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WO2025051161A1 - Inhibiteur de protéase 3cl pour le traitement ou la prévention d'une infection à coronavirus et son utilisation - Google Patents

Inhibiteur de protéase 3cl pour le traitement ou la prévention d'une infection à coronavirus et son utilisation Download PDF

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WO2025051161A1
WO2025051161A1 PCT/CN2024/116912 CN2024116912W WO2025051161A1 WO 2025051161 A1 WO2025051161 A1 WO 2025051161A1 CN 2024116912 W CN2024116912 W CN 2024116912W WO 2025051161 A1 WO2025051161 A1 WO 2025051161A1
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Chinese (zh)
Inventor
刘人鹤
胡其平
闫宁
胡松
夏岩
丁胜
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Global Health Drug Discovery Institute
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Global Health Drug Discovery Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of biomedicine, and in particular to 3CL protease inhibitors and uses thereof for treating or preventing coronavirus infection.
  • the new coronavirus (SARS-CoV-2) is a positive-strand RNA virus with the largest genome among the currently known RNA viruses. Studies have found that the new coronavirus mainly infects cells through the human respiratory mucosal system. After entering the cell, the viral gene products are cleaved by proteases to begin translation and replication of the required proteins. 3CL proteases recognize specific cleavage sites and cut polyprotein precursors into multiple non-structural proteins. They are essential for the life cycle of the virus and are excellent targets for antiviral drugs. Many marketed antiviral drugs target 3CL proteases such as HIV and HCV.
  • HIV 3CL protease inhibitors lopinavir and ritonavir have certain interactions with the 3CL protease of the new coronavirus in vitro, but have been shown to have no positive effects on patients infected with the new coronavirus in clinical tests. Therefore, strong inhibitors specific for the 3CL protease of the new coronavirus are clinically needed.
  • the present application provides a compound of formula (I) or an isotope-labeled compound thereof, or a photosensitive isomers, geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof,
  • One of X1 and X2 is N, and the other is N or CH;
  • At most one of Y1 and Y2 is hydroxy, halogen, cyano, or C1- C6 alkyl or C1 - C6 alkoxy optionally substituted by hydroxy, halogen or cyano, and the rest are H; or Y2 is hydroxy or carbonyl, and Y1, together with P1 or P3 and the carbon atom or nitrogen atom to which they are attached, forms a C3-C6 cycloalkyl , a three - membered to six- membered heterocycloalkyl, a phenyl, or a five-membered to six-membered heteroaryl optionally substituted by halogen or C1 - C3 alkyl;
  • P1 and P3 is -L1 - Z1- , and the other is selected from H, C1 - C6 alkyl or C3- C6 cycloalkyl optionally substituted by halogen or cyano, or together with Y1 and the carbon atom or nitrogen atom to which they are attached, forms C3 -C6 cycloalkyl optionally substituted by halogen or C1 - C3 alkyl, a three-membered to six -membered heterocycloalkyl, a phenyl or a five-membered to six-membered heteroaryl; P2 is -L2 - Z2- ;
  • L1 is selected from a bond, -CH2- , -NH- or -O-;
  • L2 is selected from a bond or -CH2- ;
  • Z1 is wherein the ring optionally has 1 or 2 N heteroatoms
  • Z 2 is selected from a five-membered to ten-membered heteroaryl group, wherein optionally one or more hydrogen atoms in Z 2 are each independently substituted by halogen, hydroxyl, cyano, sulfo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • R 1 , R 2 and R 5 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and optionally one or more hydrogen atoms in R 1 , R 2 and R 5 are each independently replaced by halogen. substituted with halogen, hydroxy, amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 3 and R 4 is H, and the other is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, amide, carboxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -O(CH 2 ) n1 CR 6 R 7 R 8 , -NH(CH 2 ) n1 R 10 , -O(CH 2 ) n1 R 11 , -(CH 2 ) n1 NH(CH 2 ) n2 R 12 , -(CH 2 ) n1 NHCOR 13 , -(CH 2 ) n1 NHSO 2 R 14 or -(CH 2 ) n1 R 15 , and optionally one or more hydrogen atoms in R 3 and R 4 are each independently substituted by halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or a hydroxyl protecting group;
  • R 6 and R 7 are selected from hydrogen, or together with the carbon atoms to which they are attached, they form a C 3 -C 6 cycloalkyl group or a C 3 -C 6 heterocycloalkyl group;
  • R 8 is selected from -NH 2 , -NHCOR 9 or -NHSO 2 R 9 , wherein R 9 is selected from C 1 -C 6 alkyl or phenyl;
  • R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, three-membered to six-membered heterocycloalkyl, phenyl or five-membered to six-membered heteroaryl;
  • R 15 is selected from a three-membered to six-membered heterocycloalkyl group containing at least one nitrogen atom;
  • n1 and n2 are selected from 0, 1, 2 or 3;
  • ⁇ is used to indicate that the ring is unsaturated.
