WO2023030459A1 - Composé contenant un amide de quinolinone, son procédé de préparation, composition pharmaceutique et utilisation associées - Google Patents

Composé contenant un amide de quinolinone, son procédé de préparation, composition pharmaceutique et utilisation associées Download PDF

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WO2023030459A1
WO2023030459A1 PCT/CN2022/116584 CN2022116584W WO2023030459A1 WO 2023030459 A1 WO2023030459 A1 WO 2023030459A1 CN 2022116584 W CN2022116584 W CN 2022116584W WO 2023030459 A1 WO2023030459 A1 WO 2023030459A1
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alkyl
substituted
halogen
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ring
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周宇
李佳
张磊砢
姜智冬
臧奕
张宇旻
郑淼
苏明波
冯勃
肖庚富
柳红
蒋华良
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Wuhan Institute Of Virology Chinese Academy Of Science
Shanghai Institute of Materia Medica of CAS
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Wuhan Institute Of Virology Chinese Academy Of Science
Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D471/10—Spiro-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
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a class of quinolinone amide-containing compounds as coronavirus main protease inhibitors, their preparation methods, pharmaceutical compositions containing such compounds and as main proteases (also known as 3CLpro) inhibitors, especially for the treatment of viral diseases where 3CL protease exists, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • Novel coronavirus pneumonia is a highly contagious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), a virus closely related to SARS virus.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus type 2
  • SARS-CoV-2 is mainly spread through small droplets expelled when an infected person breathes or coughs.
  • Infected individuals may be asymptomatic or present with common COVID-19 symptoms, including fever, cough, fatigue, shortness of breath, loss of smell, and severe cases can develop complications including pneumonia, acute respiratory distress syndrome, multi-organ failure, and death.
  • the pathogen causing this novel coronavirus pneumonia is SARS-CoV-2, which is a new type of coronavirus.
  • the diameter of coronavirus is about 80-120nm. It is composed of envelope and its coated single-stranded forward RNA. The 5' end of the RNA chain has a methylated cap structure, and the 3' end has a poly(A) tail. About 27-32kb long.
  • One-third of its genome RNA is used to encode structural proteins and auxiliary proteins, including envelope M protein (membrance, M), spike S protein (spike, S), envelope E protein (envelope, E), nucleocapsid Shell N protein (nucleocapsid, N).
  • ORF 1a encodes a polyprotein of about 450kDa, called pp1a
  • ORF 1a and ORF 1b jointly encode a polyprotein of about 750kDa, called pp1ab.
  • 3CL protease is one of the key enzymes of coronavirus, which plays an important role in regulating the process of virus replication.
  • 3CL protease (3C-like proteinase, 3CLpro), also known as the main protease (M pro ), can hydrolyze the original polyproteins of pp1a and pp1ab from at least 11 conserved cleavage sites, and help them form replicase complexes.
  • COVID-19 novel coronavirus pneumonia
  • Yang Haitao, Rao Zihe and his team announced the determined crystal structure of SARS-CoV-2 coronavirus 3CL protease-binding compound N3 on January 26, 2020, with a resolution of 1 (PDB ID 6LU7).
  • SARS-CoV-2 3CLpro The active form of SARS-CoV-2 3CLpro is a homodimer containing two monomers. Each monomer consists of three domains with a total of 306 residues. Domain I (residues 8-101) and domain II (residues 102-184) have an inverted ⁇ -sheet structure. Domain III (residues 201-303) contains five ⁇ -helices connected to domain II by a long loop region (residues 185-200).
  • 3CL protease is one of the key enzymes of coronavirus and norovirus, which plays an important role in the process of regulating virus replication, and 3CL protease has no human homologue.
  • SARS-CoV coronavirus
  • SARS-CoV-2 SARS-CoV-2
  • MERS ⁇ CoV MERS ⁇ CoV
  • peptidomimetic inhibitors mainly use electrophilic "warhead” groups (warhead groups) to covalently bind to cysteine residues of 3CL protease, thereby achieving irreversible inhibitory effects.
  • Non-peptidomimetic small molecule inhibitors mainly achieve inhibitory effects by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the binding pocket.
