediately transferred 20 ⁇ L incubate as a 0 min sample to wells in a "Quenching" plate followed by adding 200 ⁇ L of acetonitrile with metolazone as internal standard (IS) and pipette-mixing.
  • IS internal standard
  • Microsome Incubations Incubation mixtures were prepared in a total volume of 200 ⁇ L with final component concentrations as follows: 0.1M PBS (pH 7.4) , NADPH (2 mM) and liver microsomes (0.2 mg/mL) as well as test compound (1 ⁇ M) or Molnupiravir (1 ⁇ M) as a positive control, wherein the NADPH was added after a 5-min preincubation of all other components at 37°C.
  • Example 22 Mouse PK Study: NHC, Example compounds and molnupiravir
  • Solution A PEG 400/Tween 80 (90%/10%)
  • the Example compounds, NHC and molnupiravir were suspended in the vehicle at 0.4mol/10mL respectively.
  • the mice were dosed at 0.4 mol/kg, 10 mL/kg via oral gavage.
  • the animals were restrained manually, and approx. 150 ⁇ L of blood/time point was collected into pre-cooled EDTA-K2 tubes via retro-orbital injection.
  • Blood samples were centrifuged at 4°C (4000 g, 5 min) to obtain plasma within 15 min after sample collection. Plasma samples were stored at approximately -80°C until analysis.
  • the plasma samples were analyzed using LC-MS/MS. The results of the test are shown in FIG. 1 and in the following Table, wherein the PK parameters were estimated by non-compartmental model using Winnonlin software.
  • Example 24 Treatment with NHC, Example compounds in a Ferret /Mice Model of Influenza Infection
  • Example 25 Treatment with NHC, Example compounds in a Ferret/mice Model of SARS-CoV-2 Infection

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure relates to ester derivatives of N 4-hydroxycytidine (NHC), to pharmaceutical compositions thereof, and to the use and method of the ester derivatives of N 4-hydroxycytidine to treat viral infections.