  • P 3 is selected from H or C 1 -C 6 alkyl substituted by cyano, or forms together with Y 1 and the carbon atom to which they are attached a phenyl group optionally substituted by halogen or C 1 -C 3 alkyl; and when P 3 is -L 1 -Z 1 -, P 1 is selected from C 1 -C 6 alkyl optionally substituted by halogen or cyano, preferably -CH 2 CN, -(CH 2 ) 2 CN, -CF 3 or -CH 2 CF 3 , or forms together with Y 1 and the carbon atom or nitrogen atom to which they are attached a pyridyl or hexahydropyridyl group optionally substituted by halogen or C 1 -C 3 alkyl.
  • Z2 can be selected from a five-membered to ten-membered heteroaryl group containing 1 to 3 nitrogen atoms, preferably, Z2 can be selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole or quinolyl, wherein optionally one or more hydrogen atoms in Z2 can each be optionally substituted by halogen, hydroxyl, cyano, methyl, ethyl, trifluoromethyl or methoxy.
  • one of R3 and R4 is H, and the other may be Any one selected from the following groups:
  • R 15 may be selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl.
  • halogen may be selected from F, Cl or Br;
  • C 1 -C 6 alkyl may be selected from methyl, ethyl, propyl or isopropyl;
  • C 1 -C 6 haloalkyl may be selected from monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or trichloromethyl;
  • C 1 -C 6 alkoxy may be selected from methoxy, ethoxy or propoxy;
  • C 1 -C 6 haloalkoxy may be selected from trifluoromethoxy or trifluoroethoxy; and/or
  • C 3 -C 6 cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite may have the following structure:
  • the "compound of formula (I)” or “compound of the present application” mentioned below may also include any isotope-labeled compound of the compound of formula (I), or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites.
  • optical isomer means that when a compound has one or more chiral centers, each The amino center can exist in R configuration or S configuration, and the various isomers thus formed are optical isomers.
  • Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof.
  • optical isomers can be separated by chiral chromatographic columns or by chiral synthesis.
  • Geometric isomer means that when a double bond exists in a compound, the compound may exist as cis isomers, trans isomers, E isomers and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or a mixture thereof.
  • tautomer refers to an isomer that is produced by the rapid movement of an atom in a molecule between two positions. Those skilled in the art will understand that tautomers can transform into each other and may reach an equilibrium state and coexist under a certain state.
  • references herein to "compounds of formula (I)" or “compounds of the present invention” also encompass isotope-labeled compounds in which any atom in the compound is replaced by an isotope atom thereof.
  • the present invention includes all pharmaceutically acceptable isotope-labeled compounds of compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number as the atoms commonly found in nature but with a different atomic mass or mass number.
  • isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H (D) and 3 H (T), isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, and isotopes of sulfur, such as 35 S.