  • peptidomimetic inhibitors can be divided into two steps. First, an inhibitor molecule that mimics a natural peptide substrate binds to the 3CL protease to form a non-covalent complex. Then, the "warhead” group, which is sterically close to the catalytically active residue of the target protein, is subjected to nucleophilic attack, forming a covalent bond involving cysteine. These "warhead” groups are usually Michael acceptors, aldehydes, or ketones, which can covalently bind to cysteines in the binding pocket to produce inhibitory effects.
  • Non-peptidomimetic small molecule inhibitors mainly achieve the inhibitory effect by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the S1', S1, S2, and S4 regions of the binding pocket. These inhibitors can be obtained through high-throughput screening, screening based on existing drugs, computer molecular docking and other methods. At present, research reports on inhibitors of this type of SARS-CoV-2 3CL protease are still very limited. It is generally believed that non-covalent inhibitors have a weaker and reversible binding to amino acid residues. This reversible interaction can avoid the harm caused by off-target effects. It is less toxic than covalent inhibitors and is suitable for long-term use. Therefore, research on such small molecule non-covalent 3CL protease inhibitors is very necessary.
  • the purpose of the present invention is to provide novel 3CL protease inhibitors, and be used for the treatment of viral diseases such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus that exist 3CL protease.
  • the first aspect of the present invention provides a quinolinone amide compound with the structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture:
  • X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
  • Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1 -C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;
  • R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, - S(O) 2 OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon Substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl,
  • two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on the ring are connected end to end with The ring forms a spiro ring; and when the A ring is a piperazine ring, the R 3 is not H;
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkane Sulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7- C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 substituted by 12-membered spiro heterocyclic hydrocarbon or 9-12-membered fused heterocyclic hydrocarbon Halogenated cycloalkyl, C3-C10 aryl or heteroaryl, 3-12 membered heterocyclic
  • the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl,
  • the halogen is F, Cl, Br or I.
  • the Ring is selected from the following group: wherein m 1 , m 2 , n 1 and n 2 are selected from 0, 1, 2, 3 or 4; X 1 is selected from CH 2 , CH 2 CH 2 and O; Y is selected from CH and N.
  • the R3 is selected from substituents of the following group: hydrogen, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaryl Ring substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon substituted C1-C6 alkyl, Among them, two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on the ring are connected end to end with The ring forms a spiral ring;
  • R 5 and R 6 are selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl , C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy , C1-C6 alkoxyl substituted by halogen, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclic group.
  • each of the R4s is independently selected from the following group: substituted or unsubstituted phenyl, and the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from Base substitution: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, cyano, nitro , amino, hydroxyl, methylol, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl.
  • the R3 is selected from substituents in the following group: C1-C6 alkyl substituted by hydrogen, aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon,
  • the second aspect of the present invention provides a pharmaceutical composition, which includes: the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R- One or more of isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their Use of the mixture for preparing a pharmaceutical composition for treating or preventing diseases related to 3CL protease activity.
  • the disease is caused by a virus with 3CL protease, preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus Viruses, or a combination thereof.
  • Figure 1 shows the IC 50 data of some compounds.
  • the inventor After long-term and in-depth research, the inventor has designed and synthesized a class of quinolinone amide compounds with novel structure.
  • the compound has excellent inhibitory activity against 3CL protease, so it can be used for treatment, prevention and alleviation of 3CL Protease-related diseases, especially for the treatment of viral diseases with 3CL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • 3CL protease such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • the present invention provides a quinolinone amide compound with a structure shown in general formula I, and racemates, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof:
  • X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
  • Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
  • the ring is selected from the following group: 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
  • R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfo on ring
  • A Acyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy group, halogen substituted C1-C6 alkoxy group, C3-C8 cycloalkyl group, C3-C8 halocycloalkyl group, C6-C10 aryl group, 3-12 membered heterocyclic group, Among them, two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
  • R and R are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1 - C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7-12 membered spiro heterocyclic hydrocarbon or 9-12 membered condensed heterocyclic hydrocarbon Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl;
  • the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered hetero
  • the halogen is F, Cl, Br or I.
  • the compounds are those shown in Table A.