Description

ESTER DERIVATIVES OF N4-HYDROXYCYTIDINE AND USE THEREOF
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the priority benefit of the International Application No. PCT/CN2021/101005, filed June 18, 2021; the content of which is herein incorporated by reference in its entirety.
FIELD
The present disclosure relates to ester derivatives of N 4-hydroxycytidine (NHC) , to pharmaceutical compositions thereof, and to the use of the ester derivatives of N 4-hydroxycytidine to treat viral infections. The compounds can be administered orally to provide N 4-hydroxycytidine.
BACKGROUND
Currently, SARS-CoV-2, the virus that causes COVID-19 has infected over 100 million people worldwide and caused hundreds of thousand deaths without sign of slowing down. The world economy and human activities has been negatively impacted very significantly. Even though vaccines are being introduced recently but treatment of infected patients with oral medicine is still highly desired and can complement vaccine use. N 4-hydroxycytidine (NHC) is a ribonucleoside analog with broad-spectrum antiviral activity against various unrelated RNA viruses including influenza, Ebola, CoV, and Venezuelan equine encephalitis virus (VEEV) and most importantly the human SARS-CoV-2 virus. Although the exact molecular mechanism of action of NHC remained undefined, it was proposed that viral error catastrophe is the basis for anti-virus activity [“Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia” , Sci Transl Med. 2019 Oct 23; 11 (515) : eaax5866] , this comes from the tautomerization property of NHC:
Figure PCTCN2022099403-appb-000001
The oxime form of NHC mimics uridine, matching up with adenosine (left structure below) , while the other tautomer mimics cytidine and matches up with guanosine (right structure below) . Such mismatching might cause virus error catastrophe.
Figure PCTCN2022099403-appb-000002
One prodrug of N 4-hydroxycytidine (NHC) Molnupiravire/EIDD2801/MK4486 is currently under clinical trial for treating SARS-CoV-2, the virus that causes COVID-19. The reported phase I clinical data indicated the molecule is safe and well tolerated [1] . The compound is under phase III clinical trial for treating early infected patients by SARS-CoV-2 with planned dose of 800mg twice a day [2] . Both the high dose and BID dosing are required for sustained efficacious concentration of NHC in human body that can induce viral error catastrophe. Thus, more and potentially better prodrugs (i.e. smaller pills, less frequent dosing and more efficacious) are still needed to treat viral infections, especially urgently treat the current human calamity worldwide.
SUMMARY OF THE INVENTION
After diligent work we have discovered a series of ester derivatives of N 4-hydroxycytidine (NHC) that can deliver NHC in animal blood stream with improved bioavailability and extended exposure compared to the parent molecule NHC and compared to Molnupiravire.
The present disclosure relates to certain ester prodrugs of NHC, combinations, pharmaceutical compositions, use and methods related thereto.
The present disclosure provides a compound of formula (I) :
Figure PCTCN2022099403-appb-000003
or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof,
wherein
R 1 is RaC=O;
R 2 is H or RaC=O, and R 3 is H or RaC=O; or R 2 and R 3 are taken together with the oxygen they attached to form a 5 membered heterocycloalkyl substituted with C 1-6alkyl-O;
Ra is methyl substituted with Ra1, Ra2 and Ra3;
Ra1 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, C 3-6halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl, C 1-6alkyl-O- (CH 2)  n-, C 1-6alkyl-O-C 1-6alkyl-O- (CH 2)  n-, C 1-6haloalkyl-O- (CH 2)  n-, C 3-6cycloalkyl-O- (CH 2)  n-, C 3-6halocycloalkyl-O- (CH 2)  n-, 3-6 membered heterocycloalkyl-O- (CH 2)  n-and 3-6 membered haloheterocycloalkyl-O- (CH 2)  n-;
Ra2 is C 1-6alkyl or C 1-6alkyl-O- (CH 2)  n-;
Ra3 is selected from the group consisting of H, C 1-6alkyl and C 1-6alkyl-O- (CH 2)  n-;
or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
n is 0 or 1;
provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl or C 3-6cycloalkyl.
The compounds above as well as the compounds disclosed in the context of the present disclosure below (including the compounds of formula (I) , and the specific compounds, especially the Example compounds) or their tautomer, stereoisomer, enantiomers, diastereomers, racemate, geometric isomer, hydrate, or solvates, or pharmaceutically acceptable salt thereof are collectively called “the compound of the present invention” or “the compound of the present disclosure” .
The present disclosure also provides the compound of the present invention for use as a medicament.
The present disclosure also provides the compound of the present invention for use in treating or preventing a RNA viral infection.
The present disclosure also provides a pharmaceutical composition, comprising the compound of the present invention and optionally comprising a pharmaceutically acceptable excipient.
The present disclosure also provides a kit for treating or preventing a RNA viral infection, comprising a pharmaceutical composition of the present disclosure and an instruction for use.
The present disclosure also provides use of the compound of the present invention in the manufacture of a medicament for treating or preventing a RNA viral infection.
The present disclosure also provides use of the compound of the present invention for treating or preventing a RNA viral infection.
The present disclosure also provides a method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
The present disclosure also provides a method for increasing bioavailability of N 4-hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of the present invention.
The present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention, and at least one additional therapeutic agent.
The present disclosure also provides a process for the preparation of the compound of the present invention, and itermediates for preparing the compound of the present invention.
Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings described herein are for illustration purposes only. The drawings are not intended to limit the scope of the present disclosure.
FIG. 1 shows Mean ± SD plasma concentration-time data of Example EX-2C, Molnupiravir and NHC after a p. o. dose of EX-2C, Molnupiravir and NHC respectively in male CD1 mice (N=3/timepoint)
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
As used herein, the singular forms “a” , “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The compound of the present invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict with each other, the chemical structure is determinative of the identity of the compound.
The symbol
Figure PCTCN2022099403-appb-000004
herein means that the relevant structures are tautomers, which exist in equilibrium and are readily converted from one isomeric form to another. The compound of the present invention may exist in oxime form and the other form. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds, especially the tautomer in oxime form and the tautomer in the other form. Regardless of the tautomer that is shown, and regardless of the nature of the equilibrium between tautomers, the compound of the present invention is understood by those skilled in the art to encompass both oxime form and the other form.
“Bioavailability” refers to the rate and amount of a drug that reaches the systemic circulation of a subject following administration of the drug or prodrug thereof to the subject and can be determined by evaluating, for example, the plasma or blood concentration-versus-time profile for a drug. Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC) , the time to maximum concentration (Tmax ) , and the maximum drug concentration (Cmax ) , where Cmax is the maximum concentration of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject, and Tmax is the time to the maximum concentration (Cmax ) of a drug in the plasma or blood of a subject following administration of a dose of the drug or form of drug to the subject.
Prodrugs are derivatized forms of drugs that following administration are converted or metabolized to an active form of the parent drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a manner that enhances the therapeutic efficacy of a parent drug. For example, prodrugs are often used to enhance the oral bioavailability of a drug. To be therapeutically effective, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may need to be administered by other than oral routes, such as intravenously. Examples of prodrugs that can be used to improve bioavailability include esters, optionally substituted esters, branched esters, optionally substituted branched esters.
“Metabolic intermediate” refers to a compound that is formed in vivo by metabolism of a parent compound and that further undergoes reaction in vivo to release an active agent. Compounds of Formula (I) are protected ester prodrugs that are metabolized in vivo to provide the corresponding metabolic intermediates such as N4-hydroxycytidine (NHC) . It is desirable that the reaction products or metabolites thereof not be toxic.
“Subject” refers to a mammal, for example, a human.
“Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
“Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts, formed with inorganic acids and one or more protonable functional groups such as hydroxylamine within the parent compound. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. A salt can be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Also, “pharmaceutically acceptable salt” includes base addition salts formed by the compound of the present invention carrying an acidic moiety with pharmaceutically acceptable cations, for example, sodium, potassium, calcium, aluminum, lithium, and ammonium.
“Pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agents and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g. the compound of the present invention and said at least one additional therapeutic agent, are both administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the agents in the body of the subject.
“Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder, e.g. virus infection, (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease) . In some embodiments, “preventing” or “prevention” refers to reducing symptoms of the disease by taking the compound in a preventative fashion. The application of a therapeutic for preventing or prevention of a disease of disorder is known as prophylaxis. Compounds provided by the present disclosure can provide superior prophylaxis because of antiviral activities.
“Treating” or “treatment” of a disease or disorder, e.g. virus infection, refers to arresting or ameliorating a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the  development of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease. “Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both, and to inhibiting at least one physical parameter or manifestation that may or may not be discernible to the subject. “Treating” or “treatment” also refers to delaying the onset of the disease, e.g. virus infection, or at least one or more symptoms thereof in a subject who may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease.
The term “effective amount” as used herein refers to an amount of the compound of the present invention effective for “treating” or “preventing” , as defined above, virus infection in a subject. The effective amount may cause any changes observable or measurable in a subject as described in the definition of “treating” , “treatment” , “preventing” , or “prevention” above. The “effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the subject to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.
As used herein, “alkyl” means a straight or branched chain saturated hydrocarbon moieties such as those containing from 1 to 6 carbon atoms (C 1-6) , preferably 1-4 carbon atoms (C 1-4) or 1-3 carbon atoms (C 1-3) . For example, “C 1-6alkyl” refers to the alkyl having 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl; while branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
The term “cycloalkyl” as used herein are referred to herein saturated cyclic hydrocarbon radical having 3-6 ring carbon atoms (C 3-6) , such as 5-6 ring carbon atoms (C 5-6) . Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term “halocycloalkyl” herein refers to the cycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