  • isotopes of hydrogen such as 2 H (D) and 3 H (T)
  • isotopes of carbon such as 11 C, 13 C and 14 C
  • isotopes of chlorine such as 37 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen
  • Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to the methods described in the Examples and Preparations appended herein.
  • the compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and/or base addition salts of the compounds of formula (I).
  • pharmaceutically acceptable salts include acid addition salts or base addition salts that may occur in the compounds of formula (I).
  • Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof.
  • Acid addition salts are formed from acids that form nontoxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-na
  • Suitable base addition salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
  • Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms).
  • compounds of formula (I) are encompassed within the scope of the present invention regardless of whether they exist in solvated or unsolvated forms.
  • Certain compounds of the present invention may exist in different crystalline or amorphous forms. Regardless of the form in which they exist, the compounds of formula (I) are included within the scope of the present invention.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to humans.
  • the term refers to any national regulatory agency certified by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.
  • Prodrug refers to a drug that reacts with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by reacting with each other in the enzyme The oxidation, reduction, hydrolysis and other reactions carried out under catalysis are converted into derivatives of the compounds of the present invention.
  • Methods refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.
  • hydroxyl refers to -OH; the term “cyano” refers to -CN; the term “amino” refers to -NH 2 ; and the term “nitro” refers to -NO 2 .
  • hydroxyl protecting group refers to a protecting group introduced on a hydroxyl group to prevent the hydroxyl group from undergoing side reactions or unwanted chemical changes during reactions. Common hydroxyl protecting groups include, but are not limited to, Boc, Ms, TMS, TBS, and the like.
  • substituted means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.
  • each independently means that when the number of substituents is more than one, the substituents may be the same or different.
  • the term “optional” or “optionally” means that the event it describes can or cannot occur.
  • a group “optionally substituted” means that the group can be unsubstituted or substituted.
  • heteroatom represents oxygen (O), nitrogen (N), or S(O) m (wherein m may be 0, 1 or 2, ie, a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O) 2 ).
  • alkyl refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms.
  • C 1-8 alkyl refers to a straight or branched atomic group with 1-8 carbon atoms.
  • C 1-8 alkyl includes the terms “C 1-6 alkyl”, “C 1 -C 3 alkyl” and "C 1 -C 4 alkyl” in its definition.
  • alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R) -2-methylbutyl, (S) -2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc.
  • the alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.
  • n-membered heteroaryl refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S and N.
  • 5- 7-membered heteroaryl includes, but is not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine.
  • the heteroaryl group may be optionally substituted with one or more suitable substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom).
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom).
  • C 1-4 haloalkyl refers to a C 1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom);
  • C 1-3 haloalkyl refers to a C 1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom);
  • C 1-2 haloalkyl refers to a C 1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom).
  • C 1 haloalkyl refers to a methyl group having 1, 2 or 3 halogen substituents.
  • haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl and the like.
  • the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent a list of all integers within the range, and the ranges are only used as a simplified representation.
  • “1-4 substituents” means 1, 2, 3, or 4 substituents
  • "3-8 ring atoms” means 3, 4, 5, 6, 7, or 8 ring atoms. Therefore, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any subranges thereof, and each subrange is also deemed to be disclosed herein.
  • the compounds of the present application can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds of the specific embodiments of the present application and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, mannitol, cellulose, cellulose derivatives, saccharin sodium, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, etc.
  • the pharmaceutical composition may also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants, etc.
  • the dosage form of the pharmaceutical composition of the present application can be a liquid dosage form, a solid dosage form or a semisolid dosage form.
  • the liquid dosage form can be a solution (including a true solution and a colloidal solution), an emulsion (including an o/w type, a w/o type and a multiple emulsion), a suspension, an injection (including a water injection, a powder injection and an infusion), an eye drop, a nasal drop, a lotion and an liniment, etc.;
  • the solid dosage form can be a tablet (including a common tablet, an enteric-coated tablet, a lozenge, a dispersible tablet, a chewable tablet, an effervescent tablet, an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule, an enteric-coated capsule), a granule, a powder, a pill, a suppository, a film, a patch, an aerosol, a spray, etc.;
  • the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants ( For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarding agents (e.g., paraffin); (f) absorption accelerators (e.g., quaternary ammoni
  • Preparations suitable for parenteral administration may include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.