  • the present invention also provides a kind of preparation method of the compound represented by general formula I, and this preparation method is carried out according to the following scheme (example):
  • Step a Compound 1 is dissolved in an organic solvent, and HATU, morpholine, and DIPEA are added at room temperature to react to obtain Compound 2;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol Diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof;
  • Step b Dissolve compound 2 in an organic solvent, add BH 3 -THF complex, heat and stir until the reaction is complete, and obtain compound 3;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or their mixture; the heating temperature range is 50-80°C;
  • Step c Dissolve compound 3 in an organic solvent, add acid dioxane solution, heat and stir until the reaction is complete to obtain compound 4;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether , ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid;
  • Step d dissolving compound 4 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heat to reflux to obtain intermediate 5;
  • the aryl compound is selected from substituted or unsubstituted benzene, substituted or unsubstituted 5-12 membered heteroaromatic compounds; wherein, the substitution refers to one or more
  • the hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro
  • Step e dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 5 at room temperature to obtain compound 6;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step f dissolving compound 1 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group
  • Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano,
  • Step g Dissolve compound 2 in an organic solvent and slowly add acid under stirring at 0°C.
  • the reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is complete, it is concentrated.
  • the residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
  • Step h dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step i Charge N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanine, condensing agent, glycine methyl ester hydrochloride) and DMF in a round bottom flask. Add DIPEA to it. After stirring at room temperature for 5 minutes, the mixture was diluted with water and extracted with ether. The layers were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester as a yellow oil on concentrate , used directly in the next step.
  • the condensing agent is HATU or CMPI.
  • Steps j and k A round bottom flask was charged with N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester, DCM and TFA. After 30 minutes, the mixture was concentrated, then redissolved in 2M ammonia in MeOH and stirred overnight at room temperature, a white precipitate precipitated and the product formed was collected by filtration to give (3S)-3(cyclohexylmethyl)-2 , 5-piperazinedione.
  • Step 1 Charge (3S)-3-(cyclohexylmethyl)-2,5-piperazinedione, an organic solvent and lithium aluminum hydride in a round bottom flask. After heating to 70°C overnight, the mixture was cooled to room temperature and sodium sulfate decahydrate was added slowly. After stirring for 1 hour, the mixture was filtered, and the filtrate was concentrated to give (2S)-2-(cyclohexylmethyl)piperazine as a colorless oil, which was used crude for the next reaction.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof.
  • Step m dissolving compound 5 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 6;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino,
  • Step n dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 6 at room temperature to obtain compound 7;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step o dissolving compound 1 in an organic solvent, adding aryl compound, tridibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group
  • Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro
  • Step p Dissolve compound 2 in an organic solvent and slowly add acid under stirring conditions at 0°C.
  • the reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is completed, it is concentrated.
  • the residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
  • Step q dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step r Dissolve compound 4 in an appropriate amount of THF/H 2 O mixed solvent, add potassium hydroxide, stir and react under reflux for two hours, spin the solvent after the reaction is completed, adjust the pH to acidic with hydrochloric acid, and observe that there is solid precipitation , and the solid collected by suction filtration is Intermediate 5.
  • Step s Dissolving intermediate 5 in an organic solvent, adding a certain amount of base, condensing agent and amine to obtain compound 6;
  • R5 and R6 can be independently selected from the following group: hydrogen, halogen, cyano, nitro, amino , amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or hetero Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl.
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, Dichloromethane or a mixture thereof;
  • the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition can be used for the treatment, prevention and alleviation of diseases related to 3CL protease, especially for the treatment of viral diseases with 3CL protease, such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc. caused diseases.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg/kg) of the compound of the present invention per dose, more preferably 10-2000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 6-600 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the hydrochloride was dissolved in an appropriate amount of ethyl acetate and washed with saturated sodium carbonate solution to adjust the pH to 8-9, and extracted several times with ethyl acetate until no product remained in the aqueous phase, then the organic phases were combined and used without Dried over sodium sulfate, concentrated and spin-dried to obtain a colorless oily substance, compound 7-4 (4 g, yield 72%).
  • (2S)-2-(cyclohexylmethyl)piperazine (0.954g, 5.23mmol) and 3,4-dichlorobromobenzene (1.30g, 5.76mmol) were dissolved in 20mL of toluene, followed by Add tridibenzylideneacetone dipalladium (Pd 2 dba 3 , 193.8mg, 0.21mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos, 238.1mg, 0.5 mmol) and cesium carbonate (3.26g, 10mmol), the reaction solution was heated to 110°C and stirred overnight.