The term “heterocycloalkyl” as used herein refers to a saturated ring having 3-6 ring atoms (3-6 membered) , 4-6 ring atoms (4-6 membered) or 5-6 ring atoms (5-6 membered) , with one or more of, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, preferably O, and the remaining ring atoms being carbon. Examples of the heterocycloalkyl include, but are not limited to, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, 1, 3-dioxolane moiety and the like. Preferably, the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl. The term “haloheterocycloalkyl” herein refers to the heterocycloalkyl as defined above, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom.
The terms “halogen” and “halo” refer to fluorine and chlorine.
The term “haloalkyl” herein refers to the alkyl as defined herein, in which one or more, for example 1, 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atom.
The term “substituted” refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents. ” The molecule can be multiply substituted.
The term “optionally” as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur.
All numerical ranges herein should be understood as disclosing each and every value within the range and each and every subset of values within the range, regardless of whether they are specifically disclosed otherwise. For example, when referring to any numerical range, it should be regarded as referring to each and every numerical value in the numerical range, for example, each and every integer in the numerical range. The present disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limit of the range.
Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by a person skilled in the art, to which the present disclosure pertains.
Embodiments of the Disclosure
Embodiment 1. A compound of Formula (I) :
Figure PCTCN2022099403-appb-000005
or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof,
wherein
R 1 is RaC=O;
R 2 is H or RaC=O, and R 3 is H or RaC=O; or R 2 and R 3 are taken together with the oxygen they attached to form a 5 membered heterocycloalkyl substituted with one C 1-6alkyl-O;
Ra is methyl substituted with Ra1, Ra2 and Ra3;
Ra1 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, C 3-6halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered halo3-6 membered haloheterocycloalkyl, C 1-6alkyl-O- (CH 2)  n-, C 1-6alkyl-O-C 1-6alkyl-O- (CH 2)  n-, C 1-6haloalkyl-O- (CH 2)  n-, C 3-6cycloalkyl-O- (CH 2)  n-, C 3-6halocycloalkyl-O- (CH 2)  n-, 3-6 membered 3-6 membered haloheterocycloalkyl-O- (CH 2)  n-and 3-6 membered halo3-6 membered haloheterocycloalkyl-O- (CH 2)  n-;
Ra2 is C 1-6alkyl or C 1-6alkyl-O- (CH 2)  n-;
Ra3 is selected from the group consisting of H, C 1-6alkyl and C 1-6alkyl-O- (CH 2)  n-;
or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O; and,
n is 0 or 1;
provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl or C 3-6cycloalkyl.
Embodiment 2. A compound according to Embodiment 1, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
R 1 is RaC=O,
each of R 2 and R 3 is H, or each of R 2 and R 3 is RaC=O; or R 2 and R 3 are taken together with the oxygen they attached to form a 5 membered heterocycloalkyl substituted with one C 1-6alkyl-O;
Ra is methyl substituted with Ra1, Ra2 and Ra3;
Ra1 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6alkyl-O- (CH 2)  n-, C 1-6alkyl-O-C 1-6alkyl-O- (CH 2)  n-, C 1-6haloalkyl-O- (CH 2)  n-, C 3-6cycloalkyl-O- (CH 2)  n-and 3-6 membered heterocycloalkyl-O- (CH 2)  n-,
Ra2 is C 1-6alkyl or C 1-6alkyl-O- (CH 2)  n-, and
Ra3 is selected from the group consisting of H, C 1-6alkyl and C 1-6alkyl-O- (CH 2)  n-;
or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
n is 0 or 1;
provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl or C 3-6cycloalkyl.
Embodiment 3. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, provided that
when Ra3 is either H or C 1-6alkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl or C 3-6cycloalkyl; and
when Ra2 and Ra3 are taken together with the carbon they attached to form a C 3-6cycloalkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl and 3-6 membered heterocycloalkyl.
Embodiment 4. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
R 1 is RaC=O,
each of R 2 and R 3 is H, or each of R 2 and R 3 is RaC=O;
wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000006
Raa is selected from the group consisting of C 1-6alkyl, C 1-6haloalkyl, C 1-6alkyl-O-C 1-6alkyl-, C 3-6cycloalkyl and 3-6 membered heterocycloalkyl; preferably C 1-6alkyl.
Embodiment 5. A compound according to Embodiment 4, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000007
Figure PCTCN2022099403-appb-000008
Embodiment 6. A compound according to Embodiment 4, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000009
Embodiment 7. A compound according to Embodiment 4, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000010
Embodiment 8. A compound according to Embodiment 4, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000011
Embodiment 9. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is  selected from the group consisting of C 1-4alkyl, C 1-4haloalkyl, C 1-4alkyl-O-C 1-4alkyl-, C 3-5cycloalkyl and 4-6 membered heterocycloalkyl.
Embodiment 10. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluorosubstitued ethyl, flurosubstituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl or tetrahydro-2H-pyran-4-yl; preferably methyl, ethyl, propyl, isopropyl, oxetanyl and tetrahydro-2H-pyran-4-yl.
Embodiment 11. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.
Embodiment 12. A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 and Ra3 is independently selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-;
Ra2 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-;
or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not H or C 1-6alkyl.
Embodiment 13. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-.
Embodiment 14. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra3 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-.
Embodiment 15. A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-or C 1-6alkyl-O-CH 2-,
Ra2 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-, and
Ra3 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-.
Embodiment 16. A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-,
Ra2 is C 1-6alkyl, and
Ra3 is H or C 1-6alkyl.
Embodiment 17. A compound according to any of Embodiments 1-3, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-CH 2-, and
each of Ra2 and Ra3 is C 1-6alkyl.
Embodiment 18. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-or C 1-6alkyl-O-CH 2-, and
each of Ra2 and Ra3 is C 1-6alkyl-O-CH 2-.
Embodiment 19. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-CH 2, and
one of Ra2 and Ra3 is C 1-6alkyl, and the other is C 1-6alkyl-O-CH 2.
Embodiment 20. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-, and
Ra2 and Ra3 is independently C 1-3alkyl, preferably Ra2 and Ra3 are the same.
Embodiment 21. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is C 1-6alkyl-O-or C 1-6alkyl-O-CH 2-, and
Ra2 and Ra3 are taken together with the carbon they attached to form a C 3-6cycloalkyl.
Embodiment 22. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
Ra1 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-; and
Ra2 and Ra3 are taken together with the carbon they attached to form a 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
Preferably, Ra1 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-.
Embodiment 23. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is RaC=O, and each of R 2 and R 3 is H.
Embodiment 24. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein each of R 1, R 2 and R 3 are RaC=O.
Embodiment 25. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Ra1 is C 1-6alkyl-O-.
Embodiment 26. A compound according to any of the preceding Embodiments, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
Figure PCTCN2022099403-appb-000012
Figure PCTCN2022099403-appb-000013
Figure PCTCN2022099403-appb-000014
Figure PCTCN2022099403-appb-000015
Figure PCTCN2022099403-appb-000016
Figure PCTCN2022099403-appb-000017
Figure PCTCN2022099403-appb-000018
Figure PCTCN2022099403-appb-000019
Figure PCTCN2022099403-appb-000020
Figure PCTCN2022099403-appb-000021
Figure PCTCN2022099403-appb-000022
Embodiment 27. A compound according to any of Embodiments 1-4 and 12, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure PCTCN2022099403-appb-000023
Figure PCTCN2022099403-appb-000024
Figure PCTCN2022099403-appb-000025
Figure PCTCN2022099403-appb-000026
Figure PCTCN2022099403-appb-000027
Figure PCTCN2022099403-appb-000028
Figure PCTCN2022099403-appb-000029
Figure PCTCN2022099403-appb-000030
Figure PCTCN2022099403-appb-000031
Figure PCTCN2022099403-appb-000032
Figure PCTCN2022099403-appb-000033
Figure PCTCN2022099403-appb-000034
Figure PCTCN2022099403-appb-000035
Figure PCTCN2022099403-appb-000036
Embodiment 28. A pharmaceutical composition, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
Embodiment 29. Use of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a RNA viral infection.
Embodiment 30. The use according to Embodiment 29, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus or Barmah Forest virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus or  Powassan virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
Embodiment 31. A method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
Embodiment 32. The method according to Embodiment 31, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
Embodiment 33. The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
Embodiment 34. The compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use in treating or preventing a RNA viral infection.
Embodiment 35. The compound for use according to Embodiment 34, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
Embodiment 36. A method for increasing bioavailability of N 4-hydroxycytidine for treating or preventing a RNA viral infection comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
Embodiment 37. A pharmaceutical combination, comprising the compound of any one of claims 1-27 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
Embodiment 38. The pharmaceutical combination according to Embodiment 37, wherein additional therapeutic agent is selected from the group consisting of:
Figure PCTCN2022099403-appb-000037
Methods of Use
According to the present disclosure, the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus (including subtype H1N1, H3N2, H7N9, or H5N1) , influenza B virus or influenza C, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus, rotavirus, e.g., rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
Preferably, according to the present disclosure, the RNA virus is a human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus, orthomyxoviridae virus, paramyxoviridae virus, RSV virus, influenza A virus, influenza B virus, filoviridae virus, or Ebola virus.
More preferably, according to the presenst disclosure, the RNA virus is a human coronavirus, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
According to the present disclosure, the subject is at risk of, exhibiting symptoms of, or diagnosed with SARS-CoV-2/COVID-19 virus, influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , Dengue virus, Zika virus, chikungunya, Eastern equine encephalitis virus (EEEV) , Western equine encephalitis virus (WEEV) , Venezuelan equine encephalitis virus (VEEV) , Ross River virus, Barmah Forest virus, yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, ebola virus, marburg virus, herpes simplex virus-1 (HSV-1) , herpes simplex virus-2 (HSV-2) , varicella zoster virus (VZV) , Epstein-Barr virus (EBV) , cytomegalovirus (CMV) , herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV) , The Human T-lymphotropic virus Type I (HTLV-1) , Friend spleen focus-forming virus (SFFV) or Xenotropic MuLVRelated Virus (XMRV) . In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with a Zika virus infection.
According to the present invention, the subject is diagnosed with SARS-CoV-2/COVID-19 virus including an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any variant SARS-CoV-2/COVID-19 virus that could be treated by formula (I) compound or pharmaceuticals contain formula (1) compound.
According to the present invention, the subject is diagnosed with influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path) , and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55) , human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV) , BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV) , yellow fever virus, measles virus, mumps virus,  respiratory syncytial virus, parainfluenza viruses 1 and 3, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV) , Venezuelan equine encephalitis virus (VEEV) , western equine encephalitis virus (WEEV) , California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV) , hantavirus, Dengue virus serotypes 1, 2, 3 and 4, Zika virus, West Nile virus, Tacaribe virus, Junin, rabies virus, ebola virus, marburg virus, adenovirus, herpes simplex virus-1 (HSV-1) , herpes simplex virus-2 (HSV-2) , varicella zoster virus (VZV) , Epstein-Barr virus (EBV) , cytomegalovirus (CMV) , herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV) . In certain embodiments, the subject is diagnosed with a Zika virus infection.