  • the parenteral formulations provided herein are optionally contained in unit dose or multi-dose sealed containers (e.g., ampoules), and can be stored under freeze drying (lyophilization) conditions that require only the addition of a sterile liquid carrier (e.g., water for injection) just before use.
  • a sterile liquid carrier e.g., water for injection
  • Suitable diluents for reconstructing pharmaceutical compositions include antibacterial water for injection, 5% glucose aqueous solution, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.
  • Sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain conventional propellants, for example chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.
  • Inhalants may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions administered as nasal drops or sprays, or in the form of gels.
  • the content of the compound of the present application in its pharmaceutical composition can be adjusted according to actual needs (such as dosage form, administration method, administration object, etc.), for example, 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight, 10-80% by weight, etc.
  • the pharmaceutical composition of the present application may specifically contain 0.01-10 g (eg, 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present application.
  • the present application provides the use of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a drug for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof.
  • a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof can be used to treat or prevent coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof.
  • subject refers to any human or non-human organism that can potentially benefit from treatment with a compound of formula (I).
  • exemplary subjects include humans or mammals of any age.
  • the subject is a human.
  • treatment includes treating a disease or symptom in a mammal, particularly a human, and includes: (a) inhibiting an infection, disease or symptom, i.e., arresting or delaying the development of an infection, disease or symptom; (b) alleviating an infection, disease or symptom, i.e., causing regression of the disease or symptom, and/or (c) curing an infection, disease or symptom.
  • prevention includes prophylactic therapy in mammals, especially humans, to reduce the likelihood of infection, disease or symptoms. Patients who receive prophylactic therapy can be selected based on their increased risk of infection or disease or symptoms compared to the general population. "Prevention” can include treatment of subjects who have not yet presented with an infection or clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.
  • the compounds of the present application can inhibit coronavirus infection, for example, they can act as reversible covalent small molecule inhibitors against the 3CL protease of the new coronavirus (i.e., 3CL protease inhibitors), thereby inhibiting the viral replication of the coronavirus. Therefore, the compounds of the present application can be used to prevent or treat coronavirus infection or diseases or symptoms caused by coronavirus.
  • the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), and coronaviruses with greater than 85% homology to any of the above coronaviruses and with viral activity, including mixed infections caused by more than one coronavirus subtype.
  • the coronavirus is novel coronavirus (SARS-CoV-2).
  • the diseases or symptoms caused by the coronavirus include respiratory infections, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chills, shortness of breath, cytokine storm, etc. caused by the virus.
  • SARS acute respiratory syndrome
  • pneumonia including severe pneumonia
  • gastroenteritis including acute gastroenteritis
  • cough fever, chills, vomiting, headache, chills, shortness of breath, cytokine storm, etc. caused by the virus.
  • the present application provides a method for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.
  • a compound of formula (I) or an isotope-labeled compound thereof or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.
  • the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, oral mucosa, ocularly, pulmonary, respiratory, vaginally, rectally, intraperitoneally, intralesionally, perilesionally, and the like.
  • “Therapeutically effective amount” refers to an amount of the compound of the present application that is effective in treating or preventing coronavirus infection or diseases or symptoms caused by coronavirus when administered alone or in combination.
  • the daily dose of the compound of the present application can be particularly 0.001-150 mg/kg body weight (e.g., 0.1 mg/kg body weight, 1 mg/kg body weight, 10 mg/kg body weight or 100 mg/kg body weight, etc.).
  • the specific administration frequency can be determined by technicians in the relevant fields, for example, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, twice a day, three times a day, etc.