  • SARS-CoV-2 3CLpro protein As a proteolytic enzyme, a screening system for detecting the activity of SARS-CoV-2 3CLpro protein by fluorescence method was established.
  • the SARS-CoV-2 3CLpro protein can specifically cleave substrates whose P1 position is Gln(Q), and its activity detection can use fluorescent peptides as substrates to reflect the activity of its proteolytic enzymes by detecting the generation of fluorescent signals.
  • Fluorescent quantitative PCR was used to detect the copy number contained in each milliliter of the original virus solution.
  • TB Green Premix (Takara, Cat#RR820A) was used to mix the reaction system, and the amplification reaction and reading were performed on the StepOne Plus Real-time PCR instrument (brand: ABI). Calculate the copy number per milliliter of the original virus solution. Proceed as follows:
  • Cycle parameters 95°C for 15 seconds, 54°C for 15 seconds, 72°C for 30 seconds, a total of 40 cycles.
  • the results of the virus proliferation inhibition experiment showed that multiple tested compounds could effectively inhibit the replication of the SARS-CoV-2 virus genome in the infection supernatant at a concentration of 10 ⁇ M, and the inhibition rate was greater than 90%.
  • Some compounds have completed the IC 50 data determination, as shown in Figure 1, especially the IC 50 value of compound 5 is 0.702 ⁇ M, which is basically equivalent to the activity of the reported peptidomimetic inhibitors, and as a non-covalent small molecule inhibitor , may be less toxic than covalent inhibitors and suitable for long-term use.
  • Embodiment 3 mouse pharmacokinetic experiment
  • mice Nine healthy mice were randomly divided into 3 groups with 3 mice in each group. Gavage, intraperitoneal injection and intravenous injection were given Compound 5 respectively, and dosage was 20mg/kg for intragastric injection, 10mg/kg for intraperitoneal injection, and 5mg/kg for intravenous injection, and the medicine was prepared in the form of DMSO/Tween 80/normal saline (5:5: 90, v/v/v) formulation. Fasting 12h before the test, free to drink water. Eat uniformly 2 hours after administration.
  • Oral administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration; intraperitoneal administration: 5min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24h; intravenous Administration: 0, 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
  • the time to peak plasma concentration T max was 0.5 h, and the peak concentration C max was 865 ng/ml; the area under the drug-time curve AUC 0-t was 1350 h/ml; The elimination half-life t 1/2 is 1.13h.
  • the AUC 0-t was 1210 ng h/ml; after intraperitoneal administration of 10 mg/kg compound 5 to mice, the time to peak plasma concentration T max was 0.25 h, and the peak concentration C max was 1610 ng /ml; the area under the drug-time curve AUC 0-t was 2280 h/ml; the terminal elimination half-life t 1/2 was 0.78h.
  • the absolute bioavailability of 20 mg/kg compound 5 in mice was 28.1%.
  • the absolute bioavailability of compound 5 after intraperitoneal administration of 10 mg/kg to mice was 95.0%.

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Abstract

La présente invention concerne un composé contenant un amide de quinolinone, son procédé de préparation, une composition pharmaceutique et une utilisation associées. En particulier, la présente invention concerne un composé d'amide de quinolinone ayant une structure représentée dans la formule générale I, et un racémate, un isomère R, un isomère S, un sel pharmaceutiquement acceptable de celui-ci, ou un mélange de ceux-ci. Le composé a une excellente activité inhibitrice contre la protéase 3 CL, et peut par conséquent être utilisé dans le traitement, la prévention, et le soulagement de maladies associées à la 3CL protéase, en particulier dans le traitement de maladies virales associées à 3CL protéase, telles que des maladies provoquées par le SARS-CoV-2, le SARS-CoV, le MERS-CoV, les norovirus, etc.
PCT/CN2022/116584 2021-09-02 2022-09-01 Composé contenant un amide de quinolinone, son procédé de préparation, composition pharmaceutique et utilisation associées Ceased WO2023030459A1 (fr)

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