According to the present invention, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis.
Pharmaceutical Composition and Administration
The compounds of the present invention (such as any of the compounds of the Examples herein) alone or in combination with one or more additional therapeutic agents can be formulated into a pharmaceutical composition. The pharmaceutical composition includes: (a) an effective amount of the compound of the present invention; (b) a pharmaceutically acceptable excipient (for example, one or more pharmaceutically acceptable carriers) ; and optionally (c) at least one additional therapeutic agent.
A pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient (s) in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the subject being treated. Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy. ) , including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compounds of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
The compound of the invention can be administered in various known manners, such as orally, parenterally, by inhalation, or through the lungs, i.e., pulmonary administration, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent. The term “parenterally” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.
Oral or parenteral administration is preferred, especially oral administration.
The compound of the invention may be administered in any convenient formulation, e.g., tablets, powders, capsules, pills, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, aqueous buffer, such as a saline or phosphate buffer etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and an addtional active agent.
In general, it has been found to be advantageous in the case of parenteral administration to administer amounts of about 0.001 to 20 mg/kg, preferably about 0.01 to 10 mg/kg, of body weight to achieve effective results. In the case of oral administration, the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 15 mg/kg of body weight.
Combination Therapies
The compound described herein can be administered adjunctively with at least one additional therapeutic agent.
The additional therapeutic agents include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents. In a particular embodiment, the antiviral agent is a non-CNS targeting antiviral compound. “Adjunctive administration” , as used herein, means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents. The additional therapeutic agent (s) can be formulated for immediate release, controlled release, or combinations thereof.
The compound of the present invention and pharmaceutical compositions can be administered in combination with at least one additional therapeutic agent, such as antiviral agent (s) such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, Tenofovir Exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, molnupiravir or zidovudine and combinations thereof.
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the treatment of SARS-CoV-2/COVID-19 infection.
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO2012119559 for the prevention of SARS-CoV-2/COVID-19 infection.
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the treatment of SARS-CoV-2/COVID-19 infection.
Figure PCTCN2022099403-appb-000038
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the prevention of SARS-CoV-2/COVID-19 infection.
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the treatment of SARS-CoV-2/COVID-19 infection.
Figure PCTCN2022099403-appb-000039
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with compound-X for the prevention of SARS-CoV-2/COVID-19 infection.
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the treatment of SARS-CoV-2/COVID-19 infection.
Figure PCTCN2022099403-appb-000040
The compound of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the prevention of SARS-CoV-2/COVID-19 infection.
Accordingly, the present disclosure also provides a pharmaceutical combination, comprising the compound of the present invention and at least one additional therapeutic agent. Examples of the additional therapeutic agent include, but are not limited to, those agents mentioned above, preferably proxalutamide, Compound-X and PF-07321332.
The percentages in the tests and examples which follow are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.
Each embodiment and technical solution described in the present disclosure and the features in each embodiment and technical solution should be understood as being capable of combining with each other in any manner, and those technical solutions obtained by such combination (s) are all included in the scope of the present disclosure the same as if each and every technical solution obtained by such combination (s) were specifically and individually listed, unless the context clearly shows otherwise.
All patents, patent applications, publications, and other references cited or referred to herein are in their entirety incorporated herein by reference to the extent allowed by law. The discussion of those references is intended merely to summarize the assertions made therein. No admission is made that any such patents, patent applications, publications or references, or any portion thereof, are relevant material or prior art. The right to challenge the accuracy and pertinence of any assertion of such patents, patent applications, publications, and other references as relevant material or prior art is specifically reserved.
EXAMPLES
The following examples are set forth below to illustrate the compositions, methods, and results  according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.
Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc. ) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
All reagents and starting materials used in this invention are commercially available or prepared according to the prior art, unless specified otherwise.
1H NMR spectra were measured on a Bruker 400 MHz instrument, Chemical shifts were measured relative to the appropriate solvent peak: CDCl3 (δ 7.27) , DMSO-d6 (δ 2.50) , CD3OD (δ 3.31) , D2O (δ 4.79) . The following abbreviations were used to describe coupling: s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, m=multiplet, br=broad.  13C NMR spectra were measured on a Bruker instrument at 100 MHz with chemical shifts relative to the appropriate solvent peak: CDCl3 (δ 77.0) , DMSOd6 (δ 39.5) , CD3OD (δ 49.0) .
Abbreviations and Acronyms:
aq. aqueous solution
calc. calculated
br s broad singlet (in NMR)
DCI direct chemical ionization (in MS)
dec. decomposition point
DMF dimethylformamide
DMSO dimethyl sulphoxide
DSC dynamic differential calorimetry
eq. equivalent (s)
ESI electrospray ionization (in MS)
Et ethyl
fnd. found
h hour (s)
HPLC high-pressure high-performance liquid chromatography
HRMS high-resolution mass spectrometry
conc. concentrated
LC-MS liquid chromatography-coupled mass spectrometry
LiHMDS lithium hexamethyldisilazide
Me methyl
min minute (s)
MS mass spectrometry
NMR nuclear magnetic resonance spectrometry
Pd2 dba3 tris (dibenzylideneacetone) dipalladium
Ph phenyl
PLM polarized light microscope
RT room temperature
Rt retention time (in HPLC)
TGA thermogravimetric analysis
THF tetrahydrofuran
UV ultraviolet spectrometry
v/v volume to volume ratio (of a solution)
Preparations of starting materials and intermediates
Prepration 1: synthesis of alkoxyl substitued propionic acids and anhydrides
Figure PCTCN2022099403-appb-000041
Procedure for Synthesis of (R) -2-methoxypropanic acid (I-3) and the anhydride (I-4) :
(S) -2-Choropropanoic acid (80.0 g, 738 mmol, 1 equiv., 98%) was added to a two-neck round-bottom flask under nitrogen. 25 wt%Sodium methoxide in methanol (506 mL, 2.212 mol, 3 equiv., ) was added slowly. The reaction was heated to 60 ℃ for 16 hours and conversion was monitored until <2%starting material remained. When sufficient conversion was achieved, the reaction vessel was cooled to room temperature, and pH was adjusted with 4M HCl in dioxane (200 mL, 99%) to the point at which pH just changes from >12 to 7, indicating neutralization of excess sodium methoxide without protonating the sodium salt of the carboxylate. The reaction mixture was filtered to remove salts, and the salt cake was washed twice with 5 mL of methanol. The filtrate was concentrated, redissolved in water, acidified to pH=～2 with 6M HCl and extracted with EtOAc. The organic layer were dried with sodium sulfate and concentrated to afford compound (I-3) as a liquid (73g, 95%) which was of sufficient purity to be used without purification.  1H NMR (CD 3OD) δ 3.67 (q, 1H) , 3.33 (s, 3H) , and 1.33 ppm (d, 3H) .
In a 2-liter, four-necked glass reactor provided with a thermometer and a stirrer were placed, in a nitrogen atmosphere, 500 g of methylene chloride, 104.1 g (1.0 mol) of (R) -2-methoxypropanic acid (3) and 57.3 g (0.5 mol) of methanesulfonyl chloride. The mixture was cooled to 5℃.
Then, 101.3 g (1.0 mol, 1 equivalent relative to the acids generated from methanesulfonyl chloride) of triethylamine was added dropwise in 2 hours with the temperature of the reaction mixture being controlled at 30℃. or lower. After the completion of the dropwise addition, stirring for 1 hour with the same temperature being kept. The reaction mixture was analyzed by a gas chromatograph (GC) , which indicated that the conversion of (R) -2-methoxypropanic acid (3) was >95%.
After the completion of the reaction, 200 g of water was added to the reaction mixture to wash the reaction mixture. The reaction mixture was further washed twice each time with 200g of water, after which distillation was conducted to remove methylene chloride. 85.6 g of the (R) -2-methoxypropanic acid anhydride (I-4) obtained as a yellow liquid and it was used in the acylation step without further purification.
In the same manner as described in preparation 1, the following 2-alkoxylsubstituted propionic acid anhydrides were prepared:
Figure PCTCN2022099403-appb-000042
Figure PCTCN2022099403-appb-000043
Prepration 2: synthesis of alkoxyl substitued isobutyric acid and anhydrides
Procedure for Synthesis of 2-ethoxyisobutyric acid/2-ethoxy-2-methylpropanoic acid (I-21) and the anhydride (I-22) :
Figure PCTCN2022099403-appb-000044
2-Ethoxyisobutyric acid was prepared according to reference (Ragan, John A.; Ide, Nathan D.; Cai, Weiling; Cawley, James J.; Colon-Cruz, Roberto; Kumar, Rajesh; Peng, Zhihui; Vanderplas, Brian C. [Organic process research and development, 2010, vol. 14, #6, p. 1402 -1406] ) : In a 500 mL 3 neck round bottomed flask was dissolved 2-bromo-2-methylpropanoic acid (I-20) (40 g, 239.5 mmole) in ethanol (320 mL) and cooled to 0 to 5℃ followed by dropwise addition of DIPEA (87.4 mL, 502.9 mmole) at 0 to 5℃ and the reaction mixture was stirred at 0℃ for 30 min. The reaction mixture was warmed to 40℃ for 16 h. After 16 h, the reaction mixture was cooled to room temperature, ethanol was removed in vacuo, leaving a thick white slurry. Diethyl ether and water was added to the slurry and cooled to 0℃. The mixture was acidified with 10 %HC1 (50 mL) and the organic layer was separated and washed with brine. To the organic phase was added 10 %aq NaHSO 3 (and the mixture was stirred at room temperature for 6 h. The biphasic mixture was acidified with 10 %HC1 (50 mL) to the pH 1.0 ± 0.5. The organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated to give 30 g of 2-ethoxy-2-methylpropanoic acid (I-21) . The product, 2-ethoxy-2-methylpropanoic acid (I-21) , was carried forwarded to the next step without further purification.
In a 2-liter, four-necked glass reactor equipped with a thermometer and a stirrer were placed, in a nitrogen atmosphere, 300 g of methylene chloride, 66.1 g (0.5 mol) of 2-ethoxy-2-methylpropanoic acid (I-21) and 28.65 g (0.25 mol) of methanesulfonyl chloride. The mixture was cooled to 5℃.
Then, 50.65 g (0.5 mol, 1 equivalent relative to the acids generated from methanesulfonyl chloride) of triethylamine was added dropwise in 2 hours with the temperature of the reaction mixture being controlled at 30℃. or lower. After the completion of the dropwise addition, stirring for 1 hour with the same temperature being kept. The reaction mixture was analyzed by a gas chromatograph (GC) , which indicated that the conversion of 2-ethoxy-2-methylpropanoic acid (I-21) was >95%.
After the completion of the reaction, 100 g of water was added to the reaction mixture to wash the reaction mixture. The reaction mixture was further washed twice each time with 100g of water, after which distillation was conducted to remove methylene chloride. 51 g of the 2-ethoxy-2-methylpropanoic acid anhydride (I-22) obtained as a yellow liquid and it was used in the acylation step without further purification