  • the compounds of formula (I) of the present application can be synthesized by various methods familiar to those skilled in the art of organic synthesis.
  • the following specific examples provide some exemplary methods for synthesizing compounds of formula (I), which are well known in the field of synthetic chemistry.
  • those skilled in the art can A person skilled in the art can easily design the synthetic routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.
  • the reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex C18 75*30 mm*3 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25%-65%, 8 min) to obtain the target product GDI15-5431 (32.0 mg, 72.4 ⁇ mol, 15.7% yield, 94.8% purity) as a yellow solid.
  • ESI-MS [M+H] + , 419.1.
  • reaction solution was decompressed and dried, and purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 20%-50% B in 8 min) to obtain the target product GDI15-6450 (4.5 mg, 8.49 ⁇ mol, 9.24% yield) as a white solid.
  • ESI-MS [M+H] + , 530.0.
  • reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 25%-55% B, in 8 min) to obtain the target product GDI15-6405 (30.8 mg, 57.3 ⁇ mol, 79.0% yield, 100% purity) as a white solid.
  • ESI-MS [M+H] + ,538.2.
  • the crude product was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10%-50%, 8min) to obtain the target product GDI15-6290 (1.10 mg, 2.15 ⁇ mol, 5.50 yield) as a yellow solid.
  • ESI-MS [M+H]+, 512.2.
  • the target product GDI15-6452 (14.2 mg, 30.9 ⁇ mol, 63.0% yield, 97.9% purity) was obtained as a yellow solid by purification by high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 1%-35% B in 8 min).
  • ESI-MS [M+H] + , 450.1.
  • the target product GDI15-5944 (2 mg, 3.94 ⁇ mol, 8.0% yield) was obtained as a white solid by purification on a silica gel plate (PE/EtOAc, 0/1).
  • ESI-MS [M+H] + , 508.1.
  • ESI-MS [M+H] + , 518.1.
  • reaction solution was dried under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 15%-55% B, within 8 min) and SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2 O)]; B%: 50%-50%, 9 min) to obtain the target product GDI15-6383 (2.9 mg, 5.76 ⁇ mol, 9.67% yield) as a white solid.
  • ESI-MS [M+H] + , 562.1.
  • the reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 26%-56%, 8 min) to obtain the target product GDI15-6337 (8.8 mg, 17.1 ⁇ mol, 36.1% yield, 100% purity) as a yellow solid.
  • ESI-MS [M+H] + , 512.2.
  • reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 15%-45% B, in 8 min) to obtain the target product GDI15-6349 (20.4 mg, 38.8 ⁇ mol, 29.2% yield, 97.3% purity) as a white solid.
  • ESI-MS [M+H] + , 526.2.
  • reaction solution was filtered at normal pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 15%-45% B, in 8 min) to obtain the target product GDI15-6348 (17 mg, 30.3 ⁇ mol, 43.6% yield, 97.0% purity) as a white solid.
  • ESI-MS [M+H] + , 562.1.
  • reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex C18 75*30 mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B, in 8 min) to obtain the target product GDI15-5885 (0.022 g, 47.3 ⁇ mol, 27.7% yield, 98% purity) as a yellow solid.
  • ESI-MS [M+H] + , 454.1.
  • reaction solution was filtered at normal pressure and analyzed by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 20%- 45% B, in 8 min) to give the target product GDI15-5915 (33.7 mg, 71.4 ⁇ mol, 20.4% yield) as a yellow solid.
  • ESI-MS [M+H] + , 472.2.
  • reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 25%-50% B, in 8 min) to obtain the target product GDI15-5916 (5 mg, 10.2 ⁇ mol, 5.72% yield) as a white solid.
  • ESI-MS [M+H] + , 488.0.
  • reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 20%-50%, 10 min) to obtain the target compound GDI15-6332 (0.072 g, 153 ⁇ mol, 46.5% yield, 99% purity) as a white solid.