In the same manner as described in preparation 1, the following 2-alkoxylsubstituted 2-methylpropionic acid/2-alkoxylsubstituted isobutyric acid anhydrides were prepared:
Figure PCTCN2022099403-appb-000045
Figure PCTCN2022099403-appb-000046
Preparation 3 Synthesis of 4-alkoxytetrahydro-2H-pyran-4-carboxylic acid and anhydrides Procedure for Synthesis of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (I-36) and the anhydride (I-37) :
Commercially available methyl tetrahydro-2H-pyran-4-carboxylate was brominated according to the method described in Organic Letters, 2020, vol. 22, #10, p. 3922 -3925. The ester is then hydrolyzed to the corresponding alpha bromoacid (I-35) . The the alpha bromoacid (I-35) is then converted to the corresponding acid (I-36) and the anhydride (I-37) according to the process of Preparation 2.
Figure PCTCN2022099403-appb-000047
The following 4-alkoxytetrahydro-2H-pyran-4-carboxylic acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000048
Figure PCTCN2022099403-appb-000049
Preparation 4 Synthesis of 4-alkyltetrahydro-2H-pyran-4-carboxylic acid and anhydrides
Procedure for Synthesis of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) and the anhydride (I-47) :
Figure PCTCN2022099403-appb-000050
Commercially available tetrahydro-2H-pyran-4-carboxylic acid methyl ester (I-33) was methylated in the same manner as described in Example 64.1A in US9434690. The methyl ester was then hydrolyzed with aqueous NaOH and acidified with HCl to afford 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) as an off white solid.
4-methyltetrahydro-2H-pyran-4-carboxylic acid anhydride (I-47) was prepared according to the process of Preparation 2 as a yellowish oil.
The following 4-alkyltetrahydro-2H-pyran-4-carboxylic acid anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000051
Figure PCTCN2022099403-appb-000052
Preparation 5 Synthesis of 2-ethyl-2-alkoxyl-butyric acid and anhydrides
Procedure for Synthesis of 2-ethyl-2-methoxyl-butyric acid (I-62) and the anhydride (I-63) :
Figure PCTCN2022099403-appb-000053
2-Ethyl-2-bromo-butyric acid (I-61) is commercially available or can be prepared according to the procedure described by Doran; Shonle in Journal of Organic Chemistry, 1938, vol. 3, p. 195.
2-Ethyl-2-bromo-butyric acid (I-61) was first converted to Ethyl-2-methoxy-butyric acid (I-62) and then to Ethyl-2-methoxy-butyric acid anhdride (I-63) as a light yellowish oil as described in Preparation 2.
The following ethyl-2-alkoxy-butyric acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000054
Figure PCTCN2022099403-appb-000055
Preparation 6 Synthesis of 2-methyl-2-alkoxyl-butyric acid and anhydrides
Procedure for Synthesis of 2-methyl-2-methoxyl-butyric acid (I-72) and the anhydride (I-73) : Commercially available (R, S) -2-hydroxy-2-methylbutyric acid (I-70) was resolved into enatiomerically pure R and S isomers (I-71) and then esterified to the methyl ester (I-72) according to the method described in Preparation 74 of US2008114005.
Figure PCTCN2022099403-appb-000056
Alternatively commercially available 2-bromo-2-methylbutanoic acid was transformed to (R, S) -2-methoxy-2-methylbutyric acid (I-78) according to the method disclosed in preparation 2, (I-78) was resolved to the enatiomers (I-80) and (I-77) according to the method described in Preparation 74 of US2008114005. The chiral acid (I-75) was then transformed to the anhydride (I-76) as an oil as described in Preparation 2.
Figure PCTCN2022099403-appb-000057
The following methyl-2-alkoxy-butyric acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000058
Preparation 7 Synthesis of 2-alkyl tetrahydrofuran-2-carboxylic acids and anhydrides.
Procedure for Synthesis of 2-methyl tetrahydrofuran-2-carboxylic acids (I-112) , (I-114) and the anhydride (I-113) , (I-115) : Enatiomerically pure 2-methyl tetrahydrofuran-2-carboxylic acids (I-112) and (I-114) were prepared according to the process described by Pohl; Wollweber in European Journal of Medicinal Chemistry, 1976, vol. 11, p. 163, 168, 169. The acids are then  converted to the corresponding anhydrides (I-113) and (I-115) in the similar manner as that described in preparation 2.
Figure PCTCN2022099403-appb-000059
The following 2-alkyl tetrahydrofuran-2-carboxylic acids and the anhydrides were prepared similarly:
Figure PCTCN2022099403-appb-000060
Preparation 8 Synthesis of 2-methyl-2-alkoxymethylpropionic acid and anhydrides.
Procedure for Synthesis of 2-methyl-2-methoxymethylpropionic acid (I-130) and the anhydride (I-131) :
Figure PCTCN2022099403-appb-000061
Commercially available 2-methyl-2-hydroxymethylpropionic acid methyl ester (I-128) was first methylated and then the ester hydrolyzed to afford the 2-methyl-2-methoxymethylpropionic acid (I-130) using the processes described in Example 55 and 56 in WO2009/77608, 2009.
2-methyl-2-methoxymethylpropionic acid (I-130) was then converted to the anhydride (I-131) according to the process of Preparation 2 to afford it as an oil.
The following 2-methyl-2-alkoxymethylpropionic acid anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000062
Preparation 9 Synthesis of 1-alkyl, 2, 2-dialkoxy-isobutyric acids and anhydrides
Procedure for Synthesis of 1-Methyl-2, 2-Dimethoxy-isobutyric acids (I-142) and the anhydride (I-143) :
Figure PCTCN2022099403-appb-000063
1-Methyl-2, 2-Dimethoxy-isobutyric acid (I-142) was prepared according to the procedure described in Reference example 14 of US2004248941.
Figure PCTCN2022099403-appb-000064
Alternatively, 1-Methyl-2, 2-Dimethoxy-isobutyric acid (I-142) was prepared from commercially available 2, 2-bis (hydroxymethyl) propanoic acid according to Reference Example 14 of EP1437352.
1-Methyl-2, 2-Dimethoxy-isobutyric acid (I-142) was then converted to the anhydride (I-143) according to the process of Preparation 2 to afford it as an oil.
The following 1-Alkyl-2, 2-Dialkoxy-isobutyric acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000065
Figure PCTCN2022099403-appb-000066
Figure PCTCN2022099403-appb-000067
Figure PCTCN2022099403-appb-000068
Preparation 10 Synthesis of 1‐ (alkoxymethyl) cyclopropane‐1‐carboxylic acid and anhydrides.
Procedure for Synthesis of 1‐ (methoxymethyl) cyclopropane‐1‐carboxylic acid (I-225) and the anhydride (I-226) :
Figure PCTCN2022099403-appb-000069
1‐ (hydroxymethyl) cyclopropane‐1‐carboxylic acid methyl ester (I-223) was prepared according to the procedure described in Reference example 22-1 of US9546155. The hydroxy group was then alkylated with Methyl iodide using the similar process described by Shen, Peng-Xiang; et al., in Journal of the American Chemical Society, 2018, vol. 140, #21, p. 6545 -6549. The ester is then hydrolyzed to afford 1‐ (methoxymethyl) cyclopropane‐1‐carboxylic acid (I-225) .
1‐ (methoxymethyl) cyclopropane‐1‐carboxylic acid (I-225) was then converted to the anhydride (I-226) according to the process of Preparation 2 to afford (I-226) as an oil.
The following 1‐ (alkoxymethyl) cyclopropane‐1‐carboxylic acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000070
Preparation 11 Synthesis of 1‐ (alkoxymethyl) cyclobutane‐1‐carboxylic acid and anhydrides.
Procedure for Synthesis of 1‐ (Metoxymethyl) cyclobutane‐1‐carboxylic acid (I-238) and the anhydride (I-239) :
Figure PCTCN2022099403-appb-000071
1‐ (hydroxymethyl) cyclobutane‐1‐carboxylic acid methyl ester (I-236) was prepared according to the procedure described in Reference example 22-4 of US9546155. The hydroxy group was then alkylated with Methyl iodide followed by ester hydrolysis using the similar process described in Reference example K-19 in US10040791 to afford 1‐ (Metoxymethyl) cyclobutane‐1‐carboxylic acid (I-238) .
1‐ (Metoxymethyl) cyclobutane‐1‐carboxylic acid (I-238) was then converted to the anhydride (I-239) according to the process of Preparation 2 to afford it as an oil.
The following 1‐ (alkoxymethyl) cyclobutane‐1‐carboxylic acids and anhydrides were prepared similarly.
Figure PCTCN2022099403-appb-000072
Preparation 12 Synthesis of 1, 2, 2-trialkoxy-isobutyric acids and anhydrides
Procedure for Synthesis of 1-Methoxy-2, 2-Diethoxy-isobutyric acids (223) and the anhydride (224) :
Figure PCTCN2022099403-appb-000073
1-Hydroxy-2, 2-Diethoxy-isobutyric acids ethyl ester (I-249) was prepared according to the procedure described by Bernardon, C. et al. In Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 1502 -1505. The hydroxy group was then alkylated with Methyl iodide followed by ester hydrolysis using the similar process described in Reference example K-19 in US10040791 to afford 1-Methoxy-2, 2-Diethoxy-isobutyric acid (I-251) .
1-Methoxy-2, 2-Diethoxy-isobutyric acid (I-251) was then converted to the anhydride (I-252) according to the process of Preparation 2 to afford it as an oil.
The following 1-Alkoxy-2, 2-Dialkoxy-isobutyric acid and anhydride were prepared similarly.
Figure PCTCN2022099403-appb-000074
Figure PCTCN2022099403-appb-000075
Prepration 13: synthesis of 1-alkoxycyclobutanecarboxylic acids and anhydrides
Procedure for Synthesis of 1-methoxycyclopropanecarboxylic acid (I-291) and the anhydride (I-292) :
Commercially available methyl 2-methoxylacetate (I-289) was alkylated with dibromoethane in the same manner as those described in Example 26 3A of US10464914 to afforded the 1-methoxycyclopropanecarboxylic acid methyl ester which was then hydrolyzed under basic condition to afford the corresponding acid (I-291) . The acid (I-291) was then trnasformed to the corresponding anhydride (I-292) according to the process of Preparation 2 to afford it as an oil.
Figure PCTCN2022099403-appb-000076
In the same manner as described in the preparation above, the following 1-methoxycyclopropanecarboxylic acid and the anhydride as well as 1-alkoxycyclobutanecarboxylic acids and anhydrides can be prepared:
Figure PCTCN2022099403-appb-000077
Figure PCTCN2022099403-appb-000078
Preparation 14: Preparation of 2′, 3′-O-Isopropylideneuridine (I-318)
Figure PCTCN2022099403-appb-000079
To a solution of uridine (97.6g, 400 mmol) and a catalytic amount of p-toluenesulfonic acid (TsOH·H 2O, 7.60 g, 40.0 mmol) in acetone (2000 mL) , 2, 2-dimethoxypropane (89.2 g, 436 mmol) was added at 0 ℃. The suspension was slowly heated to a gentle reflux which was maintained for 48 hrs. The solution was then cooled to room temperature and treated with sodium bicarbonate (60.72 g, 72 mmol) and stirred at room temperature for an additional 0.5 h. The solid was filtered and the crude solution was concentrated under reduced pressure to yield a pale yellow residue. The residue was dissolved in 1000 mL of EtOAc and washed with water x 2, bicarb x 2, water, brine x 2 and dried over sodium sulfate. The colorless solution was concentrated under reduced pressure to yield a white solid. 97 g (85%) . 1H-NMR (MeOD, 400 MHz) δ (ppm) : 7.82 (1H, d) , 5.86 (1H, d) , 5.67 (1H, d) , 4.19 (1H, t) , 3.54 (3H, m) , 3.30 (1H, m) , 1.54 &1.34 (3H each, s) .
Example 1:
Synthesis of N4-hydroxycytidine (NHC) or 1- (3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -4- (hydroxyamino) pyrimidin-2-one.
Figure PCTCN2022099403-appb-000080
A mixture of cytidine (20.0 g, 82.24 mmol, 1.0 eq) and NH 2OH. AcOH (23 g, 246.7 mmol, 3.0eq) in H 2O (350 mL) was stirred for 48hrs at 40 ℃. Reaction was monitored by HPLC and after completion of reaction, water was evaporated in rotavapor to give a thick syrup, which was then suspended in 100 mL of water and placed in refrigerator for crystallization for 24hrs. The solid thus crystallized are filtered, washed with cold H 2O (～ 15.0 mL) , dried under vacuum to yield the desired N4-hydroxycytidine (NHC/EX-1) as white solid (8.48 g, 98%pure, 40%yield) . 1H NMR (400 MHz, D 2O) δ 7.0 (d, 1H) , 5.75 (d, 1H) , 5.60 (d, 1H) , 4.2 (t, 1H) , 4.06 (t, 1H) , 3.89 (m, 1H) , 3.75 (dd, 1H) , 3.60 (dd, 1H) ; Purity: 98% (assessed by HPLC) .
Example 2 Preparation of compound (EX-2A)
Figure PCTCN2022099403-appb-000081
To a solution of 2’, 3’-O-isopropylidene-uridine (I-318) (10 g, 35.2 mmol) in a mixture of CH 2Cl 2 (150 mL) and pyridine (60 mL) was added the anhydride (I-22) (17.3 g, 70.4 mmol) and DMAP (0.5 g, 3.6 mmol) at 0℃. The resulting mixture was allowed to rise to room temperature stirred at 20-40℃ for 48 hrs. After completion (TLC, 10: 1 CHCl 3-MeOH) the reaction mixture was washed with aqueous HCl three times to remove the whole amount of pyridine, and then washed with aqueous NaHCO3 and aqueous NaCl. The organic layer is concentrated. The product (I-2-1) (12.6g) was used in the next step without further purification.