  • ESI-MS [M+H] + , 472.1
  • the organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate separation (PE/EA, 0/1) and SFC separation (column: Phenomenex C18 75*30mm*3 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 36%-66%, 8min) to obtain the target product GDI15-6326 (8.40mg, 16.5 ⁇ mol, 19.7% yield) as a yellow solid.
  • ESI-MS [M+H] + , 489.2.
  • the crude product from GHDDI was purified by HPLC (column: Phenomenex C18 75*30mm*3 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 20%-50% B, in 8 min) to obtain the target product GDI15-5591 (0.2 mg, 4.35e -1 ⁇ mol, 1.11% yield) as a white solid.
  • ESI-MS [M+H] + , 460.1.
  • reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (5 mL*6), the organic phases were combined and dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15%-45%, 10 min) to obtain the target compound 4 (70 mg, 172 ⁇ mol, 43.5% yield) as a light yellow solid.
  • ESI-MS [M+H] + , 406.2.
  • the organic phases were combined and washed with 5 mL of saturated sodium chloride aqueous solution.
  • the washed organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 3C (300 mg, 1.14 mmol, 77.4% yield) as a yellow oil.
  • the mixture was stirred at 25°C for 1 hour and the reaction solution was dried.
  • the target compound GDI15-6327 (10 mg, 21.9 ⁇ mol, 41.4% yield) was obtained by purification on silica gel plate (EtOAc/MeOH, 2/1) and high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15%-35%, 8 min) as a white solid.
  • ESI-MS [M+H] + , 456.1.
  • a mixed solvent of dioxane (8 mL) and H 2 O (1 mL) was added to a system of compound 4 (80.00 mg, 0.22 mmol), compound 5 (33.79 mg, 0.22 mmol), Pd( dppf )Cl 2 (31.62 mg, 0.043 mmol) and K 3 PO 4 (91.74 mg, 0.43 mmol), and the mixture was refluxed at 60°C for 2 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was extracted with water and ethyl acetate.
  • a mixed solvent of DMF/H 2 O (2 mL) was added to the system of compound 4 (130 mg, 0.34 mmol), compound 5 (53 mg, 0.34 mmol), potassium phosphate (144 mg, 0.68 mmol) and Pd(dtbpf)Cl 2 (28 mg, 0.034 mmol), and the mixture was stirred at 60°C for 1 h under nitrogen protection.
  • the target product appeared after the disappearance of the reaction raw materials by LCMS monitoring.
  • water (20 mL) was added to the system, and the mixture was extracted with EtOAc (20 mL*3).
  • DMSO (10 mL) and TEA (211 mg, 2.09 mmol, 1.5 eq) were added to the system of compound GDI15-6547-INT 8 (680 mg, 1.39 mmol, 1.0 eq), PdAMPHOS (99 mg, 0.14 mmol, 0.1 eq) and triethylsilane (485 mg, 4.17 mmol, 3.0 eq), CO was protected, and the mixture was heated to 90°C and stirred for 8 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL*3).
  • Potassium tert-butoxide (1M in THF, 1mL, 1mmol) was added to a three-necked round-bottom flask equipped with a stirring bar, a reflux condenser and an addition funnel. The flask was cooled in a dry ice-acetonitrile bath, and a solution of TosMIC (120mg, 0.61mmol) in DME (1.5mL) was added to the system. After the system was stirred for a few minutes, a solution of compound 1 (160mg, 0.41mmol) in DME (1.5mL) was added dropwise. The addition was completed over 30min.
  • reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 30%-60% B in 8.0 min) to obtain the target product GDI15-7085 (2.2 mg, 5.2 ⁇ mol, 3.58% yield) as a white solid.
  • ESI-MS [M+H] + , 424.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18150*40mm*10 ⁇ m; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; gradient: 10%-50% B in 8.0 min) to obtain the target product GDI15-6973 (1.2 mg, 3.06 ⁇ mol, 11.9% yield, 99.2% purity) as a yellow solid.