A 500mL round bottom flask was charged with the crude product from above (20.24 g, 50.8 mmol) and MeCN (200 mL) . The reaction mixture was allowed to stir until all the starting material was dissolved. Next, 1, 2, 4-triazole (25.3 g, 365.8 mmol) was added followed by the addition of N, N-diethylethanamine (56.6 mL, 406.4 mmol) . The reaction mixture was allowed to stir at rt until all solids dissolved. The reaction was then cooled to 0℃. using an ice bath. Phosphorous oxychloride (12.2 mL, 76.2 mmol) was added slowly. The slurry that formed was allowed to stir under argon while slowly warming to rt. The reaction was then allowed to stir until complete by TLC (EtOAc) . The reaction was then quenched by the addition of 60 mL of water. The slurry then became a dark colored solution, which was then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine. The organics were then dried over sodium  sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (500 g columns) . Fractions containing product were collected and concentrated under reduced pressure to afford (I-2-2) .
A 300 mL round bottom flask was charged with the product from the previous step (5.8 g, 14.6 mmol) and isopropyl alcohol (80 mL) . The reaction mixture was allowed to stir at rt until all solids dissolved. Next, hydroxylamine (0.67 mL, 22 mmol) was added and stirring continued at ambient temperature. When the reaction was complete (HPLC) some solvent was removed under high vacuum at ambient temperature. The remaining solvent was removed under reduced pressure at 45℃. The resulting residue was dissolved in EtOAc and was washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield oil (I-2-3) .
A 100 mL round bottom flask was charged with the product from the previous step (4.0 g, 10 mmol) and formic acid (60 mL) . The reaction mixture was allowed to stir at rt overnight. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure at <35℃. to yield an oil. Next, 20 mL of ethanol was added. Solvent was then removed under reduced pressure. The resulting residue was purified on a column of silica gel using CH 2Cl 2-MeOH gradient (100: 0 to 10: 1 v/v) solvent system as the eluent to yield (EX-2A) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.0 (s, 1H) , 9.6 9 (s, 1H) , 6.9 (d, 1H) , 5.72 (d, 1H) , 5.52 (d, 1H) , 5.40 (d, 1H) , 5.25 (d, 1H) , 4.20 (d, 2H) , 4.05-3.85 (m, 3H) , 1.40 (s, 6H) , 1.00 (t, 3H) ; Purity: 98% (assessed by HPLC) .
The following examplary compounds were prepared similarly as described Example 2 using anhydride (I-24) , (I-26) , (I-28) (I-30) and (I-32) .
Figure PCTCN2022099403-appb-000082
Figure PCTCN2022099403-appb-000083
Example 3 Preparation of compound (EX-3A)
Figure PCTCN2022099403-appb-000084
Following the process of Example 2 but using angydride (I-4) , compound (EX-3A) was prepared as a white solid: 1H NMR (400 MHz, DMSO) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-6) , (I-8) and (I-10) .
Figure PCTCN2022099403-appb-000085
Figure PCTCN2022099403-appb-000086
Example 4 Preparation of compound (EX-4A)
Figure PCTCN2022099403-appb-000087
Following the process of Example 2 but using angydride (I-307) , compound (EX-4A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described above by using anhydrides (I-310) , (I-313) and (I-316) .
Figure PCTCN2022099403-appb-000088
Figure PCTCN2022099403-appb-000089
Example 5 Preparation of compound (EX-5A)
Figure PCTCN2022099403-appb-000090
Following the process of Example 2 but using angydride (I-51) , compound (EX-5A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using tetrahydro-2H-pyran-4-carboxylic anhydride, anhydrides (I-46) , (I-55) , (I-59) , (I-37) , (I-39) , (I-41) and (I-43) .
Figure PCTCN2022099403-appb-000091
Figure PCTCN2022099403-appb-000092
Example 6 Preparation of compound (EX-6A)
Figure PCTCN2022099403-appb-000093
Following the process of Example 2 but using angydride (I-63) , compound (EX-6A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-65) , (I-67) , (I-69) , (I-76) , (I-90) , (I-103) and (I-111) .
Figure PCTCN2022099403-appb-000094
Figure PCTCN2022099403-appb-000095
Example 7 Preparation of compound (EX-7A)
Figure PCTCN2022099403-appb-000096
Following the process of Example 2 but using angydride (I-115) , compound (EX-7A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using (R) -tetrahydro-2-furoic acid anhydride, (S) -tetrahydro-2-furoic acid anhydride, anhydrides (I-119) , (I-123) and (I-127) .
Figure PCTCN2022099403-appb-000097
Figure PCTCN2022099403-appb-000098
Example 8 Preparation of compound (EX-8A)
Figure PCTCN2022099403-appb-000099
Following the process of Example 2 but using angydride (I-131) , compound (EX-8A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-134) , (I-137) and (I-140) .
Figure PCTCN2022099403-appb-000100
Example 9 Preparation of compound (EX-9A)
Figure PCTCN2022099403-appb-000101
Following the process of Example 2 but using angydride (I-226) , compound (EX-9A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-229) , (I-232) and (I-235) .
Figure PCTCN2022099403-appb-000102
Example 10 Preparation of compound (EX-10A)
Figure PCTCN2022099403-appb-000103
Following the process of Example 2 but using angydride (I-239) , compound (EX-10A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-242) , (I-245) and (I-248) .
Figure PCTCN2022099403-appb-000104
Example 11 Preparation of compound (EX-11A)
Figure PCTCN2022099403-appb-000105
Following the process of Example 2 but using angydride (I-265) , compound (EX-11A) was prepared as a white solid: 1H NMR (400 MHz, D 2O) δ
The following examplary compounds were prepared similarly as described Example 2 by using anhydrides (I-268) , (I-271) , (I-274) , (I-143) , (I-149) , (I-152) , (I-155) , (I-188) , (I-191) , (I-194) , (I-197) , (I-252) , (I-255) , (I-258) , (I-261) , (I-160) , (I-163) , (I-166) , (I-169) , (I-200) , (I-203) , (I-206) , (I-209) , (I-278) , (I-281) , (I-174) , (I-177) , (I-212) , (I-215) , (I-285) , (I-288) , (I-182) , (I-185) , (I-218) and (I-221) .
Figure PCTCN2022099403-appb-000106
Figure PCTCN2022099403-appb-000107
Figure PCTCN2022099403-appb-000108
Figure PCTCN2022099403-appb-000109
Figure PCTCN2022099403-appb-000110
Example 12 Preparation of compound (EX-12A)
Figure PCTCN2022099403-appb-000111
Following the similar procedure as those described in Example 2 using commercially available 2-furancarbonyl chloride Compound (EX-12A) was prepared as a white solid. 1H NMR (400 MHz, DMSO) δ 10.0 (s, 1H) , 9.6 (s, 1H) , 8.0 (s, 1H) , 7.40 (brs, 1H) , 6.9 (d, 1H) , 6.70 (brs, 1H) , 5.75 (d, 1H) , 5.52 (d, 1H) , 5.40 (d, 1H) , 5.25 (d, 1H) , 4.40 (m, 2H) , 4.0 (m, 3H) .
Example 13 Preparation of compound (EX-13A)
Figure PCTCN2022099403-appb-000112
Following the similar procedure as those described in Example 2 using commercially available (2R) -tetrahydrofuran-2-carboxylic acid chloride, Compound (EX-13A) was prepared as a white solid. 1H NMR (400 MHz, D 2O) δ
Example 14 Preparation of compound (EX-14A)
Figure PCTCN2022099403-appb-000113
Following the similar procedure as those described in Example 2 using commercially available (2S) -tetrahydrofuran-2-carboxylic acid chloride, Compound (EX-14A) was prepared as a white solid 1H NMR (400 MHz, D 2O) δ
Example 15 Preparation of compound (EX-15A)
Figure PCTCN2022099403-appb-000114
Following the similar procedure as those described in Example 2 using anhydride (I-15-2) , Compound (EX-15A) was prepared as a white solid. HNMR (400MHz, CDCl 3) δ8.7 (s, 1H) , 8.3 (s, 1H) , 6.9 (d, 1H) , 6.1 (d, 1H) , 5.7 (d, 2H) , 5.05 (d, 1H) , 4.9 (d, 1H) , 4.40 (m, 3H) , 4.1 (multiple singlets, 6H) , 3.5 (three singlets, 9H) .
Example 16 Preparation of compound (16A)
Figure PCTCN2022099403-appb-000115
Following the similar procedure as those described in Example 2 using anhydride (I-24) and uridine, Compound (EX-16A) was prepared as a white solid. 1H NMR (400 MHz, CDCl 3) δ 8.80-9.0 (brs, 2H) , 7.05 (d, 1H) , 6.15 (d, 1H) , 5.72 (d, 1H) , 5.52 (m, 1H) , 5.35 (m, 1H) , 4.45 (m, 1H) , 4.35 (m, 1H) , 4.25 (m, 2H) , 3.28 (s, 3H) , 3.27 (s, 3H) , 3.20 (multiple singlets, 9H) , 1.30-1.50 (multiple singlets, 18H) .
Example 17 Preparation of compound (EX-17A)
Figure PCTCN2022099403-appb-000116
Following the similar procedure as those described in Example 2 using anhydride (I-24) and uridine, Compound (EX-17A) was prepared as a white solid. 1H NMR (400 MHz, CDCl 3) δ 8.80 (brs, 2H) , 7.05 (d, 1H) , 6.2 (d, 1H) , 5.72 (d, 1H) , 5.4 (m, 2H) , 4.4 (m, 1H) , 4.3 (m, 2H) , 3.5 (m, 6H) , 1.30-1.50 (multiple singlets, 18H) , 1.2 (m, 9H) .
Example 18 Preparation of compound (EX-18A)
Figure PCTCN2022099403-appb-000117
Intermediate (I-18-1) was prepared according to the method of reference example 1 of US4962193. Following the similar procedure as those described in Example 2 using isobutyric anhydride and (I-18-1) , Compound (EX-18A) was prepared as a white solid. NMR (400MHz, CDCl 3) δ8.7 (s, 1H) ,  8.2 (s, 1H) , 6.6 (d, 1H) , 6.0 (s, 1H) , 5.7 (d, 2H) , 5.0 (d, 1H) , 4.8-4.9 (d, 1H) , 4.30 (m, 3H) , 3.3 (s, 3H) , 2.5 (m, 1H) , 1.20 (s, 6H) .
Example 19 Preparation of Molnupiravir
Figure PCTCN2022099403-appb-000118
Molnupiravir is prepared according to the process of example 10 of US2020276219 using 2’, 3’-O-isopropylidene-uridine (I-318) and isobutyric anhydride to afford it as a white solid. 1H NMR (400 MHz, D 2O) δ 7.08 (d, 1H) , 6.09 (d, 1H) , 5.67 (d, 1H) , 4.33 (t, 1H) , 4.06 (t, 1H) , 3.89-3.86 (m, 2H) , 3.76 (dd, 1H) ; Purity: 98% (assessed by HPLC)
Example 20: Plasma Stability
Figure PCTCN2022099403-appb-000119
Preparation of Solutions: Stock solution (10 mM) of each of test compounds was prepared in DMSO. The stock solution for each compound was then diluted into 100 μM with acetonitrile.
Plasma Incubations: Plasma incubations were conducted in duplicate in 96-well plate at 37℃.
Plasma was prewarmed in a total volume of 198 μL for 5 min at 37℃, then added 2 μL of 100 μM test compound into an incubation well containing plasma, pipette-mixed to achieve a homogenous suspension and immediately transferred 20 μL incubate as a 0 min sample to wells in a "Quenching" plate followed by adding 200 μL of acetonitrile with metolazone as internal standard (IS) and pipette-mixing. At 2, 5, 60, and 90 min, pipette-mixed the incubate and serially transfer  samples of 20 μL incubate per time point to wells in a separate "Quenching" plate followed by adding 200 μL of acetonitrile with metolazone as IS and pipette-mixing.
Sample Analysis: The 96-well plate was centrifuged at 6000 g for 10 min. The supernatant was injected onto the LC-MS/MS system for analysis.
Example 21: Microsome Stability
Figure PCTCN2022099403-appb-000120
Preparation of Solutions: Stock solution (10 mM) of each of test compounds was prepared in DMSO. The stock solution for each compound was then diluted into 100 μM with acetonitrile.
Microsome Incubations: Incubation mixtures were prepared in a total volume of 200 μL with final component concentrations as follows: 0.1M PBS (pH 7.4) , NADPH (2 mM) and liver microsomes (0.2 mg/mL) as well as test compound (1 μM) or Molnupiravir (1 μM) as a positive control, wherein the NADPH was added after a 5-min preincubation of all other components at 37℃. Pipette-mixed to achieve a homogenous suspension and immediately transferred 20 μL incubate as a 0 min sample to wells in a "Quenching" plate followed by adding 200 μL of acetonitrile with metolazone as IS and pipette-mixing. At 2, 5, 10, and 45 min, pipette-mixed the incubate and serially transfer samples of 20 μL incubate per time point to wells in a separate "Quenching" plate followed by adding 200 μL of acetonitrile with metolazone as IS and pipette-mixing.
Sample Analysis: The 96-well plate was centrifuged at 6000 g for 10 min. The supernatant was injected onto the LC-MS/MS system for analysis.
Example 22: Mouse PK Study: NHC, Example compounds and molnupiravir
Vehicle with the following composition was prepared: Solution A (PEG 400/Tween 80 (90%/10%) : Solution B (30%Solutol/10%DMAC) =1 : 1 (v/v) . The Example compounds, NHC and molnupiravir were suspended in the vehicle at 0.4mol/10mL respectively.
CD1 mouse, 20-25 g, 6～7 weeks old, male, total N=45, N=9/compound, purchased from Shanghai Institute of Planned Parenthood Research, animal department, fasted overnight and fed 4 hr after  dosing. The mice were dosed at 0.4 mol/kg, 10 mL/kg via oral gavage. The animals were restrained manually, and approx. 150 μL of blood/time point was collected into pre-cooled EDTA-K2 tubes via retro-orbital injection. Blood samples were centrifuged at 4℃ (4000 g, 5 min) to obtain plasma within 15 min after sample collection. Plasma samples were stored at approximately -80℃ until analysis. The plasma samples were analyzed using LC-MS/MS. The results of the test are shown in FIG. 1 and in the following Table, wherein the PK parameters were estimated by non-compartmental model using Winnonlin software.
Figure PCTCN2022099403-appb-000121
Example 23: Pharmacokinetic Studies in Cynomolgus Macaques
Example 24: Treatment with NHC, Example compounds in a Ferret /Mice Model of Influenza Infection
Example 25: Treatment with NHC, Example compounds in a Ferret/mice Model of SARS-CoV-2 Infection