  • ESI-MS [M+H] + , 389.0
  • the target compound 6 (30 mg, 54.3 ⁇ mol, 37.6% yield) was purified by silica gel plate purification method (SiO 2 , EtoAc/MeOH, 10/1) as a white solid.
  • reaction solution was filtered at normal pressure and purified by HPLC column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; gradient: 25%-55% B in 8.0 min to obtain the target product GDI15-7004 (5.6 mg, 10.4 ⁇ mol, 19.2% yield) as a white solid.
  • ESI-MS [M+H] + , 538.2.
  • the reaction solution was purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 25%-55% B in 8.0 min) to obtain the target compound GDI15-7219 (5 mg, 10.5 ⁇ mol, 10.3% yield, 100% purity) as a white solid.
  • ESI-MS [M+H] + , 472.1.
  • PPTS 176.16 mg, 0.70 mmol
  • LiCl 29.72 mg, 0.70 mmol
  • the mixture was stirred at 140°C for 4 h under nitrogen protection. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3).
  • the target compound GDI15-7139 (23.6 mg, 64.2 ⁇ mol, 38.9% yield, 100% purity) was obtained as a white solid by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; gradient: 10%-45% B in 8.0 min).
  • ESI-MS [M+H] + , 368.0.
  • reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target product GDI15-7142 (47.9 mg, 124 ⁇ mol, 48.5% yield, 97.5% purity) as a white solid.
  • ESI-MS [M+H] + , 379.2.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; gradient: 25%-65% B in 8.0 min) to obtain the target product GDI15-6996 (12.8 mg, 27.8 ⁇ mol, 43.7% yield, 99.3% purity) as a yellow solid.
  • ESI-MS [M+H] + ,458.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O(10mM NH4HCO3)-ACN]; gradient: 20%-50% B in 8.0 min) to obtain the target product GDI15-7082 (13.1 mg, 24.9 ⁇ mol, 33.2% yield, 90.1% purity) as a yellow solid.
  • ESI-MS [M+H] + ,473.1
  • the reaction solution was filtered, and the filtrate was transferred to a machine branch tube, and the target compound GDI15-7126 (42.5 mg, 72.1 ⁇ mol, 40.6% yield, 97.9% purity) was obtained by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; gradient: 25%-55% B in 8.0 min) as a white solid was obtained.
  • ESI-MS [M+H] + ,577.0.
  • 1,4-Dioxane (9 mL) was added to compound 3 (900 mg, 3.10 mmol), B 2 Pin 2 (253 mg, 0.31 mmol), Pd(dppf)Cl 2 (912 mg, 9.29 mmol) and KOAc (1.57 g, 6.20 mmol), and the mixture was stirred under nitrogen protection at 100°C for 18 h. After the reaction, water was added to the system, and the mixture was extracted with EtOAc (10 mL*3).
  • 1,4-dioxane/water 6:1 (3 mL) was added to the system of compound 4 (180 mg, 0.53 mmol), compound 5 (148 mg, 0.40 mmol), K 3 PO 4 (340 mg, 1.60 mmol) and Pd(dppf)Cl 2 (44 mg, 0.0533 mmol), and the system was stirred at 50°C for 2 h. After the reaction, water was added to the system, and it was extracted with EtOAc (10 mL*3).
  • reaction solution was filtered and dried, and then analyzed by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 30%-60% B in 8.0 min) was purified to give the target product GDI15-7084 (2.1 mg, 4.25 ⁇ mol, 13.5% yield) as a white solid.
  • ESI-MS [M+H] + , 494.1.
  • reaction solution was filtered, and the filtrate was transferred to a machine branch tube and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 35%-65% B in 8.0 min) to obtain the target compound GDI15-7140 (73.6 mg, 147 ⁇ mol, 39.4% yield, 98.8% purity) as a white solid.
  • ESI-MS [M+H] + ,493.0.