Claims (19)

  1. A compound of formula (I) ,
    Figure PCTCN2022099403-appb-100001
    or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
    R 1 is RaC=O,
    each of R 2 and R 3 is H, or each of R 2 and R 3 is RaC=O; or R 2 and R 3 are taken together with the oxygen they attached to form a 5 membered heterocycloalkyl substituted with one C 1-6alkyl-O;
    Ra is methyl substituted with Ra1, Ra2 and Ra3;
    Ra1 is selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6alkyl-O- (CH 2)  n-, C 1-6alkyl-O-C 1-6alkyl-O- (CH 2)  n-, C 1-6haloalkyl-O- (CH 2)  n-, C 3-6cycloalkyl-O- (CH 2)  n-and 3-6 membered heterocycloalkyl-O- (CH 2)  n-,
    Ra2 is C 1-6alkyl or C 1-6alkyl-O- (CH 2)  n-, and
    Ra3 is selected from the group consisting of H, C 1-6alkyl and C 1-6alkyl-O- (CH 2)  n-;
    or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
    n is 0 or 1;
    provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not any of H, C 1-6alkyl, C 1-6alkyl-O-C 1-6alkyl, C 1-6haloalkyl or C 3-6cycloalkyl.
  2. A compound according to claim 1 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
    R 1 is RaC=O,
    each of R 2 and R 3 is H, or each of R 2 and R 3 is RaC=O;
    wherein RaC=O is selected from the group consisting of:
    Figure PCTCN2022099403-appb-100002
    Raa is selected from the group consisting of C 1-6alkyl, C 1-6haloalkyl, C 1-6alkyl-O-C 1-6alkyl-, C 3-6cycloalkyl and 3-6 membered heterocycloalkyl; preferably C 1-6alkyl.
  3. A compound according to Claim 2, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
    Figure PCTCN2022099403-appb-100003
    Figure PCTCN2022099403-appb-100004
  4. A compound according to claim 2, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein RaC=O is selected from the group consisting of:
    Figure PCTCN2022099403-appb-100005
  5. A compound according to any of the preceding claims, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluorosubstitued ethyl, flurosubstituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl or tetrahydro-2H-pyran-4-yl; preferably methyl, ethyl, propyl, isopropyl, oxetanyl and tetrahydro-2H-pyran-4-yl.
  6. A compound according to any of the preceding claims, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.
  7. A compound according to any of claims 1-2, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
    Ra1 and Ra3 is independently selected from the group consisting of H, C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-;
    Ra2 is selected from the group consisting of C 1-6alkyl, C 1-6alkyl-O-and C 1-6alkyl-O-CH 2-;
    or Ra2 and Ra3 are taken together with the carbon they attached to form C 3-6cycloalkyl, or 5-6 membered haloheterocycloalkyl comprising 1 ring heteroatom selected from O;
    provided that when Ra3 is either H or C 1-6alkyl, Ra1 is not H or C 1-6alkyl.
  8. A compound according to any of the preceding claims, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein
    Ra1 is C 1-6alkyl-O-, and
    Ra2 and Ra3 is independently C 1-3alkyl, preferably Ra2 and Ra3 are the same.
  9. A compound according to any of the preceding claims, or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is RaC=O, and each of R 2 and R 3 is H.
  10. A compound according to any of the preceding claims, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Ra1 is C 1-6alkyl-O-.
  11. A compound according to any of claims 1-2, or a tautomer, stereoisomer or racemate thereof or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2022099403-appb-100006
    Figure PCTCN2022099403-appb-100007
    Figure PCTCN2022099403-appb-100008
    Figure PCTCN2022099403-appb-100009
    Figure PCTCN2022099403-appb-100010
    Figure PCTCN2022099403-appb-100011
    Figure PCTCN2022099403-appb-100012
    Figure PCTCN2022099403-appb-100013
    Figure PCTCN2022099403-appb-100014
    Figure PCTCN2022099403-appb-100015
    Figure PCTCN2022099403-appb-100016
    Figure PCTCN2022099403-appb-100017
    Figure PCTCN2022099403-appb-100018
    Figure PCTCN2022099403-appb-100019
  12. A pharmaceutical composition, comprising the compound of any one of claims 1-11 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
  13. Use of the compound of any one of claims 1-11 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a RNA viral infection.
  14. A method of treating or preventing a RNA viral infection in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-28 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof.
  15. The compound of any one of claims 1-11 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  16. The compound of any one of claims 1-11 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use in treating or preventing a RNA viral infection.
  17. The use according to claim 13, the method according to claim 14 or the compound for use according to Embodiment 16, wherein the RNA virus is coronavirus, e.g., a human coronavirus, SARS coronavirus or MERS coronavirus, alphavirus, e.g., Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus or Ross River virus, filoviridae virus, e.g., ebola virus, orthomyxoviridae virus, e.g., influenza virus, influenza A virus or influenza B virus, paramyxoviridae virus, e.g., respiratory Syncytial Virus (RSV) , flavivirus, e.g., Zika virus; preferably, a SARS-CoV-2/COVID-19 virus, an alpha variant SARS-CoV-2/COVID-19 virus, a beta variant SARS-CoV-2/COVID-19 virus, a gamma variant  SARS-CoV-2/COVID-19 virus, a delta variant SARS-CoV-2/COVID-19 virus, or any other variant SARS-CoV-2/COVID-19 virus.
  18. A pharmaceutical combination, comprising the compound of any one of claims 1-11 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  19. The pharmaceutical combination according to claim 18, wherein additional therapeutic agent is selected from the group consisting of:
    Figure PCTCN2022099403-appb-100020
PCT/CN2022/099403 2021-06-18 2022-06-17 Ester derivatives of n4-hydroxycytidine and use thereof Ceased WO2022262845A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280040667.7A CN117642410A (en) 2021-06-18 2022-06-17 Ester derivatives of N4-hydroxycytidine and their uses