  • the compound (290 mg, 1.05 mmol, 1 eq) and TEA (318 mg, 3.15 mmol, 437 ⁇ L, 3 eq) were dissolved in DCM (5.8 mL), and MsCl (180 mg, 1.57 mmol, 121 ⁇ L, 1.5 eq).
  • the reaction mixture was reacted at 0°C for 1 hour.
  • LCMS detected that the reaction was complete. Ice water (10 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 13 (342 mg, 964 ⁇ mol, 91.9% yield) as a yellow oil.
  • the reaction solution was filtered, and the filtrate was transferred to a machine branch tube, and the target compound GDI15-7125 (41.8 mg, 73.5 ⁇ mol, 25.9% yield, 96.9% purity) was obtained by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; gradient: 20%-50% B in 8.0 min) as a white solid was obtained.
  • ESI-MS [M+H] + ,551.2.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*3 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 10%-40% B in 18.0 min) to obtain the target compound GDI15-7185 (80 mg, 152 ⁇ mol, 41.1% yield) as a yellow solid.
  • ESI-MS [M+H] + , 525.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O(10mM NH4HCO3)-ACN]; gradient: 25%-55% B in 8.0 min) to obtain the target product GDI15-7083 (6.7 g, 12.6 ⁇ mol, 21.8% yield, 95% purity) as a yellow solid.
  • ESI-MS [M+H] + ,507.1.
  • reaction solution was filtered, and the filtrate was transferred to a machine branch tube and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; gradient: 30%-70% B in 8.0 min) to obtain the target compound GDI15-7053 (12.8 mg, 24.2 ⁇ mol, 18.7% yield) as a white solid.
  • ESI-MS [M+H] + , 527.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7182 (4 mg, 9.55 ⁇ mol, 20.7% yield) as a white solid.
  • ESI-MS [M+H] + , 419.1.
  • reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O (0.2% FA)-ACN]; gradient: 3%-33% B in 8.0 min) to obtain the target compound GDI15-7254 (12.3 mg, 28.1 ⁇ mol, 15.5% yield) as a yellow solid.
  • ESI-MS [M+H] + , 434.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*3 ⁇ m; mobile phase: [H 2 O (0.2% FA)-ACN]; gradient: 3%-33% B in 8.0 min) to obtain the target compound GDI15-7223 (19.5 mg, 32.5 ⁇ mol, 19.6% yield) as a white solid.
  • ESI-MS [M+H] + , 538.2.
  • reaction solution was filtered and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 30%-60% B in 8.0 min) to obtain the target compound GDI15-7207 (8 mg, 17.6 ⁇ mol, 30.5% yield) as a white solid.
  • ESI-MS [M+H] + , 455.1.
  • reaction solution was filtered and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7256 (8.0 mg, 17.6 ⁇ mol, 9.16% yield) as a white solid.
  • ESI-MS [M+H] + , 454.1.
  • reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 ⁇ m; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7141 (60.8 mg, 168 ⁇ mol, 63.2% yield) as a yellow solid.
  • ESI-MS [M+H]+, 363.1.

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Abstract

La présente invention concerne un inhibiteur de protéase 3CL pour le traitement ou la prévention d'une infection à coronavirus et son utilisation. Plus particulièrement, la présente invention concerne un composé de formule (I) ou un composé marqué par un isotope de celui-ci, ou un isomère optique, un isomère géométrique, un tautomère ou un mélange d'isomères de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, ou un promédicament de celui-ci, ou un métabolite de celui-ci, et son utilisation dans la préparation d'un médicament pour le traitement ou la prévention d'une infection à coronavirus, ou d'une maladie ou d'un symptôme provoqué par un coronavirus.
PCT/CN2024/116912 2023-09-08 2024-09-04 Inhibiteur de protéase 3cl pour le traitement ou la prévention d'une infection à coronavirus et son utilisation Pending WO2025051161A1 (fr)

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