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2021/101005 2021-06-18
CN2021101005 2021-06-18

Publications (1)

Publication Number Publication Date
WO2022262845A1 true WO2022262845A1 (en) 2022-12-22

Family

ID=84526896

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/099403 Ceased WO2022262845A1 (en) 2021-06-18 2022-06-17 Ester derivatives of n4-hydroxycytidine and use thereof

Country Status (2)

Country Link
CN (1) CN117642410A (en)
WO (1) WO2022262845A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025024346A3 (en) * 2023-07-27 2025-04-10 Merck Sharp & Dohme Llc Solid dosage form of a small molecule antiviral and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119559A1 (en) * 2011-03-10 2012-09-13 Suzhou Kintor Pharmaceuticals,Inc. Androgen receptor antagonists and uses thereof
CN107427529A (en) * 2014-12-26 2017-12-01 埃莫里大学 N4‑Hydroxycytidine and its derivatives and their related antiviral uses
CN111372592A (en) * 2017-12-07 2020-07-03 埃默里大学 N4-Hydroxycytidine and its derivatives and their related antiviral uses
CN111548384A (en) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy
CN112074506A (en) * 2018-03-07 2020-12-11 埃默里大学 4' -halo-containing nucleotide and nucleoside therapeutic compositions and uses related thereto
CN112552288A (en) * 2021-02-19 2021-03-26 南京桦冠生物技术有限公司 Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine
WO2021159044A1 (en) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119559A1 (en) * 2011-03-10 2012-09-13 Suzhou Kintor Pharmaceuticals,Inc. Androgen receptor antagonists and uses thereof
CN107427529A (en) * 2014-12-26 2017-12-01 埃莫里大学 N4‑Hydroxycytidine and its derivatives and their related antiviral uses
CN111372592A (en) * 2017-12-07 2020-07-03 埃默里大学 N4-Hydroxycytidine and its derivatives and their related antiviral uses
CN112074506A (en) * 2018-03-07 2020-12-11 埃默里大学 4' -halo-containing nucleotide and nucleoside therapeutic compositions and uses related thereto
WO2021159044A1 (en) * 2020-02-07 2021-08-12 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN111548384A (en) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy
CN112552288A (en) * 2021-02-19 2021-03-26 南京桦冠生物技术有限公司 Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CADEGIANI FLÁVIO ADSUARA, MCCOY JOHN, WAMBIER CARLOS GUSTAVO, GOREN ANDY: "5-Alpha-Reductase Inhibitors Reduce Remission Time of COVID-19: Results From a Randomized Double Blind Placebo Controlled Interventional Trial in 130 SARS-CoV-2 Positive Men", MEDRXIV, 18 November 2020 (2020-11-18), XP055950355, Retrieved from the Internet <URL:https://www.medrxiv.org/content/10.1101/2020.11.16.20232512v1.full.pdf> [retrieved on 20220810], DOI: 10.1101/2020.11.16.20232512 *
HALFORD BETHANY: "Pfizer unveils its oral SARS-CoV-2 inhibitor", ACS MEETING NEWS, ACS, vol. 99, no. 13, 12 April 2021 (2021-04-12), pages 1 - 2, XP055976884 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025024346A3 (en) * 2023-07-27 2025-04-10 Merck Sharp & Dohme Llc Solid dosage form of a small molecule antiviral and uses thereof

Also Published As

Publication number Publication date
CN117642410A (en) 2024-03-01

Similar Documents

Publication Publication Date Title
US11512064B2 (en) Salts of an LSD1 inhibitor and processes for preparing the same
CN107445980B (en) 3-Substituted 5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione compounds
RU2720811C2 (en) 4&#39;-substituted nucleoside reverse transcriptase inhibitors and production thereof
JP6989509B2 (en) Aryl-substituted pyrimidines for use in influenza virus infection
JP6903658B2 (en) Heterocyclic indole for use in influenza virus infection
JP7624093B2 (en) Uracil derivatives having virus proliferation inhibitory activity and pharmaceutical compositions containing them
CA2601996A1 (en) Purine derivatives as a3 and a1 adenosine receptor agonists
AU2008271114A1 (en) Novel HIV reverse transcriptase inhibitors
US20230027361A1 (en) Mettl3 modulators
CN108473493B (en) Functionalized valeric acids for influenza virus infection
IL259862A (en) Brutonine Tyrosine Kinase Inhibitors and Methods of Using Them
JP2023145644A (en) Dihydroisoquinoline compounds
WO2022262845A1 (en) Ester derivatives of n4-hydroxycytidine and use thereof
WO2016177300A1 (en) (2&#39;r)-2&#39;-deoxy-2&#39;-halo-2&#39;-methyl uridine derivative, and preparation method and use thereof
CN117362344A (en) Phosphate compound, preparation method and application thereof
WO2024125604A1 (en) Diester derivatives of n4-hydroxycytidine and use thereof
WO2023083295A1 (en) Ester derivatives of n4-hydroxycytidine and use thereof
US20170232031A1 (en) Inhibitors of Zika Virus
CN118176202B (en) A crystal form of a cyano-substituted polypeptide compound and a preparation method thereof
WO2018103058A1 (en) Inhibitors of bruton&#39;s tyrosine kinase and methods of their use
CN120712260A (en) Compounds containing dihydrophthalazine and alkenyl and uses thereof
CN118126086A (en) Phosphate compound, preparation method and application thereof
EP0410660A1 (en) Cyclopentane derivatives
EP3752505A1 (en) Novel sulfone compounds and derivatives for the treatment and prophylaxis of virus infection
HK1229793A1 (en) 3-substituted 5-amino-6h-thiazolo[4,5-d]pyrimidine-2,7-dione compounds for the treatment and prophylaxis of virus infection

Legal Events

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

Ref document number: 22824317

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280040667.7

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22824317

Country of ref document: EP

Kind code of ref document: A1